RESUMEN
Repeat-associated non-AUG (RAN) translation of expanded repeat-mutation mRNA produces toxic peptides in neurons of patients suffering from neurodegenerative diseases. Recent findings indicate that RAN translation in diverse model systems is not inhibited by cellular stressors that impair global translation through phosphorylation of the alpha subunit of eIF2, the essential eukaryotic translation initiation factor that brings the initiator tRNA to the 40S ribosome. Using in vitro, cell-based and Drosophila models, we examined the role of alternative ternary complex factors that may function in place of eIF2, including eIF2A, eIF2D, DENR and MCTS1. Among these factors, DENR knockdown had the greatest inhibitory effect on RAN translation of expanded GGGGCC and CGG repeat reporters and its reduction improved the survival of Drosophila expressing expanded GGGGCC repeats. Taken together, these data support a role for alternative initiation factors in RAN translation and suggest these may serve as novel therapeutic targets in neurodegenerative disease.
Asunto(s)
Proteínas de Drosophila , Enfermedades Neurodegenerativas , Animales , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Factor 2 Eucariótico de Iniciación/genética , Factor 2 Eucariótico de Iniciación/metabolismo , Factores Eucarióticos de Iniciación/genética , Factores Eucarióticos de Iniciación/metabolismo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Biosíntesis de Proteínas/genética , ARN Mensajero/genética , Ribosomas/genética , Ribosomas/metabolismoRESUMEN
Microbial dysbiosis is a colorectal cancer (CRC) hallmark and contributes to inflammation, tumor growth, and therapy response. Gut microbes signal via metabolites, but how the metabolites impact CRC is largely unknown. We interrogated fecal metabolites associated with mouse models of colon tumorigenesis with varying mutational load. We find that microbial metabolites from healthy mice or humans are growth-repressive, and this response is attenuated in mice and patients with CRC. Microbial profiling reveals that Lactobacillus reuteri and its metabolite, reuterin, are downregulated in mouse and human CRC. Reuterin alters redox balance, and reduces proliferation and survival in colon cancer cells. Reuterin induces selective protein oxidation and inhibits ribosomal biogenesis and protein translation. Exogenous Lactobacillus reuteri restricts colon tumor growth, increases tumor reactive oxygen species, and decreases protein translation in vivo. Our findings indicate that a healthy microbiome and specifically, Lactobacillus reuteri, is protective against CRC through microbial metabolite exchange.
Asunto(s)
Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Microbioma Gastrointestinal , Gliceraldehído/análogos & derivados , Oxidación-Reducción , Propano/metabolismo , Animales , Biomarcadores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Metabolismo Energético , Glutatión/metabolismo , Gliceraldehído/metabolismo , Gliceraldehído/farmacología , Interacciones Microbiota-Huesped , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Metabolómica/métodos , Metagenómica/métodos , Ratones , Modelos Biológicos , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo , Propano/farmacología , Transducción de Señal , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Hyaluronic acid (HA) and leukocyte-poor platelet-rich plasma (LP-PRP) are 2 nonoperative treatment options that have been studied in patients with hip osteoarthritis (OA). PURPOSE: To compare the efficacy of intra-articular injections of low-molecular weight (LMW) HA and LP-PRP in patients with hip OA. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 34 patients (36 hips) presenting with signs of hip OA were randomized to receive 3 blinded, weekly intra-articular injections of either LP-PRP or LMW-HA. Patients were prospectively evaluated before injections and at 6 weeks and then at 3, 6, 12, and 24 months. The primary outcome, conversion to total hip arthroplasty (THA) or a hip resurfacing procedure, was analyzed along with secondary outcomes including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score and hip range of motion. RESULTS: The final analysis included 33 hips (mean Kellgren-Lawrence grade, 2.73) (LMW-HA: n = 14; LP-PRP: n = 19) in 31 patients (18 male; mean age, 53.8 years). Significantly more patients converted to THA or a hip resurfacing procedure in the LMW-HA group (7/14; 50.0%) (mean, 1.3 years after first injection) than the LP-PRP group (3/19; 15.8%) (mean, 0.73 years after first injection) (P = .035). There was no significant improvement or decline in any outcome scores within the LMW-HA group from before injections to 6 weeks or 3, 6, and 12 months. For the LP-PRP group, WOMAC overall (P = .032), joint (P = .030), and function scores (P = .025) significantly improved from before injections to 6 weeks, and WOMAC joint scores significantly improved from before injections to 6 months (P = .036). When comparing the difference between groups in internal rotation at 90° of hip flexion from before injections to 6 months, the LP-PRP group demonstrated a mean 5.0° improvement, while the LMW-HA group showed a mean 1.5° decrease (P = .028). CONCLUSION: Intra-articular hip injections of LP-PRP in patients with hip OA resulted in an improvement in WOMAC scores and hip internal rotation at 6 months and delayed the need for THA or a hip resurfacing procedure compared with treatment with LMW-HA. A longer follow-up is necessary to further compare the effects of LP-PRP and LMW-HA injections in patients with hip OA. REGISTRATION: NCT01920152 (ClinicalTrials.gov identifier).
RESUMEN
Despite attention to depression and cognitive disorders, the prevalence of other mental disorders following breast cancer chemotherapy has not been well described. The authors undertook a pilot study using insurance claims data to compare the prevalence of mental disorders other than depression in a population of breast cancer surgery patients who did versus did not receive postsurgical chemotherapy treatment. Women receiving chemotherapy in addition to surgery were more likely to be diagnosed with adjustment disorders (odds ratio=2.01, 95% CI=1.04-3.87). Prevalence of depression, anxiety, cognitive, and sleep disorders were not dependent on receipt of post-surgical chemotherapy treatment. These findings support the need for heightened awareness for mental conditions following chemotherapy.
Asunto(s)
Trastornos de Adaptación/epidemiología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/psicología , Trastornos Mentales/epidemiología , Trastornos de Adaptación/diagnóstico , Trastornos de Adaptación/etiología , Adolescente , Adulto , Anciano , Concienciación , Neoplasias de la Mama/cirugía , Terapia Combinada , Quimioterapia/psicología , Femenino , Humanos , Masculino , Trastornos Mentales/diagnóstico , Trastornos Mentales/etiología , Persona de Mediana Edad , Proyectos Piloto , PrevalenciaRESUMEN
In the United States, older adults have become the fastest growing segment of the population and are expected to double in number to 70 million by 2030. As a whole, older adults have different health care needs than younger patients, and some of these needs should be met by pharmacists. Clinical pharmacy practice affecting older adults occurs in a variety of settings, including community, ambulatory care, primary care, hospital, assisted living, nursing home, home health care, hospice, and Alzheimer's disease units. Although specialty training in geriatrics or gerontology is not required for pharmacists to care for older adults, it is extremely helpful. Pharmacy education related to the care of older adults has improved slightly in the past several years but will need to increase even more to provide all pharmacists with the basic skills and knowledge to care for this unique group of patients. In addition, pharmacotherapy research targeting older adults needs to increase. Although it can be challenging, funding for this type of research is available. Patient and political advocacy is also important to support this growing population.