RESUMEN
Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by a polyglutamine expansion in the androgen receptor (AR) and is associated with misfolding and aggregation of the mutant AR. We investigated the role of an interdomain interaction between the amino (N)-terminal FxxLF motif and carboxyl (C)-terminal AF-2 domain in a mouse model of SBMA. Male transgenic mice expressing polyQ-expanded AR with a mutation in the FxxLF motif (F23A) to prevent the N/C interaction displayed substantially improved motor function compared with N/C-intact AR-expressing mice and showed reduced pathological features of SBMA. Serine 16 phosphorylation was substantially enhanced by the F23A mutation; moreover, the protective effect of AR F23A was dependent on this phosphorylation. These results reveal an important role for the N/C interaction on disease onset in mice and suggest that targeting AR conformation could be a therapeutic strategy for patients with SBMA.
Asunto(s)
Atrofia Bulboespinal Ligada al X/fisiopatología , Receptores Androgénicos/química , Animales , Modelos Animales de Enfermedad , Inmunoprecipitación , Masculino , Ratones , Ratones Transgénicos , Fosforilación , Conformación Proteica , Estructura Terciaria de Proteína , Receptores Androgénicos/metabolismoRESUMEN
BACKGROUND: Complications from skeletal-related events (SREs) constitute a challenge in the care of cancer patients with bone metastasis (BM). OBJECTIVES: This study evaluated the comparative effectiveness of pamidronate, ibandronate, zoledronate, and denosumab in reducing the morbidity of SREs in cancer patients with BM. METHODS: Medline (1948 to January 2014), Embase (1980 to January 2014), the Cochrane Library (2014 issue 1), and Web of Science with Conference Proceedings (1970 to January 2014) were searched. Only randomized controlled trials assessing denosumab, bisphosphonates, or placebo in cancer patients with BM were included. The primary outcomes were SREs and SREs by type. The network meta-analysis (NMA) was performed with a random-effects Bayesian model. RESULTS: The NMA included 14 trials with 10,192 patients. Denosumab was superior to placebo in reducing the risk of SREs (odds ratio [OR]: 0.49; 95% confidence interval [CI]: 0.31-0.75), followed by zoledronate (OR: 0.57; 95% CI: 0.41-0.77) and pamidronate (OR: 0.55; 95% CI: 0.41-0.72). Ibandronate compared with placebo could not reduce the risk of SREs. Denosumab was superior to placebo in reducing the risk of pathologic fractures (OR: 0.50; 95% CI: 0.32-0.79), followed by zoledronate (OR: 0.61; 95% CI: 0.43-0.86). Denosumab was superior to placebo in reducing the risk of radiation (OR: 0.51; 95% CI: 0.35-0.75), followed by pamidronate (OR: 0.67; 95% CI: 0.52-0.86) and zoledronate (OR: 0.70; 95% CI: 0.52-0.96). CONCLUSION: This NMA showed that denosumab, zoledronate, and pamidronate were generally effective in preventing SREs in cancer patients with BM. Denosumab and zoledronate were also associated with reductions in the risk of pathologic fractures and radiation compared with placebo. Denosumab was shown to be the most effective of the bone-targeted agents.
Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Enfermedades Óseas/prevención & control , Neoplasias Óseas/tratamiento farmacológico , Neoplasias/patología , Enfermedades Óseas/cirugía , Neoplasias Óseas/secundario , Denosumab/uso terapéutico , Difosfonatos/uso terapéutico , Humanos , Ácido Ibandrónico , Imidazoles/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Pamidronato , Compresión de la Médula Espinal/prevención & control , Resultado del Tratamiento , Ácido ZoledrónicoRESUMEN
A single intramuscular application of the live but not UV-inactivated recombinant rabies virus (RABV) variant TriGAS in mice induces the robust and sustained production of RABV-neutralizing antibodies that correlate with long-term protection against challenge with an otherwise lethal dose of the wild-type RABV. To obtain insight into the mechanism by which live TriGAS induces long-lasting protective immunity, quantitative PCR (qPCR) analysis of muscle tissue, draining lymph nodes, spleen, spinal cord, and brain at different times after TriGAS inoculation revealed the presence of significant copy numbers of RABV-specific RNA in muscle, lymph node, and to a lesser extent, spleen for several days postinfection. Notably, no significant amounts of RABV RNA were detected in brain or spinal cord at any time after TriGAS inoculation. Differential qPCR analysis revealed that the RABV-specific RNA detected in muscle is predominantly genomic RNA, whereas RABV RNA detected in draining lymph nodes is predominantly mRNA. Comparison of genomic RNA and mRNA obtained from isolated lymph node cells showed the highest mRNA-to-genomic-RNA ratios in B cells and dendritic cells (DCs), suggesting that these cells represent the major cell population that is infected in the lymph node. Since RABV RNA declined to undetectable levels by 14 days postinoculation of TriGAS, we speculate that a transient infection of DCs with TriGAS may be highly immunostimulatory through mechanisms that enhance antigen presentation. Our results support the superior efficacy and safety of TriGAS and advocate for its utility as a vaccine.