RESUMO
Mutations in the DYNAMIN2 (DNM2) gene are frequently detected in human acute T-cell lymphoblastic leukemia (T-ALL), although the mechanisms linking these mutations to disease pathogenesis remain unknown. Using an ENU-based forward genetic screen for mice with erythroid phenotypes, we identified a heterozygous mouse line carrying a mutation in the GTPase domain of Dnm2 (Dnm2V265G) that induced a microcytic anemia. In vitro assays using the V265G mutant demonstrated loss of GTPase activity and impaired endocytosis that was comparable to other DNM2 mutants identified in human T-ALL. To determine the effects of DNM2 mutations in T-ALL, we bred the Dnm2V265G mice with the Lmo2 transgenic mouse model of T-ALL. Heterozygous Dnm2 mutants lacking the Lmo2 transgene displayed normal T-cell development, and did not develop T-ALL. In contrast, compound heterozygotes displayed an accelerated onset of T-ALL compared with mice carrying the Lmo2 oncogene alone. The leukemias from these mice exhibited a more immature immunophenotype and an expansion in leukemic stem cell numbers. Mechanistically, the Dnm2 mutation impaired clathrin-mediated endocytosis of the interleukin (IL)-7 receptor resulting in increased receptor density on the surface of leukemic stem cells. These findings suggest that DNM2 mutations cooperate with T-cell oncogenes by enhancing IL-7 signalling.
Assuntos
Dinamina II/genética , Interleucina-7/metabolismo , Leucemia de Células T/etiologia , Mutação , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Endocitose/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Proteínas com Domínio LIM/genética , Leucemia de Células T/genética , Leucemia de Células T/metabolismo , Camundongos , Oncogenes , Transdução de SinaisRESUMO
Safe and effective treatment with brachytherapy sources requires an accurate knowledge of the local tissue absorbed dose rate derived from the source reference air kerma rate. It is desirable that these air kerma rate measurements be traceable to national standards. The NPL has embarked on a programme that will enable the user to assay brachytherapy sources in a convenient manner prior to treatment. Calibration figures have been derived for the NPL secondary standard radionuclide calibrator for 192Ir brachytherapy sources manufactured by Amersham International plc. The calibration figures enable the user to accurately estimate the reference air kerma rate and activity of such sources by measuring the ionization chamber response. Calibration figures for other brachytherapy sources are also being derived.
Assuntos
Braquiterapia/normas , Radioisótopos de Irídio/normas , CalibragemAssuntos
Adolescente , Atenção à Saúde , Educação em Enfermagem , Feminino , Humanos , Masculino , Estados UnidosRESUMO
From 1987 through 1990, 34 acute supracondylar femoral fractures in 33 patients were treated with an interlocking closed-section intramedullary nail inserted retrograde into the femur through the intercondylar notch. Follow-up data of at least five months were available for 25 of these fractures. The patients suffered injuries more extensive than comparable patients reported in the literature. All fractures healed clinically and radiographically. The average arc motion at the most recent evaluation was 100 degrees. The average operative time was 156 minutes and the average estimated blood loss was 224 ml. Complications related to this treatment were successfully resolved. The genucephalic nail is a good treatment for supracondylar femoral fractures.