RESUMEN
INTRODUCTION: Since 2019, for the first time, a two-drug regimen with dolutegravir/lamivudine (DTG/3TC) has been recommended for HIV treatment as initial and subsequent therapy in the international guidelines. However, safety and efficacy data of DTG/3TC in Japanese people living with HIV (PLHIV) in clinical trials are limited and have not been evaluated in clinical practice. In this report, we evaluated safety and effectiveness of DTG/3TC in Japanese PLHIV through post-marketing surveillance. METHODS: Post-marketing surveillance was conducted to evaluate the real-world safety and effectiveness of DTG/3TC in Japanese PLHIV. One hundred ninety-seven patients who received oral DTG 50 mg/3TC 300 mg as a single-tablet fixed-dose combination regimen (STR) were registered in clinical practice. The safety was evaluated by incidence of adverse drug reactions (ADRs). The effectiveness was evaluated by plasma HIV RNA and peripheral CD4+ cell counts. RESULTS: This is a 2-year (from 2020 to 2022) report of approximately 6 years of survey, and 187 patients were registered from 21 Japanese sites. The number of antiretroviral therapy (ART)-experienced patients was 178, and > 60% of their previous antiretrovirals (ARVs) were DTG/abacavir (ABC)/3TC. There were only nine ART-naïve patients. Four of 178 ART-experienced patients (2.25%) reported ADRs, and 1 serious ADR of syphilis was reported. There was no clear causal relationship between DTG/3TC and the ADRs. Plasma HIV RNA and peripheral CD4+ cell counts maintained the pre-DTG/3TC level in ART-experienced patients. CONCLUSION: No new clinical concerns of safety and effectiveness were identified in Japanese ART-experienced PLHIV treated with DTG/3TC. We could not discuss the safety and effectiveness in ART-naïve patients because of the small sample size.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Humanos , Lamivudine/efectos adversos , Fármacos Anti-VIH/efectos adversos , Japón , Infecciones por VIH/tratamiento farmacológico , Oxazinas/uso terapéutico , Piridonas/uso terapéutico , ARN/uso terapéutico , Vigilancia de Productos ComercializadosRESUMEN
Phosphoenolpyruvate carboxykinase (PEPCK) is one of the key regulatory enzymes in gluconeogenesis. In human liver, PEPCK is about equally distributed in both cytosol (PEPCK-1) and mitochondria (PEPCK-2). The human pepck2 gene and cDNA have been reported, but the cloning of the promoter region of the pepck2 gene has not been elucidated yet. We isolated and characterized human genomic P1-artificial chromosome (PAC) clones carrying the human pepck2 gene promoter. The oligocapping method revealed that the transcriptional start point (tsp) of the human pepck2 gene is located at 97 bp upstream of the first adenine residue of the translation start site. We also determined the nucleotide sequence to 1819 bp upstream of tsp. Sequence analysis of this region revealed that it contained several potential regulatory elements, including five GC boxes and three CCAAT boxes. Reporter analysis using transient transfection with firefly luciferase synthetic gene indicated 5' flanking region up to 822 bp, and 317 bp upstream of tsp had transcriptional activity. These results suggest that these regions of the human pepck2 gene play an important role for its expression.
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Proteínas Mitocondriales/genética , Fosfoenolpiruvato Carboxiquinasa (GTP)/genética , Regiones Promotoras Genéticas/genética , Secuencia de Bases , Sitios de Unión/genética , Southern Blotting , Línea Celular Tumoral , Clonación Molecular , ADN/química , ADN/genética , Humanos , Luciferasas/genética , Luciferasas/metabolismo , Proteínas Mitocondriales/metabolismo , Datos de Secuencia Molecular , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Secuencias Reguladoras de Ácidos Nucleicos/genética , Análisis de Secuencia de ADN , Sitio de Iniciación de la Transcripción , TransfecciónRESUMEN
Gibberellin (GA) plays an important role in the induction of germination of photoblastic lettuce (Lactuca sativa L. cv. Grand Rapids) seeds. We have previously shown that gene expression of a GA 3-oxidase (Ls3h1) increased after a red light treatment, resulting in an increase in the endogenous content of GA1, bioactive GA. Since the metabolism of GAs is also important for determining the endogenous levels of bioactive GAs, cDNAs encoding GA 2-oxidases (LsGA2ox1 and LsGA2ox2, for L. sativa GA 2-oxidase), which catalyze the deactivation of GAs, were isolated from lettuce seeds to investigate the regulation of these genes by light. An expression analysis shows that the mRNA levels of both enzymes was not markedly altered under different light conditions during germination. However, the amount of LsGA2ox2 transcripts was decreased to approximately half the level by red light. This reduction might play a role in the increase in GA1 level by red light in the lettuce seeds.
Asunto(s)
Germinación , Giberelinas/metabolismo , Lactuca/metabolismo , Oxigenasas de Función Mixta/metabolismo , Semillas/metabolismo , Secuencia de Aminoácidos , Southern Blotting , Cartilla de ADN/genética , ADN Complementario/genética , Activación Enzimática , Regulación Enzimológica de la Expresión Génica , Regulación de la Expresión Génica de las Plantas , Giberelinas/genética , Lactuca/enzimología , Lactuca/genética , Lactuca/crecimiento & desarrollo , Oxigenasas de Función Mixta/química , Oxigenasas de Función Mixta/genética , Datos de Secuencia Molecular , Oxidación-Reducción , ARN de Planta/genética , ARN de Planta/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Semillas/enzimología , Semillas/genética , Semillas/crecimiento & desarrollo , Homología de Secuencia de AminoácidoRESUMEN
BACKGROUND: Understanding the role for genetic factors in human heart failure is difficult because environmental factors cannot be standardized and genetic variation is great. One approach to identify genes that modify disease outcome is to use mouse models that show strong genetic variation of the disease phenotype. METHODS AND RESULTS: In this study, we used transgenic mice that develop severe dilated cardiomyopathy due to the cardiac-specific overexpression of calsequestrin. Transgenic mice showed marked strain-specific variation of cardiac function and survival, independent of transgene expression. A reciprocal backcross strategy was employed using two inbred strains showing distinct differences in survival and cardiac function. To map the genes that modified the heart failure phenotype, progeny from the 2 reciprocal backcrosses were used in a genome-wide scan for linkage. We identified two loci significantly linked to survival with a maximum likelihood ratio statistic of 36.2 (LOD score approximately 7.8) on chromosome 2 and of 26.5 (LOD score approximately 5.7) on chromosome 3. The chromosome 3 locus was also significantly linked to cardiac function with a maximum likelihood ratio statistic of 42.9 (LOD score approximately 9.3). Because only a single strong modifier locus was found in each backcross, we applied a haplotype analysis to map crossovers and successfully narrowed the critical intervals for each locus. CONCLUSION: Using a sensitized mouse model, we identified major modifier loci that affect the genetically complex disease of heart failure. This approach should allow the rapid identification of candidate genes involved in disease susceptibility in human populations and new insights into the pathogenesis of heart failure.