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Video 1Placing a standard endoclip at the papillary side of a duodenal perforation is a simple and effective technique for prevention of papillary obstruction when using the over-the-scope clip.
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Signal transducer and activator of transcription (STAT) 3 is a key factor in multiple tyrosine kinase inhibitor (mTKI)-induced growth inhibition and apoptosis of renal cell carcinoma (RCC) cells. This study aimed to identify associations between single-nucleotide polymorphisms (SNPs) in the STAT3 gene and tumor response to mTKIs in patients with metastatic RCC (mRCC). Seventy-one patients with clear cell RCC treated with any mTKI were retrospectively genotyped to elucidate a potential association between STAT3 SNPs and overall best response to drugs. Of 50 patients included for analysis, a partial or complete response was observed in 17. A significant association was found between rs4796793 alleles and tumor response [G vs. C, odds ratio (OR) 3.25, 95 % confidence interval (CI) 1.30-8.07]. There were a higher percentage of responders with the C/C genotype at rs4796793 than with the G/C + G/G genotypes (OR 4.46, 95 % CI 1.31-15.28). Time-to-event analysis demonstrated a statistically significant difference between patients with the CC genotype and those with G/C + G/G genotypes in time-to-treatment response, but not in progression-free survival or time-to-treatment failure. The rs4796793 genotype is a novel predictive factor of the response to mTKIs in patients with mRCC. However, prospective translational trials with larger patient cohorts are required to confirm these results.
Asunto(s)
Pueblo Asiatico/genética , Carcinoma de Células Renales/genética , Neoplasias Renales/genética , Polimorfismo de Nucleótido Simple/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Factor de Transcripción STAT3/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/tratamiento farmacológico , Femenino , Humanos , Neoplasias Renales/diagnóstico , Neoplasias Renales/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Vigilancia de la Población , Valor Predictivo de las Pruebas , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Murine leukemia retrovirus (MLV) vectors are highly effective tools for introducing a foreign gene into a target host genome. However, it remains unclear how integrated retroviral promoter activity is influenced by the upstream or downstream sequences and how the host cell phenotype is influenced by the integrated promoter activity. Herein, we analyzed a set of pre-B lymphoma clones in which the MLV genome was integrated into the signal transducer and activator of transcription factor 5a (Stat5a) gene. Among the clones, the lymphoma clones with a provirus integrating into the middle position of the palindromic target sequences showed significantly higher transcription of the Stat5a gene; and p300 and other transcriptional factors formed complexes, with binding to the proviral-host junctional DNA segment. By using a luciferase assay, the upstream and downstream sequences of the provirus contributed to the up-regulation of proviral promoter activity. In concomitance with the higher Stat5a transcription, the immunoglobulin gene recombination was arrested. Antiapoptotic activity was significantly higher, with an increase in Bcl-xL, one of the targets of STAT5A, when IL-7 was supplied. Thus, a minute difference between MLV integration sites can lead to large differences in the host phenotype through the formation of transcription factor complexes on the proviral-host junctional DNA segment, suggesting that caution is necessary in monitoring integration sites when working with MLV vectors.
Asunto(s)
Secuencias Invertidas Repetidas/genética , Virus de la Leucemia Murina/genética , Linfoma de Células B/genética , Lesiones Precancerosas/genética , Factor de Transcripción STAT5/genética , Factores de Transcripción/metabolismo , Integración Viral/genética , Animales , Apoptosis/genética , Secuencia de Bases , Diferenciación Celular , Células Clonales , Factor de Transcripción GATA2/metabolismo , Genes Reporteros/genética , Cadenas Ligeras de Inmunoglobulina/genética , Linfoma de Células B/patología , Ratones , Modelos Biológicos , Datos de Secuencia Molecular , Lesiones Precancerosas/patología , Regiones Promotoras Genéticas/genética , Unión Proteica , Provirus/genética , Receptores de Interleucina-7/metabolismo , Recombinación Genética/genéticaRESUMEN
IL-7R, FLT3, and CD43 are surface antigens expressed during the transition from pro-B to pre-B cells in BM. To understand interactions between their signaling pathways, we analyzed spontaneous mouse B-LBLs with dual MLV integration into Stat5a and Fiz1 or Stat5a and Hipk2. MLV integration resulted in up-regulation of these genes in lymphoma cells compared with normal pro-B cells from the BM. In lymphomas with both integrations into Stat5a and Fiz1, increases in phosphorylated STAT5A and expression of c-Myc, a target gene of STAT5A, were observed following stimulation of the FLT3. Clones with the dual integrations grew faster in IL-7 and FLT3L-supplemented medium than clones with Stat5a integration alone. On the other hand, in lymphomas with integrations into Stat5a and Hipk2, increases in phosphorylated STAT5A and expression of c-Myc were observed following cross-linking of CD43. In conclusion, FLT3 and CD43 signaling pathways involve STAT5A via Fiz1 and Hipk2 in B-LBLs. Identification of the dual MLV integration sites in B-LBLs, therefore, will provide an excellent tool for identification of the signaling pathways in B-LBLs.
