Regulation of COX-2 protein expression by Akt in endometrial cancer cells is mediated through NF-κB/IκB pathway

BACKGROUND: Cyclooxygenase-2 (COX-2) has been shown to be highly expressed in a broad series of primary endometrial tumors and its expression may be closely associated with parameters of tumor aggressiveness. In human endometrial cancer, tumor suppressor phosphatase tensin homologue (PTEN) is frequently mutated. In the presence of a mutated PTEN protein, Akt phosphorylation levels increase leading to the activation of this survival pathway. The nuclear transcription factor κB (NF-κB) is a well establish regulator of genes encoding cytokines, cytokine receptors, and cell adhesion molecules that drive immune and inflammatory responses. More recently, NF-κB activation has been connected with multiple aspects of oncogenesis, including the control of apoptosis, cell cycle, differentiation, and cell migration. It is known that Akt may act through NF-κB pathway and that COX-2 gene has been shown to be regulated at the promoter level by NF-κB. Recently, we showed that Akt regulates COX-2 gene and protein expressions in phospho-Akt expressing endometrial cancer cells. The present study was undertaken to determine the involvement of NF-κB pathway and IκB (an inhibitor of NF-κB) in the regulation of COX-2 expression and to determine more precisely the downstream targets of Akt involved in this process. RESULTS: Three different human endometrial cancer cell lines known to have wild type PTEN (HEC 1-A) or a mutated inactive PTEN protein (RL 95-2 and Ishikawa) were used for these studies. Expression IκB and Phospho-IκB were evaluated by Western analysis. The presence of IκB phosphorylation was found in all cell lines studied. There was no difference between cell lines in term of NF-κB abundance. Inhibition of PI 3-K with Wortmannin and LY294002 blocked IκB phosphorylation, reduced NF-κB nuclear activity, reduced COX-2 expression and induced apoptosis. Transfection studies with a dominant negative Akt vector blocked IκB phosphorylation and reduced COX-2 expression. On the opposite, constitutively active Akt transfections resulted in the induction of IκB phosphorylation and up-regulation of COX-2. CONCLUSION: These results demonstrate that Akt signals through NF-κB/IκB pathway to induce COX-2 expression in mutated PTEN endometrial cancer cells

Exposure-Response Analyses of Asbestos and Lung Cancer Subtypes in a Pooled Analysis of Case-Control Studies

International audienceBACKGROUND:Evidence is limited regarding risk and the shape of the exposure-response curve at low asbestos exposure levels. We estimated the exposure-response for occupational asbestos exposure and assessed the joint effect of asbestos exposure and smoking by sex and lung cancer subtype in general population studies.METHODS:We pooled 14 case-control studies conducted in 1985-2010 in Europe and Canada, including 17,705 lung cancer cases and 21,813 controls with detailed information on tobacco habits and lifetime occupations. We developed a quantitative job-exposure-matrix to estimate job-, time period-, and region-specific exposure levels. Fiber-years (ff/ml-years) were calculated for each subject by linking the matrix with individual occupational histories. We fit unconditional logistic regression models to estimate odds ratios (ORs), 95% confidence intervals (CIs), and trends.RESULTS:The fully adjusted OR for ever-exposure to asbestos was 1.24 (95% CI, 1.18, 1.31) in men and 1.12 (95% CI, 0.95, 1.31) in women. In men, increasing lung cancer risk was observed with increasing exposure in all smoking categories and for all three major lung cancer subtypes. In women, lung cancer risk for all subtypes was increased in current smokers (ORs ~two-fold). The joint effect of asbestos exposure and smoking did not deviate from multiplicativity among men, and was more than additive among women.CONCLUSIONS:Our results in men showed an excess risk of lung cancer and its subtypes at low cumulative exposure levels, with a steeper exposure-response slope in this exposure range than at higher, previously studied levels. (See video abstract at, http://links.lww.com/EDE/B161.)

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project–imputed genotype data in up to ~370,000 women, we identify 389 independent signals (P < 5 × 10$^{−8}$) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ~7.4% of the population variance in age at menarche, corresponding to ~25% of the estimated heritability. We implicate ~250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility

Aide Mémoire TDAH

International audienc

Marseille (13) - 33 montée des Accoules, impasse Fonderie Vieille : tranche 2 . Rapport de diagnostic archéologique

Les sondages ont permis de déterminer la chronologie de l’édification des immeubles, au sein du XVIIIe siècle et de mettre au jour une latrine comblée au XIXe siècle. Sous ces constructions modernes, le substrat de poudingue stampien apparaît relativement haut, servant d’assise à certains murs. Par endroits, le rocher est recreusé, aménageant des « caves » profondes de plus de 2 m, l’une d’elles est comblée au XVIIIe siècle, avant la construction des immeubles, tandis qu’une autre a livré un important dépotoir de la seconde moitié du XIIIe siècle

Marseille (13) - 33 montée des Accoules, impasse Fonderie Vieille : tranche 2 . Rapport de diagnostic archéologique

Les sondages ont permis de déterminer la chronologie de l’édification des immeubles, au sein du XVIIIe siècle et de mettre au jour une latrine comblée au XIXe siècle. Sous ces constructions modernes, le substrat de poudingue stampien apparaît relativement haut, servant d’assise à certains murs. Par endroits, le rocher est recreusé, aménageant des « caves » profondes de plus de 2 m, l’une d’elles est comblée au XVIIIe siècle, avant la construction des immeubles, tandis qu’une autre a livré un important dépotoir de la seconde moitié du XIIIe siècle

Rapport de recherche sur les lieux recents de 'l'architecture des medias' - septembre 1994 en liaison avec l'exposition 'enquete sur les sieges de l'info' au pavillon de l'Arsenal, de juin a aout 1994

Programme Cite-ProjetsAvailable at INIST (FR), Document Supply Service, under shelf-number : RP 13599 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueSIGLEFRFranc

Suivi à long terme des effets d’un entrainement de la mémoire de travail (Cogmed) auprès des enfants présentant un TDAH

International audienc

Saint-Maximin-la-Sainte-Baume (83) - Place Malherbe. Rapport de diagnostic archéologique

Ce diagnostic a permis de mettre en évidence la richesse du sous sol de la place Malherbe qui recèle des vestiges de l'Antiquité à la période contemporaine.L'antiquité romaine est représentée par le biais de murs, d'une fosse et d'une probable sépulture, qui semblent refléter une occupation assez lâche durant le Haut-Empire.Les faubourgs médiévaux et modernes paraissent relativement bien conservés avec notamment la présence d'axes viaires autour desquels s’organisent les maisons. Ces constructions, qui s’étagent des Xème –XIème au XVIIème s., se développent à l’ouest des fossés dont la limite a pu être mise en évidence. Au nord-est de la place, un silo et un mur illustrent une implantation des X-XIe siècles, possiblement isolée. Au début du XIVe s. , une nouvelle enceinte urbaine est établie, bordée par un fossé dont le mur de contrescarpe a été observé sur une longueur de 21m. Un puissant mur situé devant l’emplacement de l’ancienne « porte d’Aix » pourrait faire partie du dispositif de franchissement de la fortification. Un quartier extra-muros se développe, dont une rue et plusieurs maisons dotées de sols de terre ont été partiellement dégagées. Les constructions sont en moellons de calcaire liés au mortier et une partie des élévations semble être montée en adobes.Ce faubourg est détruit au début de l’époque moderne et ne semble pas être reconstruit avant le XVIIIème s. Les fossés sont alors comblés et une esplanade est crée. Agrandie vers fin de l’époque moderne, cette esplanade constitue l’actuelle Place Malherbe