ETUDE DES SÉDIMENTS COTIERS DU CAP CORSE: RECONSTRUCTION PALÉOENVIRONNEMENTALE ET SUIVI DE LA CONTAMINATION EN ÉLÉMENTS TRACES MÉTALLIQUES AU COURS DE LA PÉRIODE HISTORIQUE

Les sédiments sont d’excellentes archives de la contamination de notre environnement. Depuis l’Antiquité, les activités humaines génèrent des aérosols anthropiques enrichis en métaux lourds (e.g. Pb, Zn, Cu, Cd, Hg) ou associés (As, Sb). Ces polluants métalliques se mélangent aux aérosols naturels (altération des roches) et leurs retombées sont incorporées dans les sols et les sédiments où ils sont préservés (Boyd, 2004). Sur des sédiments datés, une approche géochimique permet de quantifier l’apport anthropique en éléments métalliques par rapport aux sources naturelles et de reconstituer l’historique de la pollution. Les côtes méditerranéennes sont caractérisées par d’intenses échanges commerciaux, et ce depuis l’Antiquité. Nous proposons une reconstruction paléoenvironnementale ainsi qu’un suivi de la contamination anthropique au cours de la période historique pour différents sites du Cap Corse (France ; Figure 1). Cette région de Méditerranée se caractérise par une riche activité économique au cours de la période historique. Depuis le VIème siècle, la Corse a été colonisée successivement par les Grecs, les Carthaginois, les Etrusques puis par les Romains. En milieu continental, des témoins archéologiques (sépulture, oppidum, chapelle) attestent d’une occupation de cette zone sur une période assez longue. Cependant de nombreuses interrogations subsistent quant à l’importance des établissements, leurs périodes d’occupation, leurs activités économiques et leurs rapports commerciaux avec les autres cités du Cap Corse et des côtes méditerranéennes (de La Brière, 2010). Des carottes de 1 m à 1,5 m ont été prélevées à la tarière dans différents sites du Cap Corse. Les concentrations en éléments majeurs et en éléments traces métalliques ont été mesurées par spectrométrie de masse (ICP-MS), activation neutronique (INAA) et par XRF core scanner. Les datations 14C réalisées sur des macrorestes de matières végétales et charbons montrent que ces carottes couvrent toute la période historique, à l’exception de celle prélevée à Méria qui ne couvre qu’environ 300 ans. Cette carotte a également la particularité de contenir d’importantes concentrations en métaux lourds tels que le Sb (2000 ppm) et l’As (300 ppm). Cette contamination est d’origine locale et liée à la présence d’une ancienne mine d’antimoine à 2 km en amont de Méria. Afin d’obtenir un enregistrement sur les 2000 dernières années, un carottage plus long sera réalisé lors d’une nouvelle campagne de terrain. D’autres carottages seront également réalisés entre la mine et la côte actuelle afin d’observer la variation spatiale dans le but de quantifier l’impact environnemental des activités humaines locales et régionales

Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE).

PURPOSE: Gene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. EXPERIMENTAL DESIGN: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. RESULTS: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. CONCLUSIONS: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications.See related commentary by McMullen et al., p. 5271.Core funding for this project was provided by the National Institutes of Health (R01-CA172404, PI: S.J. Ramus; and R01-CA168758, PIs: J.A. Doherty and M.A.Rossing), the Canadian Institutes for Health Research (Proof-of-Principle I program, PIs: D.G.Huntsman and M.S. Anglesio), the United States Department of Defense Ovarian Cancer Research Program (OC110433, PI: D.D. Bowtell). A. Talhouk is funded through a Michael Smith Foundation for Health Research Scholar Award. M.S. Anglesio is funded through a Michael Smith Foundation for Health Research Scholar Award and the Janet D. Cottrelle Foundation Scholars program managed by the BC Cancer Foundation. J. George was partially supported by the NIH/National Cancer Institute award number P30CA034196. C. Wang was a Career Enhancement Awardee of the Mayo Clinic SPORE in Ovarian Cancer (P50 CA136393). D.G. Huntsman receives support from the Dr. Chew Wei Memorial Professorship in Gynecologic Oncology, and the Canada Research Chairs program (Research Chair in Molecular and Genomic Pathology). M. Widschwendter receives funding from the European Union’s Horizon 2020 European Research Council Programme, H2020 BRCA-ERC under Grant Agreement No. 742432 as well as the charity, The Eve Appeal (https://eveappeal.org.uk/), and support of the National Institute for Health Research (NIHR) and the University College London Hospitals (UCLH) Biomedical Research Centre. G.E. Konecny is supported by the Miriam and Sheldon Adelson Medical Research Foundation. B.Y. Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. H.R. Harris is 20 supported by the NIH/National Cancer Institute award number K22 CA193860. OVCARE (including the VAN study) receives support through the BC Cancer Foundation and The VGH+UBC Hospital Foundation (authors AT, BG, DGH, and MSA). The AOV study is supported by the Canadian Institutes of Health Research (MOP86727). The Gynaecological Oncology Biobank at Westmead, a member of the Australasian Biospecimen Network-Oncology group, was funded by the National Health and Medical Research Council Enabling Grants ID 310670 & ID 628903 and the Cancer Institute NSW Grants ID 12/RIG/1-17 & 15/RIG/1-16. The Australian Ovarian Cancer Study Group was supported by the U.S. Army Medical Research and Materiel Command under DAMD17-01-1-0729, The Cancer Council Victoria, Queensland Cancer Fund, The Cancer Council New South Wales, The Cancer Council South Australia, The Cancer Council Tasmania and The Cancer Foundation of Western Australia (Multi-State Applications 191, 211 and 182) and the National Health and Medical Research Council of Australia (NHMRC; ID199600; ID400413 and ID400281). BriTROC-1 was funded by Ovarian Cancer Action (to IAM and JDB, grant number 006) and supported by Cancer Research UK (grant numbers A15973, A15601, A18072, A17197, A19274 and A19694) and the National Institute for Health Research Cambridge and Imperial Biomedical Research Centres. Samples from the Mayo Clinic were collected and provided with support of P50 CA136393 (E.L.G., G.L.K, S.H.K, M.E.S.)

Natalizumab treatment shows low cumulative probabilities of confirmed disability worsening to EDSS milestones in the long-term setting.

Abstract Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance

EU/US/CTAD Task Force: Lessons Learned from Recent and Current Alzheimer's Prevention Trials

At a meeting of the EU/US/Clinical Trials in Alzheimer’s Disease (CTAD) Task Force in December 2016, an international group of investigators from industry, academia, and regulatory agencies reviewed lessons learned from ongoing and planned prevention trials, which will help guide future clinical trials of AD treatments, particularly in the pre-clinical space. The Task Force discussed challenges that need to be addressed across all aspects of clinical trials, calling for innovation in recruitment and retention, infrastructure development, and the selection of outcome measures. While cognitive change provides a marker of disease progression across the disease continuum, there remains a need to identify the optimal assessment tools that provide clinically meaningful endpoints. Patient- and informant-reported assessments of cognition and function may be useful but present additional challenges. Imaging and other biomarkers are also essential to maximize the efficiency of and the information learned from clinical trials

Etude pharmacologique d'une rutacee de la pharmacopee traditionnelle africaine, Xanthoxylum xanthoxyloides

SIGLEINIST T 73190 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Présentation du logiciel SnB ( Shake and Bake )Exemples d'applications

On présentera le principe de fonctionnement du programme de résolution de structures cristallographiques par méthode directe SnB (Shake and Bake) développé par une équipe de l'Université de Buffalo.Des exemples d'application aux petites protéines seront donnés, ainsi qu'à deux structures d'antibiotiques résolues au LMCP grâce à SnB.A cette occasion on passera rapidement en revue les caractéristiques de ces Pristinamycines

Contribution des méthodes isotopiques pour l'étude de l'alimentation humaine au Néolithique moyen méridional: le cas du site Chasséen ancien du Crès (Béziers, Hérault, France)

For several decades, the number of scientific techniques available in archaeology and anthropology has been expanding. In the second half of the 20th century, the development of physical and chemical methods has provided new possibilities in archaeology. It is within this context that we have approached one aspect of study: the use of . � 15N and . � 13C in bone collagen and its application to our understanding of the diets of Neolithic populations in the south of France. Stable isotope research makes it possible to understand the environment from which individuals draw their resources, and also their places in the trophic web. The principal objectives of this research are, on the one hand, to understand the food choices of the first Neolithic populations, and on the other hand, to see the possible sociocultural and economic distinctions at the time of the expansion of agriculture and the diversification of funerary practices, in particular by the study of the southern Chasseen site of Le Cres (Beziers, Herault, France). The first results allow us to propose a mixed diet (vegetal and animal) for the whole of this population. However, it exits a difference of protein consumption, in particular animals, between individuals, which would seem to be in favour of men.Depuis plusieurs dizaines d'années, les méthodes en archéologie et en anthropologie se diversifient. Dans la deuxième moitié du XXe siècle, le développement des méthodes physico-chimiques donnent de nouvelles perspectives à l'archéologie. Nous abordons dans ce travail un des aspects de ces champs d'étude: l'utilisation des ¿ ä15N et ¿ ä13C dans le collagène osseux et l'application à la connaissance des régimes alimentaires de populations néolithiques du sud de la France. Par ceci, nous proposons de montrer quelles méthodes d'étude et d'analyse nous employons, mais également les biais et leurs conséquences sur les interprétations. Cette méthode permet principalement de connaître l'environnement dans lequel les individus ont puisé leurs ressources et leurs places relatives dans le réseau trophique. Les objectifs principaux de recherche sont d'une part appréhender les choix alimentaires des premières populations néolithisées, d'autre part de voir les possibles distinctions socio-culturelles et économiques lors de l'expansion de l'agriculture et de la diversification des modes d'inhumation, notamment par l'étude du site Chasséen méridional du Crès (Béziers, Hérault, France). Les premiers résultats obtenus nous montrent que l'ensemble de la population du Crès a très probablement une alimentation mixte (végétale et animale). Cependant, il existe des différences plus ou moins importante de consommation de protéines, notamment animales, entre les individus, qui semble être en faveur des individus de sexe masculin

Tracing the source of Upper Palaeolithic shell beads by strontium isotope dating

International audienceWhile the identification of the source of shells used as personal ornaments is crucial for determining home range and exchange networks of prehistoric hunter-gatherers, it is often difficult to identify the coastal versus fossil origin of the shells as most genera used as beads were available both at beaches and fossil outcrops. Here we present the first application of 87Sr/86Sr isotope dating to identify the origin of Upper Palaeolithic shell beads. We analysed four out of a collection of one thousand Dentalium shells associated to the La Madeleine child burial dated to 10; 190G100 BP and one Dentalium from the occupation layers of this site. 87Sr/86Sr ratios indicate that shells were collected by Late Upper Palaeolithic beadworkers on far away beaches rather than at nearer Miocene outcrops. This may be due to the narrowness of Miocene Dentalium shells, incompatible with the size of bone needles used to sew these shell beads on clothes

Biogeochemical investigations on sediment core MD04-2876

Modern seawater profiles of oxygen, nitrate deficit, and nitrogen isotopes reveal the spatial decoupling of summer monsoon-related productivity and denitrification maxima in the Arabian Sea (AS) and raise the possibility that winter monsoon and/or ventilation play a crucial role in modulating denitrification in the northeastern AS, both today and through the past. A new high-resolution 50-ka record of d15N from the Pakistan margin is compared to five other denitrification records distributed across the AS. This regional comparison unveils the persistence of east-west heterogeneities in denitrification intensity across millennial-scale climate shifts and throughout the Holocene. The oxygen minimum zone (OMZ) experienced east-west swings across Termination I and throughout the Holocene. Probable causes are (1) changes in ventilation due to millennial-scale variations in Antarctic Intermediate Water formation and (2) postglacial reorganization of intermediate circulation in the northeastern AS following sea level rise. Whereas denitrification in the world's OMZs, including the western AS, gradually declined following the deglacial maximum (10-9 ka BP), the northeastern AS record clearly witnesses increasing denitrification from about 8 ka BP. This would have impacted the global Holocene climate through sustained N2O production and marine nitrogen loss