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3.
Leukemia ; 30(4): 906-13, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26648538

RESUMO

Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy nearly confined to the elderly. Previous studies to determine incidence and prognostic significance of somatic mutations in CMML have relied on candidate gene sequencing, although an unbiased mutational search has not been conducted. As many of the genes commonly mutated in CMML were recently associated with age-related clonal hematopoiesis (ARCH) and aged hematopoiesis is characterized by a myelomonocytic differentiation bias, we hypothesized that CMML and aged hematopoiesis may be closely related. We initially established the somatic mutation landscape of CMML by whole exome sequencing followed by gene-targeted validation. Genes mutated in ⩾10% of patients were SRSF2, TET2, ASXL1, RUNX1, SETBP1, KRAS, EZH2, CBL and NRAS, as well as the novel CMML genes FAT4, ARIH1, DNAH2 and CSMD1. Most CMML patients (71%) had mutations in ⩾2 ARCH genes and 52% had ⩾7 mutations overall. Higher mutation burden was associated with shorter survival. Age-adjusted population incidence and reported ARCH mutation rates are consistent with a model in which clinical CMML ensues when a sufficient number of stochastically acquired age-related mutations has accumulated, suggesting that CMML represents the leukemic conversion of the myelomonocytic-lineage-biased aged hematopoietic system.


Assuntos
Biomarcadores Tumorais/genética , Hematopoese/genética , Leucemia Mielomonocítica Crônica/genética , Mutação/genética , Proteínas/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Exoma , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mielomonocítica Crônica/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Proteínas de Ligação a RNA , Taxa de Sobrevida , Adulto Jovem
4.
Leukemia ; 29(12): 2328-37, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26202934

RESUMO

Activation of nuclear ß-catenin and expression of its transcriptional targets promotes chronic myeloid leukemia (CML) progression, tyrosine kinase inhibitor (TKI) resistance, and leukemic stem cell self-renewal. We report that nuclear ß-catenin has a role in leukemia cell-intrinsic but not -extrinsic BCR-ABL1 kinase-independent TKI resistance. Upon imatinib inhibition of BCR-ABL1 kinase activity, ß-catenin expression was maintained in intrinsically resistant cells grown in suspension culture and sensitive cells cultured in direct contact (DC) with bone marrow (BM) stromal cells. Thus, TKI resistance uncouples ß-catenin expression from BCR-ABL1 kinase activity. In ß-catenin reporter assays, intrinsically resistant cells showed increased transcriptional activity versus parental TKI-sensitive controls, and this was associated with restored expression of ß-catenin target genes. In contrast, DC with BM stromal cells promoted TKI resistance, but had little effects on Lef/Tcf reporter activity and no consistent effects on cytoplasmic ß-catenin levels, arguing against a role for ß-catenin in extrinsic TKI resistance. N-cadherin or H-cadherin blocking antibodies abrogated DC-based resistance despite increasing Lef/Tcf reporter activity, suggesting that factors other than ß-catenin contribute to extrinsic, BM-derived TKI resistance. Our data indicate that, while nuclear ß-catenin enhances survival of intrinsically TKI-resistant CML progenitors, it is not required for extrinsic resistance mediated by the BM microenvironment.


Assuntos
Proteínas de Fusão bcr-abl/fisiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , beta Catenina/fisiologia , Caderinas/fisiologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Mesilato de Imatinib/uso terapêutico , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Wnt/fisiologia , Proteína Wnt-5a
6.
Diabetologia ; 54(7): 1684-92, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21484216

RESUMO

AIMS/HYPOTHESIS: We sought to identify the physiological implications of genetic variation at the HLA-DRB1 region in full-heritage Pima Indians in Arizona. METHODS: Single-nucleotide polymorphisms from the HLA region on chromosome 6p were tested for association with skeletal muscle mRNA expression of HLA-DRB1 and HLA-DRA, and with type 2 diabetes mellitus and prediabetic traits. RESULTS: The A allele at rs9268852, which tags HLA-DRB1 02(1602), was associated both with higher HLA-DRB1 mRNA expression (n = 133, p = 4.27 × 10(-14)) and decreased risk of type 2 diabetes (n = 3,265, OR 0.723, p = 0.002). Among persons with normal glucose tolerance (n = 266) this allele was associated with a higher mean acute insulin response during an intravenous glucose tolerance test (p = 0.005), higher mean 30 min insulin concentration during an oral glucose tolerance test (p = 0.017) and higher body fat percentage (p = 0.010). The polymorphism was not associated with HLA-DRA mRNA expression or insulin sensitivity. CONCLUSIONS/INTERPRETATION: HLA-DRB1*02 is protective for type 2 diabetes, probably by enhancing self tolerance, thereby protecting against the autoimmune-mediated reduction of insulin secretion.


Assuntos
Diabetes Mellitus Tipo 2/genética , Antígenos HLA-DR/genética , Insulina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Predisposição Genética para Doença , Antígenos HLA-DR/metabolismo , Cadeias alfa de HLA-DR , Cadeias HLA-DRB1 , Humanos , Secreção de Insulina , Masculino , Músculo Esquelético/metabolismo , Polimorfismo de Nucleotídeo Único/genética
7.
Diabetologia ; 54(1): 78-86, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20886205

RESUMO

AIMS/HYPOTHESIS: The ability to measure insulin sensitivity across the phenotypic spectrum of diabetes may contribute to a more accurate characterisation of diabetes type. Our goal was to develop and validate an insulin sensitivity (IS) score using the euglycaemic-hyperinsulinaemic clamp in a subset (n = 85) of 12- to 19-year-old youths with diabetes participating in the SEARCH study in Colorado, USA. METHODS: Youths with a diagnosis of type 1 (n = 60) or type 2 diabetes (n = 25) underwent a 3 h clamp to measure glucose disposal rate (GDR, mg kg⁻¹ min⁻¹). Demographic (age, sex, race), clinical (BMI, waist, Tanner stage) and metabolic characteristics (HbA1(c), lipids, blood pressure, urine albumin:creatinine) were used to estimate log(e)IS score via stepwise linear regression on a model-development set (n = 53). Estimated IS score was evaluated for reproducibility on two validation sets: youths with diabetes (n = 33) and healthy control youths (n = 22). RESULTS: The best model included waist, triacylglycerol (TG) and HbA1(c) levels (R² = 0.74). Diabetes type did not enter the model and there were no significant interactions between diabetes type and other predictors. Estimated IS score correlated well (r = 0.65, p < 0.0001; r = 0.62, p = 0.002) with GDR on the two validation sets. Based on this analysis, we propose the following formula to estimate insulin sensitivity in youths with diabetes: [Formula: see text]. CONCLUSIONS/INTERPRETATION: Insulin sensitivity can be estimated in adolescents with diabetes using routinely collected measures. This score can be applied to epidemiological studies of youths with diabetes to characterise relationships between dimensions of diabetes type.


Assuntos
Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Insulina/uso terapêutico , Adolescente , Adulto , Criança , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Técnica Clamp de Glucose , Humanos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Modelos Lineares , Masculino , Triglicerídeos/sangue , Circunferência da Cintura , Adulto Jovem
10.
Am J Clin Pathol ; 46(2): 262-3, 1966 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-5330322
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