Asunto(s)
Antineoplásicos/uso terapéutico , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Anciano , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mielomonocítica Crónica/genética , Leucemia Mielomonocítica Crónica/patología , Masculino , MutaciónAsunto(s)
Antineoplásicos/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Factor 1 de Transcripción de Unión a Octámeros/genética , Piperazinas/uso terapéutico , Polimorfismo de Nucleótido Simple/genética , Pirimidinas/uso terapéutico , Benzamidas , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Factor 1 de Transcripción de Unión a Octámeros/metabolismo , Pronóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
A significant minority of chronic myeloid leukaemia patients eventually develop resistance to imatinib, often as a result of point mutations within the BCR-ABL kinase domain. Second-line tyrosine kinase inhibitors (TKIs) are effective against mutations that confer imatinib resistance; however, the T315I BCR-ABL mutant has proved resistant to all available TKIs. An assay facilitating early identification of BCR-ABL(T315I) would therefore aid in identifying high-risk patients who may benefit from alternative therapy. This report describes the development of a sensitive T315I mutation detection methodology based on real-time PCR with self-probing fluorescent primers. The technique demonstrated complete concordance with direct sequencing, correctly identifying 34 T315I-positive samples from a total of 61 samples screened. In a limiting dilution assay, the mutated clone was detectable to a level of 1% of total cells. The data show that Scorpions PCR enables rapid screening for BCR-ABL(T315I) in chronic myeloid leukaemia patients and is appropriate for use in a clinical setting.
Asunto(s)
Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Mutación Puntual , ADN Complementario/genética , ADN de Neoplasias/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Reacción en Cadena de la Polimerasa/métodos , Estudios Retrospectivos , Sensibilidad y EspecificidadAsunto(s)
Deleción Cromosómica , Proteínas de Unión al ADN/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Médula Ósea/patología , Mapeo Cromosómico , Cromosomas Humanos Par 9/genética , Proteínas de Fusión bcr-abl/metabolismo , Genes abl/genética , Humanos , Hibridación Fluorescente in Situ , Dedos de ZincAsunto(s)
Análisis Citogenético/métodos , Policitemia Vera/diagnóstico , Policitemia Vera/genética , Cromosomas Humanos Par 20 , Análisis Citogenético/normas , Reacciones Falso Negativas , Reordenamiento Génico , Humanos , Hibridación Fluorescente in Situ , Técnicas de Diagnóstico Molecular , Hibridación de Ácido NucleicoRESUMEN
Chronic myeloid leukemia (CML) is characterized by formation of the BCR-ABL fusion gene, usually as a consequence of the Philadelphia (Ph) translocation between chromosomes 9 and 22. Large deletions on the derivative chromosome 9 have recently been reported, but it was unclear whether deletions arose during disease progression or at the time of the Ph translocation. Fluorescence in situ hybridization (FISH) analysis was used to assess the deletion status of 253 patients with CML. The strength of deletion status as a prognostic indicator was then compared to the Sokal and Hasford scoring systems. The frequency of deletions was similar at diagnosis and after disease progression but was significantly increased in patients with variant Ph translocations. In patients with a deletion, all Ph(+) metaphases carried the deletion. The median survival of patients with and without deletions was 38 months and 88 months, respectively (P =.0001). By contrast the survival difference between Sokal or Hasford high-risk and non-high-risk patients was of only borderline significance (P =.057 and P =.034). The results indicate that deletions occur at the time of the Ph translocation. An apparently simple reciprocal translocation may therefore result in considerable genetic heterogeneity ab initio, a concept that is likely to apply to other malignancies associated with translocations. Deletion status is also a powerful and independent prognostic factor for patients with CML. The prognostic significance of deletion status should now be studied prospectively and, if confirmed, should be incorporated into management decisions and the analysis of clinical trials.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 9 , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Cromosoma Filadelfia , Adulto , Cromosomas Humanos Par 9/ultraestructura , Femenino , Humanos , Hibridación Fluorescente in Situ , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de SupervivenciaRESUMEN
Water lead concentrations were measured in 970 households throughout Scotland. Blood lead concentrations were measured in 283 people living in houses with water lead levels of over 0-48 mumol/l (100 mug/l). A highly significant correlation was found between lead concentrations in water and blood. Raised blood lead concentrations were associated with renal insufficiency, reflected in raised serum urea concentrations, and with hyperuricaemia, although there was no evidence of clinical disease in any of the affected people. This is further evidence that excessive lead in domestic water supplies has a harmful effect on the community's health.