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1.
Clin Exp Nephrol ; 28(3): 225-234, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37962746

RESUMEN

BACKGROUND: In the TSUBAKI study, bardoxolone methyl significantly increased measured and estimated glomerular filtration rates (GFR) in patients with multiple forms of chronic kidney disease (CKD), including Japanese patients with type 2 diabetes and stage 3-4 CKD. Since bardoxolone methyl targets the nuclear factor erythroid 2-related factor 2 pathway, this exploratory analysis of the TSUBAKI study investigated the impact of the regulatory single nucleotide polymorphism, rs6721961, on the effects of bardoxolone methyl. METHODS: Japanese patients aged 20-79 years with type 2 diabetes and stage 3-4 CKD were randomized to bardoxolone methyl 5-15 mg/day (titrated as tolerated) or placebo for 16 weeks. Genotype frequency, clinical characteristics, renal function, and adverse events were primarily assessed. RESULTS: Of 104 patients (bardoxolone methyl n = 55, placebo n = 49); 57% were genotype C/C, 32% C/A and 12% A/A. The frequency of the A/A genotype was higher among patients with diabetic kidney disease than in the general Japanese population (~ 5%). Measured and estimated GFRs increased from baseline in all genotypes receiving bardoxolone methyl. There were no significant differences between genotypes for safety parameters, including blood pressure, bodyweight, and levels of B-type natriuretic peptide, or in the type and frequency of adverse events, suggesting that the efficacy and safety of bardoxolone methyl are unaffected by the rs6721961 polymorphism-617 (C→A) genotype. CONCLUSIONS: Our approach of combining genome analysis with clinical trials for an investigational drug provides important and useful clues for exploring the efficacy and safety of the drug. TRIAL REGISTRATION: ClinicalTrials.gov; NCT02316821.


Asunto(s)
Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Ácido Oleanólico/análogos & derivados , Insuficiencia Renal Crónica , Humanos , Factor 2 Relacionado con NF-E2/genética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/genética , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/genética
2.
Expert Opin Pharmacother ; 18(18): 1903-1919, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28901796

RESUMEN

BACKGROUND: We examined the efficacy and safety of saxagliptin as an add-on to insulin in Japanese patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: We randomized 240 patients with type 2 diabetes mellitus on insulin monotherapy to 5-mg saxagliptin or placebo as add-on therapy for a 16-week, double-blind period. All patients received 5-mg saxagliptin and insulin for an additional 36 weeks (open-label extension). Change in hemoglobin A1c (HbA1c) at Week 16 was the main endpoint. RESULTS: At Week 16, the adjusted change in HbA1c from baseline increased by 0.51% with placebo and decreased by 0.40% with saxagliptin (difference -0.92% [95% confidence interval -1.07%, -0.76%; p < 0.001]). In patients receiving saxagliptin, reductions in HbA1c at Week 16 were maintained to Week 52, while switching from placebo to saxagliptin resulted in a similar reduction in HbA1c. The incidence of hypoglycemia was not markedly increased with saxagliptin versus placebo in the double-blind period and did not increase substantially during the open-label extension period. The efficacy and safety of saxagliptin was similar between the elderly and non-elderly patient groups. CONCLUSIONS: Adding saxagliptin to ongoing insulin therapy improved glycemic control and was well tolerated in Japanese patients with type 2 diabetes.


Asunto(s)
Adamantano/análogos & derivados , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipéptidos/uso terapéutico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Adamantano/efectos adversos , Adamantano/uso terapéutico , Anciano , Glucemia/análisis , Péptido C/análisis , Desoxiglucosa/sangre , Dipéptidos/efectos adversos , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada , Femenino , Glucagón/sangre , Hemoglobina Glucada/análisis , Humanos , Hipoglucemia/etiología , Japón , Masculino , Persona de Mediana Edad , Efecto Placebo , Resultado del Tratamiento
3.
Nat Genet ; 47(11): 1304-15, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26437031

RESUMEN

Adult T cell leukemia/lymphoma (ATL) is a peripheral T cell neoplasm of largely unknown genetic basis, associated with human T cell leukemia virus type-1 (HTLV-1) infection. Here we describe an integrated molecular study in which we performed whole-genome, exome, transcriptome and targeted resequencing, as well as array-based copy number and methylation analyses, in a total of 426 ATL cases. The identified alterations overlap significantly with the HTLV-1 Tax interactome and are highly enriched for T cell receptor-NF-κB signaling, T cell trafficking and other T cell-related pathways as well as immunosurveillance. Other notable features include a predominance of activating mutations (in PLCG1, PRKCB, CARD11, VAV1, IRF4, FYN, CCR4 and CCR7) and gene fusions (CTLA4-CD28 and ICOS-CD28). We also discovered frequent intragenic deletions involving IKZF2, CARD11 and TP73 and mutations in GATA3, HNRNPA2B1, GPR183, CSNK2A1, CSNK2B and CSNK1A1. Our findings not only provide unique insights into key molecules in T cell signaling but will also guide the development of new diagnostics and therapeutics in this intractable tumor.


Asunto(s)
Metilación de ADN , Exoma/genética , Genoma Humano/genética , Leucemia-Linfoma de Células T del Adulto/genética , Análisis de Secuencia de ADN/métodos , Transcriptoma/genética , Adulto , Secuencia de Aminoácidos , Variaciones en el Número de Copia de ADN , Productos del Gen tax/genética , Células HEK293 , Interacciones Huésped-Patógeno/genética , Virus Linfotrópico T Tipo 1 Humano/genética , Virus Linfotrópico T Tipo 1 Humano/fisiología , Humanos , Células Jurkat , Leucemia-Linfoma de Células T del Adulto/virología , Datos de Secuencia Molecular , Mutación , Homología de Secuencia de Aminoácido , Transducción de Señal/genética , Análisis de Supervivencia , Linfocitos T/metabolismo , Linfocitos T/virología
4.
Cancer Sci ; 104(8): 1097-106, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23600753

RESUMEN

Molecular abnormalities involved in the multistep leukemogenesis of adult T-cell leukemia (ATL) remain to be clarified. Based on our integrated database, we focused on the expression patterns and levels of Ikaros family genes, Ikaros, Helios, and Aiolos, in ATL patients and HTLV-1 carriers. The results revealed profound deregulation of Helios expression, a pivotal regulator in the control of T-cell differentiation and activation. The majority of ATL samples (32/37 cases) showed abnormal splicing of Helios expression, and four cases did not express Helios. In addition, novel genomic loss in Helios locus was observed in 17/168 cases. We identified four ATL-specific short Helios isoforms and revealed their dominant-negative function. Ectopic expression of ATL-type Helios isoform as well as knockdown of normal Helios or Ikaros promoted T-cell growth. Global mRNA profiling and pathway analysis showed activation of several signaling pathways important for lymphocyte proliferation and survival. These data provide new insights into the molecular involvement of Helios function in the leukemogenesis and phenotype of ATL cells, indicating that Helios deregulation is one of the novel molecular hallmarks of ATL.


Asunto(s)
Factor de Transcripción Ikaros/biosíntesis , Leucemia-Linfoma de Células T del Adulto/metabolismo , Leucemia-Linfoma de Células T del Adulto/patología , Linfocitos T/metabolismo , Linfocitos T/patología , Procesos de Crecimiento Celular/fisiología , Línea Celular , Línea Celular Tumoral , Citoplasma/genética , Citoplasma/metabolismo , Exones , Células HEK293 , Células HeLa , Virus Linfotrópico T Tipo 1 Humano/genética , Virus Linfotrópico T Tipo 1 Humano/metabolismo , Humanos , Factor de Transcripción Ikaros/genética , Factor de Transcripción Ikaros/metabolismo , Leucemia-Linfoma de Células T del Adulto/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transducción de Señal/genética
5.
Cancer Cell ; 21(1): 121-35, 2012 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-22264793

RESUMEN

Constitutive NF-κB activation has causative roles in adult T cell leukemia (ATL) caused by HTLV-1 and other cancers. Here, we report a pathway involving Polycomb-mediated miRNA silencing and NF-κB activation. We determine the miRNA signatures and reveal miR-31 loss in primary ATL cells. MiR-31 negatively regulates the noncanonical NF-κB pathway by targeting NF-κB inducing kinase (NIK). Loss of miR-31 therefore triggers oncogenic signaling. In ATL cells, miR-31 level is epigenetically regulated, and aberrant upregulation of Polycomb proteins contribute to miR-31 downregulation in an epigenetic fashion, leading to activation of NF-κB and apoptosis resistance. Furthermore, this emerging circuit operates in other cancers and receptor-initiated NF-κB cascade. Our findings provide a perspective involving the epigenetic program, inflammatory responses, and oncogenic signaling.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Leucemia-Linfoma de Células T del Adulto/genética , MicroARNs/genética , FN-kappa B/metabolismo , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Represoras/genética , Linfocitos T/patología , Epigénesis Genética , Perfilación de la Expresión Génica , Humanos , Leucemia-Linfoma de Células T del Adulto/metabolismo , FN-kappa B/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas del Grupo Polycomb , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Represoras/metabolismo , Proteínas Represoras/fisiología , Transducción de Señal , Linfocitos T/metabolismo , Quinasa de Factor Nuclear kappa B
6.
Nature ; 459(7247): 712-6, 2009 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-19412163

RESUMEN

A20 is a negative regulator of the NF-kappaB pathway and was initially identified as being rapidly induced after tumour-necrosis factor-alpha stimulation. It has a pivotal role in regulation of the immune response and prevents excessive activation of NF-kappaB in response to a variety of external stimuli; recent genetic studies have disclosed putative associations of polymorphic A20 (also called TNFAIP3) alleles with autoimmune disease risk. However, the involvement of A20 in the development of human cancers is unknown. Here we show, using a genome-wide analysis of genetic lesions in 238 B-cell lymphomas, that A20 is a common genetic target in B-lineage lymphomas. A20 is frequently inactivated by somatic mutations and/or deletions in mucosa-associated tissue lymphoma (18 out of 87; 21.8%) and Hodgkin's lymphoma of nodular sclerosis histology (5 out of 15; 33.3%), and, to a lesser extent, in other B-lineage lymphomas. When re-expressed in a lymphoma-derived cell line with no functional A20 alleles, wild-type A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by downregulation of NF-kappaB activation. The A20-deficient cells stably generated tumours in immunodeficient mice, whereas the tumorigenicity was effectively suppressed by re-expression of A20. In A20-deficient cells, suppression of both cell growth and NF-kappaB activity due to re-expression of A20 depended, at least partly, on cell-surface-receptor signalling, including the tumour-necrosis factor receptor. Considering the physiological function of A20 in the negative modulation of NF-kappaB activation induced by multiple upstream stimuli, our findings indicate that uncontrolled signalling of NF-kappaB caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas.


Asunto(s)
Cisteína Endopeptidasas/genética , Cisteína Endopeptidasas/metabolismo , Silenciador del Gen , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Linfoma de Células B/genética , Linfoma de Células B/fisiopatología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Animales , Apoptosis/fisiología , Línea Celular , Proteínas de Unión al ADN , Expresión Génica , Genoma/genética , Humanos , Ratones , FN-kappa B/genética , FN-kappa B/metabolismo , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa
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