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1.
Br J Cancer ; 107(8): 1392-8, 2012 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-22976798

RESUMEN

BACKGROUND: Multiple clinical risk factors and genetic profiles have been demonstrated to predict progression of non-muscle invasive bladder cancer; however, no easily clinical applicable gene signature has been developed to predict disease progression independent of disease stage and grade. METHODS: We measured the intra-patient variation of an 88-gene progression signature using 39 metachronous tumours from 17 patients. For delineation of the optimal quantitative reverse transcriptase PCR panel of markers, we used 115 tumour samples from patients in Denmark, Sweden, UK and Spain. RESULTS: Analysis of intra-patient variation of the molecular markers showed 71% similar classification results. A final panel of 12 genes was selected, showing significant correlation with outcome. In multivariate Cox regression analysis, we found that the 12-gene signature was an independent prognostic factor (hazard ratio=7.4 (95% confidence interval: 3.4-15.9), P<0.001) when adjusting for stage, grade and treatment. Independent validation of the 12-gene panel and the determined cut-off values is needed and ongoing. CONCLUSION: Intra-patient marker variation in metachronous tumours is present. Therefore, to increase test sensitivity, it may be necessary to test several metachronous tumours from a patient's disease course. A PCR-based 12-gene signature significantly predicts disease progression in patients with non-muscle invasive bladder cancer.


Asunto(s)
Neoplasias Primarias Secundarias/genética , Reacción en Cadena de la Polimerasa , Análisis de Matrices Tisulares , Neoplasias de la Vejiga Urinaria/genética , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/patología , Pronóstico , Transferencia de Tecnología , Neoplasias de la Vejiga Urinaria/patología
2.
Am J Respir Cell Mol Biol ; 20(3): 441-7, 1999 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-10030842

RESUMEN

A role for endothelial nitric oxide synthase (NOS3) in the susceptibility of individuals with alpha1-antitrypsin (alpha1AT) deficiency to destructive lung disease was evaluated. Six polymorphic sites were identified within the NOS3 gene (i.e., -924A/G, -788C/T, -691C/T, 774C/T, 894G/T, and 1998C/G). The genotype distribution was determined in 339 patients and 94 control individuals. Frequency of the 774T allele in severely affected individuals was 0.417 versus 0.269 in control subjects (P = 0.018), whereas the 894T allele frequency was 0.427 versus 0.280 in control subjects (P = 0.024). Patients with less severe lung disease had the 774T and 894T allele frequencies of 0.289 and 0.344, respectively, similar to frequencies in a control group (P > 0.3). No direct correlation between pulmonary function and five other NOS3 polymorphisms was observed. Thus, functional allelic variants that are in linkage disequilibrium with the 774C/T and 894G/T may be present in the specified genomic area. These data are consistent with a modulatory role for NOS3 in destructive lung disease associated with alpha1AT deficiency.


Asunto(s)
Enfisema/etiología , Óxido Nítrico Sintasa/genética , Deficiencia de alfa 1-Antitripsina/enzimología , Adulto , Susceptibilidad a Enfermedades , Frecuencia de los Genes , Genotipo , Heterocigoto , Homocigoto , Humanos , Desequilibrio de Ligamiento , Persona de Mediana Edad , Óxido Nítrico Sintasa de Tipo III , Polimorfismo Genético , Análisis de Secuencia de ADN
3.
Alcohol Clin Exp Res ; 19(5): 1105-10, 1995 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-8561277

RESUMEN

Genetic deficiency of the mitochondrial aldehyde dehydrogenase (ALDH2) is frequent in Asian peoples where it is an important factor negatively regulating drinking behavior. To obtain additional information on gene geography of known ALDH2 alleles, and look for new variants, ALDH2 genes were evaluated in a Chinese population from Taiwan, a Yakut population of Siberia, and in five North American Indian populations. A novel approach based on a single-strand conformation polymorphism assay, and polymerase chain reaction-directed mutagenesis was developed for genotyping. In the Taiwan Chinese population, the ALDH2(2) allele frequency was 0.319 +/- 0.025, and this allele was not detected in the Yakut population nor in the five North American Indian populations. However, a new allele, ALDH2(3), was detected in Pima Indians at a frequency of 0.044 +/- 0.022, and this allele was also observed in 1 of 49 Pueblo samples. ALDH2(3) is a silent transition 1464 G-->A, and it possibly has a wide distribution among North American Indians. A new subtype of the ALDH2(2) allele, designated as ALDH2(2Taiwan), was found in 1 of 174 Chinese from Taiwan. ALDH2(2Taiwan) is characterized by two G-->A transitions at bases 1486 and 1510, resulting in Glu-->Lys substitutions at both the 479 and 487 positions. Thus, this second nonconservative ALDH2 substitution occurs within the sequence of the already inactive ALDH2(2) allele.


Asunto(s)
Alcoholismo/genética , Aldehído Deshidrogenasa/genética , Pueblo Asiatico/genética , Indígenas Norteamericanos/genética , Isoenzimas/genética , Mitocondrias Hepáticas/enzimología , Polimorfismo Genético/genética , Alcoholismo/enzimología , Alcoholismo/etnología , Aldehído Deshidrogenasa/deficiencia , Alelos , Composición de Base/genética , ADN/genética , Frecuencia de los Genes , Humanos , Isoenzimas/deficiencia , Datos de Secuencia Molecular , Valores de Referencia , Taiwán , Estados Unidos
4.
Nucleic Acids Res ; 23(12): 2287-91, 1995 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-7610057

RESUMEN

To predict alterations in single-strand DNA mobility in non-denaturing electrophoretic gels, Zuker's RNA folding program was modified. Energy files utilized by the LRNA RNA folding algorithm were modified to emulate folding of single-strand DNA. Energy files were modified to disallow G-T base pairing. Stacking energies were corrected for DNA thermodynamics. Constraints on loop nucleotide sequences were removed. The LRNA RNA folding algorithm using the DNA fold energy files was applied to predict folding of PCR generated single-strand DNA molecules from polymorphic human ALDH2 and TPH alleles. The DNA-Fold version 1.0 program was used to design primers to create and abolish SSCP mobility shifts. Primers were made that add a 5' tag sequence or alter complementarity to an internal sequence. Differences in DNA secondary structure were assessed by SSCP analysis and compared to single-strand DNA secondary structure predictions. Results demonstrate that alterations in single-strand DNA conformation may be predicted using DNA-Fold 1.0.


Asunto(s)
Aldehído Deshidrogenasa/genética , ADN de Cadena Simple/química , Conformación de Ácido Nucleico , Polimorfismo Conformacional Retorcido-Simple , Triptófano Hidroxilasa/genética , Algoritmos , Alelos , Secuencia de Bases , Humanos , Datos de Secuencia Molecular , Termodinámica
5.
Alcohol ; 12(2): 163-7, 1995.
Artículo en Inglés | MEDLINE | ID: mdl-7772269

RESUMEN

Deficiency of mitochondrial aldehyde dehydrogenase (ALDH2) has been previously reported in South American Indians. We therefore assayed five individuals from each of five South American Indian populations (Quechua, Karitiana, Ticuna, Surui, Guahiba), and two North American populations (Maya and Moskoke) for the presence of the Oriental ALDH2(2) variant. These samples were also surveyed for other alleles altering ALDH2 function. Allele-specific amplification assay (ASA) did not detect the ALDH2(2) allele in any of the New World populations studied. The entire coding sequence of the ALDH2 cDNA was enzymatically amplified in partially overlapping fragments. Each fragment was digested using restriction endonucleases and subfragments 148-285 b.p. in length were analyzed by the single-stranded conformation polymorphism (SSCP) technique. No variants were detected within the coding region of the ALDH2 gene in any of the seven American Indian populations. Three potentially correct explanations for these results are suggested. First, an ALDH2 polymorphism is present but undetectable by SSCP; second, none of the studied individuals were ALDH2 negative; third, the polymorphism occurs beyond the coding region of ALDH2 gene.


Asunto(s)
Aldehído Deshidrogenasa/genética , Indígenas Norteamericanos/genética , Indígenas Sudamericanos/genética , Polimorfismo Genético , Alelos , Pueblo Asiatico/genética , Secuencia de Bases , Mapeo Cromosómico , ADN Complementario/genética , Humanos , Sondas Moleculares/genética , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Transcripción Genética
6.
Alcohol ; 12(2): 159-61, 1995.
Artículo en Inglés | MEDLINE | ID: mdl-7772268

RESUMEN

The activity of mitochondrial aldehyde dehydrogenase (ALDH2) was tested by isoelectric focusing of hair root extracts from 50 Chachi Indians (Ecuador). Quality of extracts and the intactness of cytoplasmic and mitochondrial enzymes were ascertained by assaying of phosphoglucomutase (PGM) and malate dehydrogenase (MDH) in the same extracts. Three of the 39 successfully assayed Chachi Indian samples showed virtual absence of the ALDH2 band on the isoelectropherogram, and the control enzymes were stained normally in these subjects. These data confirm the existence of a mitochondrial ALDH deficiency among South American Indians. The molecular origin of the ALDH2 deficiency in this population is unknown.


Asunto(s)
Aldehído Deshidrogenasa/deficiencia , Indígenas Sudamericanos , Adolescente , Adulto , Aldehído Deshidrogenasa/metabolismo , Niño , Preescolar , Ecuador/etnología , Femenino , Cabello/enzimología , Humanos , Focalización Isoeléctrica , Malato Deshidrogenasa/metabolismo , Masculino , Persona de Mediana Edad , Mitocondrias/enzimología , Fosfoglucomutasa/metabolismo
7.
Hum Biol ; 65(5): 689-710, 1993 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-8262501

RESUMEN

Genetic polymorphisms of blood groups, serum proteins, red cell enzymes, PTC tasting, and cerumen types are reported for five Mongoloid populations of Buryats from the Lake Baikal region of Siberia (Russia). These groups are characterized by relatively high frequencies of alleles ABO*B, RH*D, cerumen D, GC*1F, ACP1*B, ESD*2, and PGD*C. Significant genetic heterogeneity between populations was demonstrated for the loci RH, MN, cerumen, PGD, ABO, GC, GLO, TF, and PGM1. Genetic distance analyses using five loci revealed a lower level of genetic microdifferentiation within the Buryat populations compared with other native Siberian groups. The distribution of gene markers in Buryats is similar to that found in neighboring Central Asian groups, such as the Yakuts and the Mongols. Intrapopulational analyses of the five Buryat subdivisions, based on R matrix and rii, indicate that one of the subdivisions is reproductively more isolated than the others and that two of the communities have received considerable gene flow. A nonlinear relationship was demonstrated between geographic and genetic distances of Buryat population subdivisions.


Asunto(s)
Alelos , Antígenos de Grupos Sanguíneos , Genética de Población , Polimorfismo Genético , Grupos Raciales , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico , Femenino , Frecuencia de los Genes , Tamización de Portadores Genéticos , Marcadores Genéticos , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Siberia
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