RESUMO
Background: Long-term data with immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are limited. Two phase III trials demonstrated improved overall survival (OS) and a favorable safety profile with the anti-programmed death-1 antibody nivolumab versus docetaxel in patients with previously treated advanced squamous (CheckMate 017) and nonsquamous (CheckMate 057) NSCLC. We report results from ≥3 years' follow-up, including subgroup analyses of patients with liver metastases, who historically have poorer prognosis among patients with NSCLC. Patients and methods: Patients were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks) until progression or discontinuation. The primary end point of each study was OS. Patients with baseline liver metastases were pooled across studies by treatment for subgroup analyses. Results: After 40.3 months' minimum follow-up in CheckMate 017 and 057, nivolumab continued to show an OS benefit versus docetaxel: estimated 3-year OS rates were 17% [95% confidence interval (CI), 14% to 21%] versus 8% (95% CI, 6% to 11%) in the pooled population with squamous or nonsquamous NSCLC. Nivolumab was generally well tolerated, with no new safety concerns identified. Of 854 randomized patients across both studies, 193 had baseline liver metastases. Nivolumab resulted in improved OS compared with docetaxel in patients with liver metastases (hazard ratio, 0.68; 95% CI, 0.50-0.91), consistent with findings from the overall pooled study population (hazard ratio, 0.70; 95% CI, 0.61-0.81). Rates of treatment-related hepatic adverse events (primarily grade 1-2 liver enzyme elevations) were slightly higher in nivolumab-treated patients with liver metastases (10%) than in the overall pooled population (6%). Conclusions: After 3 years' minimum follow-up, nivolumab continued to demonstrate an OS benefit versus docetaxel in patients with advanced NSCLC. Similarly, nivolumab demonstrated an OS benefit versus docetaxel in patients with liver metastases, and remained well tolerated. Clinical trial registration: CheckMate 017: NCT01642004; CheckMate 057: NCT01673867.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Docetaxel/uso terapêutico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/secundário , Docetaxel/efeitos adversos , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida , Resultado do TratamentoRESUMO
The group I intron (AnCOB) of the mitochondrial apocytochrome b gene from Aspergillus nidulans encodes a bi-functional maturase protein that is also a DNA endonuclease. Although the AnCOB intron self-splices, the encoded maturase protein greatly facilitates splicing, in part, by stabilizing RNA tertiary structure. To determine their role in self-splicing and in protein-assisted splicing, several peripheral RNA sub-domains in the 313 nucleotide intron were deleted (P2, P9, P9.1) or truncated (P5ab, P6a). The sequence in two helices (P2 and P9) was also inverted. Except for P9, the deleted regions are not highly conserved among group I introns and are often dispensable for catalytic activity. Nevertheless, despite the very tight binding of AnCOB RNA to the maturase and the high activity of the bimolecular complex (the rate of 5' splice-site cleavage was >20 min(-1) with guanosine as the cofactor), the intron was surprisingly sensitive to these modifications. Several mutations inactivated splicing completely and virtually all impaired splicing to varying degrees. Mutants containing comparatively small deletions in various regions of the intron significantly decreased binding affinity (generally >10(4)-fold), indicating that none of the domains that remained constitutes the primary recognition site of the maturase. The data argue that tight binding requires tertiary interactions that can be maintained by only a relatively intact intron RNA, and that the binding mechanism of the maturase differs from those of two other well-characterized group I intron splicing factors, CYT-18 and Cpb2. A model is proposed in which the protein promotes widespread cooperative folding of an RNA lacking extensive initial tertiary structure.
Assuntos
Aspergillus nidulans/genética , Endodesoxirribonucleases/metabolismo , Íntrons/genética , Splicing de RNA/genética , RNA Catalítico/genética , RNA Catalítico/metabolismo , DNA Polimerase Dirigida por RNA/metabolismo , Proteínas de Saccharomyces cerevisiae , Apoproteínas/genética , Sequência de Bases , Ligação Competitiva , Grupo dos Citocromos b/genética , Citocromos b , Endodesoxirribonucleases/genética , Guanosina/genética , Guanosina/metabolismo , Hidrólise , Cinética , Dados de Sequência Molecular , Complexos Multienzimáticos/genética , Complexos Multienzimáticos/metabolismo , Conformação de Ácido Nucleico , Ligação Proteica , Sítios de Splice de RNA/genética , Estabilidade de RNA , RNA Catalítico/química , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , DNA Polimerase Dirigida por RNA/genética , Deleção de Sequência/genética , Especificidade por SubstratoRESUMO
The human hydroxysteroid sulfotransferase (SULT) family is comprised of two subfamilies, SULT2A1 and SULT2B1. We characterized the substrate specificity, in vitro biochemical properties, and tissue distribution patterns of human SULT2B1a and SULT2B1b. In contrast to the wide substrate specificity of SULT2A1, SULT2B1a and SULT2B1b specifically catalyzed the sulfonation of 3beta-hydroxysteroids with high catalytic efficiency. Both SULT2B1 enzymes also sulfonated dihydrotestosterone. In vitro studies revealed that the biochemical properties of SULT2B1a and SULT2B1b were not significantly different from each other. However, tissue expression analysis suggested that they are differentially regulated. In contrast to the limited tissue distribution of SULT2A1, SULT2B1 was detected in a variety of hormone-responsive tissues including placenta, ovary, uterus, and prostate. The catalytic activity toward dehydroepiandrosterone and dihydrotestosterone, biologically important androgens, coupled with expression in prostate suggests that SULT2B1 may play a novel regulatory role that protects against the mitogenic effects of androgens.
Assuntos
Sulfotransferases/metabolismo , Sequência de Aminoácidos , Desidroepiandrosterona/metabolismo , Di-Hidrotestosterona/metabolismo , Estabilidade Enzimática , Humanos , Hidroxiesteroides/metabolismo , Cinética , Dados de Sequência Molecular , RNA Mensageiro/biossíntese , Proteínas Recombinantes/metabolismo , Homologia de Sequência de Aminoácidos , Estereoisomerismo , Especificidade por Substrato , Sulfotransferases/genética , Distribuição TecidualRESUMO
The mitochondrial genome of Aspergillus nidulans contains several group-I introns. Each one has been assayed for its ability to self-splice in vitro in the absence of proteins. The intron from the apocytochrome b gene is unusual among subgroup IB4 introns in being able to self-splice, unlike a similar intron from Saccharomyces cerevisiae. The first intron in the cytochrome oxidase subunit-1 gene self-splices but only correctly completes the first step of splicing; cryptic 3' splice-sites are recognized instead and these are also used at a low frequency in vivo. The highly homologous intron from Podospora anserina completes both steps in vitro. The remaining introns do not self-splice. The correlation between subgroup category, the likely presence of specific tertiary interactions, and self-splicing activity is discussed.