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Growing evidence supports a role for the unfolded protein response (UPR) in carcinogenesis; however, the precise molecular mechanisms underlying this phenomenon remain elusive. Herein, we identified the circadian clock PER1 mRNA as a novel substrate of the endoribonuclease activity of the UPR sensor IRE1α. Analysis of the mechanism shows that IRE1α endoribonuclease activity decreased PER1 mRNA in tumor cells without affecting PER1 gene transcription. Inhibition of IRE1α signaling using either siRNA-mediated silencing or a dominant-negative strategy prevented PER1 mRNA decay, reduced tumorigenesis, and increased survival, features that were reversed upon PER1 silencing. Clinically, patients showing reduced survival have lower levels of PER1 mRNA expression and increased splicing of XBP1, a known IRE-α substrate, thereby pointing toward an increased IRE1α activity in these patients. Hence, we describe a novel mechanism connecting the UPR and circadian clock components in tumor cells, thereby highlighting the importance of this interplay in tumor development. Cancer Res; 73(15); 4732–43. ©2013 AACR.

Background Aggregatibacter aphrophilus, a commensal of the oro-pharyngeal flora and member of the HACEK group of organisms, is an uncommonly encountered clinical pathogen. It has already been described as the causative agent of brain abscesses, empyema, meningitis, sinusitis, otitis media, bacteriemia, pneumonia, osteomyelitis, peritonitis, endocarditis and wound infections. Herein we report the first case of bartholinitis due to A. aphrophilus. Case presentation A 33-year-old woman was admitted for a 3-day genital pain without fever and urinary functional signs. The abscess was incised and drained; A. aphrophilus was the only micro-organism that grew from the pus. The patient received no antibiotics; the clinical course was favourable. Conclusion This case highlights the importance of an effective treatment of recurrent bartholinitis such as a cold resection of the gland. It is presented for its rarity.

International audience; Conference: 12th Meeting of the European-Association-of-Neuro-Oncology Location: GERMANY Date: OCT 12-16, 2016 - Meeting Abstract: OS1.8

// Clementine Druelle 1,6,* , Claire Drullion 1,* , Julie Desle 1,* , Nathalie Martin 1 , Laure Saas 1 , Johanna Cormenier 1 , Nicolas Malaquin 1,7 , Ludovic Huot 2 , Christian Slomianny 3 , Fatima Bouali 1 , Chantal Vercamer 1 , David Hot 2 , Albin Pourtier 1 , Eric Chevet 4,5 , Corinne Abbadie 1 and Olivier Pluquet 1 1 Universite de Lille, Institut Pasteur de Lille, CNRS UMR8161, Mechanisms of Tumourigenesis and Targeted Therapies, Lille, France 2 Universite de Lille, Institut Pasteur de Lille, INSERM, CNRS UMR8204, Centre d’Infection et d’Immunite de Lille, Lille, France 3 Universite de Lille, INSERM U1003, Villeneuve d’Ascq, France 4 Oncogenesis, Stress, Signaling, INSERM ER-440 Universite de Rennes, Rennes, France 5 Centre de Lutte Contre le Cancer Eugene Marquis, Rennes, France 6 Department of Anatomy and Neuroscience, Biosciences Institute, University College Cork, Cork, Ireland 7 Institut du Cancer de Montreal, Montreal, QC, Canada * These authors have contributed equally to this work Correspondence to: Olivier Pluquet, email: // Keywords : senescence, unfolded protein response, ATF6α, endoplasmic reticulum, normal human dermal fibroblast, Gerotarget Received : June 22, 2016 Accepted : August 02, 2016 Published : August 22, 2016 Abstract Cellular senescence is known as an anti-tumor barrier and is characterized by a number of determinants including cell cycle arrest, senescence associated β-galactosidase activity and secretion of pro-inflammatory mediators. Senescent cells are also subjected to enlargement, cytoskeleton-mediated shape changes and organelle alterations. However, the underlying molecular mechanisms responsible for these last changes remain still uncharacterized. Herein, we have identified the Unfolded Protein Response (UPR) as a player controlling some morphological aspects of the senescent phenotype. We show that senescent fibroblasts exhibit ER expansion and mild UPR activation, but conserve an ER stress adaptive capacity similar to that of exponentially growing cells. By genetically invalidating the three UPR sensors in senescent fibroblasts, we demonstrated that ATF6α signaling dictates senescence-associated cell shape modifications. We also show that ER expansion and increased secretion of the pro-inflammatory mediator IL6 were partly reversed by silencing ATF6α in senescent cells. Moreover, ATF6α drives the increase of senescence associated-β-galactosidase activity. Collectively, these findings unveil a novel and central role for ATF6α in the establishment of morphological features of senescence in normal human primary fibroblasts.

We report a case of postoperative endophthalmitis due to an as yet unclassified Acinetobacter gyllenbergii-like isolate. The functional outcome was rapidly negative despite antibacterial therapy. This novel species, which cannot be identified by classical biochemical methods, may represent an underestimated opportunistic pathogen responsible for acute pyogenic infections.

International audience; The IGA code (a French acronym standing for actinides gamma isotopy) is a tool developed by the CEA LIST to determine the isotopic composition of plutonium and uranium, based on the automatic analysis of the γ/X spectrum emitted by a nuclear sample. Its main feature is its generic approach of the problem. As a consequence, the IGA code is a very flexible tool, because no particular experimental setup is imposed to the user for the acquisitions, in terms of energy range, gain, channel number or detector resolution. However, these experimental conditions can have an impact on the quality of the results. So, a study has been carried out to evaluate the effect of different experimental parameters on the IGA performances for plutonium spectra and quantify these performances. The study has been led according to three different approaches: analysis of IGA results on a whole spectrum database coming from French laboratories, analysis on artificially modified spectra, and finally analysis of results on new real spectra acquired in the laboratory on certified samples.

BACKGROUND: Carbapenemase‐producing Enterobacteriaceae (CPE) have become a major public health issue. The objective of the present study was to prospectively assess the analytical performance of a CPE detection algorithm based on phenotypic tests (the screening test) and MALDI‐ToF hydrolysis (the confirmatory test). METHODS: Over a 6‐month period and based on a disk diffusion method, 74 carbapenem‐resistant strains were included in this study. RESULTS: Of the collected isolates, 54 turned out to be negative after phenotypic tests. Hence, 20 strains (including all of the CPEs) were checked with the confirmation test. Seven strains were positive. After molecular biology assessments in a reference center, three of the seven were found to be false positives. The algorithm had a negative predictive value and a sensitivity of 100%, a specificity of 77%, and a positive predictive value of 20%. CONCLUSION: The algorithm has a 24‐hour turnaround time and helps to avoid using expensive molecular biology tests; we consider that it can be used on a routine basis for screening clinical strains.

En 2012, le conseil regional Nord-Pas-de-Calais s’investit et cofinance differentes actions dans le domaine de la sante au travail. L’objectif est d’accompagner 10 000 tres petites entreprises (TPE) dans leurs demarches de prevention et d’evaluation des risques professionnels. Dans ce projet, la priorite fut donnee aux TPE, a celles nouvellement installees, puis a des entreprises presentant des risques specifiques (beaute coiffure, boulangers, bâtiments travaux publics, ferrailleurs, funeraire, tailleurs de pierre…). Pour pole sante travail, ce projet fut une opportunite : – de donner un sens au travail realise par les equipes en interne a travers la fiche d’entreprise, sa mise en visibilite par une action – de continuite vers une aide au document unique ; – de positionner le metier d’assistant sante–travail comme un generaliste competent entre l’entreprise (TPE) et l’equipe pluridisciplinaire pour une premiere evaluation collective des situations reelles de travail et d’identification des risques professionnels ; – de developper une culture de la prevention aupres des chefs d’entreprise. Ce projet a favorise la construction du geste professionnel des assistants sante–travail. L’enchainement des actions (accueil nouvel adherent, realisation de la fiche d’entreprise, aide a l’identification des situations de danger et aide a l’evaluation des risques professionnels) contribue a eclairer l’entreprise sur un diagnostic reel sante–travail afin de co-construire un plan de prevention. Cette action a permis d’introduire de nouvelles formes de cooperation pluridisciplinaire entre les acteurs de la sante au travail et de renforcer l’image de la sante au travail en nous positionnant en tant qu’interlocuteur privilegie pour discuter des questions de sante au travail en TPE. Au sein de pole sante travail, le travail en pluridisciplinarite s’inscrit de plus en plus dans une demarche continue au benefice d’un collectif de travail ou d’une entreprise. Il est donc primordial de comprendre en quoi la pluridisciplinarite est un atout des services de sante au service de la sante au travail des entreprises. Nathalie Esteves, Delphine Kasprzak : referents ast, Sabine Pluquet : assistante, Nathalie Delattre : responsable du developpement de la pluridisciplinarite.

Assay technologies that were originally developed for high-throughput screening (HTS) have recently proven useful in drug discovery for activities located upstream (target identification and validation) and downstream (ADMET) of HTS. Here the authors investigated and characterized the biological properties of a novel target, IRE1alpha, a bifunctional kinase/RNase stress sensor of the endoplasmic reticulum (ER). They have developed a novel assay platform using the HTS technology AlphaScreen to monitor the dimerization/oligomerization and phosphorylation properties of the cytosolic domain of IRE1alpha. They show in vitro that dimerization/oligomerization of the cytosolic domain of IRE1 correlated with the autophosphorylation ability of this domain and its endoribonuclease activity toward XBP1 mRNA. Using orthogonal in vitro and cell-based approaches, the authors show that the results obtained using AlphaScreen were biologically relevant. Preliminary characterization of assay robustness indicates that both AlphaScreen assays should be useful in HTS for the identification of IRE1 activity modulators.

Introduction The aim of this study was to describe the characteristics and epidermal growth factor receptor (EGFR) mutational status of patients with non-small cell lung cancer (NSCLC) with osteoblastic reactions diagnosed before or during treatment with EGFR tyrosine kinase inhibitors (TKIs). Methods Retrospective study including patients with 36 NSCLC with at least one site of osteoblastic reaction at the time of diagnosis or during treatment with EGFR-TKI. Results The rate of patients with mutated EGFR tumors with osteoblastic reactions before or after EGFR-TKI treatment was similar. Median progression-free survival (PFS) for the entire group was more than 9 months and median survival was more than 12 months. There was no statistically significant difference in survival between patients with osteoblastic reactions before initiation of TKI and those diagnosed during TKI treatment. Patients with extraosseous metastases when treated with TKI had the lowest survival (P Conclusions In patients with NSCLC treated with TKI, initial or development of an osteoblastic reaction seems to be related to a more favorable outcome. In patients with osteoblastic reactions, tumors present with clinical and biologic characteristics of better survival and response to TKI. The occurrence of osteoblastic reactions during treatment with TKI, while primary tumor and metastases are stable or in response, should not be considered as disease progression.

Calnexin is a type I integral membrane phosphoprotein resident of the endoplasmic reticulum. Its intraluminal domain has been deduced to function as a lectin chaperone coordinating the timing of folding of newly synthesized N-linked glycoproteins of the secretory pathway. Its C-terminal cytosolic oriented extension has an ERK1 phosphorylation site at Ser(563) affecting calnexin association with the translocon. Here we find an additional function for calnexin phosphorylation at Ser(563) in endoplasmic reticulum quality control. A low dose of the misfolding agent l-azetidine 2-carboxylic acid slows glycoprotein maturation and diminishes the extent and rate of secretion of newly synthesized secretory alpha1-antitrypsin. Under these conditions the phosphorylation of calnexin is enhanced at Ser(563). Inhibition of this phosphorylation by the MEK1 inhibitor PD98059 enhanced the extent and rate of alpha1-antitrypsin secretion comparable with that achieved by inhibiting alpha-mannosidase activity with kifunensine. This is the first report in which the phosphorylation of calnexin is linked to the efficiency of secretion of a cargo glycoprotein.

Object versioning refers to how an application can have access to previous states of its objects. Implementing this mechanism is hard because it needs to be efficient in space and time, and well integrated with the programming language. This paper presents HistOOry, an object versioning system that uses an efficient data structure to store and retrieve past states. It needs only three primitives, and existing code does not need to be modified to be versioned. It provides fine-grained control over what parts of objects are versioned and when. It stores all states, past and present, in memory. Code can be executed in the past of the system and will see the complete system at that point in time. We have implemented our model in Smalltalk and used it for three applications that need versioning: checked postconditions, stateful execution tracing and a planar point location implementation. Benchmarks are provided to asses the practical complexity of our implementation.

Resume Introduction Les cancers bronchopulmonaires representent une entite de mauvais pronostic. Les innovations therapeutiques en oncologie et l’optimisation de la prise en charge en reanimation ont ameliore le pronostic du patient cancereux bronchique presentant une detresse vitale. Observation Nous rapportons le cas d’un patient atteint d’un cancer bronchique et presentant une hemoptysie de moyenne abondance hospitalise en reanimation medicale. Apres une discussion pluridisciplinaire, il est decide d’intuber ce patient devant une recidive hemorragique responsable d’une detresse respiratoire. L’evolution a ete favorable. Quatre mois apres sa sortie de reanimation, ce patient est toujours en vie et autonome. Discussion Apres des annees de pessimisme, la litterature fait etat d’une amelioration de la survie des patients atteints de cancers bronchopulmonaires hospitalises en reanimation. Les detresses respiratoires et les etats de choc dominent les motifs d’admission. Les facteurs de risque de deces sont davantage lies a la pathologie aigue qu’a la maladie cancereuse. L’admission des patients doit s’effectuer avant le stade de defaillance multiviscerale et avec la mise en place de therapeutiques non invasives. Le concept de reanimation d’attente est un outil interessant pour ameliorer la prise en charge en reanimation. Conclusion Pour decider d’hospitaliser en reanimation un patient atteint de cancer, il est important de tenir compte de l’evenement aigu. Une admission precoce, si elle est indiquee, est souhaitable. L’evolution dans les 72 premieres heures donne une bonne idee du devenir du patient et aide a sa prise en charge optimale.

The endoplasmic reticulum (ER) has emerged as a major site of cellular homeostasis regulation, particularly in the unfolded protein response, which is being found to play a major role in cancer and many other diseases. Here, we address ER-mediated signaling and regulations in the context of environmental challenges in cancer, such as hypoxia, angiogenesis, and chemotherapeutic resistance, and we discuss how ER-resident molecular machines become deregulated and involved in cancer-related pathology. Further exploration of how the ER senses, signals, and adapts to stress may redefine and deepen our understanding of its functions in cancer pathobiology. [Cancer Res 2007;67(22):10631–4]

Phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) is mediated by a family of kinases that respond to various forms of environmental stress. The eIF2alpha kinases are critical for mRNA translation, cell proliferation, and apoptosis. Activation of the tumor suppressor p53 results in cell cycle arrest and apoptosis in response to various types of stress. We previously showed that, unlike the majority of stress responses that stabilize and activate p53, induction of endoplasmic reticulum stress leads to p53 degradation through an Mdm2-dependent mechanism. Here, we demonstrate that the endoplasmic reticulum-resident eIF2alpha kinase PERK mediates the proteasomal degradation of p53 independently of translational control. This role is not specific for PERK, because the eIF2alpha kinase PKR also promotes p53 degradation in response to double-stranded RNA. We further establish that the eIF2alpha kinases induce glycogen synthase kinase 3 to promote the nuclear export and proteasomal degradation of p53. Our findings reveal a novel cross-talk between the eIF2alpha kinases and p53 with implications in cell proliferation and tumorigenesis.

Resume Les patients porteurs d’un cancer bronchique non a petites cellules (CBNPC) avance, en mauvais etat general sont souvent peu representes dans les essais cliniques. Ceci entraine une definition souvent empirique de leur prise en charge. Plusieurs travaux recents demontrent l’interet de la chimiotherapie chez les patients de PS (performance status) 2, qui ameliore a la fois les symptomes et probablement la survie. En revanche, il persiste un debat sur l’interet d’une monotherapie ou d’une bitherapie dans ce groupe de patients. Les inhibiteurs de tyrosine kinase de l’EGFR ont demontre leur interet chez les patients pretraites, apportant a la fois un benefice clinique et un benefice de survie dans des etudes randomisees qui ont inclus un nombre significatif de patients en mauvais etat general.

Sorafenib is the treatment of reference for advanced hepatocellular carcinoma (HCC). A decrease in the serum levels of Alpha-fetoprotein (AFP) is reported to be the biological parameter that is best associated with disease control by sorafenib. In order to provide a biological rationale for the variations of AFP, we analyzed the various steps of AFP production in human HCC cell lines exposed to sorafenib. Sorafenib dramatically reduced the levels of AFP produced by HCC cells independently of its effect on cell viability. The mRNA levels of AFP decreased upon sorafenib treatment, while the AFP protein remained localized in the Golgi apparatus. Sorafenib activated the Regulated Inositol-Requiring Enzyme-1α (IRE-1α) and the PKR-like ER Kinase (PERK)-dependent arms of the Unfolded Protein Response (UPR). The inhibition of IRE-1α partially restored the mRNA levels of AFP upon treatment with sorafenib. The inhibition of both pathways partially prevented the drop in the production of AFP induced by sorafenib. The findings provide new insights on the regulation of AFP, and identify it as a biomarker suitable for the exploration of HCC cell proteostasis in the context of therapeutic targeting.

Intensional views and relations have been proposed as a way of actively documenting high-level structural regularities in the source code of a software system. By checking conformance of these intensional views and relations against the source code, they supposedly facilitate a variety of software maintenance and evolution tasks. In this paper, by performing a case study on three different versions of the SmallWiki application, we critically analyze in how far the model of intensional views and its current generation of tools provide support for co-evolving high-level design and source code of a software system.

The micropattern gaseous detector Micromegas has been developed for several years in Saclay and presents good performance for neutron detection. A prototype for neutron imaging has been designed and new results obtained in thermal neutron beams are presented. Based on previous results demonstrating a good 1D spatial resolution, a tomographic image of a multiwire cable has been performed using a 1D Micromegas prototype. The number of pillars supporting the micromesh is too large and leads to local losses of efficiency that distort the tomographic reconstruction. Nevertheless, this first tomographic image achieved with this kind of detector is very encouraging. The next worthwhile development for neutron imaging is to achieve a bi-dimensional detector, which is presented in the second part of this study. The purpose of measurements was to investigate various operational parameters to optimize the spatial resolution. Through these measurements the optimum spatial resolution has been found to be around 160 microns (standard deviation) using Micromegas operating in double amplification mode. Several 2D imaging tests have been carried out. Some of these results have revealed fabrication defects that occurred during the manufacture of Micromegas and that are limiting the full potential of the present neutron imaging system., 6 pages, 10 figures, presented at IEEE 2004 conference in Roma, Italy

Inactivation of the tumor suppressor p53 by degradation is a mechanism utilized by cells to adapt to endoplasmic reticulum (ER) stress. However, the mechanisms of p53 destabilization by ER stress are not known. We demonstrate here that the E3 ubiquitin-ligase Hdm2 is essential for the nucleocytoplasmic transport and proteasome-dependent degradation of p53 in ER-stressed cells. We also demonstrate that p53 phosphorylation at S315 and S376 is required for its nuclear export and degradation by Hdm2 without interfering with the ubiquitylation process. Furthermore, we show that p53 destabilization in unstressed cells utilizes the cooperative action of Hdm2 and glycogen synthase kinase 3beta, a process that is enhanced in cells exposed to ER stress. In contrast to other stress pathways that stabilize p53, our findings further substantiate a negative role of ER stress in p53 activation with important implications for the function of the tumor suppressor in cells with a dysfunctional ER.

Background The herpes simplex virus type 1 (HSV-1) VP22 protein has the property to mediate intercellular trafficking of heterologous proteins fused to its C- or N-terminus. We have previously shown improved delivery and enhanced therapeutic effect in vitro and in vivo with a P27-VP22 fusion protein. In this report, we were interested in studying the spread and biological activity of VP22 fused to the P53 tumor suppressor. Methods Expression of the VP22-P53 and P53-VP22 fusion proteins was shown by Western blot and intercellular spreading was monitored by immunofluorescence on transiently transfected cells. In vitro antiproliferative activity of wild-type (wt) P53 and P53-VP22 was assessed by proliferation assays and transactivating ability was studied by a reporter gene test and a gel-shift assay. Antitumor activity was also tested in vivo by intratumoral injections of naked DNA in a model of subcutaneous tumors implanted in nude mice. Results Our results show that the C-terminal fusion or the N-terminal P53-VP22 fusion proteins are not able to spread as efficiently as VP22. Moreover, we demonstrate that VP22-P53 does not possess any transactivating ability. P53-VP22 has an antiproliferative activity, but this activity is not superior to the one of P53 alone, in vitro or in vivo. Conclusions Our study indicates that a gene transfer strategy using VP22 cannot be considered as a universal system to improve the delivery of any protein. Copyright © 2005 John Wiley & Sons, Ltd.

The tumor suppressor p53, a sensor of multiple forms of cellular stress, is regulated by post-translational mechanisms to induce cell-cycle arrest, senescence, or apoptosis. We demonstrate that endoplasmic reticulum (ER) stress inhibits p53-mediated apoptosis. The mechanism of inhibition involves the increased cytoplasmic localization of p53 due to phosphorylation at serine 315 and serine 376, which is mediated by glycogen synthase kinase-3 β (GSK-3β). ER stress induces GSK-3β binding to p53 in the nucleus and enhances the cytoplasmic localization of the tumor suppressor. Inhibition of apoptosis caused by ER stress requires GSK-3β and does not occur in cells expressing p53 with mutation(s) of serine 315 and/or serine 376 to alanine(s). As a result of the increased cytoplasmic localization, ER stress prevents p53 stabilization and p53-mediated apoptosis upon DNA damage. It is concluded that inactivation of p53 is a protective mechanism utilized by cells to adapt to ER stress.

WR1065 is an aminothiol with selective cytoprotective effects in normal compared to cancer cells, which is used to protect tissues against the damaging effect of radiation and chemotherapeutic drugs. WR1065 has been shown to induce wild-type p53 accumulation and activation in cultured cells, suggesting a role of p53 in cytoprotection. However, the molecular mechanisms by which WR1065 activates p53 remain unclear. Here, we demonstrated that p53 accumulation by WR1065 in MCF-7 cells did not result from the formation of DNA-damage as measured by DNA fragmentation and Comet assay, nor from oxidative stress as detected by measurement of glutathione levels, lipid peroxidation and reactive oxygen species production. p53 activation by WR1065 was not prevented by inhibition of PI-3 kinases, and was still detectable in MCF-7 cells stably transfected with the oncoprotein E6, which repressed p53 induction by DNA damage. These data provided evidence that WR1065 induces p53 by a pathway different than the one elicited by DNA-damage. Direct reduction by WR1065 of key cysteines in p53 may play an important role in this alternative pathway, as shown by the fact that WR1065 activated the redox-dependent, DNA-binding activity of p53 in vitro.

The aminothiol WR1065, the active metabolite of the cytoprotector amifostine, exerts its antimutagenic effects through free-radical scavenging and other unknown mechanisms. In an earlier report, we showed that WR1065 activates wild-type p53 in MCF-7 cells, leading to p53-dependent arrest in the G(1) phase of the cell cycle. To determine whether WR1065 activates p53 by modulating protein conformation, we analyzed its effects on p53 conformation and activity in the esophageal cancer cell line TE-1. This cell line contains a mutation in codon 272 of p53 (p53(V272M), with methionine instead of a valine), conferring temperature-sensitive properties to the p53 protein. At the nonpermissive temperature (37 degrees C), p53(V272M) adopts the mutant p53 conformation (nonreactive with the antibody PAb1620), does not bind specifically to DNA, and is not activated in response to DNA-damaging treatment. However, treatment with 0.5-4 mM WR1065 partially restored wild-type conformation at 37 degrees C, stimulated DNA binding activity, and increased the expression of p53 target genes WAF-1, GADD45, and MDM2, leading to cell-cycle arrest in G(1). These results suggest that WR1065 activates p53 through a mechanism distinct from DNA-damage signaling, which involves modulation of p53 protein conformation.

In the past 20 years both the circadian clock and endoplasmic reticulum (ER) stress signaling have emerged as major players in oncogenesis and cancer development. Although several lines of evidence have established functional links between these two molecular pathways, their interconnection and the subsequent functional implications in cancer development remain to be fully characterized. Herein, we provide an extensive review of the literature depicting the molecular connectivity linking ER stress signaling and the circadian clock and elaborate on the potential use of these functional interactions in cancer therapeutics.

Copyright @ 2014 Martin et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Background: Epidemiological data show that the incidence of carcinomas in humans is highly dependent on age. However, the initial steps of the age-related molecular oncogenic processes by which the switch towards the neoplastic state occurs remain poorly understood, mostly due to the absence of powerful models. In a previous study, we showed that normal human epidermal keratinocytes (NHEKs) spontaneously and systematically escape from senescence to give rise to pre-neoplastic emerging cells.Methods: Here, this model was used to analyze the gene expression profile associated with the early steps of age-related cell transformation. We compared the gene expression profiles of growing or senescent NHEKs to post-senescent emerging cells. Data analyses were performed by using the linear modeling features of the limma package, resulting in a two-sided t test or F-test based on moderated statistics. The p-values were adjusted for multiple testing by controlling the false discovery rate according to Benjamini Hochberg method.The common gene set resulting of differential gene expression profiles from these two comparisons revealed a post-senescence neoplastic emergence (PSNE) gene signature of 286 genes.Results: About half of these genes were already reported as involved in cancer or premalignant skin diseases. However, bioinformatics analyses did not highlight inside this signature canonical cancer pathways but metabolic pathways, including in first line the metabolism of xenobiotics by cytochrome P450. In order to validate the relevance of this signature as a signature of pretransformation by senescence evasion, we invalidated two components of the metabolism of xenobiotics by cytochrome P450, AKR1C2 and AKR1C3. When performed at the beginning of the senescence plateau, this invalidation did not alter the senescent state itself but significantly decreased the frequency of PSNE. Conversely, overexpression of AKR1C2 but not AKR1C3 increased the frequency of PSNE.Conclusions: To our knowledge, this study is the first to identify reprogrammation of metabolic pathways in normal keratinocytes as a potential determinant of the switch from senescence to pre-transformation. © 2014 Martin et al.; licensee BioMed Central Ltd. This work was supported by grants from the Association pour la Recherche sur le Cancer (ARC), the Ligue contre le Cancer, the European Regional Development Fund, the PPF Bioinfo of University Lille 1, the Europe RISC-RAD project and the Centre National de la Recherche Scientifique (CNRS).

Since the initial concept of p53 as a sensor of DNA-damage, the picture of the role of p53 has widened to include the sensing of much more diverse forms of stress, including hypoxia and constitutive activation of growth-promoting cascades. The pathways by which these processes regulate p53 are partially overlapping, but imply different patterns of post-translational modifications. In this review, we summarize current knowledge on post-translational modifications of p53, and we discuss how hypoxia and oncogene activation stresses may induce p53 independently of DNA damage.

An experimental study of the 241Am incineration in a high-intensity thermal neutron flux was carried out at the high-flux reactor of the Institut Laue-Langevin in Grenoble. The combination of nuclear γ -ray spectroscopy and off-line mass spectrometry methods made possible the measurement of several parameters of the transmutation chain and the first experimental determination of the unknown 242gsAm thermal neutron capture cross section, which plays an essential role in the 241Am incineration process. During a 19 days irradiation in a thermal neutron flux of 5.6×10 14 n /( s cm 2 ) , (46±5) % of the initial 241Am was transmuted by neutron capture of which (22±8) % was incinerated by nuclear fission. A value of the thermal neutron cross section of 242gsAm( n ,γ ) of (330±50) barns was obtained. We show that this keeps the option open to incinerate 241Am by high-intensity moderated neutron fluxes.

We previously reported that nitric oxide (NO) released from S-nitrosoglutathione induces conformational change of the p53 tumor-suppressor protein that impairs its DNA-binding activity in vitro. We now demonstrate that MCF-7 cells preincubated in the presence of 0.5-1 mM S-nitrosoglutathione for 4 h before gamma-irradiation failed to arrest in the G1 phase of the cell cycle, whereas those gamma-irradiated without S-nitrosoglutathione exhibited a normal cell cycle arrest. The S-nitrosoglutathione-treated cells did not express the p53 target gene p21(waf-1) after gamma-irradiation, although p21(waf-1) was strongly expressed in cells irradiated in the absence of S-nitrosoglutathione. These results strongly suggest that NO impairs the function of p53 possibly via conformational change and/or amino acid modifications. On the other hand, cells incubated for 16 h in the presence of 1 mM S-nitrosoglutathione underwent apoptosis with accumulation of the pro-apoptotic protein Bax. This Bax accumulation, however, was shown to occur via a p53-independent pathway.

The Dunkirk RH-OB was one of the first in Europe and started in 1984. Since the beginning, its production has increased steadily and the proportion of decarburization treatments has become predominant. This performance has been made possible thanks to investments like an increased capacity of the vacuum pump and an enlargment of the diameter of the snorkel and to improvements in the process. The carbon level and the treatment time have been reduced continuously.

The phosphoaminothiol WR1065, the active metabolite of the pro-drug amifostine (WR2721), protects cultured cells and tissues against cytotoxic exposure to radiation or chemotherapeutic agents. We show here that WR1065 and the pro-drug WR2721 activate the p53 tumor suppressor protein and induce the expression of the cyclin-dependent kinase inhibitor p21waf-1 in the breast cancer cell line MCF-7, and in the mouse fibroblast cell line balb/c 3T3. Using two MCF-7 derived cell lines, MN1 and MDD2, we show that induction of p21waf-1 is detectable in MN1 (expressing a functional p53) but not in MDD2 (p53 disabled). These effects are observed at concentrations of WR1065 (0.5 to 1 mM) identical to those required to protect against cytotoxicity by hydrogen peroxide. Induction of p53 is not prevented by addition of aminoguanidine, an inhibitor of Cu-dependent amine-oxidases which blocks the extra-cellular degradation of WR1065 into toxic metabolites. Moreover, spermidine, a natural polyamine structurally related to amifostine, does not activate p53. Induction of p53 by WR1065 results in a delay in the G1/S transition in MCF-7 and MN-1 cells, but not in the p53 disabled cells MDD2. These data indicate that WR1065, a polyamine analog with thiol anti-oxidant properties, activates a cell cycle check-point involving p53.

In the context of a two-flavour approximation we reinterpret the published NOMAD limit on ν μ → ν τ oscillations in terms of ν e → ν τ oscillations. At 90% C.L. we obtain sin 2 2θ eτ 5.2×10 −2 for large Δm 2 , while for sin 2 2 θ eτ =1 the confidence region includes Δm 2 2 / c 4 .

Une campagne d’essais effectuee au reacteur RH-OB de Sollac Dunkerque a permis, grâce a l’analyse des gaz extraits, de mesurer la cinetique de decarburation de l’acier dans le domaine des ultra-basses teneurs en carbone (< 10 ppm C). Une modelisation dynamique de la cinetique de decarburation, basee sur une description physique des differents sites reactionnels, explique ces resultats avec une bonne precision. Cette modelisation permet de prevoir l’influence de variations des conditions de process et de decrire le comportement d’autres installations.

With additional data and improved algorithms, we have enhanced the sensitivity of our appearance search for $\numunutau$ oscillations in the NOMAD detector in the CERN-SPS wide-band neutrino beam. The search uses kinematic criteria to identify $\nutau$ charged current interactions followed by decay of the $\tau^-$ to one of several decay modes. Our ``blind'' analyses of deep-inelastic scattering data taken in 1996 and 1997, combined with consistent reanalyses of previously reported 1995 data, yield no oscillation signal. For the two-family oscillation scenario, we present the contour outlining a 90\% C.L. confidence region in the $\sin^22\theta_{\mu \tau} - \Delta m^2$ plane. At large $\Delta m^2$, the confidence region includes $\sin^22\theta_{\mu\tau}\ \ 1.2\times10^{-3}$ (a limit 3.5 times more stringent than in our previous publication), while at $\sin^22\theta_{\mu \tau}=1$, the confidence region includes $\Delta m^2 1.2$ eV$^2$/$c^4$.

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This work aimed at displaying and studying morphological and sedimentological features of Corsican seafloor from the coast to depths of -100m. It also aimed at a better knowledge of sediment dynamics under hydrodynamic conditions, and at a reconstitution of the late Quaternary shorelines evolution. Careful analysis of the bathymetry has revealed a very contrasted morphology between the different areas of Corsican shelves, as it has been displayed on an synthetic geomorphological map. In addition, an homogeneous and overall map of surficial sediments of the Corsican shelves seabed was established and two areas, the Balagne and Agriates' platforms to the North of Corsica, and the Bonifacio Straits to the South, were mapped into details. The various sedimentary facies that have been identified are characteristics of the NW Mediterranean shelves. The very thin cover of Holocene sediments and the high content of the organogenic fraction demonstrate low continental terrigenous supply. Moreover, this study shows that the sediment bedform types and distributions are closely linked to strong bottom currents in the Bonifacio Straits and to storms influence offshore Northern Corsica (Balagne).New data on the evolution of the shoreline during late Quaternary are brought: major stillstands evidences of the Flandrian transgression that form a worldwide sequence, have been observed on the Corsican insular platform and an older submerged shoreline at -75m has been dated to 28,400 ± 300 years BP on the outer shelf of Agriates (N Corsica)., Cette étude avait pour objectifs de reconnaître et d'étudier les grands traits morphologiques et sédimentologiques des fonds marins entre 0 et -100m de profondeur autour de la Corse, d'évaluer la dynamique sédimentaire en relation avec les conditions hydrodynamiques et de reconstituer l'évolution du littoral au cours du Quaternaire récent.L'analyse de la bathymétrie a permis de découvrir une morphologie très contrastée d'un secteur à l'autre et d'aboutir à une carte géomorphologique de synthèse couvrant l'ensemble des plates-formes de la Corse.Une cartographie générale homogène des sédiments superficiels des fonds marins insulaires a été dressée et une cartographie détaillée des plates-formes de la Balagne aux Agriates, et de celle des Bouches de Bonifacio, a été établie. Les différents faciès sédimentaires reconnus sont caractéristiques des sédimentations récentes des plates-formes de la Méditerranée nord-occidentale. La couverture de sédiments meubles est en général mince, et la teneur très élevée de la fraction organogène de ces sédiments traduit la faiblesse des apports terrigènes venant du continent. Cette étude montre en outre que la répartition des figures sédimentaires est intimement liée à la présence de forts courants de fond (Bouches de Bonifacio) et à l'influence prépondérante des tempêtes (Balagne).Enfin, des informations nouvelles sur l'évolution du littoral de la Corse à la fin du Quaternaire ont été apportées. Les principaux paliers de la transgression flandrienne formant une séquence au niveau mondial ont été identifiés dans les fonds marins insulaires et un paléo-rivage plus ancien, à -75m, a été daté à 28 400 ± 300 ans BP au Nord des Agriates.