The orphan receptor ERRα interferes with steroid signaling

The estrogen receptor-related receptor α (ERRα) is an orphan member of the nuclear receptor superfamily that has been shown to interfere with the estrogen-signaling pathway. In this report, we demonstrate that ERRα also cross-talks with signaling driven by other steroid hormones. Treatment of human prostatic cells with a specific ERRα inverse agonist reduces the expression of several androgen-responsive genes, in a manner that does not involve perturbation of androgen receptor expression or activity. Furthermore, ERRα activates the expression of androgen response elements (ARE)-containing promoters, such as that of the prostate cancer marker PSA, in an ARE-dependent manner. In addition, promoters containing a steroid response element can be activated by all members of the ERR orphan receptor subfamily, and this, even in the presence of antisteroid compounds

TGF-beta 1 modulates Fas (APO-1/CD95)-mediated apoptosis of human pre-B cell lines

International audienceWe have previously shown that Fas-induced apoptosis is markedly enhanced by IL-7 in human pre-B but not pro-B cell lines. In addition, pre-B cell receptor (pre-BCR) ligation significantly potentiates the IL-7 effects on Fas-triggered pre-B cell death. We show herein that transforming growth factor (TGF)-beta1 sharply reduces Fas-induced death rate of pre-B but not pro-B cells. TGF-beta1 causes inhibition of Fas-mediated disruption of mitochondrial transmembrane potential and cleavage of caspase 8, Bid and caspase 3. Bcl2 expression is markedly increased in TGF-beta1-treated pre-B cells, whereas cellular FLICE-like inhibitory protein long (c-FLIPL), Bcl-XL, Bax, and Bad expression remains unchanged. TGF-beta1 causes a selective growth arrest of pre-B cells in G0/G1 phase of the cell cycle and induces a partial down-modulation of both Fas and pre-BCR expression. All TGF-beta1-mediated effects, but Bcl2 up-regulation, can be reproduced by the LY294002 phosphatidylinositol 3-kinase (Pl3K)/Akt inhibitor but not by inhibitors of the MAPK/ERK (MEK) and Janus kinase (Jak)/STAT pathways, which promote cell death. Akt phosphorylation is strongly inhibited by TGF-beta1 in pre-B but not pro-B cells and is not modified by Fas engagement. Altogether, our findings suggest that TGF-beta1 prevents Fas-induced apoptosis of pre-B lines by inhibiting Pl3K pathway and by enhancing expression of Bcl2. They also suggest that the Pl3K/Akt pathway is involved in the control of Fas and pre-BCR expression, a checkpoint in B cell development

POLÍTICAS DE EDUCAÇÃO CORPORATIVA E O PROCESSO DE CERTIFICAÇÃO BANCÁRIA: DISTINTOS ATORES E PERSPECTIVAS

RESUMO As iniciativas de educação corporativa vêm se institucionalizando como elemento de competitividade entre países (LANVIN; EVANS, 2013), organizações (EBOLI et al. 2010) e indivíduos (SARSUR, 2010). Como parte do resultado da melhor estruturação da educação corporativa, a qualificação da mão de obra traz no seu bojo os processos de certificação profissional. Neste contexto, o sistema financeiro brasileiro revela instituições mais efetivas na intermediação financeira e na geração de resultados, lastreadas em ações de educação corporativa e políticas de gestão de pessoas. O presente artigo delineia esta perspectiva analisando o movimento de certificação de trabalhadores bancários no Brasil, sob a égide de atores distintos como o órgão regulador; os bancos e suas universidades corporativas; as certificadoras; os sindicatos e os bancários. Verificaram-se por meio de pesquisa qualitativa de cunho descritivo, utilizando-se como instrumentos de coleta de dados a análise documental, entrevistas e grupo de foco, as políticas de gestão de pessoas sob o escopo da educação corporativa e o processo de certificação bancária sob a perspectiva destes atores. Os principais achados indicam que o Banco Central do Brasil normatiza o mercado, os bancos induzem ao processo de certificação bancária como mecanismo de ampliação de competitividade e pressão sobre o indivíduo enquanto trabalhador, e por sua vez os sindicatos atuam como coadjuvantes no processo

Sentinel lymph node biopsy and morbidity outcomes in early cervical cancer: Results of a multicentre randomised trial (SENTICOL-2)

International audienceAbstract Background No systemic treatment has been established for meningioma progressing after local therapies. Methods This randomized, multicenter, open-label, phase II study included adult patients with recurrent WHO grade 2 or 3 meningioma. Patients were 2:1 randomly assigned to intravenous trabectedin (1.5 mg/m2 every 3 weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), objective radiological response, safety, quality of life (QoL) assessment using the QLQ-C30 and QLQ-BN20 questionnaires, and we performed tissue-based exploratory molecular analyses. Results Ninety patients were randomized (n = 29 in LOC, n = 61 in trabectedin arm). With 71 events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR] = 1.42; 80% CI, 1.00-2.03; P = .294) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) and 21.1% (95% CI, 11.3%-32.9%), respectively. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR = 0.98; 95% CI, 0.54-1.76; P = .94). Grade ≥3 adverse events occurred in 44.4% of patients in the LOC and 59% of patients in the trabectedin arm. Enrolled patients had impeded global QoL and overall functionality and high fatigue before initiation of systemic therapy. DNA methylation class, performance status, presence of a relevant co-morbidity, steroid use, and right hemisphere involvement at baseline were independently associated with OS. Conclusions Trabectedin did not improve PFS and OS and was associated with higher toxicity than LOC treatment in patients with non-benign meningioma. Tumor DNA methylation class is an independent prognostic factor for OS

Voxel-based evidence of perfusion normalization in glioblastoma patients included in a phase I\textendashII trial of radiotherapy/tipifarnib combination

International audienc

Evidence for a protective role of the STAT5 transcription factor against oxidative stress in human leukemic pre-B cells

International audienceSTAT5 transcription factors are involved in normal B lymphocyte development and in leukemogenesis. We show that the inhibition of STAT5A expression or activity in the NALM6, 697 and Reh leukemic pre-B cell lines, results in a higher spontaneous apoptosis and an increased FAS-induced cell death. However, the molecular mechanisms underlying the altered pre-B cell survival are unclear. We used a proteomic approach to identify proteins that are differentially regulated in cells expressing (NALM6Δ5A) or not a dominant negative form of STAT5A. Among the 14 proteins identified, six were involved in the control of the oxidative stress like glutathione (GSH) synthetase and DJ-1. Accordingly, we showed increased levels of reactive oxygen species (ROS) in NALM6Δ5A cells and suppression of the increased sensitivity to Fas-mediated apoptosis by the GSH tripeptide. Similar results were observed when NALM6 cells were treated with TAT-STAT5Δ5A fusion proteins or STAT5A shRNA. In addition, the 697 and Reh pre-B cells were found to share number of molecular changes observed in NALM6Δ5A cells including ROS generation, following inhibition of STAT5 expression or function. Our results point out to a hitherto undescribed link between STAT5 and oxidative stress and provide new insights into STAT5 functions and their roles in leukemogenesis