Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Background & Aims: The severity of liver diseases is exacerbated by the death of hepatocytes, which can be induced by the sensing of pathogen associated molecular patterns (PAMPs) derived from the gut microbiota. The molecular mechanisms regulating these cell death pathways are poorly documented. In this study, we investigated the role of the receptor interacting protein kinase 1 (RIPK1), a protein known to regulate cell fate decisions, in the death of hepatocytes using two in vivo models of PAMP-induced hepatitis. Methods: Hepatitis was induced in mice by independent injections of two different bacterial PAMPs: lipopolysaccharide (LPS) and unmethylated CpG oligodeoxynucleotide (CpG-DNA) motifs. The role of RIPK1 was evaluated by using mice specifically lacking RIPK1 in liver parenchymal cells (Ripk1(LPC-KO)). Administration of liposome-encapsulated clodronate served to investigate the role of Kupffer cells in the establishment of the disease. Etanercept, a tumor necrosis factor (TNF)-decoy receptor, was used to study the contribution of TNF-alpha during LPS-mediated liver injury. Results: Whereas RIPK1 deficiency in liver parenchymal cells did not trigger basal hepatolysis, it greatly sensitized hepatocytes to apoptosis and liver damage following a single injection of LPS or CpG-DNA. Importantly, hepatocyte death was prevented by previous macrophage depletion or by TNF inhibition. Conclusions: Our data highlight the pivotal function of RIPK1 in maintaining liver homeostasis in conditions of macrophage-induced TNF burst in response to PAMPs sensing. Lay summary: Excessive death of hepatocytes is a characteristic of liver injury. A new programmed cell death pathway has been described involving upstream death ligands such as TNF and downstream kinases such as RIPK1. Here, we show that in the presence of LPS liver induced hepatic injury was due to secretion of TNF by liver macrophages, and that RIPK1 acts as a powerful protector of hepatocyte death. This newly identified pathway in the liver may be helpful in the management of patients to predict their risk of developing acute liver failure. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
ISSN: 0168-8278

hal-01532060
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01532060
DOI : 10.1016/j.jhep.2017.01.005
PUBMED : 28088582

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Cancer cells display alterations in many cellular processes. One core hallmark of cancer is the Warburg effect which is a glycolytic reprogramming that allows cells to survive and proliferate. Although the contributions of environmental contaminants to cancer development are widely accepted, the underlying mechanisms have to be clarified. Benzo[a]pyrene (B[a]P), the prototype of polycyclic aromatic hydrocarbons, exhibits genotoxic and carcinogenic effects, and it is a human carcinogen according to the International Agency for Research on Cancer. In addition to triggering apoptotic signals, B[a]P may induce survival signals, both of which are likely to be involved in cancer promotion. We previously suggested that B[a]P-induced mitochondrial dysfunctions, especially membrane hyperpolarization, might trigger cell survival signaling in rat hepatic epithelial F258 cells. Here, we further characterized these dysfunctions by focusing on energy metabolism. We found that B[a]P promoted a metabolic reprogramming. Cell respiration decreased and lactate production increased. These changes were associated with alterations in the tricarboxylic acid cycle which likely involve a dysfunction of the mitochondrial complex II. The glycolytic shift relied on activation of the Na+/H+ exchanger 1 (NHE1) and appeared to be a key feature in B[a]P-induced cell survival related to changes in cell phenotype (epithelial-to-mesenchymal transition and cell migration).
ISSN: 2045-2322

Droits : http://creativecommons.org/licenses/by/
hal-01359569
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359569
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359569/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359569/file/The%20environmental%20carcinogen-CCBY%20%281%29.pdf
DOI : 10.1038/srep30776

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Mapping spatial distributions of disease occurrence can serve as a useful tool for identifying exposures of public health concern. Infant mortality is an important indicator of the health status of a population. Recent literature suggests that neighborhood deprivation status can modify the effect of air pollution on preterm delivery, a known risk factor for infant mortality. We investigated the effect of neighborhood social deprivation on the association between exposure to ambient air NO2 and infant mortality in the Lille and Lyon metropolitan areas, north and center of France, respectively, between 2002 and 2009. We conducted an ecological study using a neighborhood deprivation index estimated at the French census block from the 2006 census data. Infant mortality data were collected from local councils and geocoded using the address of residence. We generated maps using generalized additive models, smoothing on longitude and latitude while adjusting for covariates. We used permutation tests to examine the overall importance of location in the model and identify areas of increased and decreased risk. The average death rate was 4.2‰ and 4.6‰ live births for the Lille and Lyon metropolitan areas during the period. We found evidence of statistically significant precise clusters of elevated infant mortality for Lille and an east-west gradient of infant mortality risk for Lyon. Exposure to NO2 did not explain the spatial relationship. The Lille MA, socioeconomic deprivation index explained the spatial variation observed. These techniques provide evidence of clusters of significantly elevated infant mortality risk in relation with the neighborhood socioeconomic status. This method could be used for public policy management to determine priority areas for interventions. Moreover, taking into account the relationship between social and environmental exposure may help identify areas with cumulative inequalities.
ISSN: 0048-9697

inserm-00838330
http://www.hal.inserm.fr/inserm-00838330
DOI : 10.1016/j.scitotenv.2013.03.027
PUBMED : 23563257

Éditeur(s) : HAL CCSD Oxford University Press (OUP)
Résumé : International audience
ISSN: 0022-1899

hal-01123839
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01123839
DOI : 10.1093/infdis/jiv129
PUBMED : 25737560

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Transmembrane CD95L (Fas ligand) can be cleaved to release a promigratory soluble ligand, cl-CD95L, which can contribute to chronic inflammation and cancer cell dissemination. The motility signaling pathway elicited by cl-CD95L remains poorly defined. Here, we show that in the presence of cl-CD95L, CD95 activates the Akt and RhoA signaling pathways, which together orchestrate an allosteric activation of the Na+/H+ exchanger NHE1. Pharmacologic inhibition of Akt or ROCK1 independently blocks the cl-CD95L-induced migration. Confirming these pharmacologic data, disruption of the Akt and ROCK1 phosphorylation sites on NHE1 decreases cell migration in cells exposed to cl-CD95L. Together, these findings demonstrate that NHE1 is a novel molecular actor in the CD95 signaling pathway that drives the cl-CD95L-induced cell migration through both the Akt and RhoA signaling pathways.
ISSN: 2045-2322

hal-01334067
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01334067
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01334067/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01334067/file/Cleaved%20FAS%20ligand%20CC-BY.pdf
DOI : 10.1038/srep28008

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) patients expressed CD95L and that after cleavage, cl-CD95L promoted T helper 17 (Th17) lymphocyte transmigration across the endothelial barrier at the expense of T regulatory cells. T cell migration relied on a direct interaction between the CD95 domain called calcium-inducing domain (CID) and the Src homology 3 domain of phospholipase C gamma 1. Th17 cells stimulated with cl-CD95L produced sphingosine-1-phosphate (S1P), which promoted endothelial transmigration by activating the S1P receptor 3. We generated a cell-penetrating CID peptide that prevented Th17 cell transmigration and alleviated clinical symptoms in lupus mice. Therefore, neutralizing the CD95 non-apoptotic signaling pathway could be an attractive therapeutic approach for SLE treatment.
ISSN: 1074-7613

hal-01359568
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359568
DOI : 10.1016/j.immuni.2016.06.028
PUBMED : 27438772

Éditeur(s) : HAL CCSD
Résumé : International audience
BACKGROUND: Africa faces a number of unique environmental challenges. Unfortunately, it lacks the infrastructure needed to support the comprehensive environmental studies that could provide the scientific basis to inform environmental policies. There are a number of known sources of endocrine-disrupting chemicals (EDCs) and other hazardous chemicals in Africa. However, a coordinated approach to identify and monitor these contaminants and to develop strategies for public health interventions has not yet been made. OBJECTIVES: This commentary summarizes the scientific evidence presented by experts at the First African Endocrine Disruptors meeting. We describe a "call to action" to utilize the available scientific knowledge to address the impact of EDCs on human and wildlife health in Africa. DISCUSSION: We identify existing knowledge gaps about exposures to EDCs in Africa and describe how well-designed research strategies are needed to address these gaps. A lack of resources for research and a lag in policy implementation slows down intervention strategies and poses a challenge to advancing future health in Africa. CONCLUSION: To address the many challenges posed by EDCs, we argue that Africans should take the lead in prioritization and evaluation of environmental hazards, including EDCs. We recommend the institution of education and training programs for chemical users, adoption of the precautionary principle, establishment of biomonitoring programs, and funding of community-based epidemiology and wildlife research programs led and funded by African institutes and private companies. https://doi.org/10.1289/EHP1774.
Environmental Health Perspectives

hal-01616487
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01616487
DOI : 10.1289/EHP1774
PUBMED : 28935616

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Low-level exposure to polychlorinated biphenyl-153 (PCB-153) and dichlorodiphenyldichloroethylene (p-p'-DDE) can impair fetal growth; however, the exposure-response relationship and effect modifiers of such association are not well established. This study is an extension of an earlier European meta-analysis. Our aim was to explore exposure-response relationship between PCB-153 and p-p'-DDE and birth outcomes; to evaluate whether any no exposure-effect level and susceptible subgroups exist; and to assess the role of maternal gestational weight gain (GWG). We used a pooled dataset of 9377 mother-child pairs enrolled in 14 study populations from 11 European birth cohorts. General additive models were used to evaluate the shape of the relationships between organochlorine compounds and birth outcomes. We observed an inverse linear exposure-response relationship between prenatal exposure to PCB-153 and birth weight [decline of 194g (95% CI -314, -74) per 1μg/L increase in PCB-153]. We showed effects on birth weight over the entire exposure range, including at low levels. This reduction seems to be stronger among children of mothers who were non-Caucasian or had smoked during pregnancy. The most susceptible subgroup was girls whose mothers smoked during pregnancy. After adjusting for absolute GWG or estimated fat mass, a reduction in birth weight was still observed. This study suggests that the association between low-level exposure to PCB-153 and birth weight exists and follows an inverse linear exposure-response relationship with effects even at low levels, and that maternal smoking and ethnicity modify this association.
ISSN: 0160-4120

hal-01118572
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01118572
PUBMED : 25314142
DOI : 10.1016/j.envint.2014.09.013

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Toxicology Letters
Stockholm, Sweden

hal-01122645
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01122645
DOI : 10.1016/j.toxlet.2012.03.439

Éditeur(s) : HAL CCSD National Institute of Environmental Health Sciences
Résumé : International audience
BACKGROUND: Women of reproductive age can be exposed to endocrine-disrupting chemicals (EDCs) at work, and exposure to EDCs in pregnancy may affect fetal growth. OBJECTIVES: We assessed whether maternal occupational exposure to EDCs during pregnancy as classified by application of a job exposure matrix was associated with birth weight, term low birth weight (LBW), length of gestation, and preterm delivery. METHODS: Using individual participant data from 133,957 mother-child pairs in 13 European cohorts spanning births from 1994 through 2011, we linked maternal job titles with exposure to 10 EDC groups as assessed through a job exposure matrix. For each group, we combined the two levels of exposure categories (possible and probable) and compared birth outcomes with the unexposed group (exposure unlikely). We performed meta-analyses of cohort-specific estimates. RESULTS: Eleven percent of pregnant women were classified as exposed to EDCs at work during pregnancy, based on job title. Classification of exposure to one or more EDC group was associated with an increased risk of term LBW [odds ratio (OR) = 1.25; 95% CI: 1.04, 1.49], as were most specific EDC groups; this association was consistent across cohorts. Further, the risk increased with increasing number of EDC groups (OR = 2.11; 95% CI: 1.10, 4.06 for exposure to four or more EDC groups). There were few associations (p < 0.05) with the other outcomes; women holding job titles classified as exposed to bisphenol A or brominated flame retardants were at higher risk for longer length of gestation. CONCLUSION: Results from our large population-based birth cohort design indicate that employment during pregnancy in occupations classified as possibly or probably exposed to EDCs was associated with an increased risk of term LBW.
ISSN: 0091-6765

hal-01405823
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01405823
DOI : 10.1289/EHP208
PUBMED : 27152464

Éditeur(s) : HAL CCSD BioMed Central
Résumé : International audience
BACKGROUND: Hepatocellular carcinoma (HCC) is a particularly severe disease characterized by a high rate of recurrence and death even after surgical resection. Molecular characterization of HCC helps refine prognosis and may facilitate the development of improved therapy. Phosphatidylinositol 4-kinases have recently been identified as cellular factors associated with cancer. Also, phosphatidylinositol 4-kinase type IIIα (PI4KA) is necessary for the propagation of the hepatitis C virus, a major etiological factor for HCC. METHODS: Reverse transcription, quantitative real-time PCR was used to assay PI4KA mRNA. The expression levels were investigated both in a collection of molecularly and clinically characterized hepatic tissues from 344 patients with diverse liver diseases and in human hepatocyte cell lines whose proliferative and differentiation status was controlled by specific culture conditions. Analytical microarray data for 60 HCC and six normal liver tissue samples were exploited to study correlations between PI4KA mRNA levels and cell proliferation markers in vivo. Postoperative disease-specific survival and time to recurrence in a set of 214 patients with HCC were studied by univariate and multivariate analyses. RESULTS: PI4KA mRNA was more abundant in HCC than normal healthy tissues. This upregulation correlated significantly with both poor differentiation and the active proliferation rate in HCC. These associations were confirmed with in vitro models. Moreover, patients with HCC who had been treated by surgical resection and had higher PI4KA mRNA concentrations in their tumor tissue exhibited a higher risk of tumor recurrence (median time: 20 months versus 49 months, P = 0.0012) and shorter disease-specific survival (first quartile time: 16 months versus 48 months, P = 0.0004). Finally, the abundance of PI4KA mRNA proved to be an independent prognostic marker of survival for cases of HCC (hazard ratio = 2.36, P = 0.0064). CONCLUSIONS: PI4KA mRNA could be used as a new molecular marker to improve established prognostic models for HCC. These findings also indicate possible new lines of research for the development of innovative therapeutic approaches targeting PI4KA.
ISSN: 1471-2407

inserm-00934294
http://www.hal.inserm.fr/inserm-00934294
http://www.hal.inserm.fr/inserm-00934294/document
http://www.hal.inserm.fr/inserm-00934294/file/1471-2407-14-7.pdf
DOI : 10.1186/1471-2407-14-7

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Sphingolipids, in particular ceramide, have been described as important components of cellular signalling pathways. Ceramide can be produced via multiple mechanisms including through the hydrolysis of sphingomyelin by acid and neutral sphingomyelinase or by a de novo synthesis pathway. Recent studies have identified sphingomyelinases and ceramide synthases as important targets for γ-irradiation and chemotherapeutic drugs. Likewise, common cancer treatment modalities, such as γ-irradiation and many chemotherapeutic agents, induce cell death via the generation of ceramide. This suggests that the manipulation of ceramide production and metabolism could offer promising a means for the enhancement of anti-tumor therapies. The focus of this mini-review will be to discuss contemporary evidence suggesting that ceramide forming pathways and ceramide itself are important targets for the treatment of tumors and the development of novel tumor treatment strategies.
ISSN: 0304-3835

hal-00682458
https://hal.archives-ouvertes.fr/hal-00682458
DOI : 10.1016/j.canlet.2011.07.010
PUBMED : 21862212

Éditeur(s) : HAL CCSD Cold Spring Harbor Laboratory Press
Résumé : “Human and Environmental Genomics” platform (Rennes) for Illumina sequencing / Proteomics Core Facility of the Cambridge Institute (Cancer Research UK)
International audience
Epigenetic mechanisms are believed to play key roles in the establishment of cell-specific transcription programs. Accordingly, the modified bases 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) have been observed in DNA of genomic regulatory regions such as enhancers, and oxidation of 5mC into 5hmC by Ten-eleven translocation (TET) proteins correlates with enhancer activation. However, the functional relationship between cytosine modifications and the chromatin architecture of enhancers remains elusive. To gain insights into their function, 5mC and 5hmC levels were perturbed by inhibiting DNA methyltransferases and TETs during differentiation of mouse embryonal carcinoma cells into neural progenitors, and chromatin characteristics of enhancers bound by the pioneer transcription factors FOXA1, MEIS1, and PBX1 were interrogated. In a large fraction of the tested enhancers, inhibition of DNA methylation was associated with a significant increase in monomethylation of H3K4, a characteristic mark of enhancer priming. In addition, at some specific enhancers, 5mC oxidation by TETs facilitated chromatin opening, a process that may stabilize MEIS1 binding to these genomic regions.
ISSN: 1088-9051

Droits : http://creativecommons.org/licenses/by-nc/
hal-01533248
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01533248
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01533248/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01533248/file/Genome%20Res.-2017-Mah%C3%A9-947-58.pdf
DOI : 10.1101/gr.211466.116

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Recent research has linked early life exposure to selective serotonin reuptake inhibitor medications (SSRIs) to modifications of social behaviors in children. Serotonin is a key regulator of neurodevelopment, social behaviors and mental health, and with the growing use of SSRIs to treat maternal affective disorders during the perinatal period, questions have been raised about the benefits and risks of perinatal SSRI exposure on the developing child. This review will highlight how perinatal SSRIs affect maternal care and neurodevelopmental outcomes related to social affiliative behaviors in offspring; such as play behaviors, social interactions, reproductive behaviors, and maternal care of the next generation. We will also review how early life exposure to SSRIs can alter related neurobiology, and the epigenome. Both clinical research and findings from animal models will be discussed. Understanding the impact of perinatal SSRIs on neurobehavioral outcomes will improve the health and well-being of subsequent generations.
ISSN: 0149-7634

hal-01619303
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01619303
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01619303/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01619303/file/Perinatal%20selective%20serotonin%20reuptake%20inhibitor%20medication_revised.pdf
DOI : 10.1016/j.neubiorev.2017.04.023

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
This study investigates if acclimatization to residual pesticide contamination in agricultural soils is reflected in detoxification, antioxidant enzyme activities and energy budget of earthworms. Five fields within a joint agricultural area exhibited different chemical and farming histories from conventional cultivation to organic pasture. Soil multiresidual pesticide analysis revealed up to 9 molecules including atrazine up to 2.4 ng g(-1) dry soil. Exposure history of endogeic Aporrectodea caliginosa and Allolobophora chlorotica modified their responses to pesticides. In the field, activities of soluble glutathione-S-transferases (sGST) and catalase increased with soil pesticide contamination in A. caliginosa. Pesticide stress was reflected in depletion of energy reserves in A. chlorotica. Acute exposure of pre-adapted and naïve A. caliginosa to pesticides (fungicide Opus(®), 0.1 μg active ingredient epoxiconazole g(-1) dry soil, RoundUp Flash(®), 2.5 μg active ingredient glyphosate g(-1) dry soil, and their mixture), revealed that environmental pre-exposure accelerated activation of the detoxification enzyme sGST towards epoxiconazole.
ISSN: 0269-7491

hal-01063923
https://hal.archives-ouvertes.fr/hal-01063923
DOI : 10.1016/j.envpol.2014.05.001
PUBMED : 24874794

Éditeur(s) : HAL CCSD Wiley
Résumé : International audience
BACKGROUND: This study examines gene-environment interaction between the MTHFR C667T polymorphism and folic acid in the etiology of orofacial clefts (OFC). We used a pooled-analytical approach on four studies that used similar methods. METHODS: We used logistic regression to analyze the pooled sample of 1149 isolated cases and 1161 controls. Fetal and maternal MTHFR C677T genotypes, and maternal periconceptional exposure to smoking, alcohol, vitamin containing folic acid and folic acid supplements were contrasted between the cleft types [non-syndromic clefts lip or without cleft palate (CL(P)) and non-syndromic cleft palate (CP)] and control groups. RESULTS: There was a reduced risk of CL(P) with maternal folic acid use (p = 0.008; OR = 0.70, 95% CI: 0.65-0.94) and with supplements containing folic acid (p = 0.028, OR = 0.80, 95% CI: 0.65-0.94). Maternal smoking increased the risk of both CL(P) (p < 10 e-3; OR = 1.62, 95% CI: 1.35-1.95) and CP (p = 0.028; OR = 1.38, 95% CI: 1.04-1.83). No significant risk was observed with either maternal or fetal MTHFR C677T genotypes. CONCLUSION: This individual participant data (IPD) meta-analysis affords greater statistical power and can help alleviate the problems associated with aggregate-level data-sharing. The result of this IPD meta-analysis is consistent with previous reports suggesting that folic acid and smoking influence OFC outcomes.
ISSN: 1542-0752

hal-00875899
https://hal.archives-ouvertes.fr/hal-00875899
DOI : 10.1002/bdra.23133
PUBMED : 23670871

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
BACKGROUND: The insecticide chlordecone was extensively used in the French West Indies to control banana root borer. Its persistence in soils has led to the widespread pollution of the environment, and human beings are still exposed to this chemical. Chlordecone has been shown to impair neurological and behavioural functions in rodents when exposed gestationally or neonatally. OBJECTIVES: The aim of the study was to evaluate the impact of prenatal and postnatal exposure to chlordecone on the cognitive, visual, and motor development of 7-month-old infants from Guadeloupe. METHODS: Infants were tested at 7 months (n=153). Visual recognition memory and processing speed were assessed with the Fagan Tests of Infant Intelligence (FTII), visual acuity with the Teller Acuity Card, and fine motor development with the Brunet-Lezine. Samples of cord blood and breast milk at 3 months (n=88) were analyzed for chlordecone concentrations. Postnatal exposure was determined through breast feeding and frequency of contaminated food consumption by the infants. RESULTS: Cord chlordecone concentrations in tertiles were associated with reduced novelty preference on the FTII in the highly exposed group (β=-0.19, p=0.02). Postnatal exposure through contaminated food consumption was marginally related to reduced novelty preference (β=-0.14, p=0.07), and longer processing speed (β=0.16, p=0.07). Detectable levels of chlordecone in cord blood were associated with higher risk of obtaining low scores on the fine motor development scale (OR=1.25, p<0.01). CONCLUSION: These results suggest that pre- and postnatal low chronic exposure to chlordecone is associated with negative effects on cognitive and motor development during infancy.
ISSN: 0013-9351

hal-00875939
https://hal.archives-ouvertes.fr/hal-00875939
DOI : 10.1016/j.envres.2012.07.006
PUBMED : 22910562

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
CYLD is a tumour suppressor gene mutated in familial cylindromatosis, a genetic disorder leading to the development of skin appendage tumours. It encodes a deubiquitinating enzyme that removes Lys63- or linear-linked ubiquitin chains. CYLD was shown to regulate cell proliferation, cell survival and inflammatory responses, through various signalling pathways. Here we show that CYLD localizes at centrosomes and basal bodies via interaction with the centrosomal protein CAP350 and demonstrate that CYLD must be both at the centrosome and catalytically active to promote ciliogenesis independently of NF-κB. In transgenic mice engineered to mimic the smallest truncation found in cylindromatosis patients, CYLD interaction with CAP350 is lost disrupting CYLD centrosome localization, which results in cilia formation defects due to impairment of basal body migration and docking. These results point to an undiscovered regulation of ciliogenesis by Lys63 ubiquitination and provide new perspectives regarding CYLD function that should be considered in the context of cylindromatosis.
ISSN: 2041-1723

hal-01063915
https://hal.archives-ouvertes.fr/hal-01063915
DOI : 10.1038/ncomms5585
PUBMED : 25134987

Éditeur(s) : HAL CCSD Oxford University Press (OUP)
Résumé : International audience
BACKGROUND: HIV cohort collaborations, which pool data from diverse patient cohorts, have provided key insights into outcomes of antiretroviral therapy (ART). However, the extent of, and reasons for, between-cohort heterogeneity in rates of AIDS and mortality are unclear. METHODS: We obtained data on adult HIV-positive patients who started ART from 1998 without a previous AIDS diagnosis from 17 cohorts in North America and Europe. Patients were followed up from 1 month to 2 years after starting ART. We examined between-cohort heterogeneity in crude and adjusted (age, sex, HIV transmission risk, year, CD4 count and HIV-1 RNA at start of ART) rates of AIDS and mortality using random-effects meta-analysis and meta-regression. RESULTS: During 61 520 person-years, 754/38 706 (1.9%) patients died and 1890 (4.9%) progressed to AIDS. Between-cohort variance in mortality rates was reduced from 0.84 to 0.24 (0.73 to 0.28 for AIDS rates) after adjustment for patient characteristics. Adjusted mortality rates were inversely associated with cohorts' estimated completeness of death ascertainment [excellent: 96-100%, good: 90-95%, average: 75-89%; mortality rate ratio 0.66 (95% confidence interval 0.46-0.94) per category]. Mortality rate ratios comparing Europe with North America were 0.42 (0.31-0.57) before and 0.47 (0.30-0.73) after adjusting for completeness of ascertainment. CONCLUSIONS: Heterogeneity between settings in outcomes of HIV treatment has implications for collaborative analyses, policy and clinical care. Estimated mortality rates may require adjustment for completeness of ascertainment. Higher mortality rate in North American, compared with European, cohorts was not fully explained by completeness of ascertainment and may be because of the inclusion of more socially marginalized patients with higher mortality risk.
ISSN: 0300-5771

hal-00875138
https://hal.archives-ouvertes.fr/hal-00875138
DOI : 10.1093/ije/dys164
PUBMED : 23148105

Éditeur(s) : HAL CCSD American Chemical Society
Résumé : International audience
The HIWATE (Health Impacts of long-term exposure to disinfection byproducts in drinking WATEr) project was a systematic analysis that combined the epidemiology on adverse pregnancy outcomes and other health effects with long-term exposure to low levels of drinking water disinfection byproducts (DBPs) in the European Union. The present study focused on the relationship of the occurrence and concentration of DBPs with in vitro mammalian cell toxicity. Eleven drinking water samples were collected from five European countries. Each sampling location corresponded with an epidemiological study for the HIWATE program. Over 90 DBPs were identified; the range in the number of DBPs and their levels reflected the diverse collection sites, different disinfection processes, and the different characteristics of the source waters. For each sampling site, chronic mammalian cell cytotoxicity correlated highly with the numbers of DBPs identified and the levels of DBP chemical classes. Although there was a clear difference in the genotoxic responses among the drinking waters, these data did not correlate as well with the chemical analyses. Thus, the agents responsible for the genomic DNA damage observed in the HIWATE samples may be due to unresolved associations of combinations of identified DBPs, unknown emerging DBPs that were not identified, or other toxic water contaminants. This study represents the first to integrate quantitative in vitro toxicological data with analytical chemistry and human epidemiologic outcomes for drinking water DBPs.
ISSN: 0013-936X

hal-00875923
https://hal.archives-ouvertes.fr/hal-00875923
DOI : 10.1021/es3024226
PUBMED : 22958121