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Stéphane Baciocchi et Pascal Cristofoli, ingénieurs d’étudesArnaud Bringé et Bénédicte Garnier, ingénieurs à l’INED Atelier « Analyse des données relationnelles » Pour cette année, les deux composantes de l’atelier (« Introduction à l’analyse des données relationnelles » et « Études de cas ») ont été regroupées de sorte à présenter de manière intégrée et continue l’ensemble des opérations qui règlent la conduite des enquêtes sur les sources et données relationnelles. Nous avons rassemblé, au ..

Targeting the Lactate Transporter MCT1 in Endothelial Cells Inhibits Lactate-Induced HIF-1 Activation and Tumor Angiogenesis

Switching to a glycolytic metabolism is a rapid adaptation of tumor cells to hypoxia. Although this metabolic conversion may primarily represent a rescue pathway to meet the bioenergetic and biosynthetic demands of proliferating tumor cells, it also creates a gradient of lactate that mirrors the gradient of oxygen in tumors. More than a metabolic waste, the lactate anion is known to participate to cancer aggressiveness, in part through activation of the hypoxia-inducible factor-1 (HIF-1) pathway in tumor cells. Whether lactate may also directly favor HIF-1 activation in endothelial cells (ECs) thereby offering a new druggable option to block angiogenesis is however an unanswered question. In this study, we therefore focused on the role in ECs of monocarboxylate transporter 1 (MCT1) that we previously identified to be the main facilitator of lactate uptake in cancer cells. We found that blockade of lactate influx into ECs led to inhibition of HIF-1-dependent angiogenesis. Our demonstration is based on the unprecedented characterization of lactate-induced HIF-1 activation in normoxic ECs and the consecutive increase in vascular endothelial growth factor receptor 2 (VEGFR2) and basic fibroblast growth factor (bFGF) expression. Furthermore, using a variety of functional assays including endothelial cell migration and tubulogenesis together with in vivo imaging of tumor angiogenesis through intravital microscopy and immunohistochemistry, we documented that MCT1 blockers could act as bona fide HIF-1 inhibitors leading to anti-angiogenic effects. Together with the previous demonstration of MCT1 being a key regulator of lactate exchange between tumor cells, the current study identifies MCT1 inhibition as a therapeutic modality combining antimetabolic and anti-angiogenic activities

Role of the BRO + HO 2 reaction in the stratospheric chemistry of bromine

International audienceThe impact of new laboratory data for the reaction BrO + HO2-> HOBr + 02 has been estimated in a one-dimensional photochemical modelling of bromine/ozone stratospheric chemistry. The reported 6 fold increase in the measured value for the rate constant of this reaction significantly increases both the HOBr mixing ratio and the global ozone depletion due to bromine compounds (the calculated ozone loss increases from 1.14% to 1.45% for a 20 ppt total bromine content). The higher rate constant makes the bromine partitioning and the ozone depletion very sensitive to the branching ratio of the potential channel forming HBr in the BrO + HO 2 reaction. The influence of the existing uncertainty in the photolysis rate of HOBr is also analysed

Impact of neonatal digestion on the physiology of breast milk bacteria and their immunomodulation capacities

International audienceExclusive breastfeeding in the first months of life has protective effects on infant health compared to formula-fed infants including a lower risk of gastrointestinal and respiratory infections and of metabolic and immune disorders. These observable differences in 'health effect' are likely due to differences in composition between breast milk and infant formula. In particular, breast milk contains a wide variety of bacterial species that are present at low dose. This microbial counterpart contributes to the development of the newborn's gut microbiota after digestion of milk matrix. It was also suggested to influence more largely intestinal homeostasis, acting on the gut immunity and intestinal barrier, and thus to contribute to breastmilk health promoting effects [1]. Several studies have investigated the impact of commensal bacteria on gut homeostasis. However, they generally do not include the different phases of digestion, like gastric (G) or intestinal (I) phases, which could have an impact on the physiological state and properties of the bacteria. The aim of this study was to evaluate the impact of newborn digestion on the physiology of breastmilk bacteria and on their mmunomodulatory potential. For this study, six strains representative of the prevalent bacteria in breast milk were selected. The strains were digested in a static in vitro model of digestion, at full-term infant stage, in a milk matrix. Following the G and I phases, bacterial cultivability was measured and the immunomodulation properties were determined through the quantification of IL-10 and TNF-α released by macrophages (THP-1 line: human monocytic cell line differentiated into macrophages). The impact of the G and I digestion phases on both viability and immunomodulation properties was strain-dependent, pointing out the interest to consider these steps for the determination of ingested bacteria properties.This study is part of the PROLIFIC project and was financially supported by the Régions Bretagne and Pays de Loire and the Milkvalley-BBA consortium

Prognostic impact of phenotype heterogeneity of grade 1-2 metastatic gastroenteropancreatic neuroendocrine tumors documented by 18FDG PET-CT and 68Ga-DOTANOC PET-CT

International audienc

Directional guidance of oligodendroglial migration by class 3 semaphorins and netrin-1

Oligodendrocytes, the myelin-forming cells of the CNS, are generated from multiple foci distributed along the developing neural tube. Little is known about the endogenous guidance cues controlling the migration of oligodendrocyte precursor cells (OPCs) from their site of emergence toward their final destination, mainly the future white matter tracts. During embryonic development, the optic nerve is populated by OPCs originating in the diencephalon that migrate from the chiasm toward the retina. Here we show that OPCs migrating into the embryonic optic nerve express the semaphorin receptors neuropilin-1 and-2, as well as deleted in colorectal cancer (DCC) and, to a lesser extend unc5H1, two of the netrin-1 receptors. Using a functional migration assay, we provide evidence that Sema 3A and netrin-1 exert opposite chemotactic effects, repulsive or attractive, respectively, on embryoni

Immunohematologic tolerance of chronic transfusion exchanges with erythrocytapheresis in sickle cell disease

International audienceBACKGROUND:Sickle cell disease (SCD) has become a major public health issue. Hydroxyurea and red blood cell (RBC) transfusion are the cornerstone treatments. Erythrocytapheresis (ECP) is an automated method for transfusion exchange. Given that ECP requires more blood than conventional transfusion, there is concern about alloimmunization and hemolytic transfusion reactions. We evaluate the incidence of hemolytic transfusion reactions and alloimmunization rates in patients receiving conventional blood transfusions and in patients participating in long-term blood exchange programs with ECP.STUDY DESIGN AND METHODS:All hemolytic transfusion reactions and alloimmunizations in SCD patients were recorded over the period 2006 to 2011. Conventional transfusions and ECP were compared.RESULTS:The cohort consisted of 188 SCD patients. The median (±SD) age was 23 (±14) years. The ECP and conventional transfusion groups comprised 49 and 139 patients, respectively. The prevalence of alloimmunization was 33% in the ECP group and 22% in the conventional transfusion group (p = 0.1797). The alloimmunization/RBC unit (RBCU) ratio was lower in the ECP group than in the conventional transfusion group (1.6 and 11.6 per 1000, respectively; p < 0.0001). Although patients in the ECP group received more than 10 times more RBCUs than patients in the conventional transfusion group (206 vs. 19 RBCUs per patient, respectively; p < 0.0001), none of the four recorded hemolytic transfusion reactions (n = 4) occurred.CONCLUSION:Regarding alloimmunization, ECP exhibits a good immunohematologic safety profile relative to conventional transfusion in a large SCD mainly adult cohort

Head-to-Head Comparison of 18F-DOPA PET/CT and 68Ga-DOTANOC PET/CT in Patients With Midgut Neuroendocrine Tumors

International audiencePurpose: The aim of this study was to compare retrospectively F-DOPA PET/CT versus Ga-DOTANOC PET/CT in a group of patients affected by midgut NET.Patients and methods: Patients with histologically proven grade 1 or grade 2 midgut NET were explored after injection of 150 MBq of Ga-DOTANOC and 210 MBq of F-DOPA. The PET/CTs were analyzed visually and semiquantitatively at the patient level, regional level (7 defined regions), and lesion level (maximum of 5 lesions/organ). The criterion standard was determined on the basis of histology and imaging follow-up.Results: Thirty patients (17 males and 13 females; median age, 63.5 years [37-82 years]) were included. Both PET/CTs were negative in 3 patients and positive in 25 patients. PET/CTs were discordant in 2 patients, with F-DOPA positive and Ga-DOTANOC negative. F-DOPA PET/CT detected more involved regions and more metastatic lesions than Ga-DOTANOC PET/CT in 6 (20%) and 10 (33.3%) patients, respectively. Of the 81 confirmed affected regions, 77 (95%) were detected by F-DOPA PET/CT and 71 (87.7%) by Ga-DOTANOC PET/CT (P < 0.0001). F-DOPA PET/CT detected significantly more lesions (211/221) than Ga-DOTANOC PET/CT (195/221), corresponding to a sensitivity of 95.5% and 88.2%, respectively (P < 0.0001). Tumor-to-background ratios were more favorable in liver for F-DOPA than for Ga-DOTANOC. Interestingly, a correlation was found between F-DOPA SUVmax and tumor burden and especially with the number of regions involved by the disease (P = 0.019).Conclusions: F-DOPA PET/CT is superior to Ga-DOTANOC PET/CT for the detection of lesions, and when available, this tracer may be recommended as the first-line examination for an accurate staging of midgut NET