RESUMEN
The BRAF gene and the TERT promoter are among the most frequently altered genomic loci in low-grade (LGG) and high-grade-glioma (HGG), respectively. The coexistence of BRAF and TERT promoter aberrations characterizes a subset of aggressive glioma. Therefore, we investigated interactions between those alterations in malignant glioma. We analyzed co-occurrence of BRAFV600E and TERT promoter mutations in our clinical data (n = 8) in addition to published datasets (n = 103) and established a BRAFV600E-positive glioma cell panel (n = 9) for in vitro analyses. We investigated altered gene expression, signaling events and TERT promoter activity upon BRAF- and E-twenty-six (ETS)-factor inhibition by qRT-PCR, chromatin immunoprecipitation (ChIP), Western blots and luciferase reporter assays. TERT promoter mutations were significantly enriched in BRAFV600E-mutated HGG as compared to BRAFV600E-mutated LGG. In vitro, BRAFV600E/TERT promoter double-mutant glioma cells showed exceptional sensitivity towards BRAF-targeting agents. Remarkably, BRAF-inhibition attenuated TERT expression and TERT promoter activity exclusively in double-mutant models, while TERT expression was undetectable in BRAFV600E-only cells. Various ETS-factors were broadly expressed, however, only ETS1 expression and phosphorylation were consistently downregulated following BRAF-inhibition. Knock-down experiments and ChIP corroborated the notion of a functional role for ETS1 and, accordingly, all double-mutant tumor cells were highly sensitive towards the ETS-factor inhibitor YK-4-279. In conclusion, our data suggest that concomitant BRAFV600E and TERT promoter mutations synergistically support cancer cell proliferation and immortalization. ETS1 links these two driver alterations functionally and may represent a promising therapeutic target in this aggressive glioma subgroup.
Asunto(s)
Neoplasias Encefálicas/genética , Glioma/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteína Proto-Oncogénica c-ets-1/genética , Proteínas Proto-Oncogénicas B-raf/genética , Telomerasa/genética , Antineoplásicos/farmacología , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Glioma/metabolismo , Células HEK293 , Humanos , Indoles/farmacología , Mutación/genética , Regiones Promotoras Genéticas/genética , Proteína Proto-Oncogénica c-ets-1/antagonistas & inhibidores , Proteína Proto-Oncogénica c-ets-1/biosíntesis , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/biosíntesis , Telomerasa/biosíntesisRESUMEN
INTRODUCTION: Erectile dysfunction (ED) is an increasing health problem that demands effective treatment. There is evidence that phosphodiesterase-5 inhibitors (PDE5-Is) and psychological intervention (PI) are effective treatment options; however, little is known about their comparative efficacy and the efficacy of combined treatments. AIM: The aim of this systematic review and meta-analysis is to evaluate the comparative efficacy of PI, PDE5-Is, and their combination in the treatment of ED. MAIN OUTCOME MEASURES: Primary outcome was ED symptoms, and secondary outcome was sexual satisfaction of the patient. METHODS: A systematic literature search was conducted in order to identify relevant articles published between 1998 and 2012. We included randomized controlled trials and controlled trials comparing PI with PDE5-I treatment or one of them against a combination of both. RESULTS: Eight studies with a total number of 562 patients were included in the meta-analysis. The results of the included studies are inconclusive, though they show a trend towards a larger effect of combined treatment compared with PI or PDE5-I treatment alone. The meta-analysis found that, overall, combined treatment was more efficacious for ED symptoms than PDE5-I treatment or PI alone. Combined treatment was more efficacious than PDE5-I use alone on sexual satisfaction. No differences were found between PDE5-Is and PI as stand-alone treatments. None of the moderators (treatment duration, methodological quality, or researcher allegiance) altered the effects. CONCLUSIONS: The combination of PI and PDE5-Is is a promising strategy for a favorable outcome in ED and can be considered as a first-choice option for ED patients. Stronger RCTs are required to confirm this initial finding.
Asunto(s)
Disfunción Eréctil/terapia , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Psicoterapia/métodos , Adulto , Anciano , Terapia Combinada/métodos , Disfunción Eréctil/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Satisfacción del Paciente , Ensayos Clínicos Controlados Aleatorios como Asunto , Consejo Sexual/métodos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Psychotropic drugs are associated with sexual dysfunction. Symptoms may concern penile erection, lubrication, orgasm, libido, retrograde ejaculation, sexual arousal, or overall sexual satisfaction. These are major aspects of tolerability and can highly affect patients' compliance. OBJECTIVES: To determine the effects of different strategies (e.g. dose reduction, drug holidays, adjunctive medication, switching to another drug) for treatment of sexual dysfunction due to antipsychotic therapy. SEARCH METHODS: An updated search was performed in the Cochrane Schizophrenia Group's Trials Register (3 May 2012) and the references of all identified studies for further trials. SELECTION CRITERIA: We included all relevant randomised controlled trials involving people with schizophrenia and sexual dysfunction. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data we calculated random effects risk ratios (RR) with 95% confidence intervals (CI), for crossover trials we calculated Odds Ratios (OR) with 95% CI. For continuous data, we calculated mean differences (MD) on the basis of a random-effects model. We analysed cross-over trials under consideration of correlation of paired measures. MAIN RESULTS: Currently this review includes four pioneering studies (total n = 138 , duration two weeks to four months), two of which are cross-over trials. One trial reported significantly more erections sufficient for penetration when receiving sildenafil compared with when receiving placebo (n = 32, MD 3.20 95% CI 1.83 to 4.57), a greater mean duration of erections (n = 32, MD 1.18 95% CI 0.52 to 1.84) and frequency of satisfactory intercourse (n = 32, MD 2.84 95% CI 1.61 to 4.07). The second trial found no evidence for selegiline as symptomatic treatment for antipsychotic-induced sexual dysfunction compared with placebo (n = 10, MD change on Aizenberg's sexual functioning scale -0.40 95% CI -3.95 to 3.15). No evidence was found for switching to quetiapine from risperidone to improve sexual functioning (n = 36, MD -2.02 95% CI -5.79 to 1.75). One trial reported significant improvement in sexual functioning when participants switched from risperidone or an typical antipsychotic to olanzapine (n = 54, MD -0.80 95% CI -1.55 to -0.05). AUTHORS' CONCLUSIONS: We are not confident that cross-over studies are appropriate for this participant group as they are best for conditions that are stable and for interventions with no physiological and psychological carry-over. Sildenafil may be a useful option in the treatment of antipsychotic-induced sexual dysfunction in men with schizophrenia, but this conclusion is based only on one small short trial. Switching to olanzapine may improve sexual functioning in men and women, but the trial assessing this was a small, open label trial. Further well designed randomised control trials that are blinded and well conducted and reported, which investigate the effects of dose reduction, drug holidays, symptomatic therapy and switching antipsychotic on sexual function in people with antipsychotic-induced sexual dysfunction are urgently needed.