Pax6 Represses Androgen Receptor-Mediated Transactivation by Inhibiting Recruitment of the Coactivator SPBP

The androgen receptor (AR) has a central role in development and maintenance of the male reproductive system and in the etiology of prostate cancer. The transcription factor Pax6 has recently been reported to act as a repressor of AR and to be hypermethylated in prostate cancer cells. SPBP is a transcriptional regulator that previously has been shown to enhance the activity of Pax6. In this study we have identified SPBP to act as a transcriptional coactivator of AR. We also show that Pax6 inhibits SPBP-mediated enhancement of AR activity on the AR target gene probasin promoter, a repression that was partly reversed by increased expression of SPBP. Enhanced expression of Pax6 reduced the amount of SPBP associated with the probasin promoter when assayed by ChIP in HeLa cells. We mapped the interaction between both AR and SPBP, and AR and Pax6 to the DNA-binding domains of the involved proteins. Further binding studies revealed that Pax6 and SPBP compete for binding to AR. These results suggest that Pax6 represses AR activity by displacing and/or inhibiting recruitment of coactivators to AR target promoters. Understanding the mechanism for inhibition of AR coactivators can give rise to molecular targeted drugs for treatment of prostate cancer

Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D Study

Peer reviewe

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Patients’ Perceptions of Risky Developments During Psychotherapy

Research on risks and unwanted effects is largely missing in psychotherapy. Using exploratory factor analysis six dimensions of personal therapy situation were identified in a preliminary study, three of them were associated with risky developments during the psychotherapeutic process: (1) (poor) quality of therapeutic relationship, (2) burden caused by psychotherapy, and (3) dependency/isolation. Based on the finding of this study an online survey was performed to examine these three dimensions. Aside from these three factors another variable was associated with risky therapy developments: the online questionnaire also asked for premature terminations of psychotherapy as a consequence of risky conditions for the therapeutic development. Risky conditions were found to be associated with the following variables: (1) the combination of female patient–male therapist, (2) the therapeutic orientation (particularly with the psychodynamic approaches) and (3) the duration of therapy. Fewer humanistic and systemic psychotherapies were found among the high risk-prone group of patients who were at risk in at least three of the four variables which were associated with risky developments. Differences in the findings of the study regarding the four therapeutic orientations stress the importance of an extensive differential indication and a cooperative partnership between patient and therapist, in order to facilitate a positive patient participation towards the choice of therapy method and subsequent successful participation throughout the course of treatment. Further studies should also focus on female patient and male therapist psychotherapies

Effects of four soil-originated Bacillus spp. on the great spruce bark beetle, Dendroctonus micans (Kugelann) (Coleoptera: Curculionidae, Scolytinae)

WOS: 000443093100001fifty bacterial cultures were isolated from 156 soil samples. In order to identify six bacteria in both systems, a fatty acid methyl ester (FAMEs) analysis was conducted, and carbon utilization profiles were assessed, using microbial identification, Biolog Microplac Systems, and the VITEK bacterial identification systems (bioMerieux, Prod. No. 21341 and 21342). Results showed that four species of Bacillus ssp., isolated from soil, were safe and efficient biological control agent for plant pests in Ordu, Turkey. These bacteria were Bacillus mycoides, B. cereus, B. thuringiensis, Paenibacillus validus, B. atrophaeus, and Arthrobacter globiformis. Laboratory tests were conducted to assess the potential of the isolates against the great spruce bark beetle, Dendroctonus micans (Kugelann) (Coleoptera: Curculionidae, Scolytinae) (Curculionidae, Scolytinae). Mortality rates of larvae and adults were 60 and 50%, 40 and 30%, and 80 and 70% when using B. mycoides, B. cereus, and B. thuringiensis, respectively. P. valid us, B. atrophaeus, and A. globiformis showed insufficient rates of mortality, 30 and 20% on the larvae and adults of D. micans, respectively. Also, these isolates had no antimicrobial effect on pathogen microorganisms. They have, however, a lethal effect on some insect groups that are agriculture and forest pests. The results indicated that the Bacillus isolates in question can be used as one of the biological control agent