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1.
Hum Mol Genet ; 23(3): 590-601, 2014 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-24045615

RESUMO

Acute lymphoblastic leukemia (ALL) accounts for ∼25% of pediatric malignancies. Of interest, the incidence of ALL is observed ∼20% higher in males relative to females. The mechanism behind the phenomenon of sex-specific differences is presently not understood. Employing genome-wide genetic aberration screening in 19 ALL samples, one of the most recurrent lesions identified was monoallelic deletion of the 5' region of SLX4IP. We characterized this deletion by conventional molecular genetic techniques and analyzed its interrelationships with biological and clinical characteristics using specimens and data from 993 pediatric patients enrolled into trial AIEOP-BFM ALL 2000. Deletion of SLX4IP was detected in ∼30% of patients. Breakpoints within SLX4IP were defined to recurrent positions and revealed junctions with typical characteristics of illegitimate V(D)J-mediated recombination. In initial and validation analyses, SLX4IP deletions were significantly associated with male gender and ETV6/RUNX1-rearranged ALL (both overall P < 0.0001). For mechanistic validation, a second recurrent deletion affecting TAL1 and caused by the same molecular mechanism was analyzed in 1149 T-cell ALL patients. Validating a differential role by sex of illegitimate V(D)J-mediated recombination at the TAL1 locus, 128 out of 1149 T-cell ALL samples bore a deletion and males were significantly more often affected (P = 0.002). The repeatedly detected association of SLX4IP deletion with male sex and the extension of the sex bias to deletion of the TAL1 locus suggest that differential illegitimate V(D)J-mediated recombination events at specific loci may contribute to the consistent observation of higher incidence rates of childhood ALL in boys compared with girls.


Assuntos
Proteínas de Transporte/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Recombinases/genética , Recombinação V(D)J , Adolescente , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Criança , Pré-Escolar , Estudos de Coortes , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Deleção de Genes , Humanos , Lactente , Masculino , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Proteína 1 de Leucemia Linfocítica Aguda de Células T
2.
Future Cardiol ; 10(1): 53-62, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24344663

RESUMO

AIM: Cardiotrophin-1 (CT-1) is upregulated by hypoxemia and hemodynamic overload and is characterized by potent hypertrophic and protective properties on cardiac cells. This study aimed to investigate whether CT-1 is differentially induced in the myocardium of infants with congenital cardiac defects depending on hypoxemia. METHODS & RESULTS: Infants with Tetralogy of Fallot (n = 8) or with large nonrestrictive ventricular septal defect (n = 8) undergoing corrective surgery were investigated. Expression of CT-1 was assessed at mRNA and protein levels in the right atrial and ventricular myocardium. The activation of the STAT-3 and VEGF were measured. Degradation of cardiac troponin-I served as a marker of myocardial damage. CT-1 was detected in all patients with levels negatively correlating to the arterial oxygen saturation. Higher CT-1 expression in Tetralogy of Fallot patients was associated with activation of the JAK/STAT pathway and higher cardiac troponin-I degradation. CONCLUSION: CT-1 may mediate myocardial hypertrophy and dysfunction in infants with congenital cardiac defects, particularly in those with hypoxemia.


Assuntos
Cardiomegalia/etiologia , Citocinas/metabolismo , Comunicação Interventricular/metabolismo , Hipóxia/metabolismo , Tetralogia de Fallot/metabolismo , Citocinas/genética , Feminino , Comunicação Interventricular/etiologia , Comunicação Interventricular/cirurgia , Humanos , Hipóxia/etiologia , Hipóxia/cirurgia , Lactente , Recém-Nascido , Masculino , Miocárdio/metabolismo , RNA Mensageiro/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/fisiologia , Tetralogia de Fallot/etiologia , Tetralogia de Fallot/cirurgia , Fator A de Crescimento do Endotélio Vascular/metabolismo
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