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1. The complete genome sequence of Corynebacterium pseudotuberculosis FRC41 isolated from a 12-year-old girl with necrotizing lymphadenitis reveals insights into gene-regulatory networks contributing to virulence

Author

Anderson Miyoshi, Vasco Azevedo, Lisa Ott, Andreas Burkovski, Flávia S. Rocha, Fernanda Alves Dorella, Olivier Join-Lambert, Eva Trost, Samer Kayal, Alexander Goesmann, Nicole Guiso, Peter Husemann, Jens Stoye, Artur Silva, Andreas Tauch, Vivian D'Afonseca, Sebastian Jaenicke, Jerónimo Saiz Ruiz, Siomar de Castro Soares, Jessica Schneider, Jasmin Schröder, Institut für Genomforschung und Systembiologie, Universität Bielefeld-Centrum für Biotechnologie, CLIB Graduate Cluster Industrial Biotechnology, Lehrstuhl für Mikrobiologie, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Bioinformatics Resource Facility, AG Genominformatik, Universität Bielefeld-Technische Fakultät, Laboratório de Genética Celular e Molecular, Instituto de Ciências Biológicas [Goiânia, Brésil] (ICB)-Universidade Federal de Minas Gerais, Cellular and Molecular Parasitology / Parasitologia Celular e Molecular [Belo Horizonte, Brésil], Fiocruz Minas - René Rachou Research Center / Instituto René Rachou [Belo Horizonte, Brésil], Fundação Oswaldo Cruz (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Fundação Oswaldo Cruz (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Instituto de Ciências Biológicas, Federal University of Para - Universidade Federal do Pará - UFPA [Belém, Brazil] (UFPA), Prévention et Thérapie Moléculaires des Maladies Infectieuses Humaines, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Service de Microbiologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Faculté de Médecine-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pontchaillou [Rennes], Bielefeld University and the Ministry of Innovation, Science, Research and Technology of North Rhine-Westphalia. LO and AB were supported by the Deutsche Forschungsgemeinschaft in frame of SFB 796 (project B5)., BMC, Ed., Fundação Oswaldo Cruz / Oswaldo Cruz Foundation (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Fundação Oswaldo Cruz / Oswaldo Cruz Foundation (FIOCRUZ), Federal University of Para - Universidade Federal do Para [Belem - Brésil], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centrum für Biotechnologie-Universität Bielefeld, Friedrich-Alexander Universität Erlangen-Nürnberg ( FAU ), Instituto de Ciências Biológicas [Goiânia, Brésil] ( ICB ) -Universidade Federal de Minas Gerais, Cellular and Molecular Parasitology Laboratory, Rene Rachou Research Center-Fundação Oswaldo Cruz ( FIOCRUZ ), Universidade Federal do Pará, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), and Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Faculté de Médecine-CHU Necker - Enfants Malades [AP-HP]

Subjects
MESH : Virulence Factors, MESH: Sequence Analysis, DNA, Transcription, Genetic, Corynebacterium pseudotuberculosis, MESH : Molecular Sequence Annotation, MESH: Base Sequence, MESH: Virulence, MESH: Genome, Bacterial, MESH: Zinc, MESH : Iron, Bacterial Adhesion, MESH : Child, MESH: Child, MESH : Female, Gene Regulatory Networks, Child, Pathogen, Histiocytic Necrotizing Lymphadenitis, MESH: Gene Regulatory Networks, 0303 health sciences, MESH: Iron, Virulence, MESH : Genes, Bacterial, MESH : Fimbriae, Bacterial, MESH : Virulence, Zinc, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Regulon, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, DNA microarray, MESH: Genes, Bacterial, Research Article, Biotechnology, lcsh:QH426-470, MESH : Bacterial Adhesion, Virulence Factors, Iron, lcsh:Biotechnology, MESH : Genome, Bacterial, MESH : Regulon, MESH: Manganese, MESH: Molecular Sequence Annotation, Biology, Regulon, Microbiology, MESH: Fimbriae, Bacterial, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], lcsh:TP248.13-248.65, Genetics, Humans, MESH: Bacterial Adhesion, 030304 developmental biology, MESH: Virulence Factors, Whole genome sequencing, Manganese, MESH : Corynebacterium pseudotuberculosis, MESH: Humans, Base Sequence, 030306 microbiology, MESH: Transcription, Genetic, MESH : Humans, MESH : Transcription, Genetic, Molecular Sequence Annotation, MESH : Zinc, MESH : Histiocytic Necrotizing Lymphadenitis, Sequence Analysis, DNA, MESH: Corynebacterium pseudotuberculosis, MESH: Histiocytic Necrotizing Lymphadenitis, lcsh:Genetics, Genes, Bacterial, MESH : Gene Regulatory Networks, Fimbriae, Bacterial, Pyrosequencing, Caseous lymphadenitis, MESH : Base Sequence, MESH : Manganese, MESH: Female, Genome, Bacterial, MESH : Sequence Analysis, DNA
Abstract

Background Corynebacterium pseudotuberculosis is generally regarded as an important animal pathogen that rarely infects humans. Clinical strains are occasionally recovered from human cases of lymphadenitis, such as C. pseudotuberculosis FRC41 that was isolated from the inguinal lymph node of a 12-year-old girl with necrotizing lymphadenitis. To detect potential virulence factors and corresponding gene-regulatory networks in this human isolate, the genome sequence of C. pseudotuberculosis FCR41 was determined by pyrosequencing and functionally annotated. Results Sequencing and assembly of the C. pseudotuberculosis FRC41 genome yielded a circular chromosome with a size of 2,337,913 bp and a mean G+C content of 52.2%. Specific gene sets associated with iron and zinc homeostasis were detected among the 2,110 predicted protein-coding regions and integrated into a gene-regulatory network that is linked with both the central metabolism and the oxidative stress response of FRC41. Two gene clusters encode proteins involved in the sortase-mediated polymerization of adhesive pili that can probably mediate the adherence to host tissue to facilitate additional ligand-receptor interactions and the delivery of virulence factors. The prominent virulence factors phospholipase D (Pld) and corynebacterial protease CP40 are encoded in the genome of this human isolate. The genome annotation revealed additional serine proteases, neuraminidase H, nitric oxide reductase, an invasion-associated protein, and acyl-CoA carboxylase subunits involved in mycolic acid biosynthesis as potential virulence factors. The cAMP-sensing transcription regulator GlxR plays a key role in controlling the expression of several genes contributing to virulence. Conclusion The functional data deduced from the genome sequencing and the extended knowledge of virulence factors indicate that the human isolate C. pseudotuberculosis FRC41 is equipped with a distinct gene set promoting its survival under unfavorable environmental conditions encountered in the mammalian host.

Published
2010

2. Surrogate endpoints for overall survival in digestive oncology trials: which candidates? A questionnaires survey among clinicians and methodologists

Author

Nicolas Methy, Franck Bonnetain, Laurent Bedenne, BMC, Ed., Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre d'épidémiologie des populations ( CEP ), and Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL )

Subjects
Oncology, Cancer Research, Time Factors, Digestive System Neoplasms, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, Quality of life, Surveys and Questionnaires, Medicine, 030212 general & internal medicine, MESH: Treatment Outcome, Response rate (survey), MESH : Evidence-Based Medicine, Clinical Trials as Topic, Evidence-Based Medicine, MESH: Endpoint Determination, MESH: Research Design, MESH : Questionnaires, MESH : Research Design, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, MESH: Reproducibility of Results, medicine.anatomical_structure, Treatment Outcome, Research Design, 030220 oncology & carcinogenesis, Data Interpretation, Statistical, MESH: Survival Analysis, MESH : Disease-Free Survival, MESH : Endpoint Determination, France, MESH : Time Factors, Research Article, medicine.medical_specialty, MESH: Clinical Trials as Topic, Endpoint Determination, Rectum, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH : Treatment Outcome, lcsh:RC254-282, Disease-Free Survival, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Genetics, Humans, MESH : Data Interpretation, Statistical, MESH : France, Survival analysis, MESH: Humans, business.industry, Surrogate endpoint, MESH: Digestive System Neoplasms, MESH : Reproducibility of Results, MESH: Questionnaires, MESH : Humans, MESH: Time Factors, Cancer, Reproducibility of Results, MESH: Quality of Life, MESH : Quality of Life, medicine.disease, Survival Analysis, MESH : Clinical Trials as Topic, MESH: France, Localized disease, MESH: Disease-Free Survival, Quality of Life, MESH : Digestive System Neoplasms, MESH : Survival Analysis, business, MESH: Data Interpretation, Statistical, MESH: Evidence-Based Medicine
Abstract

Background Overall survival (OS) is the gold standard for the demonstration of a clinical benefit in cancer trials. Replacement of OS by a surrogate endpoint allows to reduce trial duration. To date, few surrogate endpoints have been validated in digestive oncology. The aim of this study was to draw up an ordered list of potential surrogate endpoints for OS in digestive cancer trials, by way of a survey among clinicians and methodologists. Secondary objective was to obtain their opinion on surrogacy and quality of life (QoL). Methods In 2007 and 2008, self administered sequential questionnaires were sent to a panel of French clinicians and methodologists involved in the conduct of cancer clinical trials. In the first questionnaire, panellists were asked to choose the most important characteristics defining a surrogate among six proposals, to give advantages and drawbacks of the surrogates, and to answer questions about their validation and use. Then they had to suggest potential surrogate endpoints for OS in each of the following tumour sites: oesophagus, stomach, liver, pancreas, biliary tract, lymphoma, colon, rectum, and anus. They finally gave their opinion on QoL as surrogate endpoint. In the second questionnaire, they had to classify the previously proposed candidate surrogates from the most (position #1) to the least relevant in their opinion. Frequency at which the endpoints were chosen as first, second or third most relevant surrogates was calculated and served as final ranking. Results Response rate was 30% (24/80) in the first round and 20% (16/80) in the second one. Participants highlighted key points concerning surrogacy. In particular, they reminded that a surrogate endpoint is expected to predict clinical benefit in a well-defined therapeutic situation. Half of them thought it was not relevant to study QoL as surrogate for OS. DFS, in the neoadjuvant settings or early stages, and PFS, in the non operable or metastatic settings, were ranked first, with a frequency of more than 69% in 20 out of 22 settings. PFS was proposed in association with QoL in metastatic primary liver and stomach cancers (both 81%). This composite endpoint was ranked second in metastatic oesophageal (69%), colorectal (56%) and anal (56%) cancers, whereas QoL alone was also suggested in most metastatic situations. Other endpoints frequently suggested were R0 resection in the neoadjuvant settings (oesophagus (69%), stomach (56%), pancreas (75%) and biliary tract (63%)) and response. An unexpected endpoint was metastatic PFS in non operable oesophageal (31%) and pancreatic (44%) cancers. Quality and results of surgical procedures like sphincter preservation were also cited as eligible surrogate endpoints in rectal (19%) and anal (50% in case of localized disease) cancers. Except for alpha-FP kinetic in hepatocellular carcinoma (13%) and CA19-9 decline (6%) in pancreas, few endpoints based on biological or tumour markers were proposed. Conclusion The overall results should help prioritise the endpoints to be statistically evaluated as surrogate for OS, so that trialists and clinicians can rely on endpoints that ensure relevant clinical benefit to the patient.

Published
2010

3. Chronology of prescribing error during the hospital stay and prediction of pharmacist's alerts overriding: a prospective analysis

Author

Vanida Bruni, Florence Gillaizeau, Thibaut Caruba, Brigitte Sabatier, Patrice Prognon, Virginie Korb, Dominique Bégué, Isabelle Colombet, Pierre Durieux, Service de pharmacie, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Laboratoire Interdisciplinaire de Recherche en Economie de Santé, Informatique Hospitalière, Evaluation et Santé Publique, Centre D'investigation Épidémiologique 4, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Risque Thrombotique et Mecanismes de l'Hemostase ( U765 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de pharmacie [CHU HEGP], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Risque Thrombotique et Mécanismes de l'Hémostase (U765), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Risque Thrombotique et Mecanismes de l'Hemostase (U765), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and BMC, Ed.

Subjects
MESH: Pharmacists, MESH: Drug Interactions, MESH : Drug Prescriptions, MESH : Prospective Studies, MESH : Pharmacists, MESH: Medication Errors, MESH: Hospitalization, Pharmacists, 030226 pharmacology & pharmacy, Health informatics, MESH: Regression Analysis, MESH: Length of Stay, Health administration, Hospitals, University, 0302 clinical medicine, MESH: Drug Prescriptions, Computerized physician order entry, MESH : Regression Analysis, Medication Errors, Drug Interactions, 030212 general & internal medicine, Prospective Studies, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Health Policy, Nursing research, lcsh:Public aspects of medicine, Regression analysis, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, 3. Good health, MESH: Medical Order Entry Systems, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Hospitalization, MESH : Length of Stay, Regression Analysis, MESH : Hospitalization, MESH : Medical Staff, Hospital, France, medicine.medical_specialty, MESH : Interprofessional Relations, MESH : Medication Errors, Interprofessional Relations, Pharmacist, MESH: Medical Staff, Hospital, Drug Prescriptions, Medical Order Entry Systems, 03 medical and health sciences, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, MESH: Interprofessional Relations, Research article, medicine, Medical Staff, Hospital, Humans, Medical prescription, MESH : France, MESH : Hospitals, University, MESH: Hospitals, University, MESH: Humans, business.industry, MESH : Humans, lcsh:RA1-1270, Length of Stay, MESH: Prospective Studies, MESH : Drug Interactions, MESH: France, MESH : Medical Order Entry Systems, [ SDV.SP ] Life Sciences [q-bio]/Pharmaceutical sciences, Emergency medicine, Prescribing error, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background: Drug prescribing errors are frequent in the hospital setting and pharmacists play an important role in detection of these errors. The objectives of this study are (1) to describe the drug prescribing errors rate during the patient’s stay, (2) to find which characteristics for a prescribing error are the most predictive of their reproduction the next day despite pharmacist’s alert (i.e. override the alert). Methods: We prospectively collected all medication order lines and prescribing errors during 18 days in 7 medical wards’ using computerized physician order entry. We described and modelled the errors rate according to the chronology of hospital stay. We performed a classification and regression tree analysis to find which characteristics of alerts were predictive of their overriding (i.e. prescribing error repeated). Results: 12 533 order lines were reviewed, 117 errors (errors rate 0.9%) were observed and 51% of these errors occurred on the first day of the hospital stay. The risk of a prescribing error decreased over time. 52% of the alerts were overridden (i.e error uncorrected by prescribers on the following day. Drug omissions were the most frequently taken into account by prescribers. The classification and regression tree analysis showed that overriding pharmacist’s alerts is first related to the ward of the prescriber and then to either Anatomical Therapeutic Chemical class of the drug or the type of error. Conclusions: Since 51% of prescribing errors occurred on the first day of stay, pharmacist should concentrate his analysis of drug prescriptions on this day. The difference of overriding behavior between wards and according drug Anatomical Therapeutic Chemical class or type of error could also guide the validation tasks and programming of electronic alerts. Background Drug prescribing errors are defined as a prescribing decision or prescription writing process that results in an unintentional, significant reduction in the probability of treatment being timely and effective or increase in the risk of harm, when compared with generally accepted practice. High rates of inpatient prescribing errors have been reported: 1.5-5.3 per 100 drug orders, or 1.4 errors per admission [1,2].

Published
2010

4. A national cross-sectional study among drug-users in France: epidemiology of HCV and highlight on practical and statistical aspects of the design

Author

Nicolas Razafandratsima, J Emmanuelli, Marie Jauffret-Roustide, Jean-Claude Desenclos, Marc Rondy, Damien Thierry, Elisabeth Couturier, Yann Le Strat, Gaelle Guibert, Francis Barin, Martine Quaglia, Département des maladies infectieuses, Institut de Veille Sanitaire (INVS), Virus, pseudo-virus: Morphogénèse et Antigénicité, Université de Tours-EA3856, Centre de référence du HIV, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre de Recherche Psychotropes, Santé Mentale, Société (CESAMES), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Institute of Demographic Studies, This work was supported by the French National Agency for HIV and Hepatitis Research (ANRS)., CHRU Tours, Centre de Recherche Psychotropes, Santé Mentale, Société ( CESAMES ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Tours (UT)-EA3856, and BMC, Ed.

Subjects
Male, MESH : Drug Users, Multivariate analysis, Cross-sectional study, Prevalence, HIV Infections, Drug Users, 0302 clinical medicine, MESH : Cross-Sectional Studies, Risk Factors, Seroepidemiologic Studies, MESH: Risk Factors, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Surveys and Questionnaires, Epidemiology, MESH : Seroepidemiologic Studies, 030212 general & internal medicine, education.field_of_study, MESH : Questionnaires, Hepatitis C, MESH: HIV Infections, MESH : Adult, MESH : Risk Factors, 3. Good health, Substance abuse, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Infectious Diseases, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 030211 gastroenterology & hepatology, France, Research Article, Adult, medicine.medical_specialty, MESH : Male, Population, MESH: Multivariate Analysis, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, MESH: Cross-Sectional Studies, MESH: Drug Users, medicine, MESH : HIV Infections, Humans, Seroprevalence, lcsh:RC109-216, education, MESH : France, MESH: Hepatitis C, MESH: Seroepidemiologic Studies, MESH: Humans, business.industry, MESH: Questionnaires, MESH : Humans, MESH : Multivariate Analysis, MESH: Adult, MESH : Hepatitis C, medicine.disease, Virology, MESH: Male, MESH: France, Cross-Sectional Studies, Multivariate Analysis, business, Demography
Abstract

Background Epidemiology of HCV infection among drug users (DUs) has been widely studied. Prevalence and sociobehavioural data among DUs are therefore available in most countries but no study has taken into account in the sampling weights one important aspect of the way of life of DUs, namely that they can use one or more specialized services during the study period. In 2004–2005, we conducted a national seroepidemiologic survey of DUs, based on a random sampling design using the Generalised Weight Share Method (GWSM) and on blood testing. Methods A cross-sectional multicenter survey was done among DUs having injected or snorted drugs at least once in their life. We conducted a two stage random survey of DUs selected to represent the diversity of drug use. The fact that DUs can use more than one structure during the study period has an impact on their inclusion probabilities. To calculate a correct sampling weight, we used the GWSM. A sociobehavioral questionnaire was administered by interviewers. Selected DUs were asked to self-collect a fingerprick blood sample on blotting paper. Results Of all DUs selected, 1462 (75%) accepted to participate. HCV seroprevalence was 59.8% [95% CI: 50.7–68.3]. Of DUs under 30 years, 28% were HCV seropositive. Of HCV-infected DUs, 27% were unaware of their status. In the month prior to interview, 13% of DUs shared a syringe, 38% other injection parapharnelia and 81% shared a crack pipe. In multivariate analysis, factors independently associated with HCV seropositivity were age over 30, HIV seropositivity, having ever injected drugs, opiate substitution treatment (OST), crack use, and precarious housing. Conclusion This is the first time that blood testing combined to GWSM is applied to a DUs population, which improve the estimate of HCV prevalence. HCV seroprevalence is high, indeed by the youngest DUs. And a large proportion of DUs are not aware of their status. Our multivariate analysis identifies risk factors such as crack consumption and unstable housing.

Published
2009

5. Innate immunity in ocular Chlamydia trachomatis infection: contribution of IL8 and CSF2 gene variants to risk of trachomatous scarring in Gambians

Author

David Mabey, Dominic P. Kwiatkowski, Gaia Luoni, Matthew J. Burton, Hassan Joof, Kirk A. Rockett, Robin L. Bailey, Martin J. Holland, Jeremy Hull, Angels Natividad, BMC, Ed., London School of Hygiene and Tropical Medicine (LSHTM), Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, Medical Research Council Laboratories, This work was supported by the Medical Research Council, UK and The Wellcome Trust, UK., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), University of Oxford [Oxford], London School of Hygiene and Tropical Medicine ( LSHTM ), Génétique Humaine des Maladies Infectieuses ( Inserm U980 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), and Wellcome Trust Centre for Human Genetics

Subjects
Male, MESH : Aged, MESH: Base Sequence, Blindness, Linkage Disequilibrium, MESH: Blindness, MESH : Child, MESH : Gambia, MESH: Child, MESH: Epistasis, Genetic, Genetics(clinical), MESH: Genetic Variation, Child, Aged, 80 and over, 0303 health sciences, education.field_of_study, MESH: Middle Aged, MESH: Polymorphism, Single Nucleotide, MESH : Trachoma, MESH: Granulocyte-Macrophage Colony-Stimulating Factor, MESH : Granulocyte-Macrophage Colony-Stimulating Factor, MESH: Case-Control Studies, 3. Good health, MESH: Linkage Disequilibrium, MESH: Young Adult, Child, Preschool, Chromosomes, Human, Pair 5, Gambia, Chromosomes, Human, Pair 4, MESH: Trachoma, MESH : Case-Control Studies, MESH : Young Adult, Locus (genetics), 03 medical and health sciences, Cicatrix, MESH : Adolescent, Genetics, Humans, MESH : Middle Aged, MESH : Aged, 80 and over, education, lcsh:RC31-1245, MESH : Haplotypes, Trichiasis, Alleles, Aged, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, 030306 microbiology, MESH : Humans, MESH: Child, Preschool, Genetic Variation, Epistasis, Genetic, MESH: Adult, MESH: Matrix Metalloproteinase 9, MESH: Haplotypes, MESH : Cicatrix, medicine.disease, Immunity, Innate, MESH: Interleukin-8, Case-Control Studies, MESH : Blindness, Immunology, MESH : Alleles, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Chlamydia trachomatis, MESH: Female, Linkage disequilibrium, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH : Child, Preschool, medicine.disease_cause, MESH : Chromosomes, Human, Pair 5, MESH: Aged, 80 and over, MESH : Chromosomes, Human, Pair 4, Risk Factors, MESH: Risk Factors, MESH : Female, MESH : Matrix Metalloproteinase 9, Genetics (clinical), Keratoconjunctivitis, MESH : Epistasis, Genetic, MESH: Aged, MESH : Linkage Disequilibrium, MESH : Polymorphism, Single Nucleotide, MESH : Adult, MESH : Immunity, Innate, Middle Aged, MESH : Risk Factors, Trachoma, Matrix Metalloproteinase 9, Female, MESH: Immunity, Innate, Adult, MESH: Chromosomes, Human, Pair 5, MESH : Interleukin-8, lcsh:Internal medicine, MESH: Chromosomes, Human, Pair 4, Adolescent, lcsh:QH426-470, MESH : Male, Population, Biology, Polymorphism, Single Nucleotide, Young Adult, MESH : Genetic Variation, Research article, medicine, Allele, 030304 developmental biology, MESH: Cicatrix, Base Sequence, MESH: Alleles, Interleukin-8, Granulocyte-Macrophage Colony-Stimulating Factor, MESH: Male, lcsh:Genetics, MESH: Gambia, Haplotypes, MESH : Base Sequence
Abstract

Background: Trachoma, a chronic keratoconjunctivitis caused by Chlamydia trachomatis, is the world's commonest infectious cause of blindness. Blindness is due to progressive scarring of the conjunctiva (trachomatous scarring) leading to in-turning of eyelashes (trichiasis) and corneal opacification. We evaluated the contribution of genetic variation across the chemokine and cytokine clusters in chromosomes 4q and 5q31 respectively to risk of scarring trachoma and trichiasis in a large case-control association study in a Gambian population. Methods: Linkage disequilibrium (LD) mapping was used to investigate risk effects across the 4q and 5q31 cytokine clusters in relation to the risk of scarring sequelae of ocular Ct infection. Disease association and epistatic effects were assessed in a population based study of 651 case-control pairs by conditional logistic regression (CLR) analyses. Results: LD mapping suggested that genetic effects on risk within these regions mapped to the pro-inflammatory innate immune genes interleukin 8 (IL8) and granulocyte-macrophage colony stimulatory factor (CSF2) loci. The IL8-251 rare allele (IL8-251 TT) was associated with protection from scarring trachoma (OR = 0.29 p = 0.027). The intronic CSF2_27348 A allele in chromosome 5q31 was associated with dose dependent protection from trichiasis, with each copy of the allele reducing risk by 37% (p = 0.005). There was evidence of epistasis, with effects at IL8 and CSF2 loci interacting with those previously reported at the MMP9 locus, a gene acting downstream to IL8 and CSF2 in the inflammatory cascade. Conclusion: innate immune response SNP-haplotypes are linked to ocular Ct sequelae. This work illustrates the first example of epistatic effects of two genes on trachoma.

Published
2009

6. Impact of previous sepsis on the accuracy of procalcitonin for the early diagnosis of blood stream infection in critically ill patients

Author

André Pechinot, Aurélie Snauwaert, Jean-Pierre Quenot, Jean-Marc Doise, Sébastien Prin, Niels-Olivier Olsson, Serge Aho, Sylvain Ladoire, Pierre Emmanuel Charles, Bernard Blettery, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Laboratoire de Microbiologie Médicale et Moléculaire, Université de Bourgogne (UB), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), and Université de Bourgogne ( UB )

Subjects
Male, MESH: Protein Precursors, MESH : Retrospective Studies, MESH : Aged, [ SDV.MP.BAC ] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH : Critical Illness, MESH : Early Diagnosis, Procalcitonin, law.invention, Leukocyte Count, MESH: Aged, 80 and over, 0302 clinical medicine, MESH: Early Diagnosis, law, MESH : Female, 030212 general & internal medicine, MESH : Protein Precursors, MESH: Sepsis, Aged, 80 and over, MESH: Aged, First episode, MESH: Middle Aged, Middle Aged, MESH : Leukocyte Count, Intensive care unit, MESH: Predictive Value of Tests, 3. Good health, C-Reactive Protein, Infectious Diseases, Predictive value of tests, MESH: Critical Illness, Female, MESH : Sepsis, SOFA score, Research Article, Calcitonin, medicine.medical_specialty, Calcitonin Gene-Related Peptide, Critical Illness, MESH : Male, MESH: Multivariate Analysis, lcsh:Infectious and parasitic diseases, Sepsis, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, Intensive care, MESH: C-Reactive Protein, medicine, Humans, MESH : Middle Aged, lcsh:RC109-216, MESH : Predictive Value of Tests, Protein Precursors, MESH : Aged, 80 and over, Intensive care medicine, Aged, Retrospective Studies, MESH: Humans, MESH: Calcitonin, business.industry, MESH : Humans, MESH : Multivariate Analysis, MESH: Retrospective Studies, 030208 emergency & critical care medicine, MESH : C-Reactive Protein, medicine.disease, bacterial infections and mycoses, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Male, MESH : Calcitonin, Systemic inflammatory response syndrome, Early Diagnosis, MESH: Leukocyte Count, Multivariate Analysis, business, MESH: Female
Abstract

Background Blood stream infections (BSI) are life-threatening infections in intensive care units (ICU), and prognosis is highly dependent on early detection. Procalcitonin levels have been shown to accurately and quickly distinguish between BSI and noninfectious inflammatory states in critically ill patients. It is, however, unknown to what extent a recent history of sepsis (namely, secondary sepsis) can affect diagnosis of BSI using PCT. Methods review of the medical records of every patient with BSI in whom PCT dosage at the onset of sepsis was available between 1st September, 2006 and 31st July, 2007. Results 179 episodes of either primary (n = 117) or secondary (n = 62) sepsis were included. Procalcitonin levels were found to be markedly lower in patients with secondary sepsis than in those without (6.4 [9.5] vs. 55.6 [99.0] ng/mL, respectively; p < 0.001), whereas the SOFA score was similar in the two groups. Although patients in the former group were more likely to have received steroids and effective antibiotic therapy prior to the BSI episode, and despite a higher proportion of candidemia in this group, a low PCT value was found to be independently associated with secondary sepsis (Odd Ratio = 0.33, 95% Confidence Interval: 0.16–0.70; p = 0.004). Additional patients with suspected but unconfirmed sepsis were used as controls (n = 23). Thus, diagnostic accuracy of PCT as assessed by the area under the receiver-operating characteristic curves (AUROCC) measurement was decreased in the patients with secondary sepsis compared to those without (AUROCC = 0.805, 95% CI: 0.699–0.879, vs. 0.934, 95% CI: 0.881–0.970, respectively; p < 0.050). Conclusion In a critically ill patient with BSI, PCT elevation and diagnosis accuracy could be lower if sepsis is secondary than in those with a first episode of infection.

Published
2008

7. Eight previously unidentified mutations found in the OA1 ocular albinism gene

Author

Josseline Kaplan, Elise Heon, Daniel F. Schorderet, Helene Mayeur, Alex V. Levin, Dominique Bonneau, Maurice Menasche, Marc Abitbol, Hélène Dollfus, Joanne Sutherland, Eedy Mezer, Dominique Marchant, Cécile Marsac, Didier Lacombe, Olivier Roche, Jean-Louis Dufier, Carolina Jaliffa, Francis L. Munier, Edith Said, Christelle Vêtu, EA no 2502 du ministère de la Recherche, de l'Enseignement Supérieur et la Technologie, Université Paris Descartes - Paris 5 (UPD5)-CERTO, Service d'ophtalmologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Jules Gonin Eye Hospital, Institut de Recherche en Ophtalmologie (IRO), Institut de Recherche en Ophtalmologie, Department of Ophthalmology and Vision Sciences, The Hospital for sick children [Toronto] (SickKids), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Department of Pediatrics and Medical Genetics, St. Luke's Hospital, Alberto Moscona Department of Ophthalmology, Rambam Health Care Campus, Handicaps génétiques de l'enfant (Inserm U393), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), We would like to thank Rétina France, Président Claude Foucher, Pr Jean- Louis Dufier, Dean Patrick Berche, Genespoir, Fondation pour la Recherche Médicale, Fondation de France, Lions Club de France, Fondation de L'Avenir, Association Française contre les Myopathies, ORPHANET, INSERM, CNRS, Ministère de la Recherche, de l'Enseignement Supérieur et de la Technologie, Faculté de Médecine René Descartes, Brandan's Eye Research Fund (AL) and Essilor for their support., Autard, Delphine, Université Paris Descartes - Paris 5 ( UPD5 ) -CERTO, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université d'Angers ( UA ) -CHU Angers, Institut de Recherche en Ophtalmologie ( IRO ), The Hospital for Sick Children, Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Handicaps génétiques de l'enfant ( Inserm U393 ), and Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
MESH : Point Mutation, Male, MESH : Molecular Sequence Data, genetic structures, MESH: Membrane Glycoproteins, DNA Mutational Analysis, MESH : Membrane Glycoproteins, MESH: RNA Splice Sites, MESH: Amino Acid Sequence, [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, MESH: Research Support, Non-U.S. Gov't, Exon, 0302 clinical medicine, MESH : Research Support, Non-U.S. Gov't, MESH: Eye Proteins, Gene duplication, MESH : Female, Genetics(clinical), MESH: DNA Mutational Analysis, Genetics (clinical), Sequence Deletion, Genetics, 0303 health sciences, Mutation, Membrane Glycoproteins, MESH : Amino Acid Sequence, Albinism, Ocular, Amino Acid Sequence, Eye Proteins, Female, Humans, Molecular Sequence Data, Pedigree, Point Mutation, RNA Splice Sites, MESH: Sequence Deletion, 3. Good health, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, [ SDV.MHEP.OS ] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Ocular albinism type 1, MESH : Mutation, MESH : RNA Splice Sites, Research Article, Ocular albinism, lcsh:Internal medicine, MESH: Mutation, lcsh:QH426-470, MESH: Pedigree, MESH : Male, MESH : DNA Mutational Analysis, Biology, 03 medical and health sciences, MESH : Eye Proteins, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, lcsh:RC31-1245, Gene, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, MESH: Albinism, Ocular, MESH: Point Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Molecular Sequence Data, MESH : Albinism, Ocular, Point mutation, MESH : Sequence Deletion, Alternative splicing, MESH : Humans, medicine.disease, Molecular biology, MESH: Male, eye diseases, lcsh:Genetics, MESH : Pedigree, 030221 ophthalmology & optometry, sense organs, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Female
Abstract

Background Ocular albinism type 1 (OA1) is an X-linked ocular disorder characterized by a severe reduction in visual acuity, nystagmus, hypopigmentation of the retinal pigmented epithelium, foveal hypoplasia, macromelanosomes in pigmented skin and eye cells, and misrouting of the optical tracts. This disease is primarily caused by mutations in the OA1 gene. Methods The ophthalmologic phenotype of the patients and their family members was characterized. We screened for mutations in the OA1 gene by direct sequencing of the nine PCR-amplified exons, and for genomic deletions by PCR-amplification of large DNA fragments. Results We sequenced the nine exons of the OA1 gene in 72 individuals and found ten different mutations in seven unrelated families and three sporadic cases. The ten mutations include an amino acid substitution and a premature stop codon previously reported by our team, and eight previously unidentified mutations: three amino acid substitutions, a duplication, a deletion, an insertion and two splice-site mutations. The use of a novel Taq polymerase enabled us to amplify large genomic fragments covering the OA1 gene. and to detect very likely six distinct large deletions. Furthermore, we were able to confirm that there was no deletion in twenty one patients where no mutation had been found. Conclusion The identified mutations affect highly conserved amino acids, cause frameshifts or alternative splicing, thus affecting folding of the OA1 G protein coupled receptor, interactions of OA1 with its G protein and/or binding with its ligand.

Published
2006

8. Genetic variability in MCF-7 sublines: evidence of rapid genomic and RNA expression profile modifications

Author

Catherine Nguyen, Charles Theillet, Lisa Ursule, Julie A. Vendrell, Pascale A. Cohen, Paul Chuchana, Béatrice Orsetti, Daniel Birnbaum, Emmanuel J. P. Douzery, Mélanie Nugoli, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cancérologie expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), This work was supported by funds from the Association pour la Recherche sur le Cancer grant#5122, la Ligue Contre le Cancer program CIT, le Ministère de la Recherche et de la Technologie, Groupement des Entreprises en Lutte contre le Cancer and Génopole Montpellier-Languedoc-Roussillon. cDNA clones used to set up the arrays were provided by the HGMP (UK-MRC, Cambridge, UK). The contribution of EJPD was the one 2003-026 of the Institut des Sciences de l'Evolution de Montepellier (UMR 5554 CNRS)., Institut de Génétique Moléculaire de Montpellier ( IGMM ), Centre National de la Recherche Scientifique ( CNRS ) -Université de Montpellier ( UM ), Technologies avancées pour le génôme et la clinique ( TAGC ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut des Sciences de l'Evolution de Montpellier ( ISEM ), Université de Montpellier ( UM ) -Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique ( CNRS ), Le Ster, Yves, Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UR226

Subjects
Cancer Research, Gene Expression, MESH : Breast Neoplasms, MESH : Microsatellite Repeats, MESH: Research Support, Non-U.S. Gov't, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, MESH: Variation (Genetics), 0302 clinical medicine, MESH : Research Support, Non-U.S. Gov't, Gene expression, Cluster Analysis, MESH : Female, RNA, Neoplasm, MESH: Phylogeny, skin and connective tissue diseases, Phylogeny, Genetics, 0303 health sciences, Phylogenetic tree, MESH : Variation (Genetics), lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Phenotype, Oncology, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Research Article, MESH: Cell Line, Tumor, MESH: Gene Expression, MESH : Chromosome Aberrations, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH : Ch, MESH: Ch, lcsh:RC254-282, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Phylogenetics, Cell Line, Tumor, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetic variation, Humans, MESH : Cluster Analysis, MESH: Chromosome Aberrations, Genetic variability, Gene, 030304 developmental biology, Chromosome Aberrations, MESH: Humans, MESH : Cell Line, Tumor, MESH : Humans, Genetic Variation, RNA, MESH : Phylogeny, MESH: RNA, Neoplasm, MESH: Cluster Analysis, MESH : Gene Expression, MESH : RNA, Neoplasm, MESH: Microsatellite Repeats, MESH: Female, MESH: Breast Neoplasms, Microsatellite Repeats
Abstract

Background Both phenotypic and cytogenetic variability have been reported for clones of breast carcinoma cell lines but have not been comprehensively studied. Despite this, cell lines such as MCF-7 cells are extensively used as model systems. Methods In this work we documented, using CGH and RNA expression profiles, the genetic variability at the genomic and RNA expression levels of MCF-7 cells of different origins. Eight MCF-7 sublines collected from different sources were studied as well as 3 subclones isolated from one of the sublines by limit dilution. Results MCF-7 sublines showed important differences in copy number alteration (CNA) profiles. Overall numbers of events ranged from 28 to 41. Involved chromosomal regions varied greatly from a subline to another. A total of 62 chromosomal regions were affected by either gains or losses in the 11 sublines studied. We performed a phylogenetic analysis of CGH profiles using maximum parsimony in order to reconstruct the putative filiation of the 11 MCF-7 sublines. The phylogenetic tree obtained showed that the MCF-7 clade was characterized by a restricted set of 8 CNAs and that the most divergent subline occupied the position closest to the common ancestor. Expression profiles of 8 MCF-7 sublines were analyzed along with those of 19 unrelated breast cancer cell lines using home made cDNA arrays comprising 720 genes. Hierarchical clustering analysis of the expression data showed that 7/8 MCF-7 sublines were grouped forming a cluster while the remaining subline clustered with unrelated breast cancer cell lines. These data thus showed that MCF-7 sublines differed at both the genomic and phenotypic levels. Conclusions The analysis of CGH profiles of the parent subline and its three subclones supported the heteroclonal nature of MCF-7 cells. This strongly suggested that the genetic plasticity of MCF-7 cells was related to their intrinsic capacity to generate clonal heterogeneity. We propose that MCF-7, and possibly the breast tumor it was derived from, evolved in a node like pattern, rather than according to a linear progression model. Due to their capacity to undergo rapid genetic changes MCF-7 cells could represent an interesting model for genetic evolution of breast tumors.

Published
2003

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