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1.
Nat Commun ; 12(1): 5071, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417470

RESUMO

Identification of causal variants and genes underlying genome-wide association study (GWAS) loci is essential to understand the biology of alcohol use disorder (AUD) and drinks per week (DPW). Multi-omics integration approaches have shown potential for fine mapping complex loci to obtain biological insights to disease mechanisms. In this study, we use multi-omics approaches, to fine-map AUD and DPW associations at single SNP resolution to demonstrate that rs56030824 on chromosome 11 significantly reduces SPI1 mRNA expression in myeloid cells and lowers risk for AUD and DPW. Our analysis also identifies MAPT as a candidate causal gene specifically associated with DPW. Genes prioritized in this study show overlap with causal genes associated with neurodegenerative disorders. Multi-omics integration analyses highlight, genetic similarities and differences between alcohol intake and disordered drinking, suggesting molecular heterogeneity that might inform future targeted functional and cross-species studies.


Assuntos
Alcoolismo/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica , Doenças Neurodegenerativas/genética , Encéfalo/metabolismo , Epigênese Genética , Feto/metabolismo , Redes Reguladoras de Genes , Loci Gênicos , Marcadores Genéticos , Humanos , Desequilíbrio de Ligação/genética , Análise da Randomização Mendeliana , Mapeamento Físico do Cromossomo , Regiões Promotoras Genéticas/genética , Locos de Características Quantitativas/genética
2.
Nat Genet ; 52(11): 1219-1226, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33106634

RESUMO

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.


Assuntos
Hematopoiese Clonal/genética , Segunda Neoplasia Primária/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/efeitos da radiação , Criança , Pré-Escolar , Evolução Clonal , Hematopoiese Clonal/efeitos dos fármacos , Estudos de Coortes , Feminino , Aptidão Genética , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide/genética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Seleção Genética , Adulto Jovem
3.
Leukemia ; 34(3): 799-810, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31628430

RESUMO

RAS-pathway mutations are recurrent events in myeloid malignancies. However, there is limited data on the significance of RAS-pathway mutations in patients with myelofibrosis (MF). We analyzed next-generation sequencing data of 16 genes, including RAS-pathway genes, from 723 patients with primary and secondary MF across three international centers and evaluated their significance. N/KRAS variants were present in 6% of patients and were typically sub-clonal (median VAF = 20%) relative to other genes variants. RAS variants were associated with advanced MF features including leukocytosis (p = 0.02), high somatic mutation burden (p < 0.01) and the presence of established "molecular high-risk" (MHR) mutations. MF patients with N/KRAS mutations had shorter 3-year overall survival (OS) (34% vs 58%, p < 0.001) and higher incidence of acute myeloid leukemia at 3 years (18% vs 11%, p = 0.03). In a multivariate Cox model, RAS mutations were associated with decreased OS (HR 1.93, p < 0.001). We created a novel score to predict OS incorporating RAS mutations, and it predicted OS across training and validation cohorts. Patients with intermediate risk/high-risk DIPSS with RAS mutations who received ruxolitinib had a nonsignificant longer 2-year OS relative to those who did not receive ruxolitinib. These data demonstrate the importance of identifying RAS mutations in MF patients.


Assuntos
Genes ras , Mutação , Mielofibrose Primária/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Policitemia Vera/genética , Mielofibrose Primária/diagnóstico , Prognóstico , Modelos de Riscos Proporcionais , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Pirazóis/farmacologia , Estudos Retrospectivos , Risco , Trombocitemia Essencial/genética , Resultado do Tratamento , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genética
4.
Nat Commun ; 10(1): 2691, 2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-31217428

RESUMO

The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08-2750 (Ro) binds directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrates in vivo inhibition of c-MYC and reduces disease burden in a murine AML leukemia model. Thus, we identify a small molecule that targets MSI's oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.


Assuntos
Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Leucemia Experimental/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Pteridinas/farmacologia , Proteínas de Ligação a RNA/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Perfilação da Expressão Gênica , Humanos , Leucemia Experimental/sangue , Leucemia Mieloide Aguda/sangue , Masculino , Camundongos , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-myc/metabolismo , Pteridinas/uso terapêutico , RNA/metabolismo , Motivo de Reconhecimento de RNA/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Transcriptoma/efeitos dos fármacos , Células Tumorais Cultivadas
5.
Haematologica ; 104(7): 1378-1387, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30523054

RESUMO

Measurable residual disease is associated with inferior outcomes in patients with acute myeloid leukemia (AML). Measurable residual disease monitoring enhances risk stratification and may guide therapeutic intervention. The European LeukemiaNet working party recently came to a consensus recommendation incorporating leukemia associated immunophenotype-based different from normal approach by multi-color flow cytometry for measurable residual disease evaluation. However, the analytical approach is highly expertise-dependent and difficult to standardize. Here we demonstrate that loss of plasmacytoid dendritic cell differentiation after 7+3 induction in AML is highly specific for measurable residual disease positivity (specificity 97.4%) in a uniformly treated patient cohort. Moreover, loss of plasmacytoid dendritic cell differentiation as determined by a blast-to-plasmacytoid dendritic cell ratio >10 was strongly associated with inferior overall and relapse-free survival (RFS) [Hazard ratio 2.79, 95% confidence interval (95%CI): 0.98-7.97; P=0.077) and 3.83 (95%CI: 1.51-9.74; P=0.007), respectively), which is similar in magnitude to measurable residual disease positivity. Importantly, measurable residual disease positive patients who reconstituted plasmacytoid dendritic cell differentiation (blast/ plasmacytoid dendritic cell ratio <10) showed a higher rate of measurable residual disease clearance at later pre-transplant time points compared to patients with loss of plasmacytoid dendritic cell differentiation (blast/ plasmacytoid dendritic cell ratio <10) (6 of 12, 50% vs 2 of 18, 11%; P=0.03). Furthermore pre-transplant plasmacytoid dendritic cell recovery was associated with superior outcome in measurable residual disease positive patients. Our study provides a novel, simple, broadly applicable, and quantitative multi-color flow cytometry approach to risk stratification in AML.


Assuntos
Células Dendríticas/patologia , Leucemia Mieloide Aguda/mortalidade , Recidiva Local de Neoplasia/mortalidade , Neoplasia Residual/mortalidade , Adulto , Idoso , Estudos de Casos e Controles , Terapia Combinada , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Neoplasia Residual/patologia , Neoplasia Residual/terapia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
6.
Nat Med ; 23(11): 1369-1376, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28920958

RESUMO

N6-methyladenosine (m6A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m6A modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the m6A-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation. Conversely, overexpression of wild-type METTL3, but not of a catalytically inactive form of METTL3, inhibits cell differentiation and increases cell growth. METTL3 mRNA and protein are expressed more abundantly in acute myeloid leukemia (AML) cells than in healthy HSPCs or other types of tumor cells. Furthermore, METTL3 depletion in human myeloid leukemia cell lines induces cell differentiation and apoptosis and delays leukemia progression in recipient mice in vivo. Single-nucleotide-resolution mapping of m6A coupled with ribosome profiling reveals that m6A promotes the translation of c-MYC, BCL2 and PTEN mRNAs in the human acute myeloid leukemia MOLM-13 cell line. Moreover, loss of METTL3 leads to increased levels of phosphorylated AKT, which contributes to the differentiation-promoting effects of METTL3 depletion. Overall, these results provide a rationale for the therapeutic targeting of METTL3 in myeloid leukemia.


Assuntos
Adenosina/análogos & derivados , Células da Medula Óssea/citologia , Diferenciação Celular/fisiologia , Leucemia Mieloide Aguda/patologia , Metiltransferases/fisiologia , Adenosina/biossíntese , Células Cultivadas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Humanos , Células Tumorais Cultivadas
7.
Am J Health Behav ; 27(6): 623-32, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14672393

RESUMO

OBJECTIVES: To examine gender differences in attitudes towards nutrition therapy within first- and fourth-year medical students. METHODS: Participants (n = 128) completed a computer self-administered questionnaire assessing attitudes towards nutrition therapy. RESULTS: Analysis of covariance revealed that females report significantly more positive attitudes toward nutrition than males do, controlling for age. The magnitude of the difference was the same in beginning and graduating medical students. CONCLUSIONS: Gender differences in attitudes towards nutrition are not moderated by medical school socialization. Standardized nutrition education may be required to address disparities in knowledge, attitudes, and efficacy with regard to nutrition and preventive care measures.


Assuntos
Atitude do Pessoal de Saúde , Conhecimentos, Atitudes e Prática em Saúde , Terapia Nutricional , Estudantes de Medicina/psicologia , Adulto , Análise de Variância , Educação de Graduação em Medicina , Feminino , Florida , Humanos , Masculino , Reprodutibilidade dos Testes , Fatores Sexuais , Estudantes de Medicina/estatística & dados numéricos , Inquéritos e Questionários
8.
Med Educ Online ; 6(1): 4530, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28253748

RESUMO

Despite pharmacological advances in diabetes treatment, medical nutrition therapy (MNT) continues to be an essential component of diabetes management. Nonetheless, physicians have missed opportunities to provide nutrition counseling to their patients. This presents a problem because type 2 diabetes is an epidemic with severe consequences that result from non-adherence to nutrition protocols. The goals of this article are: 1) to explore reasons for the continued paucity of nutrition education in medical training programs, 2) to describe how a power educative approach can be used to improve patient outcomes, and 3) to identify considerations for improving nutrition literacy among physicians. These analyses lead to several recommendations for improving nutrition education for physicians.

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