Effets de couches nourricières murines et humaines sur la préservation des capacités prolifératrices des cellules épithéliales humaines cultivées in vitro

Les feuillets de cellules épidermiques cultivés en laboratoire sont des substituts cutanés pour le traitement des grands brûlés. Notre équipe a démontré que la couche nourricière de fibrobiastes (CNF) murine accroît la survie des kératinocytes (cellules épidermiques) humains en y maintenant l'expression du facteur de transcription Spl. Notre hypothèse est que l'utilisation d'une CNF irradiée accroit la survie des cellules souches épithéliales cutanées en culture, ce qui permet d'augmenter le potentiel de prolifération et de retarder la différenciation des kératinocytes en culture. Le but de ce projet est d'analyser l'effet des CNF d'origine humaine sur la prolifération et la différenciation des kératinocytes et de comprendre les mécanismes par lesquels Spl influence la survie de ces cellules, notamment en évaluant la régulation de la transcriptase inverse de la télomérase (hTERT). Des kératinocytes ont été cultivés sur une CNF humaine ou murine irradiées ainsi que sans CNF pendant une vingtaine de passages ou jusqu'à différenciation terminale. Des extraits de protéines, d'ARN et de cellules ont été prélevés à chaque passage. Le niveau d'expression de la protéine Spl ainsi que l'activité de la télomérase ont été analysés en fonction des passages. Les résultats obtenus montrent que la CNF humaine possède des caractéristiques similaires à la CNF murine tel que vérifié par le nombre de passages atteints avant différenciation ainsi que par l'expression du facteur de transcription Spl. De plus, il existe une forte corrélation entre l'expression de Spl et le taux de croissance des cellules, ce qui suggère un mécanisme par lequel Spl aiderait la prolifération des kératinocytes. Sans couche nourricière, l'activité de la télomérase et l'expression de Spl sont nettement diminuées. Par contre, les CNF humaines permettent une bonne prolifération des kératinocytes ainsi que le maintien de l'expression de Spl et de l'activité de la télomérase. En conclusion, nos résultats suggèrent que la survie des cellules épithéliales souches en culture passe par des mécanismes moléculaires impliquant Spl et le maintien de l'activité de la télomérase

La reconnaissance de plan des adversaires

Ce mémoire propose une approche pour la reconnaissance de plan qui a été conçue pour les environnements avec des adversaires, c'est-à-dire des agents qui veulent empêcher que leurs plans soient reconnus. Bien qu'il existe d'autres algorithmes de reconnaissance de plan dans la littérature, peu sont adaptés pour de tels environnements. L'algorithme que nous avons conçu et implémenté (PROBE, Provocation for the Recognition of Opponent BEhaviours ) est aussi capable de choisir comment provoquer l'adversaire, en espérant que la réaction de ce dernier à la provocation permette de donner des indices quant à sa véritable intention. De plus, PROBE utilise des machines à états finis comme représentation des plans, un formalisme différent de celui utilisé par les autres approches et qui est selon nous mieux adapté pour nos domaines d'intérêt. Les résultats obtenus suite à différentes expérimentations indiquent que notre algorithme réussit généralement à obtenir une bonne estimation des intentions de l'adversaire dès le départ et que cette estimation s'améliore lorsque de nouvelles actions sont observées. Une comparaison avec un autre algorithme de reconnaissance de plan démontre aussi que PROBE est plus efficace en temps de calcul et en utilisation de la mémoire, sans pourtant sacrifier la qualité de la reconnaissance. Enfin, les résultats montrent que notre algorithme de provocation permet de réduire l'ambiguïté sur les intentions de l'adversaire et ainsi améliorer la justesse du processus de reconnaissance de plan en sélectionnant une provocation qui force l'adversaire, d'une certaine façon, à révéler son intention

Validation Française de l’Échelle de la Personnalité Temporelle (French Validation of the Time Personality Indicator)

RÉSUMÉ Certains auteurs ont développé un intérêt pour la compréhension des aptitudes associées à la gestion du temps. Ainsi, plusieurs définitions théoriques ont été proposées afin de mieux cerner ce concept et une multitude de questionnaires a été développée afin de le mesurer. La présente étude visait à valider la traduction française d’un de ces outils, soit le Time Personality Indicator (TPI). Des analyses exploratoires et confirmatoires ont été effectuées sur l’ensemble des données recueillies auprès de 1 267 étudiants et employés de l’Université Laval ayant complété la version française du TPI ainsi que d’autres mesures de la personnalité. Les résultats ont révélé qu’une solution à huit facteurs permet de mieux décrire les données de l’échantillon. La discussion présente les raisons pour lesquelles la version française du TPI est valide, identifie certaines limites de la présente étude et souligne l’utilité de cet outil pour la recherche sur la gestion du temps. (ABSTRACT: Numerous authors have developed an interest towards the understanding of the abilities related to time management. As a consequence, multiple theoretical definitions have been proposed to explain time management. Likewise, several questionnaires have been developed in order to measure this concept. The aim of this study was to validate a French version of one of these tools, namely the Time Personality Indicator (TPI). The French version of the TPI and other personality questionnaires were completed by 1267 students and employees of Université Laval. The statistical approach used included exploratory and confirmatory analyses. Results revealed that an eight factor model provided a better adjustment to the data. The discussion provides arguments supporting the validity of the French version of the TPI and underlines the importance of such a tool for the research on time management

WNT signalling in prostate cancer

Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours-particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT-β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRASG13D

Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRASG13D) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRASG13D (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes.This work was supported by European Union FP7 Grant No. 278568 “PRIMES” and Science Foundation Ireland Investigator Program Grant 14/IA/2395 to W.K. B.K. is supported by SmartNanoTox (Grant no. 686098), NanoCommons (Grant no. 731032), O.R. by MSCA-IF-2016 SAMNets (Grant no. 750688). D.M. is supported by Science Foundation Ireland Career Development award 15-CDA-3495. I.J. is supported by the Canada Research Chair Program (CRC #225404), Krembil Foundation, Ontario Research Fund (GL2-01-030 and #34876), Natural Sciences Research Council (NSERC #203475), Canada Foundation for Innovation (CFI #225404, #30865), and IBM. O.S. is supported by ERC investigator Award ColonCan 311301 and CRUK. I.S. is supported by the Canadian Cancer Society Research Institute (#703889), Genome Canada via Ontario Genomics (#9427 & #9428), Ontario Research fund (ORF/ DIG-501411 & RE08-009), Consortium Québécois sur la Découverte du Médicament (CQDM Quantum Leap) & Brain Canada (Quantum Leap), and CQDM Explore and OCE (#23929). T.C. was supported by a Teagasc Walsh Fellowshi

Who is accessing public-sector anti-retroviral treatment in the Free State, South Africa? An exploratory study of the first three years of programme implementation

<p>Abstract</p> <p>Background</p> <p>Although South Africa has the largest public-sector anti-retroviral treatment (ART) programme in the world, anti-retroviral coverage in adults was only 40.2% in 2008. However, longitudinal studies of who is accessing the South African public-sector ART programme are scarce. This study therefore had one main research question: who is accessing public-sector ART in the Free State Province, South Africa? The study aimed to extend the current literature by investigating, in a quantitative manner and using a longitudinal study design, the participants enrolled in the public-sector ART programme in the period 2004-2006 in the Free State Province of South Africa.</p> <p>Methods</p> <p>Differences in the demographic (age, sex, population group and marital status) socio-economic (education, income, neo-material indicators), geographic (travel costs, relocation for ART), and medical characteristics (CD4, viral load, time since first diagnosis, treatment status) among 912 patients enrolled in the Free State public-sector ART programme between 2004 and 2006 were assessed with one-way analysis of variance, Bonferroni post-hoc analysis, and cross tabulations with the chi square test.</p> <p>Results</p> <p>The patients accessing treatment tended to be female (71.1%) and unemployed (83.4%). However, although relatively poor, those most likely to access ART services were not the most impoverished patients. The proportion of female patients increased (<it>P </it>< 0.05) and their socio-economic situation improved between 2004 and 2006 (<it>P </it>< 0.05). The increasing mean transport cost (<it>P </it>< 0.05) to visit the facility is worrying, because this cost is an important barrier to ART uptake and adherence. Encouragingly, the study results revealed that the interval between the first HIV-positive diagnosis and ART initiation decreased steadily over time (<it>P </it>< 0.05). This was also reflected in the increasing baseline CD4 cell count at ART initiation (<it>P </it>< 0.05).</p> <p>Conclusions</p> <p>Our analysis showed significant changes in the demographic, socio-economic, geographic, and medical characteristics of the patients during the first three years of the programme. Knowledge of the characteristics of these patients can assist policy makers in developing measures to retain them in care. The information reported here can also be usefully applied to target patient groups that are currently not reached in the implementation of the ART programme.</p

Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability.

The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case-control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (

Metabolic reprogramming and dysregulated metabolism: cause, consequence and/or enabler of environmental carcinogenesis?

Environmental contributions to cancer development are widely accepted, but only a fraction of all pertinent exposures have probably been identified. Traditional toxicological approaches to the problem have largely focused on the effects of individual agents at singular endpoints. As such, they have incompletely addressed both the pro-carcinogenic contributions of environmentally relevant low-dose chemical mixtures and the fact that exposures can influence multiple cancer-associated endpoints over varying timescales. Of these endpoints, dysregulated metabolism is one of the most common and recognizable features of cancer, but its specific roles in exposure-associated cancer development remain poorly understood. Most studies have focused on discrete aspects of cancer metabolism and have incompletely considered both its dynamic integrated nature and the complex controlling influences of substrate availability, external trophic signals and environmental conditions. Emerging high throughput approaches to environmental risk assessment also do not directly address the metabolic causes or consequences of changes in gene expression. As such, there is a compelling need to establish common or complementary frameworks for further exploration that experimentally and conceptually consider the gestalt of cancer metabolism and its causal relationships to both carcinogenesis and the development of other cancer hallmarks. A literature review to identify environmentally relevant exposures unambiguously linked to both cancer development and dysregulated metabolism suggests major gaps in our understanding of exposure-associated carcinogenesis and metabolic reprogramming. Although limited evidence exists to support primary causal roles for metabolism in carcinogenesis, the universality of altered cancer metabolism underscores its fundamental biological importance, and multiple pleiomorphic, even dichotomous, roles for metabolism in promoting, antagonizing or otherwise enabling the development and selection of cancer are suggested

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology