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['Furthermore', ',', 'PAX3', '-', 'FKHR', 'and', 'PAX7', '-', 'FKHR', 'overexpression', 'occurs', 'by', 'distinct', 'mechanisms', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-867 | Furthermore, PAX3-FKHR and PAX7-FKHR overexpression occurs by distinct mechanisms. | 0 |
['Transcription', 'of', 'PAX3', '-', 'FKHR', 'is', 'increased', 'relative', 'to', 'wild', '-', 'type', 'PAX3', 'by', 'a', 'copy', 'number', '-', 'independent', 'process', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-868 | Transcription of PAX3-FKHR is increased relative to wild-type PAX3 by a copy number-independent process. | 0 |
['In', 'contrast', ',', 'PAX7', '-', 'FKHR', 'overexpression', 'results', 'from', 'fusion', 'gene', 'amplification', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-869 | In contrast, PAX7-FKHR overexpression results from fusion gene amplification. | 0 |
['Thus', ',', 'gene', '-', 'specific', 'mechanisms', 'were', 'selected', 'to', 'overexpress', 'PAX3', '-', 'FKHR', 'and', 'PAX7', '-', 'FKHR', 'in', 'alveolar', 'rhabdomyosarcoma', ',', 'presumably', 'due', 'to', 'differences', 'in', 'regulation', 'between', 'the', 'wild', '-', 'type', 'loci', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-870 | Thus, gene-specific mechanisms were selected to overexpress PAX3-FKHR and PAX7-FKHR in alveolar rhabdomyosarcoma, presumably due to differences in regulation between the wild-type loci. | 1 |
['We', 'postulate', 'that', 'these', 'overexpression', 'mechanisms', 'ensure', 'a', 'critical', 'level', 'of', 'gene', 'product', 'for', 'the', 'oncogenic', 'effects', 'of', 'these', 'fusions', '.', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-871 | We postulate that these overexpression mechanisms ensure a critical level of gene product for the oncogenic effects of these fusions.. | 0 |
['atm', 'and', 'p53', 'cooperate', 'in', 'apoptosis', 'and', 'suppression', 'of', 'tumorigenesis', ',', 'but', 'not', 'in', 'resistance', 'to', 'acute', 'radiation', 'toxicity', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 0] | validation-872 | atm and p53 cooperate in apoptosis and suppression of tumorigenesis, but not in resistance to acute radiation toxicity. | 1 |
['Mutations', 'in', 'atm', 'and', 'p53', 'cause', 'the', 'human', 'cancer', '-', 'associated', 'diseases', 'ataxia', '-', 'telangiectasia', 'and', 'Li', '-', 'Fraumeni', 'syndrome', ',', 'respectively', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 2, 1, 2, 2, 0, 1, 2, 2, 2, 0, 0, 0] | validation-873 | Mutations in atm and p53 cause the human cancer-associated diseases ataxia-telangiectasia and Li-Fraumeni syndrome, respectively. | 1 |
['The', 'two', 'genes', 'are', 'believed', 'to', 'interact', 'in', 'a', 'number', 'of', 'pathways', ',', 'including', 'regulation', 'of', 'DNA', 'damage', '-', 'induced', 'cell', '-', 'cycle', 'checkpoints', ',', 'apoptosis', 'and', 'radiation', 'sensitivity', ',', 'and', 'cellular', 'proliferation', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-874 | The two genes are believed to interact in a number of pathways, including regulation of DNA damage-induced cell-cycle checkpoints, apoptosis and radiation sensitivity, and cellular proliferation. | 0 |
['Atm', '-', 'null', 'mice', ',', 'as', 'well', 'as', 'those', 'null', 'for', 'p53', ',', 'develop', 'mainly', 'T', '-', 'cell', 'lymphomas', ',', 'supporting', 'the', 'view', 'that', 'these', 'genes', 'have', 'similar', 'roles', 'in', 'thymocyte', 'development', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-875 | Atm-null mice, as well as those null for p53, develop mainly T-cell lymphomas, supporting the view that these genes have similar roles in thymocyte development. | 1 |
['To', 'study', 'the', 'interactions', 'of', 'these', 'two', 'genes', 'on', 'an', 'organismal', 'level', ',', 'we', 'bred', 'mice', 'heterozygous', 'for', 'null', 'alleles', 'of', 'both', 'atm', 'and', 'p53', 'to', 'produce', 'all', 'genotypic', 'combinations', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-876 | To study the interactions of these two genes on an organismal level, we bred mice heterozygous for null alleles of both atm and p53 to produce all genotypic combinations. | 0 |
['Mice', 'doubly', 'null', 'for', 'atm', 'and', 'p53', 'exhibited', 'a', 'dramatic', 'acceleration', 'of', 'tumour', 'formation', 'relative', 'to', 'singly', 'null', 'mice', ',', 'indicating', 'that', 'both', 'genes', 'collaborate', 'in', 'a', 'significant', 'manner', 'to', 'prevent', 'tumorigenesis', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-877 | Mice doubly null for atm and p53 exhibited a dramatic acceleration of tumour formation relative to singly null mice, indicating that both genes collaborate in a significant manner to prevent tumorigenesis. | 1 |
['With', 'respect', 'to', 'their', 'roles', 'in', 'apoptosis', ',', 'loss', 'of', 'atm', 'rendered', 'thymocytes', 'only', 'partly', 'resistant', 'to', 'irradiation', '-', 'induced', 'apoptosis', ',', 'whereas', 'additional', 'loss', 'of', 'p53', 'engendered', 'complete', 'resistance', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-878 | With respect to their roles in apoptosis, loss of atm rendered thymocytes only partly resistant to irradiation-induced apoptosis, whereas additional loss of p53 engendered complete resistance. | 0 |
['This', 'implies', 'that', 'the', 'irradiation', '-', 'induced', 'atm', 'and', 'p53', 'apoptotic', 'pathways', 'are', 'not', 'completely', 'congruent', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-879 | This implies that the irradiation-induced atm and p53 apoptotic pathways are not completely congruent. | 0 |
['Finally', '-', 'and', 'in', 'contrast', 'to', 'prior', 'predictions', '-', 'atm', 'and', 'p53', 'do', 'not', 'appear', 'to', 'interact', 'in', 'acute', 'radiation', 'toxicity', ',', 'suggesting', 'a', 'separate', 'atm', 'effector', 'pathway', 'for', 'this', 'DNA', 'damage', 'response', 'and', 'having', 'implications', 'for', 'the', 'prognosis', 'and', 'treatment', 'of', 'human', 'tumours', '.', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0] | validation-880 | Finally-and in contrast to prior predictions-atm and p53 do not appear to interact in acute radiation toxicity, suggesting a separate atm effector pathway for this DNA damage response and having implications for the prognosis and treatment of human tumours.. | 1 |
['Trinucleotide', 'repeat', 'expansion', 'at', 'the', 'myotonic', 'dystrophy', 'locus', 'reduces', 'expression', 'of', 'DMAHP', '.'] | [0, 0, 0, 0, 0, 1, 2, 0, 0, 0, 0, 0, 0] | validation-881 | Trinucleotide repeat expansion at the myotonic dystrophy locus reduces expression of DMAHP. | 1 |
['Myotonic', 'dystrophy', ',', 'or', 'dystrophia', 'myotonica', '(', 'DM', ')', ',', 'is', 'an', 'autosomal', 'dominant', 'multisystem', 'disorder', 'caused', 'by', 'the', 'expansion', 'of', 'a', 'CTG', 'trinucleotide', 'repeat', 'in', 'the', '3', 'untranslated', 'region', 'of', 'the', 'DMPK', 'protein', 'kinase', 'gene', 'on', 'chromosome', '19q13', '.'] | [1, 2, 0, 0, 1, 2, 0, 1, 0, 0, 0, 0, 1, 2, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-882 | Myotonic dystrophy, or dystrophia myotonica (DM), is an autosomal dominant multisystem disorder caused by the expansion of a CTG trinucleotide repeat in the 3 untranslated region of the DMPK protein kinase gene on chromosome 19q13. | 1 |
['3', '(', 'refs', '1', '-', '3', ')', '.'] | [0, 0, 0, 0, 0, 0, 0, 0] | validation-883 | 3 (refs 1-3). | 0 |
['Although', 'the', 'DM', 'mutation', 'was', 'identified', 'more', 'than', 'five', 'years', 'ago', ',', 'the', 'pathogenic', 'mechanisms', 'underlying', 'this', 'most', 'prevalent', 'form', 'of', 'hereditary', 'adult', 'neuromuscular', 'disease', 'remain', 'elusive', '.'] | [0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 0, 0, 0] | validation-884 | Although the DM mutation was identified more than five years ago, the pathogenic mechanisms underlying this most prevalent form of hereditary adult neuromuscular disease remain elusive. | 1 |
['Previous', 'work', 'from', 'our', 'laboratory', 'demonstrated', 'that', 'a', 'DNase', 'l', '-', 'hypersensitive', 'site', 'located', 'adjacent', 'to', 'the', 'repeats', 'on', 'the', 'wild', '-', 'type', 'allele', 'is', 'eliminated', 'by', 'repeat', 'expansion', ',', 'indicating', 'that', 'large', 'CTG', '-', 'repeat', 'arrays', 'may', 'be', 'associated', 'with', 'a', 'local', 'chromatin', 'environment', 'that', 'represses', 'gene', 'expression', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-885 | Previous work from our laboratory demonstrated that a DNase l-hypersensitive site located adjacent to the repeats on the wild-type allele is eliminated by repeat expansion, indicating that large CTG-repeat arrays may be associated with a local chromatin environment that represses gene expression. | 0 |
['Here', 'we', 'report', 'that', 'the', 'hypersensitive', 'site', 'contains', 'an', 'enhancer', 'element', 'that', 'regulates', 'transcription', 'of', 'the', 'adjacent', 'DMAHP', 'homeobox', 'gene', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-886 | Here we report that the hypersensitive site contains an enhancer element that regulates transcription of the adjacent DMAHP homeobox gene. | 0 |
['Analysis', 'of', 'DMAHP', 'expression', 'in', 'the', 'cells', 'of', 'DM', 'patients', 'with', 'loss', 'of', 'the', 'hypersensitive', 'site', 'revealed', 'a', 'two', '-', 'to', 'fourfold', 'reduction', 'in', 'steady', '-', 'state', 'DMAHP', 'transcript', 'levels', 'relative', 'to', 'wild', '-', 'type', 'controls', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-887 | Analysis of DMAHP expression in the cells of DM patients with loss of the hypersensitive site revealed a two-to fourfold reduction in steady-state DMAHP transcript levels relative to wild-type controls. | 1 |
['Allele', '-', 'specific', 'analysis', 'of', 'DMAHP', 'expression', 'showed', 'that', 'steady', '-', 'state', 'transcript', 'levels', 'from', 'the', 'expanded', 'allele', 'were', 'greatly', 'reduced', 'in', 'comparison', 'to', 'those', 'from', 'the', 'wild', '-', 'type', 'allele', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-888 | Allele-specific analysis of DMAHP expression showed that steady-state transcript levels from the expanded allele were greatly reduced in comparison to those from the wild-type allele. | 0 |
['Together', ',', 'these', 'results', 'demonstrate', 'that', 'CTG', '-', 'repeat', 'expansions', 'can', 'suppress', 'local', 'gene', 'expression', 'and', 'implicate', 'DMAHP', 'in', 'DM', 'pathogenesis', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0] | validation-889 | Together, these results demonstrate that CTG-repeat expansions can suppress local gene expression and implicate DMAHP in DM pathogenesis. | 1 |
['Constitutively', 'methylated', 'CpG', 'dinucleotides', 'as', 'mutation', 'hot', 'spots', 'in', 'the', 'retinoblastoma', 'gene', '(', 'RB1', ')', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0] | validation-890 | Constitutively methylated CpG dinucleotides as mutation hot spots in the retinoblastoma gene (RB1). | 1 |
['A', 'wide', 'spectrum', 'of', 'mutations', ',', 'ranging', 'from', 'point', 'mutations', 'to', 'large', 'deletions', ',', 'have', 'been', 'described', 'in', 'the', 'retinoblastoma', 'gene', '(', 'RB1', ')', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0] | validation-891 | A wide spectrum of mutations, ranging from point mutations to large deletions, have been described in the retinoblastoma gene (RB1). | 1 |
['Mutations', 'have', 'been', 'found', 'throughout', 'the', 'gene', ';', 'however', ',', 'these', 'genetic', 'alterations', 'do', 'not', 'appear', 'to', 'be', 'homogeneously', 'distributed', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-892 | Mutations have been found throughout the gene;however, these genetic alterations do not appear to be homogeneously distributed. | 0 |
['In', 'particular', ',', 'a', 'significant', 'proportion', 'of', 'disease', '-', 'causing', 'mutations', 'results', 'in', 'the', 'premature', 'termination', 'of', 'protein', 'synthesis', ',', 'and', 'the', 'majority', 'of', 'these', 'mutations', 'occur', 'as', 'C', '-', '-', '>', 'T', 'transitions', 'at', 'CpG', 'dinucleotides', '(', 'CpGs', ')', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-893 | In particular, a significant proportion of disease-causing mutations results in the premature termination of protein synthesis, and the majority of these mutations occur as C-->T transitions at CpG dinucleotides (CpGs). | 0 |
['Such', 'recurrent', 'CpG', 'mutations', ',', 'including', 'those', 'found', 'in', 'RB1', ',', 'are', 'likely', 'the', 'result', 'of', 'the', 'deamination', 'of', '5', '-', 'methylcytosine', 'within', 'these', 'CpGs', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-894 | Such recurrent CpG mutations, including those found in RB1, are likely the result of the deamination of 5-methylcytosine within these CpGs. | 0 |
['In', 'the', 'present', 'study', ',', 'we', 'used', 'the', 'sodiumbisulfite', 'conversion', 'method', 'to', 'detect', 'cytosine', 'methylation', 'in', 'representative', 'exons', 'of', 'RB1', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-895 | In the present study, we used the sodiumbisulfite conversion method to detect cytosine methylation in representative exons of RB1. | 0 |
['We', 'analyzed', 'DNA', 'from', 'a', 'variety', 'of', 'tissues', 'and', 'specifically', 'targeted', 'CGA', 'codons', 'in', 'RB1', ',', 'where', 'recurrent', 'premature', 'termination', 'mutations', 'have', 'been', 'reported', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-896 | We analyzed DNA from a variety of tissues and specifically targeted CGA codons in RB1, where recurrent premature termination mutations have been reported. | 0 |
['We', 'found', 'that', 'DNA', 'methylation', 'within', 'RB1', 'exons', '8', ',', '14', ',', '25', ',', 'and', '27', 'appeared', 'to', 'be', 'restricted', 'to', 'CpGs', ',', 'including', 'six', 'CGA', 'codons', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-897 | We found that DNA methylation within RB1 exons 8, 14, 25, and 27 appeared to be restricted to CpGs, including six CGA codons. | 0 |
['Other', 'codons', 'containing', 'methylated', 'cytosines', 'have', 'not', 'been', 'reported', 'to', 'be', 'mutated', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-898 | Other codons containing methylated cytosines have not been reported to be mutated. | 0 |
['Therefore', ',', 'disease', '-', 'causing', 'mutations', 'at', 'CpGs', 'in', 'RB1', 'appear', 'to', 'be', 'determined', 'by', 'several', 'factors', ',', 'including', 'the', 'constitutive', 'presence', 'of', 'DNA', 'methylation', 'at', 'cytosines', 'within', 'CpGs', ',', 'the', 'specific', 'codon', 'within', 'which', 'the', 'methylated', 'cytosine', 'is', 'located', ',', 'and', 'the', 'particular', 'region', 'of', 'the', 'gene', 'within', 'which', 'that', 'codon', 'resides', '.', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-899 | Therefore, disease-causing mutations at CpGs in RB1 appear to be determined by several factors, including the constitutive presence of DNA methylation at cytosines within CpGs, the specific codon within which the methylated cytosine is located, and the particular region of the gene within which that codon resides.. | 0 |
['The', 'von', 'Hippel', '-', 'Lindau', 'tumor', 'suppressor', 'gene', 'product', 'interacts', 'with', 'Sp1', 'to', 'repress', 'vascular', 'endothelial', 'growth', 'factor', 'promoter', 'activity', '.'] | [0, 1, 2, 2, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-900 | The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity. | 1 |
['The', 'von', 'Hippel', '-', 'Lindau', 'tumor', 'suppressor', 'gene', '(', 'VHL', ')', 'has', 'a', 'critical', 'role', 'in', 'the', 'pathogenesis', 'of', 'clear', '-', 'cell', 'renal', 'cell', 'carcinoma', '(', 'RCC', ')', ',', 'as', 'VHL', 'mutations', 'have', 'been', 'found', 'in', 'both', 'von', 'Hippel', '-', 'Lindau', 'disease', '-', 'associated', 'and', 'sporadic', 'RCCs', '.'] | [0, 1, 2, 2, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 2, 2, 2, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 2, 2, 2, 2, 2, 2, 2, 0] | validation-901 | The von Hippel-Lindau tumor suppressor gene (VHL) has a critical role in the pathogenesis of clear-cell renal cell carcinoma (RCC), as VHL mutations have been found in both von Hippel-Lindau disease-associated and sporadic RCCs. | 1 |
['Recent', 'studies', 'suggest', 'that', 'vascular', 'endothelial', 'growth', 'factor', '(', 'VEGF', ')', 'mRNA', 'is', 'upregulated', 'in', 'RCC', '-', 'and', 'von', 'Hippel', '-', 'Lindau', 'disease', '-', 'associated', 'tumors', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 2, 2, 2, 2, 2, 2, 2, 2, 0] | validation-902 | Recent studies suggest that vascular endothelial growth factor (VEGF) mRNA is upregulated in RCC-and von Hippel-Lindau disease-associated tumors. | 1 |
['We', 'have', 'therefore', 'assessed', 'the', 'effect', 'of', 'the', 'VHL', 'gene', 'product', 'on', 'VEGF', 'expression', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-903 | We have therefore assessed the effect of the VHL gene product on VEGF expression. | 0 |
['VEGF', 'promoter', '-', 'luciferase', 'constructs', 'were', 'transiently', 'cotransfected', 'with', 'a', 'wild', '-', 'type', 'VHL', '(', 'wt', '-', 'VHL', ')', 'vector', 'in', 'several', 'cell', 'lines', ',', 'including', '293', 'embryonic', 'kidney', 'and', 'RCC', 'cell', 'lines', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0] | validation-904 | VEGF promoter-luciferase constructs were transiently cotransfected with a wild-type VHL (wt-VHL) vector in several cell lines, including 293 embryonic kidney and RCC cell lines. | 1 |
['wt', '-', 'VHL', 'protein', 'inhibited', 'VEGF', 'promoter', 'activity', 'in', 'a', 'dose', '-', 'dependent', 'manner', 'up', 'to', '5', '-', 'to', '10', '-', 'fold', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-905 | wt-VHL protein inhibited VEGF promoter activity in a dose-dependent manner up to 5-to 10-fold. | 0 |
['Deletion', 'analysis', 'defined', 'a', '144', '-', 'bp', 'region', 'of', 'the', 'VEGF', 'promoter', 'necessary', 'for', 'VHL', 'repression', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-906 | Deletion analysis defined a 144-bp region of the VEGF promoter necessary for VHL repression. | 0 |
['This', 'VHL', '-', 'responsive', 'element', 'is', 'GC', 'rich', 'and', 'specifically', 'binds', 'the', 'transcription', 'factor', 'Sp1', 'in', 'crude', 'nuclear', 'extracts', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-907 | This VHL-responsive element is GC rich and specifically binds the transcription factor Sp1 in crude nuclear extracts. | 0 |
['In', 'Drosophila', 'cells', ',', 'cotransfected', 'VHL', 'represses', 'Sp1', '-', 'mediated', 'activation', 'but', 'not', 'basal', 'activity', 'of', 'the', 'VEGF', 'promoter', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-908 | In Drosophila cells, cotransfected VHL represses Sp1-mediated activation but not basal activity of the VEGF promoter. | 0 |
['We', 'next', 'demonstrated', 'in', 'coimmunoprecipitates', 'that', 'VHL', 'and', 'Sp1', 'were', 'part', 'of', 'the', 'same', 'complex', 'and', ',', 'by', 'using', 'a', 'glutathione', '-', 'S', '-', 'transferase', '-', 'VHL', 'fusion', 'protein', 'and', 'purified', 'Sp1', ',', 'that', 'VHL', 'and', 'Sp1', 'directly', 'interact', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-909 | We next demonstrated in coimmunoprecipitates that VHL and Sp1 were part of the same complex and, by using a glutathione-S-transferase-VHL fusion protein and purified Sp1, that VHL and Sp1 directly interact. | 0 |
['Furthermore', ',', 'endogenous', 'VEGF', 'mRNA', 'levels', 'were', 'suppressed', 'in', 'permanent', 'RCC', 'cell', 'lines', 'expressing', 'wt', '-', 'VHL', ',', 'and', 'nuclear', 'run', '-', 'on', 'studies', 'indicated', 'that', 'VHL', 'regulation', 'of', 'VEGF', 'occurs', 'at', 'least', 'partly', 'at', 'the', 'transcriptional', 'level', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-910 | Furthermore, endogenous VEGF mRNA levels were suppressed in permanent RCC cell lines expressing wt-VHL, and nuclear run-on studies indicated that VHL regulation of VEGF occurs at least partly at the transcriptional level. | 1 |
['These', 'observations', 'support', 'a', 'new', 'mechanism', 'for', 'VHL', '-', 'mediated', 'transcriptional', 'repression', 'via', 'a', 'direct', 'inhibitory', 'action', 'on', 'Sp1', 'and', 'suggest', 'that', 'loss', 'of', 'Sp1', 'inhibition', 'may', 'be', 'important', 'in', 'the', 'pathogenesis', 'of', 'von', 'Hippel', '-', 'Lindau', 'disease', 'and', 'RCC', '.', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 2, 2, 0, 1, 0, 0] | validation-911 | These observations support a new mechanism for VHL-mediated transcriptional repression via a direct inhibitory action on Sp1 and suggest that loss of Sp1 inhibition may be important in the pathogenesis of von Hippel-Lindau disease and RCC.. | 1 |
['Adult', 'onset', 'globoid', 'cell', 'leukodystrophy', '(', 'Krabbe', 'disease', ')', ':', 'analysis', 'of', 'galactosylceramidase', 'cDNA', 'from', 'four', 'Japanese', 'patients', '.'] | [1, 2, 2, 2, 2, 0, 1, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-912 | Adult onset globoid cell leukodystrophy (Krabbe disease):analysis of galactosylceramidase cDNA from four Japanese patients. | 1 |
['We', 'examined', 'galactosylceramidase', '(', 'GALC', ')', 'cDNA', 'in', 'four', 'Japanese', 'patients', 'with', 'adult', 'onset', 'globoid', 'cell', 'leukodystrophy', '(', 'Krabbe', 'disease', ';', 'AO', '-', 'GLD', ')', 'by', 'polymerase', 'chain', 'reaction', '/', 'single', '-', 'strand', 'conformation', 'polymorphism', '(', 'PCR', '-', 'SSCP', ')', 'analysis', ',', 'subsequent', 'sequence', 'determination', ',', 'and', 'restriction', 'enzyme', 'digestion', 'of', 'PCR', 'products', ',', 'initial', 'symptoms', 'were', 'the', 'onset', 'of', 'slowly', 'progressive', 'spastic', 'paraplegia', 'from', 'the', 'middle', 'of', 'the', 'second', 'decade', ',', 'and', 'all', 'patients', 'had', 'diminished', 'GALC', 'activity', 'in', 'their', 'leukocytes', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 2, 2, 0, 1, 2, 0, 1, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 0, 0, 0, 0] | validation-913 | We examined galactosylceramidase (GALC) cDNA in four Japanese patients with adult onset globoid cell leukodystrophy (Krabbe disease;AO-GLD) by polymerase chain reaction/single-strand conformation polymorphism (PCR-SSCP) analysis, subsequent sequence determination, and restriction enzyme digestion of PCR products, initial symptoms were the onset of slowly progressive spastic paraplegia from the middle of the second decade, and all patients had diminished GALC activity in their leukocytes. | 1 |
['We', 'identified', 'three', 'missense', 'mutations', '(', 'I66M', ',', 'G270D', ',', 'L618S', ')', 'and', 'one', 'exon', '-', '6', 'skipping', '(', '535', '-', '573del', ')', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-914 | We identified three missense mutations (I66M, G270D, L618S) and one exon-6 skipping (535-573del). | 0 |
['Two', 'of', 'the', 'patients', 'had', 'only', 'the', 'I66M', 'mutant', 'mRNA', ',', 'and', 'one', 'only', 'the', 'G27OD', 'mutant', 'mRNA', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-915 | Two of the patients had only the I66M mutant mRNA, and one only the G27OD mutant mRNA. | 0 |
['The', 'fourth', 'patient', 'carried', 'a', 'compound', 'heterozygous', 'mutation', 'of', '535', '-', '573del', 'and', 'L618S', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-916 | The fourth patient carried a compound heterozygous mutation of 535-573del and L618S. | 0 |
['To', 'determine', 'the', 'enzymatic', 'activities', 'produced', 'by', 'these', 'mutations', ',', 'we', 'constructed', 'mutated', 'GALC', 'cDNAs', 'and', 'expressed', 'them', 'in', 'COS', '-', '1', 'cells', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-917 | To determine the enzymatic activities produced by these mutations, we constructed mutated GALC cDNAs and expressed them in COS-1 cells. | 0 |
['Three', 'mutations', ',', 'viz', '.', ',', 'G270D', ',', 'L618S', ',', 'and', 'exon', '-', '6', 'skipping', '(', '535', '-', '573del', ')', ',', 'produced', 'diminished', 'GALC', 'activity', 'as', 'expected', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 0, 0, 0] | validation-918 | Three mutations, viz., G270D, L618S, and exon-6 skipping (535-573del), produced diminished GALC activity as expected. | 1 |
['The', 'I66M', 'mutation', 'in', 'the', 'wild', '-', 'type', 'GALC', 'cDNA', '(', 'I289', ')', 'had', 'normal', 'activity', ',', 'but', 'when', 'this', 'mutation', 'and', 'the', 'V289', 'polymorphism', 'were', 'introduced', 'into', 'the', 'same', 'allele', ',', 'it', 'had', 'decreased', 'activity', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-919 | The I66M mutation in the wild-type GALC cDNA (I289) had normal activity, but when this mutation and the V289 polymorphism were introduced into the same allele, it had decreased activity. | 0 |
['Thus', ',', 'the', 'combination', 'of', 'a', 'unique', 'mutation', 'and', 'polymorphism', 'causes', 'conformational', 'change', 'in', 'the', 'GALC', 'enzyme', ',', 'resulting', 'in', 'low', 'enzymatic', 'activity', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0] | validation-920 | Thus, the combination of a unique mutation and polymorphism causes conformational change in the GALC enzyme, resulting in low enzymatic activity. | 0 |
['AO', '-', 'GLD', 'mutations', ',', 'including', 'those', 'found', 'here', ',', 'are', 'located', 'in', 'the', 'N', '-', 'terminus', '(', 'I66M', ',', 'G270D', ',', '535', '-', '573del', ')', 'or', 'C', '-', 'terminus', '(', 'L618S', ')', 'of', 'the', 'GALC', 'enzyme', ',', 'whereas', 'the', 'reported', 'mutations', 'in', 'the', 'infantile', 'form', '(', 'IF', '-', 'GLD', ')', 'are', 'in', 'the', 'central', 'domain', '.'] | [1, 2, 2, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 2, 2, 0, 0, 0, 0, 0, 0, 0] | validation-921 | AO-GLD mutations, including those found here, are located in the N-terminus (I66M, G270D, 535-573del) or C-terminus (L618S) of the GALC enzyme, whereas the reported mutations in the infantile form (IF-GLD) are in the central domain. | 1 |
['This', 'difference', 'in', 'mutation', 'sites', 'may', 'affect', 'the', 'clinical', 'features', 'of', 'GLD', '.'] | [0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 0] | validation-922 | This difference in mutation sites may affect the clinical features of GLD. | 1 |
[] | [] | validation-923 | null | 0 |
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