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Biblio - Bibliographie IAL
Bibliographie IAL

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Recherche bibliographique scientifique

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Accueil > Références bibliographiques

biblio

2010



  • Bouchahda, M, Karaboué, A, Saffroy, R, Innominato, P, Gorden, L, Guettier, C, Adam, R & Lévi, F 2010, « Acquired KRAS mutations during progression of colorectal cancer metastases: possible implications for therapy and prognosis », Cancer Chemother Pharmacol, vol. 66, no. 3, p. 605-9, viewed sans date, .
    Résumé : PURPOSE: Documentation of a wild-type (wt) KRAS gene in tumor has become mandatory for the prescription of anti-EGFR monoclonal antibodies in patients with colorectal cancer (CRC). Acquired KRAS mutations have seldom been reported in metastases from wt KRAS primary CRC. We report the first case of multiple KRAS mutations acquired during the metastatic phase of CRC, and retrospectively reviewed all patients with CRC, in whom KRAS was analyzed in at least two tumor samples from distinct lesions. METHODS: Genomic DNA purified from paraffin-embedded tissues was used after histological quantification of tumor tissue. The seven KRAS mutations located within codons 12 and 13 were screened using the allelic discrimination assay. RESULTS: A 35-year-old woman with CRC liver metastasis, resistant to all conventional cytotoxic agents, experienced for the first time significant tumor shrinkage while cetuximab was added, allowing hepatic resection. Further liver relapse occurred on cetuximab, but a new hepatic resection was attempted. No mutation in KRAS was detected in the primary colon tumor or in synchronous liver metastases. In contrast, in metachronous liver metastasis samples, two distinct mutations at codon 13 and 12 were detected. No acquired mutations were found in all the other 12 CRC cases with at least two serially performed KRAS analyses. CONCLUSIONS: Our findings suggest that late switch in KRAS mutational status could occur more frequently than currently recognized and account for acquired resistance to anti-EGFR therapies. Prospective studies are warranted to better estimate the incidence of change in KRAS mutational status and assess their clinical relevance.
    Mots-clés : Adult Antineoplastic Agents/pharmacology/therapeutic use Colorectal Neoplasms/drug therapy/genetics/ pathology Drug Resistance, Multiple Drug Resistance, Neoplasm Female Follow-Up Studies Humans Liver Neoplasms/drug therapy/genetics/ secondary Mutation Neoplasm Metastasis Proto-Oncogene Proteins/ genetics Retrospective Studies ras Proteins/ genetics.
    Note Note
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    <p>20361188</p>
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    <p>20361188</p>
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    <p>20361188</p>

  • Bouley, J, Pionneau, C, Varinot, J, Biard, D, Genestie, C, Antoine, M, Coulet, F, Stern, MH, Stoppa-Lyonnet, D & Soubrier, F 2010, « Proteomic analysis of BRCA1-depleted cell line reveals a putative role for replication protein A2 up-regulation in BRCA1 breast tumor development », Proteomics Clinical Applications, vol. 4, no. 5, p. 489-498, viewed sans date, <<Go to ISI>://WOS:000278432700002>.
    Résumé : Purpose: Germline mutations in BRCA1 result in a strong predisposition to breast cancer, with frequent loss of heterozygosity of the remaining wild-type allele. The development of BRCA1 tumors is likely to depend on additional genetic alterations and gene expression changes which follow growth and DNA repair defects associated with BRCA1 deficiency. The identification of these modifications offers an opportunity to find surrogate markers of BRCA1 tumors. Here, we sought to identify differentially expressed proteins related to BRCA1 depletion. Experimental design: We used isogenic HeLa cells either stably knocked-down or not for BRCA1 (BRCA1(KD)) and compared protein profiles of these cells by DIGE. Results: We detected increased levels of Replication protein A2 (RPA2) in BRCA1(KD) cells as compared to control cells. RPA2 is an essential protein required for DNA replication and repair. We further demonstrated that depletion of RPA2 subunit delays growth of BRCA1KD respect to isogenic control cells. Strikingly, elevated levels of RPA2 were more frequently observed in BRCA1 tumors when triple-negative tumors from BRCA1 mutation carriers n = 13) and non-carriers (n = 36) were stained in situ for RPA2. Conclusions and clinical relevance: RPA2 up-regulation may thus be involved in the growth and/or survival of BRCA1 tumor cells and useful in immunohistochemical discrimination of triple-negative BRCA1 tumors.
  • Brechot, C, Kremsdorf, D, Soussan, P, Pineau, P, Dejean, A, Paterlini-Brechot, P & Tiollais, P 2010, « Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC): molecular mechanisms and novel paradigms », Pathol Biol (Paris), vol. 58, no. 4, p. 278-87.
    Résumé : Chronic hepatitis B (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Most HCCs complicate the evolution of an active or inactive cirrhosis. However, some tumors occur on livers with minimal histological changes; the prevalence of such cases varies from one geographical region to the other, being much higher in the Southern half of Africa (around 40% of HCCs) than in Asia, America and Europe, where at least 90% of HCCs are associated in the cirrhosis. This heterogeneity is probably a reflection of different environmental and genetic factors. This review will summarise the current knowledge on the mechanisms involved in HBV-related liver carcinogenesis. It will show in particular how viruses can be viewed as tools to discover and dissect new cellular pathways involved in cancer development and emphasize the potential synergistic effects between HBV and hepatitis C virus (HCV), as well as between viral infections and other environmental factors, such as alcohol.
    Mots-clés : Alcoholism Animals Carcinoma, Chronic/ complications/virology Hepatitis C/complications Humans Liver Cirrhosis/complications/virology Liver Neoplasms/epidemiology/ genetics/ virology Mice Risk Factors Trans-Activators/genetics/physiology, Hepatocellular/epidemiology/ genetics/ virology DNA, Viral/blood Hepacivirus Hepatitis B Surface Antigens/blood Hepatitis B virus/genetics Hepatitis B.


  • Cailleteau, L, Estrach, S, Thyss, R, Boyer, L, Doye, A, Domange, B, Johnsson, N, Rubinstein, E, Boucheix, C, Ebrahimian, T, Silvestre, J-S, Lemichez, E, Meneguzzi, G & Mettouchi, A 2010, « alpha2beta1 integrin controls association of Rac with the membrane and triggers quiescence of endothelial cells », J Cell Sci, vol. 123, no. Pt 14, p. 2491-501, viewed sans date, .
    Résumé : Integrin receptors and their extracellular matrix ligands provide cues to cell proliferation, survival, differentiation and migration. Here, we show that alpha2beta1 integrin, when ligated to the basement membrane component laminin-1, triggers a proliferation arrest in primary endothelial cells. Indeed, in the presence of strong growth signals supplied by growth factors and fibronectin, alpha2beta1 engagement alters assembly of mature focal adhesions by alpha5beta1 and leads to impairment of downstream signaling and cell-cycle arrest in the G1 phase. Although the capacity of alpha5beta1 to signal for GTP loading of Rac is preserved, the joint engagement of alpha2beta1 interferes with membrane anchorage of Rac. Adapting the 'split-ubiquitin' sensor to screen for membrane-proximal alpha2 integrin partners, we identified the CD9 tetraspanin and further establish its requirement for destabilization of focal adhesions, control of Rac subcellular localization and growth arrest induced by alpha2beta1 integrin. Altogether, our data establish that alpha2beta1 integrin controls endothelial cell commitment towards quiescence by triggering a CD9-dependent dominant signaling.
    Note Note
    <p>20592186</p>
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    <p>20592186</p>
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    <p>20592186</p>
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    <p>20592186</p>
  • Cairo, S, Wang, Y, de Reynies, A, Duroure, K, Dahan, J, Redon, MJ, Fabre, M, McClelland, M, Wang, XW, Croce, CM & Buendia, MA 2010, « Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer », Proc Natl Acad Sci U S A, vol. 107, no. 47, p. 20471-6.
    Résumé : Myc activation has been implicated in the pathogenesis of hepatoblastoma (HB), a rare embryonal neoplasm derived from liver progenitor cells. Here, microRNA (miR) expression profiling of 65 HBs evidenced differential patterns related to developmental stage and Myc activity. Undifferentiated aggressive HBs overexpressed the miR-371-3 cluster with concomitant down-regulation of the miR-100/let-7a-2/miR-125b-1 cluster, evoking an ES cell expression profile. ChIP and Myc inhibition assays in hepatoma cells demonstrated that both miR clusters are regulated by Myc in an opposite manner. We show that the two miR clusters exert antagonistic effects on cell proliferation and tumorigenicity. Moreover, their combined deregulation cooperated in modulating the hepatic tumor phenotype, implicating stem cell-like regulation of Myc-dependent miRs in poorly differentiated HBs. Importantly, a four-miR signature representative of these clusters efficiently stratified HB patients, and when applied to 241 hepatocellular carcinomas (HCCs), it identified invasive tumors with a poor prognosis. Our data argue that Myc-driven reprogramming of miR expression patterns contributes to the aggressive phenotype of liver tumors originating from hepatic progenitor cells.
    Mots-clés : Cell Line, Neoplastic/ physiology Hepatoblastoma/ genetics Humans Liver Neoplasms/ genetics MicroRNAs/ genetics/ metabolism Microarray Analysis Polymerase Chain Reaction Proto-Oncogene Proteins c-myc/ metabolism, Tumor Chromatin Immunoprecipitation France Gene Expression Profiling Gene Expression Regulation.
    Note Note
    <p>2996672</p>
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    <p>2996672</p>
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    <p>2996672</p>
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    <p>2996672</p>
  • Calmus, Y, Kamar, N, Gugenheim, J, Duvoux, C, Ducerf, C, Wolf, P, Samuel, D, Vanlemmens, C, Neau-Cransac, M, Salame, E, Chazouilleres, O, Declerck, N, Pageaux, GP, Dubel, L & Rostaing, L 2010, « Assessing renal function with daclizumab induction and delayed tacrolimus introduction in liver transplant recipients », Transplantation, vol. 89, no. 12, p. 1504-10.
    Résumé : BACKGROUND: Calcineurin inhibitor-induced renal dysfunction is a major problem in liver transplantation. Interleukin-2 receptor antagonist induction followed by delayed tacrolimus (Tac) administration may minimize the renal insult without compromising immunoprotection. METHODS: This open, randomized, multicenter trial evaluated the benefit of daclizumab induction with delayed Tac on renal function at 6 months; an observational study was continued for 18 months. Liver transplant patients with a 12-hr serum creatinine (SrC) level less than 180 micromol/L received either delayed Tac with daclizumab induction (n=98) or standard Tac (n=101) both combined with mycophenolate mofetil and steroids. The primary endpoint was the incidence of SrC level more than 130 micrommol/L at 6 months. RESULTS: The incidence was 22.4% with delayed Tac and 29.7% with standard Tac (P=ns), which remained unchanged at 12 months (21.6% and 23.9%) but increasing slightly at 24 months (29.0% and 32.9%), respectively. A post hoc analysis of renal function was done based on patients stratification by SrC at 12 hr (<or=100micromol/L or >100 micromol/L) showing no difference in SrC values at 6 months regardless of the 12-hr values despite a trend toward better estimated glomerular filtration rate for patients with 12-hr value less than 100 micromol/L in the delayed Tac group. Biopsy-proven acute rejection was similar at 6 months (17.5% and 18.75%), 12 months (23.5% and 23.8%), and 24 months (24.5% and 25.7%), respectively. Patient and graft survival in both groups were comparable and good. Similar types and incidences of adverse events were reported in both groups at all time. CONCLUSIONS: Delay of Tac does not benefit renal function in liver transplant recipients with a good renal function at baseline.
    Mots-clés : Adult Antibodies, Monoclonal, Monoclonal/ therapeutic use Antibodies.

  • Capron, C, Lacout, C, Lecluse, Y, Jalbert, V, Chagraoui, H, Charrier, S, Galy, A, Bennaceur-Griscelli, A, Cramer-Borde, E & Vainchenker, W 2010, « A major role of TGF-beta 1 in the homing capacities of murine hematopoietic stem cell/progenitors », Blood, vol. 116, no. 8, p. 1244-1253, viewed sans date, .
    Résumé : Transforming growth factor-beta 1 (TGF-beta 1) is a pleiotropic cytokine with major in vitro effects on hematopoietic stem cells (HSCs) and lymphocyte development. Little is known about hematopoiesis from mice with constitutive TGF-beta 1 inactivation largely because of important embryonic lethality and development of a lethal inflammatory disorder in TGF-beta 1(-/-) pups, making these studies difficult. Here, we show that no sign of the inflammatory disorder was detectable in 8- to 10-day-old TGF-beta 1(-/-) neonates as judged by both the number of T-activated and T-regulator cells in secondary lymphoid organs and the level of inflammatory cytokines in sera. After T-cell depletion, the inflammatory disease was not transplantable in recipient mice. Bone marrow cells from 8- to 10-day-old TGF-beta 1(-/-) neonates showed strikingly impaired short-and long-term reconstitutive activity associated with a parallel decreased in vivo homing capacity of lineage negative (Lin(-)) cells. In addition an in vitro-reduced survival of immature progenitors (Lin(-) Kit(+) Sca(+)) was observed. Similar defects were found in liver cells from TGF-beta 1(-/-) embryos on day 14 after vaginal plug. These data indicate that TGF-beta 1 is a critical regulator for in vivo homeostasis of the HSCs, especially for their homing potential. (Blood. 2010; 116(8): 1244-1253)
  • Carbonell, N, Verstuyft, C, Massard, J, Letierce, A, Cellier, C, Deforges, L, Saliba, F, Delchier, JC & Becquemont, L 2010, « CYP2C9*3 Loss-of-Function Allele Is Associated With Acute Upper Gastrointestinal Bleeding Related to the Use of NSAIDs Other Than Aspirin », Clin Pharmacol Ther, vol. 87, no. 6, p. 693-8.
    Résumé : Nonsteroidal anti-inflammatory drugs (NSAIDs), other than aspirin, are to some extent metabolized by cytochrome P450 2C9 (CYP2C9). The CYP2C9 359Leu (CYP2C9*3) loss-of-function allele could be a risk factor for acute upper gastrointestinal bleeding (AUGIB) related to the use of NSAIDs other than aspirin. To test this hypothesis, we performed a prospective, multicenter, case-case study in patients hospitalized for AUGIB related to the use of NSAIDs. A total of 131 patients had been treated with aspirin and 57 patients had been treated with an NSAID other than aspirin (non-ASP). In the aspirin group, 12 patients (9.2%) had the CYP2C9 359Leu allele as compared with 19 (33.3%) in the non-ASP group (odds ratio (OR) = 5.0; 95% confidence interval 2.2-11.1, P < 0.0001). In a multivariate analysis, CYP2C9 359Leu remained associated with the non-ASP group (OR = 7.2 (2.6-20.3), P = 0.0002) even though 40% of these patients were under treatment with antiulcer drugs at the time of admission. Therefore the results of the study support the hypothesis that the CYP2C9 359Leu allele is a robust risk factor for AUGIB related to the use of NSAIDs other than aspirin.
    Mots-clés : 80 and over Alleles Anti-Inflammatory Agents, Aged Aged.

  • Carvalho, G, Le Guelte, A, Demian, C, Vazquez, A, Gavard, J & Bidere, N 2010, « Interplay between BCL10, MALT1 and IkappaBalpha during T-cell-receptor-mediated NFkappaB activation », J Cell Sci, vol. 123, no. Pt 14, p. 2375-80, viewed sans date, .
    Résumé : T-cell-receptor (TCR) signalling to NFkappaB requires the assembly of a large multiprotein complex containing the serine/threonine kinase CK1alpha, the scaffold protein CARMA1, the heterodimer BCL10-MALT1 (the CBM complex) and the IkappaB kinase complex (IKK). Although the mechanisms regulating recruitment and activation of IKK within the CBM microenvironment have been extensively studied, there is little understanding of how IKK subsequently binds and phosphorylates IkappaBalpha, the inhibitor of NFkappaB, to promote IkappaBalpha ubiquitylation and proteasomal degradation. Here, we show that BCL10, MALT1 and IKK inducibly associate with IkappaBalpha in a complex that is physically distinct from the early CK1alpha-CBM signalosome. This IkappaBalpha-containing complex probably maturates from the CBM, because siRNA-based knockdown of CARMA1, CK1alpha and BCL10 hampered its assembly, leading to a reduction in NFkappaB activation. By contrast, CK1alpha normally recruited both BCL10 and ubiquitylated species of MALT1 when IkappaBalpha levels were reduced. However, knockdown of IkappaBalpha led to an altered ubiquitylation profile of BCL10-MALT1 combined with a defect in MALT1 reorganisation within large cytoplasmic structures, suggesting that, following stimulation, IkappaBalpha might also participate in MALT1 recycling. Altogether, our data suggest a two-step mechanism to connect active IKK to IkappaBalpha, and further unveil a potential role for IkappaBalpha in resetting TCR-mediated signalling.
    Mots-clés : Adaptor Proteins, Antigen, Small Interfering/genetics Receptors, T-Cell/immunology/metabolism T-Lymphocytes/immunology/*metabolism/pathology Transcriptional Activation/genetics Ubiquitination/genetics.

  • Castanier, C & Arnoult, D 2010, « [Mitochondrial dynamics during apoptosis] », Med Sci (Paris), vol. 26, no. 10, p. 830-5, viewed sans date, .
    Résumé : Mitochondria exist as dynamic networks that often change shape and subcellular distribution. The morphology of mitochondria within a cell is controlled by precisely regulated rates of organelle fusion and fission. Several reports have described dramatic alterations in mitochondrial morphology during the early stages of apoptosis: a fragmentation of the network and the cristae remodeling. However, whether this mitochondrial fragmentation is a required step for apoptosis is highly debated. In this review the recent progress in understanding the mechanisms governing mitochondrial morphology during apoptosis and the latest advances connecting the regulation of mitochondrial morphology with apoptosis are discussed.
    Mots-clés : Animals Apoptosis/genetics/*physiology Cytochromes c/metabolism *DNA Fragmentation Humans Mitochondria/genetics/*physiology/ultrastructure Models, Biological Morphogenesis/physiology Organelles/physiology/ultrastructure bcl-2 Homologous Antagonist-Killer Protein/metabolism bcl-2-Associated X Protein/metabolism.

  • Castanier, C, Garcin, D, Vazquez, A & Arnoult, D 2010, « Mitochondrial dynamics regulate the RIG-I-like receptor antiviral pathway », EMBO Rep, vol. 11, no. 2, p. 133-8, viewed sans date, .
    Résumé : The intracellular retinoic acid-inducible gene I-like receptors (RLRs) sense viral ribonucleic acid and signal through the mitochondrial protein mitochondrial antiviral signalling (MAVS) to trigger the production of type I interferons and proinflammatory cytokines. In this study, we report that RLR activation promotes elongation of the mitochondrial network. Mimicking this elongation enhances signalling downstream from MAVS and favours the binding of MAVS to stimulator of interferon genes, an endoplasmic reticulum (ER) protein involved in the RLR pathway. By contrast, enforced mitochondrial fragmentation dampens signalling and reduces the association between both proteins. Our finding that MAVS is associated with a pool of mitofusin 1, a protein of the mitochondrial fusion machinery, suggests that MAVS is capable of regulating mitochondrial dynamics to facilitate the mitochondria-ER association required for signal transduction. Importantly, we observed that viral mitochondria-localized inhibitor of apoptosis, a cytomegalovirus (CMV) antiapoptotic protein that promotes mitochondrial fragmentation, inhibits signalling downstream from MAVS, suggesting a possible new immune modulation strategy of the CMV.
    Mots-clés : Antiviral Agents/*metabolism Cells, Cultured HeLa Cells Humans Immunity, Innate/*physiology Membrane Proteins/metabolism Mitochondria/immunology/*metabolism/*physiology Mitochondrial Proteins/metabolism Organelle Shape/immunology Organelle Size/immunology Protein Binding Receptors, Retinoic Acid/metabolism/*physiology Signal Transduction/immunology Virus Diseases/immunology/metabolism.
    Note Note
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  • Chambrion, C & Le Naour, F 2010, « The tetraspanins CD9 and CD81 regulate CD9P1-induced effects on cell migration », PLoS One, vol. 5, no. 6, p. e11219.
    Résumé : CD9P-1 is a cell surface protein with immunoglobulin domains and an unknown function that specifically associates with tetraspanins CD9 and CD81. Overexpression of CD9P-1 in HEK-293 cells induces dramatic changes in cell spreading and migration on various matrices. Experiments using time-lapse videomicroscopy revealed that CD9P-1 expression has led to higher cell motility on collagen I but lower motility on fibronectin through a beta1-integrins dependent mechanism. On collagen I, the increase in cell motility induced by CD9P-1 expression was found to involve integrin alpha2beta1 and CD9P-1 was observed to associate with this collagen receptor. The generation of CD9P-1 mutants demonstrated that the transmembrane and the cytoplasmic domains are necessary for inducing effects on cell motility. On the other hand, expression of tetraspanins CD9 or CD81 was shown to reverse the effects of CD9P-1 on cell motility on collagen I or fibronectin with a concomitant association with CD9P-1. Thus, the ratio of expression levels between CD9P-1 and its tetraspanin partners can regulate cell motility.
    Mots-clés : Animals Antigens, CD/ metabolism Antigens, CD81 Antigens, Tertiary Rats.
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  • Champion, L, Durrbach, A, Lang, P, Delahousse, M, Chauvet, C, Sarfati, C, Glotz, D & Molina, JM 2010, « Fumagillin for treatment of intestinal microsporidiosis in renal transplant recipients », Am J Transplant, vol. 10, no. 8, p. 1925-30, viewed sans date, .
    Résumé : We report 10 cases of intestinal microsporidiosis due to Enterocytozoon bieneusi in renal transplant (RT) recipients who were treated with fumagillin. All patients presented with afebrile subacute diarrhea (median of 2 weeks), associated with abdominal cramps (n = 5), and weight loss (n = 6), a mean of 68 months after RT. The diagnosis was made by the identification of microsporidial spores in stools with the use of appropriate staining and confirmed by a specific polymerase chain reaction assay for E. bieneusi in 7 patients. Median CD4 cell count was 292 cells/mm(3). All patients received a median of 14 days of oral fumagillin (20 mg tid), and four patients also discontinued or tapered their immunosuppressive regimen (mycophenolate mofetil in 3, and azathioprine in 2). Clinical symptoms resolved rapidly with the clearance of microsporidial spores from stools in all patients. A severe but reversible thrombocytopenia was observed in one patient during fumagillin therapy, and another patient presented with abdominal cramps. Trough levels of tacrolimus measured in seven patients dropped below 5 ng/mL in six of them after 7-14 days of fumagillin. Intestinal microsporidiosis can cause subacute diarrhea in RT recipients. Fumagillin is an effective treatment with an acceptable safety profile, but monitoring of tacrolimus levels is warranted.
    Mots-clés : Adult Aged Cyclohexanes/*therapeutic use *Enterocytozoon Fatty Acids, Parasitic/*drug therapy Kidney Transplantation/*adverse effects Male Microsporidiosis/*drug therapy Middle Aged Retrospective Studies Sesquiterpenes/therapeutic use, Unsaturated/*therapeutic use Female Humans Intestinal Diseases.

  • Chang, CR, Manlandro, CM, Arnoult, D, Stadler, J, Posey, AE, Hill, RB & Blackstone, C 2010, « A lethal de novo mutation in the middle domain of the dynamin-related GTPase Drp1 impairs higher order assembly and mitochondrial division », J Biol Chem, vol. 285, no. 42, p. 32494-503, viewed sans date, .
    Résumé : Mitochondria dynamically fuse and divide within cells, and the proper balance of fusion and fission is necessary for normal mitochondrial function, morphology, and distribution. Drp1 is a dynamin-related GTPase required for mitochondrial fission in mammalian cells. It harbors four distinct domains: GTP-binding, middle, insert B, and GTPase effector. A lethal mutation (A395D) within the Drp1 middle domain was reported in a neonate with microcephaly, abnormal brain development, optic atrophy, and lactic acidemia (Waterham, H. R., Koster, J., van Roermund, C. W., Mooyer, P. A., Wanders, R. J., and Leonard, J. V. (2007) N. Engl. J. Med. 356, 1736-1741). Mitochondria within patient-derived fibroblasts were markedly elongated, but the molecular mechanisms underlying these findings were not demonstrated. Because the middle domain is particularly important for the self-assembly of some dynamin superfamily proteins, we tested the hypothesis that this A395D mutation, and two other middle domain mutations (G350D, G363D) were important for Drp1 tetramerization, higher order assembly, and function. Although tetramerization appeared largely intact, each of these mutations compromised higher order assembly and assembly-dependent stimulation of Drp1 GTPase activity. Moreover, mutant Drp1 proteins exhibited impaired localization to mitochondria, indicating that this higher order assembly is important for mitochondrial recruitment, retention, or both. Overexpression of these middle domain mutants markedly inhibited mitochondrial division in cells. Thus, the Drp1 A395D lethal defect likely resulted in impaired higher order assembly of Drp1 at mitochondria, leading to decreased fission, elongated mitochondria, and altered cellular distribution of mitochondria.
    Mots-clés : Tertiary Recombinant Fusion Proteins/genetics/metabolism Sequence Alignment Two-Hybrid System Techniques.
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  • Chio-Srichan, S, Oudrhiri, N, Bennaceur-Griscelli, A, Turhan, AG, Dumas, P & Refregiers, M 2010, « Toxicity and phototoxicity of Hypocrellin A on malignant human cell lines, evidence of a synergistic action of photodynamic therapy with Imatinib mesylate », Journal of Photochemistry and Photobiology B-Biology, vol. 99, no. 2, p. 100-104, viewed sans date, <<Go to ISI>://WOS:000277820400006>.
    Résumé : Photodynamic therapy combines a photosensitizer, localised preferentially in malignant cells with light activation. Hypocrellin A (HA), a lipid-soluble peryloquinone, is considered as a high potential photosensitizer. We report dose and light irradiation effects of HA on HeLa. Calu and K562 cell lines, the latter including a subclone resistant to Imatinib mesylate (IM, Gleevec). All cell lines and subclones tested are sensitive to HA PDT. In the epithelial tumour cell lines, we observe a significant photosensitizing effect in the presence of HA. In the leukemic K562 cells, HA exposure led to an inhibitory effect, which was not seen in the K562 cells resistant to Imatinib mesylate. However, experiments using IM and HA led to a reversal of IM-resistant phenotype in this cell line, with evidence of a major sensitizing effect of photodynamic therapy. Overall our results suggest a phototoxicity of HA in epithelial cell lines and demonstrate for the first time, a synergy between IM and photodynamic therapy to circumvent IM-resistance. (C) 2010 Elsevier B.V. All rights reserved.

  • Chok, MK, Conti, M, Almolki, A, Ferlicot, S, Loric, S, Durrbach, A, Benoit, G, Droupy, S & Eschwege, P 2010, « Renoprotective potency of amifostine in rat renal ischaemia-reperfusion », Nephrol Dial Transplant, vol. 25, no. 12, p. 3845-51, viewed sans date, .
    Résumé : PURPOSE: Kidneys from haemodynamically unstable donors may suffer from renal ischaemia-reperfusion (RIR) injury. RIR is associated with reactive oxygen species production that induces inflammation and activates the arachidonic acid (AA) pathway which converts AA into prostaglandin E(2). Amifostine was investigated for its renoprotective potential in RIR. MATERIALS AND METHODS: The effect of amifostine (25 mg/kg = 910 mg/m(2)) on the COX pathway, enzymatic antioxidant activity, the lipid peroxidation marker MDA, serum creatinine and apoptosis was determined in rats. Kidneys were subjected to 45 min of ischaemia and 1 or 24 h of reperfusion. Control groups (sham: coeliotomy, no ischaemia; r1: 45 min ischaemia/1 h reperfusion; r2: 45 min ischaemia/24 h reperfusion) were administered physiological saline intraperitoneally, and treated groups (E1: 45 min ischaemia/1 h reperfusion; E2: 45 min ischaemia/24 h reperfusion) received amifostine 30 min before reperfusion. RESULTS: Serum creatinine increased in non-treated control rats: r1 vs sham (1.6-fold; P <0.007), r2 vs sham (2-fold; P <0.007). Amifostine decreased serum creatinine levels in treated rats: E1 vs r1 (8%; P <0.0025), E2 vs r2 (44%; P <0.0025). Amifostine reduced acute tubular necrosis (25%) 24 h after reperfusion: E1 vs r1 (P <0.004), E2 vs r2 (P <0.03) and reduced COX-2 and microsomal prostaglandin E synthase expression: E1 vs r1 (P <0.03), E2 vs r2 (P <0.02). Amifostine decreased MDA (P <0.04) and reduced caspase-3 expression but did not alter enzymatic antioxidant activity after RIR. CONCLUSIONS: Amifostine decreased the degree and severity of tubular damage after reperfusion, probably by scavenging oxygen free radicals and attenuating the cytotoxic effects of inflammatory infiltrates and apoptosis.
    Mots-clés : Animal Necrosis Rats Rats, Sprague-Dawley Reactive Oxygen Species/metabolism Reperfusion Injury/metabolism/pathology/*prevention & control Treatment Outcome.

  • Chomel, JC, Bonnet, ML, Sorel, N, Bertrand, A, Meunier, MC, Melkus, M, Bennaceur-Griscelli, A, Guilhot, F & Turhan, AG 2010, « Persistence of BCR-ABL-Expressing LEUKEMIC STEM CELLS IN Chronic MYELOID LEUKEMIA (CML) PATIENTS IN COMPLETE REMISSION with Undetectable MOLECULAR Disease », Blood, vol. 116, no. 21, p. 386-387, viewed sans date, <<Go to ISI>://WOS:000289662200884>.
    Résumé : Chomel, Jean-Claude Bonnet, Marie Laure Sorel, Nathalie Bertrand, Angelina Meunier, Marie Claude Melkus, Michael Bennaceur-Griscelli, Annelise Guilhot, Francois Turhan, Ali G. 52nd Annual Meeting of the American-Society-of-Hematology (ASH) Dec 04-07, 2010 Orlando, FL Amer Soc Hematol

  • Chomel, J-C, Sorel, N, Bonnet, M-L, Bertrand, A, Brizard, F, Roy, L, Guilhot, F & Turhan, AG 2010, « Extensive analysis of the T315I substitution and detection of additional ABL mutations in progenitors and primitive stem cell compartment in a patient with tyrosine kinase inhibitor-resistant chronic myeloid leukemia », Leuk Lymphoma, vol. 51, no. 11, p. 2103-11, viewed sans date, .
    Résumé : Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML). However, resistance is occasionally observed, mainly due to mutations within the BCR-ABL kinase domain. The T315I substitution confers complete resistance to all TKIs commonly used in clinical practice. To date, the hierarchical level of stem cells in which this mutation initially appears has not been studied. The aim of this study was to evaluate the behavior of T315I mutated cells and to study the presence of potential additional mutations in progenitors and stem cells from a patient with CML. A comprehensive analysis of BCR-ABL(315I) mRNA expressing cells in mononuclear cells, in CD34+ cell populations, and in their primitive long-term culture-initiating cell (LTC-IC) derived progenitors was performed. We show that the T315I substitution arises in primitive Ph1 stem cells without altering their myeloid and erythroid terminal differentiation potential. Leukemic cells expressing a T315I mutated BCR-ABL display a progressive decline in LTC-IC assays as described for non-mutated CML cells at diagnosis. Finally, in our experiments, additional non-315 ABL mutations were identified in hematopoietic stem cell colonies. This observation is suggestive of genetic instability affecting CML progenitors.
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  • Christin-Maitre, S & Tachdjian, G 2010, « Genome-wide association study and premature ovarian failure », Annales D Endocrinologie, vol. 71, no. 3, p. 218-221, viewed sans date, <<Go to ISI>://WOS:000277894800019>.
    Résumé : Premature ovarian failure (POF) is defined as an amenorrhea for more than 4 months, associated with elevated gonadotropins, usually higher than 20 mIU/ml, occurring in a woman before the age of 40. Some candidate genes have been identified in the past 15 years, such as FOXL2, FSHR, BMP15, GDF9, Xfra premutation. However, POF etiology remains unknown in more than 90% of cases. The first strategy to identify candidate gene, apart from studying genes involved in ovarian failure in animal models, relies on the study of X chromosome deletions and X;autosome translocations in patients. The second strategy is based on linkage analysis, the third one on Comparative Genomic Hybridization (CGH) array. The latest strategy relies on Genome-Wide Association Studies (GWAS). This technique consists in screening single nucleotide polymorphisms (SNPs) in patients and controls. So far, three studies have been performed and have identified different loci potentially linked to POF, such as PTHB1 and ADAMTS19. However, replications in independent cohorts need to be performed. GWAS studies on large cohorts of women with POF should find new candidate genes in the near future. (C) 2010 Published by Elsevier Masson SAS.

  • Coant, N, Ben Mkaddem, S, Pedruzzi, E, Guichard, C, Treton, X, Ducroc, R, Freund, JN, Cazals-Hatem, D, Bouhnik, Y, Woerther, PL, Skurnik, D, Grodet, A, Fay, M, Biard, D, Lesuffleur, T, Deffert, C, Moreau, R, Groyer, A, Krause, KH, Daniel, F & Ogier-Denis, E 2010, « NADPH Oxidase 1 Modulates WNT and NOTCH1 Signaling To Control the Fate of Proliferative Progenitor Cells in the Colon », Molecular and Cellular Biology, vol. 30, no. 11, p. 2636-2650, viewed sans date, <<Go to ISI>://WOS:000277558300006>.
    Résumé : The homeostatic self-renewal of the colonic epithelium requires coordinated regulation of the canonical Wnt/beta-catenin and Notch signaling pathways to control proliferation and lineage commitment of multipotent stem cells. However, the molecular mechanisms by which the Wnt/beta-catenin and Notch1 pathways interplay in controlling cell proliferation and fate in the colon are poorly understood. Here we show that NADPH oxidase 1 (NOX1), a reactive oxygen species (ROS)-producing oxidase that is highly expressed in colonic epithelial cells, is a pivotal determinant of cell proliferation and fate that integrates Wnt/beta-catenin and Notch1 signals. NOX1-deficient mice reveal a massive conversion of progenitor cells into postmitotic goblet cells at the cost of colonocytes due to the concerted repression of phosphatidylinositol 3-kinase (PI3K)/AKT/Wnt/beta-catenin and Notch1 signaling. This conversion correlates with the following: (i) the redox-dependent activation of the dual phosphatase PTEN, causing the inactivation of the Wnt pathway effector beta-catenin, and (ii) the downregulation of Notch1 signaling that provokes derepression of mouse atonal homolog 1 (Math1) expression. We conclude that NOX1 controls the balance between goblet and absorptive cell types in the colon by coordinately modulating PI3K/AKT/Wnt/beta-catenin and Notch1 signaling. This finding provides the molecular basis for the role of NOX1 in cell proliferation and postmitotic differentiation.

  • Corruble, E, Durrbach, A, Charpentier, B, Lang, P, Amidi, S, Dezamis, A, Barry, C & Falissard, B 2010, « Progressive increase of anxiety and depression in patients waiting for a kidney transplantation », Behav Med, vol. 36, no. 1, p. 32-6, viewed sans date, .
    Résumé : Because of the increasing duration of the waiting-list period for kidney transplantation, we hypothesized that this period was associated with a progressive increase in depressive and anxious symptoms in patients waitlisted for a kidney transplantation. In a prospective naturalistic follow-up cohort study, 390 patients on a waiting list for kidney transplant were assessed for anxiety and depression at the time of inclusion on the waiting list, 12 months later, 24 months later, and 3 months after transplantation. The Beck Depression Inventory-Short Version (Short-BDI) and the State and Trait Anxiety Inventory (STAI) were used for this assessment. We found that in this sample, anxious and depressive symptoms progressively increased before transplantation and showed a marked decrease after transplantation. We conclude that to limit anxious and depressive symptoms in patients waiting for a kidney transplantation, the duration of the waiting list period should be reduced as far as possible.
    Mots-clés : *Anxiety, *Depression, *Waiting, Aged, Analysis, Diseases/psychology/surgery, Factors, Female, Follow-Up, Humans, Kidney, Lists, Male, Middle, of, Prospective, Psychiatric, Rating, Scales, Status, Studies, Time, Transplantation/*psychology, Variance.
  • de Carvalho, L, Parise, ER & Samuel, D 2010, « Factors associated with nutritional status in liver transplant patients who survived the first year after transplantation », J Gastroenterol Hepatol, vol. 25, no. 2, p. 391-6.
    Résumé : BACKGROUND AND AIMS: Most studies published focus on the evaluation of the impact of nutritional status on the morbidity and mortality during the immediate postoperative period or on the short-term evolution of liver transplant patients. The aim of the study was to evaluate long-term trends in nutritional status. METHODS: Seventy patients consecutively submitted to liver transplantation were studied. Nutritional assessment was performed the day before transplantation and the 45, 90, 180 and 365 days after transplantation, consisting of determination of dietary intake, anthropometric and biochemical analysis. RESULTS: Sixty-nine percent of the patients presented with malnutrition on the day before liver transplantation, decreasing to 44% at end of the first year. The prevalence of protein-calorie malnutrition (PCM) was 63% at 90 days post-transplant. A significant difference of PCM was observed between patients with cirrhosis and non-cirrhotic disease (53.6% x 100%) at 90 days post-transplant. The pre-transplant nutritional diagnosis and 90-day calorie intake were identified as variables independently associated with nutritional status at 90 days post-transplant. The variables independently associated with nutritional status in the 1-year assessment were pre-transplant PCM and 365-day calorie requirements. CONCLUSION: No influence on nutritional status was observed for peri- or postoperative factors after 3 or 12 months of follow up. As expected, dietary factors, especially adequate calorie intake, were always associated with nutritional status during all periods analyzed.
    Mots-clés : Adult, Aged, Assessment, Biological, Body, Chi-Square, Communicable, Diseases/etiology, Distribution, Energy, etiology/physiopathology, Factors, Female, Graft, Humans, Index, Intake, Liver, Logistic, Male, Malnutrition/blood/, Markers/blood, Mass, Middle, Models, Nutrition, Nutritional, Outcome, Protein-Energy, Risk, Status, Survival, Time, Transplantation, Treatment, Young.

  • de Haas, RJ, Adam, R, Wicherts, DA, Azoulay, D, Bismuth, H, Vibert, E, Salloum, C, Perdigao, F, Benkabbou, A & Castaing, D 2010, « Comparison of simultaneous or delayed liver surgery for limited synchronous colorectal metastases », Br J Surg, vol. 97, no. 8, p. 1279-89, viewed sans date, .
    Résumé : BACKGROUND: The optimal surgical strategy for patients with synchronous colorectal liver metastases (CLMs) is still unclear. The aim of this study was to compare simultaneous colorectal and hepatic resection with a delayed strategy in patients who had a limited hepatectomy (fewer than three segments). METHODS: All patients with synchronous CLMs who underwent limited hepatectomy between 1990 and 2006 were included retrospectively. Short-term outcome, overall and progression-free survival were compared in patients having simultaneous colorectal and hepatic resection and those treated by delayed hepatectomy. RESULTS: Of 228 patients undergoing hepatectomy for synchronous CLMs, 55 (24.1 per cent) had a simultaneous colorectal resection and 173 (75.9 per cent) had delayed hepatectomy. The mortality rate following hepatectomy was similar in the two groups (0 versus 0.6 per cent respectively; P = 0.557), but cumulative morbidity was significantly lower in the simultaneous group (11 per cent versus 25.4 per cent in the delayed group; P = 0.015). Three-year overall and progression-free survival rates were 74 and 8 per cent respectively in the simultaneous group, compared with 70.3 and 26.1 per cent in the delayed group (overall survival: P = 0.871; progression-free survival: P = 0.005). Significantly more recurrences were observed in the simultaneous group at 3 years (85 versus 63.6 per cent; P = 0.002); a simultaneous strategy was an independent predictor of recurrence. CONCLUSION: Combining colorectal resection with a limited hepatectomy is safe in patients with synchronous CLMs and associated with less cumulative morbidity than a delayed procedure. However, the combined strategy has a negative impact on progression-free survival.
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  • de Haas, RJ, Wicherts, DA, Flores, E, Ducreux, M, Lévi, F, Paule, B, Azoulay, D, Castaing, D, Lemoine, A & Adam, R 2010, « Tumor marker evolution: comparison with imaging for assessment of response to chemotherapy in patients with colorectal liver metastases », Ann Surg Oncol, vol. 17, no. 4, p. 1010-23, viewed sans date, .
    Résumé : BACKGROUND: As the real clinical significance of carcinoembryonic antigen (CEA) and carbohydrate antigen 19.9 (CA19.9) evolution during preoperative chemotherapy for colorectal liver metastases (CLM) is still unknown, we explored the correlation between biological and radiological response to chemotherapy, and their comparative impact on outcome after hepatectomy. METHODS: All patients resected for CLM at our hospital between 1990 and 2004 with the following eligibility criteria were included in the study: (1) preoperative chemotherapy, (2) complete resection of CLM, (3) no extrahepatic disease, and (4) elevated baseline tumor marker values. A 20% change of tumor marker levels while on chemotherapy was used to define biological response (decrease) or progression (increase). Correlation between biological and radiological response at computed tomography (CT) scan, and their impact on overall survival (OS) and progression-free survival (PFS) after hepatectomy were determined. RESULTS: Among 119 of 695 consecutive patients resected for CLM who fulfilled the inclusion criteria, serial CEA and CA19.9 were available in 113 and 68 patients, respectively. Of patients with radiological response or stabilization, 94% had similar biological evolution for CEA and 91% for CA19.9. In patients with radiological progression, similar biological evolution was observed in 95% of cases for CEA and in 64% for CA19.9. On multivariate analysis, radiological response (but not biological evolution) independently predicted OS. However, progression of CA19.9, but not radiological response, was an independent predictor of PFS. CONCLUSIONS: In patients with CLM and elevated tumor markers, biological response is as accurate as CT imaging to assess "clinical" response to chemotherapy. With regards to PFS, CA19.9 evolution has even better prognostic value than does radiological response. Assessment of tumor markers could be sufficient to evaluate chemotherapy response in a nonsurgical setting, limiting the need of repeat imaging.
    Mots-clés : Biological/ metabolism, X-Ray Computed Treatment Outcome Tumor Markers.
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  • de Haas, RJ, Wicherts, DA, Salloum, C, Andreani, P, Sotirov, D, Adam, R, Castaing, D & Azoulay, D 2010, « Long-term outcomes after hepatic resection for colorectal metastases in young patients », Cancer, vol. 116, no. 3, p. 647-58, viewed sans date, .
    Résumé : BACKGROUND: Long-term outcomes after hepatectomy for colorectal liver metastases in relatively young patients are still unknown. The aim of the current study was to evaluate long-term outcomes in patients < or = 40 years old, and to compare them with patients >40 years old. METHODS: All consecutive patients who underwent hepatectomy for colorectal liver metastases at the authors' hospital between 1990 and 2006 were included in the study. Patients < or = 40 years old were compared with all other patients treated during the same period. Overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS) rates were determined, and prognostic factors were identified. RESULTS: In total, 806 patients underwent hepatectomy for colorectal liver metastases, of whom 56 (7%) were aged < or = 40 years. Among the young patients, more colorectal liver metastases were present at diagnosis, and they were more often diagnosed synchronous with the primary tumor. Five-year OS was 33% in young patients, compared with 51% in older patients (P = .12). Five-year PFS was 2% in young patients, compared with 16% in older patients (P < .001). DFS rates were comparable between the groups (17% vs 23%, P = .10). At multivariate analysis, age < or = 40 years was identified as an independent predictor of poor PFS. CONCLUSIONS: In young patients, colorectal liver metastases seem to be more aggressive, with a trend toward lower OS, more disease recurrences, and a significantly shorter PFS after hepatectomy. However, DFS rates were comparable between young and older patients, owing to an aggressive multimodality treatment approach, consisting of chemotherapy and repeat surgery. Therefore, physicians should recognize the poor outcome of colorectal liver metastases in young patients and should consider an aggressive approach to diagnosis and early treatment.
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  • de Preobrajensky, N, Mrejen, S, Adam, R, Ayello-Scheer, S, Gendron, G, Rodallec, T, Sahel, J-A & Barale, P-O 2010, « 23-Gauge Transconjunctival Sutureless Vitrectomy: A Retrospective Study of 164 Consecutive Cases », J Fr Ophtalmol, vol. 33, no. 2, p. 99-104, viewed sans date, .
    Résumé : PURPOSE: To describe our initial experience and to evaluate the outcomes of patients treated with 23-gauge transconjunctival sutureless vitrectomy for a variety of vitreoretinal conditions. METHODS: A single-center, retrospective chart review of 164 consecutive 23-gauge vitrectomy cases done by five vitreoretinal surgeons at the CHNO des XV-XX from May 2006 through December 2007. The main outcome measures included visual acuity and intraoperative and postoperative complications. RESULTS: The mean follow-up duration was 145 days. Mean overall acuity improved from 20/410 (0.5/10) at baseline to 20/101 (2/10) (p<0.0001) and the improvement in visual acuity was statistically significant for patients with macular hole, epiretinal membranes, retinal detachment, nonclearing vitreous hemorrhage, and silicone oil removal. There was a single case of intraoperative retinal tear. There were no postoperative complications of endophthalmitis or choroidal effusion and three cases of hypotony, which resolved spontaneously. Thirty-six of 80 phakic eyes had worsening of cataract, 29 of which occurred in the 1st postoperative month. Twenty patients had cataract surgery during the follow-up. Postoperative retinal detachment occurred in two cases after surgery for nonclearing vitreous hemorrhage. Retinal re-detachment after surgery for retinal detachment occurred in nine of 66 cases (14%). CONCLUSIONS: Twenty-three-gauge transconjunctival sutureless vitrectomy is an effective surgical technique for a variety of vitreoretinal surgical indications. The safety and efficacy profile compared favorably with the published literature on 20-gauge surgery.
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  • DeGeer, D, Gallipoli, P, Chen, M, Sloma, I, Jorgensen, H, Forrest, D, Lambie, K, Nakamoto, H, Saw, KM, Chan, M, Newmarch, K, Zhou, L, Turhan, AG, Arlinghaus, RB, Eaves, AC, Eaves, CJ, Holyoake, TL & Jing, XY 2010, « Combined Targeting of BCR-ABL and JAK2 with ABL and JAK2 Inhibitors Is Effective Against CML Patients' Leukemic Stem/Progenitor Cells », Blood, vol. 116, no. 21, p. 1393-1394, viewed sans date, <<Go to ISI>://WOS:000289662203735>.
    Résumé : DeGeer, Donna Gallipoli, Paolo Chen, Min Sloma, Ivan Jorgensen, Heather Forrest, Donna Lambie, Karen Nakamoto, Helen Saw, Kyi Min Chan, Matthew Newmarch, Kathleen Zhou, Leon Turhan, Ali G. Arlinghaus, Ralph B. Eaves, Allen C. Eaves, Connie J. Holyoake, Tessa L. Jing, Xiaoyan 52nd Annual Meeting of the American-Society-of-Hematology (ASH) Dec 04-07, 2010 Orlando, FL Amer Soc Hematol
  • Degos, F, Perez, P, Roche, B, Mahmoudi, A, Asselineau, J, Voitot, H & Bedossa, P 2010, « Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study) », J Hepatol, vol. 53, no. 6, p. 1013-21.
    Résumé : BACKGROUND & AIMS: The diagnostic accuracy of non-invasive liver fibrosis tests that may replace liver biopsy in patients with chronic hepatitis remains controversial. We assessed and compared the accuracy of FibroScan(R) and that of the main biomarkers used for predicting cirrhosis and significant fibrosis (METAVIR >/= F2) in patients with chronic viral hepatitis. METHODS: A multicenter prospective cross-sectional diagnostic accuracy study was conducted in the Hepatology departments of 23 French university hospitals. Index tests and reference standard (METAVIR fibrosis score on liver biopsy) were measured on the same day and interpreted blindly. Consecutive patients with chronic viral hepatitis (hepatitis B or C virus, including possible Human Immunodeficiency Virus co-infection) requiring liver biopsy were recruited in the study. RESULTS: The analysis was first conducted on the total population (1839 patients), and after excluding 532 protocol deviations, on 1307 patients (non-compliant FibroScan(R) examinations). The overall accuracy of FibroScan(R) was high (AUROC 0.89 and 0.90, respectively) and significantly higher than that of biomarkers in predicting cirrhosis (AUROC 0.77-0.86). All non-invasive methods had a moderate accuracy in predicting significant fibrosis (AUROC 0.72-0.78). Based on multilevel likelihood ratios, non-invasive tests provided a relevant gain in the likelihood of diagnosis in 0-60% of patients (cirrhosis) and 9-30% of patients (significant fibrosis). CONCLUSIONS: The diagnostic accuracy of non-invasive tests was high for cirrhosis, but poor for significant fibrosis. A clinically relevant gain in the likelihood of diagnosis was achieved in a low proportion of patients. Although the diagnosis of cirrhosis may rely on non-invasive tests, liver biopsy is warranted to diagnose intermediate stages of fibrosis.
    Mots-clés : Adult Biological Markers/blood Biopsy, Chronic/blood/diagnosis Hepatitis, Chronic/blood/diagnosis Hepatitis C, Human/blood/ diagnosis Humans Liver Cirrhosis/blood/ diagnosis Male Middle Aged Predictive Value of Tests Prospective Studies, Needle Cross-Sectional Studies Elasticity Imaging Techniques/ methods Female France Hepatitis B, Viral.

  • Deroure, B, Kamar, N, Depreneuf, H, Jacquet, A, Francois, H, Charpentier, B, Rostaing, L & Durrbach, A 2010, « Expanding the criteria of renal kidneys for transplantation: use of donors with acute renal failure », Nephrol Dial Transplant, vol. 25, no. 6, p. 1980-6, viewed sans date, .
    Résumé : BACKGROUND: Increased numbers of patients waiting for renal transplantation have led to widening selection criteria for grafts. Thus, we have evaluated the outcome of transplanted kidneys procured in the presence of acute renal failure (ARF). METHODS: Transplant patients (n = 52) with a kidney procured with ARF were studied. Clinical data from donors and recipients, serum creatinine (SCr), creatinine clearance [estimated glomerular filtration rate (eGFR)], cold ischaemia duration, time to urine flow recovery or renal function recovery, and the number of haemodialysis sessions, were collected retrospectively. RESULTS: Mean donor age was 45.7 +/- 12.7 years, and the mean SCr at the time of harvesting was 276.3 +/- 104.2 micromol/l. Recipients' mean age was 51.1 +/- 12.1 years. After transplantation, recovery of renal function was observed after 7.6 +/- 7.1 days, and required 1.9 +/- 3.0 haemodialysis sessions. SCr was 124.6 +/- 49.5 micromol/l, and eGFR was 56.2 +/- 19.8 ml/min at last follow-up. eGFR was significantly lower if the donor's death was due to stroke or cerebral haemorrhage (CH), or if the donors had previous cardiovascular disease (CVD) (P < 0.02). Patients with eGFR of <50 ml/min (n = 23) had donors who were older, and whose cause of death was more frequently related to CVD factors or to CH/stroke (P < 0.03). There were no significant differences between the two groups regarding age of recipient, gender of the donor or recipient, cold ischaemia time, occurrence of cardiac arrest, collapse or acute rejection. Linear regression analysis indicated that donor age and occurrence of acute rejection were independent factors associated with eGFR. CONCLUSIONS: ARF before organ procurement does not have a negative effect on subsequent renal function. However, old age, CVD risk factors or CH, and late renal function recovery after transplantation are correlated with subsequent lower renal function. Thus, renal grafts with ARF can be used for renal transplantations.
    Mots-clés : Acute Kidney Injury/*physiopathology Adolescent Adult Aged Cadaver Female France Glomerular Filtration Rate Graft Rejection/etiology Humans Kidney Failure, Chronic/physiopathology/surgery *Kidney Transplantation/adverse effects/physiology Male Middle Aged Patient Selection Risk Factors *Tissue Donors *Tissue and Organ Procurement Treatment Outcome Young Adult.
  • Desbois, D, Couturier, E, Mackiewicz, V, Graube, A, Letort, MJ, Dussaix, E & Roque-Afonso, AM 2010, « Epidemiology and genetic characterization of hepatitis A virus genotype IIA », J Clin Microbiol, vol. 48, no. 9, p. 3306-15.
    Résumé : Three hepatitis A virus (HAV) genotypes, I, II, and III, divided into subtypes A and B, infect humans. Genotype I is the most frequently reported, while genotype II is hardly ever isolated, and its genetic diversity is unknown. From 2002 to 2007, a French epidemiological survey of HAV identified 6 IIA isolates, mostly from patients who did not travel abroad. The possible African origin of IIA strains was investigated by screening the 2008 mandatory notification records of HAV infection: 171 HAV strains from travelers to West Africa and Morocco were identified. Genotyping was performed by sequencing of the VP1/2A junction in 68 available sera. Entire P1 and 5' untranslated regions of IIA strains were compared to reference sequences of other genotypes. The screening retrieved 5 imported IIA isolates. An additional autochthonous case and 2 more African cases were identified in 2008 and 2009, respectively. A total of 14 IIA isolates (8 African and 6 autochthonous) were analyzed. IIA sequences presented lower nucleotide and amino acid variability than other genotypes. The highest variability was observed in the N-terminal region of VP1, while for other genotypes the highest variability was observed at the VP1/2A junction. Phylogenetic analysis identified 2 clusters, one gathering all African and two autochthonous cases and a second including only autochthonous isolates. In conclusion, most IIA strains isolated in France are imported by travelers returning from West Africa. However, the unexplained contamination mode of autochthonous cases suggests another, still to be discovered geographical origin or a French reservoir to be explored.
    Mots-clés : 5' Untranslated Regions Adult Cluster Analysis France/epidemiology Genotype Hepatitis A/ epidemiology/ virology Hepatitis A Virus, DNA Sequence Homology Travel Viral Structural Proteins/genetics, Human/ classification/ genetics/isolation & purification Humans Middle Aged Molecular Epidemiology Molecular Sequence Data Phylogeny RNA, Viral/genetics Sequence Analysis.
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  • Dos Santos, A, Court, M, Thiers, V, Sar, S, Guettier, C, Samuel, D, Brechot, C, Garin, J, Demaugre, F & Masselon, CD 2010, « Identification of cellular targets in human intrahepatic cholangiocarcinoma using laser microdissection and accurate mass and time tag proteomics », Mol Cell Proteomics, vol. 9, no. 9, p. 1991-2004.
    Résumé : Obtaining accurate protein profiles from homogeneous cell populations in heterogeneous tissues can enhance the capability to discover protein biomarkers. In this context, methodologies to access specific cellular populations and analyze their proteome with exquisite sensitivity have to be selected. We report here the results of an investigation using a combination of laser microdissection and accurate mass and time tag proteomics. The study was aimed at the precise determination of proteome alterations in intrahepatic cholangiocarcinoma ICC, a markedly heterogeneous tumor. This cancer, which is difficult to diagnose and carries a very poor prognosis, has shown an unexplained increase in incidence over the last few years. Among a pool of 574 identified proteins, we were able to report on altered abundance patterns affecting 39 proteins conforming to a variety of potential tumorigenic pathways. The reliability of the proteomics results was confirmed by Western blot and immunohistochemistry on matched samples. Most of the proteins displaying perturbed abundances had not yet been described in the setting of ICC. These include proteins involved in cell mobility and actin cytoskeleton remodeling, which may participate in the epithelial to mesenchymal transition, a process invoked in migration and invasion of cancer cells. The biological relevance of these findings was explored using a tissue microarray. An increased abundance of vimentin was thus detected in 70% of ICC and none of the controls. These results suggest that vimentin could play a role in the aggressiveness of ICC and provide a basis for the serious outcome of this cancer.
    Mots-clés : Adult Aged Bile Duct Neoplasms/pathology Blotting, Liquid Female Fourier Analysis Humans Immunohistochemistry Liver Neoplasms/pathology Male Middle Aged Proteomics Tandem Mass Spectrometry, Western Cholangiocarcinoma/pathology Chromatography.
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  • Duclos-Vallee, JC 2010, « Liver transplantation in HIV infected patients: indications and results », Acta Gastroenterol Belg, vol. 73, no. 3, p. 380-2.
    Résumé : Liver transplantation (LT) is now feasible in HIV infected patients. To date, criteria of liver transplantation are no different from the other indications of liver transplantation; however an undetectable HIV viral load at the time of liver transplantation is desirable goal. History of opportunistic infections and CD4+ count < 100/mL do not constitute exclusion criteria. Long-term outcomes for HBV/HIV are excellent. Outcomes for HCV/HIV coinfected patients are more variable because of potentially severe recurrence on the liver graft. More effective antiviral therapy at an early stage post LT is required.
    Mots-clés : Antiretroviral Therapy, Chronic/ epidemiology/mortality/ surgery Hepatitis C, Chronic/ epidemiology/surgery Humans Immunosuppressive Agents Liver Transplantation, Highly Active HIV Infections/ epidemiology/mortality Hepatitis B.

  • Durrbach, A, Francois, H, Beaudreuil, S, Jacquet, A & Charpentier, B 2010, « Advances in immunosuppression for renal transplantation », Nat Rev Nephrol, vol. 6, no. 3, p. 160-7, viewed sans date, .
    Résumé : The development of immunosuppressants with minimal adverse and nephrotoxic effects is important to improve outcomes, such as acute and chronic antibody-mediated rejection, after organ transplantation. In addition, the application of expanded criteria for donors and transplantation in immunized patients necessitates the development of new therapies. Drug development over the past 10 years has generally been disappointing, but several new promising compounds have been or are being developed to prevent acute and chronic transplant rejection. In this Review, we report on several compounds that have been developed to remove allogenic T cells and/or to inhibit T-cell activation. We also discuss compounds that interfere with antibody-mediated rejection.
    Mots-clés : Agents/pharmacology/*therapeutic, Analysis, Animals, Assessment, effects/*immunology/methods, effects/immunology, effects/physiology, Female, Forecasting, Graft, Haplorhini, Humans, Immunology/*drug, Immunosuppression/methods/*trends, Immunosuppressive, Kidney, Male, Management, Outcome, Prognosis, Rejection, Risk, Safety, Survival, Tolerance/drug, Transplantation, Transplantation/adverse, Treatment, use.

  • Durrbach, A, Francois, H, Jacquet, A, Beaudreuil, S & Charpentier, B 2010, « Co-signals in organ transplantation », Curr Opin Organ Transplant, vol. 15, no. 4, p. 474-80, viewed sans date, .
    Résumé : PURPOSE OF REVIEW: The nonimmune effects of currently used immunosuppressive drugs result in a high incidence of late graft loss due to nephrotoxicity and death. As an immune-specific alternative to conventional immunosuppressants, new biotechnology tools can be used to block the costimulation signal of T-cell activation. RECENT FINDINGS: Many experimental studies, particularly preclinical studies in nonhuman primates, have focused on blocking 'classical' B7/CD28 and CD40/CD40L pathways, which are critical in primary T-cell activation, but also on new B7/CD28 and TNF/TNF-R pathways families of costimulatory molecules that can deliver positive or negative costimulation signals to regulate the alloimmune response. SUMMARY: Belatacept is a new fusion protein derived from CTLA4-Ig that can be used to prevent acute rejection in renal transplantation instead of calcineurin inhibitors. Belatacept can also prevent acute rejection efficiently in humans and, more interestingly, can improve renal function and cardiovascular risk factors in this population.
    Mots-clés : &, *Graft, *Immunosuppression/adverse, *Lymphocyte, *Signal, Activation/drug, Agents/therapeutic, Animals, control, effects, effects/*immunology, effects/methods, Graft, Humans, Immunoconjugates/therapeutic, Immunosuppressive, Kidney, Outcome, Rejection/immunology/*prevention, Survival/drug, T-Lymphocytes/drug, Transduction/drug, Transplantation/*immunology, Treatment, use.

  • Durrbach, A, Pestana, JM, Pearson, T, Vincenti, F, Garcia, VD, Campistol, J, Rial Mdel, C, Florman, S, Block, A, Di Russo, G, Xing, J, Garg, P & Grinyo, J 2010, « A phase III study of belatacept versus cyclosporine in kidney transplants from extended criteria donors (BENEFIT-EXT study) », Am J Transplant, vol. 10, no. 3, p. 547-57, viewed sans date, .
    Résumé : Recipients of extended criteria donor (ECD) kidneys are at increased risk for graft dysfunction/loss, and may benefit from immunosuppression that avoids calcineurin inhibitor (CNI) nephrotoxicity. Belatacept, a selective costimulation blocker, may preserve renal function and improve long-term outcomes versus CNIs. BENEFIT-EXT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-EXTended criteria donors) is a 3-year, Phase III study that assessed a more (MI) or less intensive (LI) regimen of belatacept versus cyclosporine in adult ECD kidney transplant recipients. The co-primary endpoints at 12 months were composite patient/graft survival and a composite renal impairment endpoint. Patient/graft survival with belatacept was similar to cyclosporine (86% MI, 89% LI, 85% cyclosporine) at 12 months. Fewer belatacept patients reached the composite renal impairment endpoint versus cyclosporine (71% MI, 77% LI, 85% cyclosporine; p = 0.002 MI vs. cyclosporine; p = 0.06 LI vs. cyclosporine). The mean measured glomerular filtration rate was 4-7 mL/min higher on belatacept versus cyclosporine (p = 0.008 MI vs. cyclosporine; p = 0.1039 LI vs. cyclosporine), and the overall cardiovascular/metabolic profile was better on belatacept versus cyclosporine. The incidence of acute rejection was similar across groups (18% MI; 18% LI; 14% cyclosporine). Overall rates of infection and malignancy were similar between groups; however, more cases of posttransplant lymphoproliferative disorder (PTLD) occurred in the CNS on belatacept. ECD kidney transplant recipients treated with belatacept-based immunosuppression achieved similar patient/graft survival, better renal function, had an increased incidence of PTLD, and exhibited improvement in the cardiovascular/metabolic risk profile versus cyclosporine-treated patients.
    Mots-clés : &, Adult, Aged, Agents/therapeutic, Calcineurin/antagonists, Cardiovascular, Cyclosporine/*therapeutic, Diseases/etiology, Female, Graft, Humans, Immunoconjugates/*therapeutic, Immunosuppressive, inhibitors, Kidney, Kidney/pathology, Male, Middle, Rejection, Risk, Survival, Transplantation/*methods, use.
  • Dusko Ehrlich, S & consortium, MHIT 2010, « [Metagenomics of the intestinal microbiota: potential applications] », Gastroenterol Clin Biol, vol. 34 Suppl 1, p. S23-8.
    Résumé : A major challenge in the human metagenomics field is to identify associations of the bacterial genes and human phenotypes and act to modulate microbial populations in order to improve human health and wellbeing. MetaHIT project addresses this ambitious challenge by developing and integrating a number of necessary approaches within the context of the gut microbiome. Among the first results is the establishment of a broad catalog of the human gut microbial genes, which was achieved by an original application of the new generation sequencing technology. The catalog contains 3.3 million non-redundant genes, 150-fold more than the human genome equivalent and includes a large majority of the gut metagenomic sequences determined across three continents, Europe, America and Asia. Its content corresponds to some 1000 bacterial species, which likely represent a large fraction of species associated with humankind intestinal tract. The catalog enables development of the gene profiling approaches aiming to detect associations of bacterial genes and phenotypes. These should lead to the speedy development of diagnostic and prognostic tools and open avenues to reasoned approaches to the modulation of the individual's microbiota in order to optimize health and well-being.
    Mots-clés : Bacteria/classification/genetics Bacterial Toxins/genetics Contig Mapping/methods Genes, Bacterial Genome, Bacterial Health Status Humans Inflammatory Bowel Diseases/genetics/microbiology/prevention & control/therapy Intestine, DNA/methods, Large/ microbiology Intestine, Small/ microbiology Metagenome/ genetics Metagenomics/ methods Phenotype Sequence Analysis.

  • El Aouni, N, Francois, H, Frangie, C, Guettier, C & Ferlicot, S 2010, « [An unusual kidney lesion in a renal transplant] », Ann Pathol, vol. 30, no. 2, p. 156-8, viewed sans date, .
    Résumé : El Aouni, Nadra Francois, Helene Frangie, Carlos Guettier, Catherine Ferlicot, Sophie fre Case Reports France 2010/05/11 06:00 Ann Pathol. 2010 Apr;30(2):156-8. doi: 10.1016/j.annpat.2010.02.001. Epub 2010 Apr 7.
    Mots-clés : *Transplants, Acid-Schiff, Acute, Aged, Agents/therapeutic, Anti-Bacterial, Biopsy, coli, Complications/diagnosis/*pathology, Cyclic, Diseases/complications/diagnosis/metabolism/*pathology, Escherichia, GMP/metabolism, Histiocytes/ultrastructure, Humans, Infections/complications/diagnosis/drug, Injury/etiology, Ischemia/etiology, Kidney, Kidney/blood, Malacoplakia/complications/diagnosis/metabolism/*pathology, Male, Middle, Periodic, Postoperative, Pyelonephritis/drug, Reaction, supply/*pathology, Therapy, therapy/microbiology/pathology, Tract, Urinary, use.

  • Esposti, DD, Domart, M-C, Sebagh, M, Harper, F, Pierron, G, Brenner, C & Lemoine, A 2010, « Autophagy is induced by ischemic preconditioning in human livers formerly treated by chemotherapy to limit necrosis », Autophagy, vol. 6, no. 1, p. 172-4, viewed sans date, .
    Résumé : The effectiveness of ischemic preconditioning (IP) against hepatic ischemia/reperfusion injury during human liver surgery is linked to decreased apoptotic cell death as well as preservation of the ATP content in liver tissue. Overproduction of Bcl-2 is reported in preconditioned organs. In human liver biopsies exhibiting steatosis and/or vascular injuries (mainly peliosis) induced by chemotherapy, we find that the expression of Bcl-2 in centrolobular and peliotic areas colocalizes with the autophagy protein Beclin 1 in IP livers. Increased expression of phosphorylated Bcl-2 in preconditioned livers is associated with decreased immunoprecipitation of Beclin 1 and increased expression of LC3-II. The increased number of autophagic vacuoles seen by electron microscopy confirmed that IP could trigger autophagy in chemotherapy-injured livers, probably to reduce the pro-inflammatory necrotic cell death of hepatocytes or endothelial cells and to increase ATP levels. Indeed, necrosis is less frequent (p = 0.04) in IP livers than in the others although no change in apoptosis as assessed by TUNEL assay or caspase-3, -8 and -9 expressions is observed. In conclusion, Bcl-2 and Beclin 1 could be major targets in the regulation of cell death during ischemia/reperfusion injury modulating autophagy to switch on/off necrosis and/or apoptosis.
    Mots-clés : Antineoplastic Combined Chemotherapy Protocols/ adverse effects Apoptosis/physiology Autophagy/ physiology Cell Survival/physiology Humans Ischemic Preconditioning/methods Liver/ blood supply/drug effects/ pathology/surgery Models, Biological Necrosis/chemically induced/pathology/prevention & control Preoperative Care/methods Reperfusion Injury/pathology/prevention & control.
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  • Fabre, M, Leroy-Willig, A, Denis, CV, Ba, N, Schoevaert, D, Guettier, C & Geldwerth-Feniger, D 2010, « In vivo MRI and ex vivo quantification of iron and Kupffer cells demonstrate residual phagocytic activity in mouse liver after a gadolinium chloride injection », Biochimie, vol. 92, no. 10, p. 1343-53.
    Résumé : Kupffer cells (KCs), the resident macrophages of the liver, display a phagocytic activity that is not well quantified in animal models. Its experimental invalidation in rodents has been carried out by various means, among which the gadolinium chloride (GdCl(3)) injection has been widely used, and has been generally monitored by ex vivo techniques. The aim of our study was to determine the KC phagocytic activity induced in mouse liver following a single GdCl(3) injection, through Magnetic Resonance Imaging (MRI) measurement of liver uptake of Ferumoxide in vivo, and through ex vivo quantification of Perls positive and F4/80 labeled macrophages. In this study, we showed that 24 h after an IV injection at a dose of 50 mg/kg body weight, GdCl(3) did not induce any hepato-cellular damage, nor did it strongly suppress liver phagocytic activity, as demonstrated by the persistent hepatic uptake of the iron-based MRI contrast agent Ferumoxide. In the GdCl(3)-treated mice, the injection of Ferumoxide produced an increase in the liver proton transverse relaxation rate R2 which averaged 71 +/- 24% of that of the control animals. The ex vivo iron and immune phenotypic quantification, performed after the Ferumoxide injection and MRI, confirmed the presence of activated phagocytes in the liver of the GdCl(3)-treated animals, with a global iron score and F4/80 positive cell count respectively averaging 85 +/- 26% and 46 +/- 13% of their values in the untreated mice. In vivo MRI evaluation of the liver phagocytic activity using Ferumoxide may further prove useful in the follow up of both experimental and human pathologies.
    Mots-clés : &, Analysis, Animals, Cells/, Contrast, dosage/adverse, drug, effects, effects/, Gadolinium/administration, Imaging/, immunology, Iron/, Kupffer, Liver/immunology, Magnetic, Media/pharmacokinetics, methods, Mice, Phagocytosis/, pharmacology, Resonance.

  • Fallani, M, Young, D, Scott, J, Norin, E, Amarri, S, Adam, R, Aguilera, M, Khanna, S, Gil, A, Edwards, CA, Doré, J & Team, OM of the INFABIO 2010, « Intestinal microbiota of 6-week-old infants across Europe: geographic influence beyond delivery mode, breast-feeding, and antibiotics », J Pediatr Gastroenterol Nutr, vol. 51, no. 1, p. 77-84, viewed sans date, .
    Résumé : OBJECTIVES: : There are many differences in diet and lifestyle across Europe that may influence the development of the infant gut microbiota. This work aimed to assess the impact of geographic area, mode of delivery, feeding method, and antibiotic treatment on the fecal microbiota of infants from 5 European countries with different lifestyle characteristics: Sweden, Scotland, Germany, Italy, and Spain. PATIENTS AND METHODS: : Fecal samples from 606 infants (age 6 weeks) recruited within the European project INFABIO were analyzed by fluorescent in situ hybridization combined with flow cytometry using a panel of 10 rRNA targeted group- and species-specific oligonucleotide probes. Information on factors potentially affecting gut microbiota composition was collected with questionnaires and associations were evaluated with multivariate analyses. RESULTS: : The Bifidobacterium genus was predominant (40% average proportion of total detectable bacteria), followed by Bacteroides (11.4%) and enterobacteria (7.5%). Northern European countries were associated with higher proportions of bifidobacteria in infant feces, whereas a more diverse microbiota with more bacteroides characterized southern countries. Bifidobacteria dominated the microbiota of breast-fed infants, whereas formula-fed babies had significantly higher proportions of Bacteroides and members of the Clostridium coccoides and Lactobacillus groups. Newborns delivered by cesarean section or from mothers treated with antibiotics perinatally had lower proportions of Bacteroides and members of the Atopobium cluster. CONCLUSIONS: : Delivery mode and feeding method influenced the fecal microbiota of European infants at 6 weeks, as expected, but the effect of country of birth was more pronounced, with dominant bifidobacteria in northern countries and greater early diversification in southern European countries.
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  • Ferlicot, S, Vernochet, A, Romana, S, Ortin-Serrano, M, Letierce, A, Bregerie, O, Durrbach, A & Guettier, C 2010, « Microchimerism in renal allografts: clinicopathological associations according to the type of chimeric cells », Histopathology, vol. 56, no. 2, p. 188-97, viewed sans date, .
    Résumé : AIMS: Recent studies have highlighted the presence of microchimerism in various solid allografts. The biological significance of these chimeric cells is controversial. They may be beneficial, leading to better tolerance of grafts or participating in tissue repair or, in contrast, deleterious if involved in chronic lesions. The aim was to assess the frequency and cellular nature of microchimerism in female renal grafts of male recipients by combined fluorescence in situ hybridization (FISH) for Y chromosome and immunohistochemistry and to investigate associations between intragraft microchimerism and histological lesions or allograft outcome. METHODS AND RESULTS: We screened 33 renal biopsy specimens, including 11 with acute T-cell-mediated rejection and nine with transplant glomerulopathy, from 22 male recipients transplanted with female kidneys by FISH and immunohistochemistry with antibodies against smooth muscle actin (mesangial cells), CD31 (endothelial cells), KL1 (epithelial cells), CD45 (leucocyte common antigen) and glomerular epithelial protein 1 (podocytes). Tubular microchimerism was detected in 71% of the patients with a mean percentage of chimeric epithelial cells of 1.4%. Glomerular microchimerism involving podocytes, mesangial and endothelial cells was present with a mean number of chimeric cells per glomerular section of, respectively, 0.6, 2.66 and 3.53. There was an association between endothelial microchimerism and a previous episode of acute T-cell-mediated rejection. CONCLUSIONS: In conclusion, microchimerism in renal grafts occurs frequently, but at a low level and affects tubular cells and all glomerular cell compartments in human renal allografts.
    Mots-clés : Biopsy *Chimerism Chromosomes, Fluorescence Kidney Transplantation/*pathology/physiology Kidney Tubules/*metabolism/pathology Male Mesangial Cells/*metabolism/pathology Podocytes/*metabolism/pathology Sex Factors T-Lymphocytes Transplantation, Homologous, Human, Y/genetics Endothelial Cells/*metabolism/pathology Female Glomerulonephritis/*genetics Graft Rejection/*genetics Humans In Situ Hybridization.

  • Flamant, S, Ritchie, W, Guilhot, J, Holst, J, Bonnet, ML, Chomel, JC, Guilhot, F, Turhan, AG & Rasko, JEJ 2010, « Micro-RNA response to imatinib mesylate in patients with chronic myeloid leukemia », Haematologica-the Hematology Journal, vol. 95, no. 8, p. 1325-1333, viewed sans date, <<Go to ISI>://WOS:000281568000014>.
    Résumé : Background Micro-RNAs (miRNAs) control gene expression by destabilizing targeted transcripts and inhibiting their translation. Aberrant expression of miRNAs has been described in many human cancers, including chronic myeloid leukemia. Current first-line therapy for newly diagnosed chronic myeloid leukemia is imatinib mesylate, which typically produces a rapid hematologic response. However the effect of imatinib on miRNA expression in vivo has not been thoroughly examined. Design and Methods Using a TaqMan Low-Density Array system, we analyzed miRNA expression in blood samples from newly diagnosed chronic myeloid leukemia patients before and within the first two weeks of imatinib therapy. Quantitative real-time PCR was used to validate imatinib-modulated miRNAs in sequential primary chronic myeloid leukemia samples (n=11, plus 12 additional validation patients). Bioinformatic target gene prediction analysis was performed based on changes in miRNA expression. Results We observed increased expression of miR-150 and miR-146a, and reduced expression of miR-142-3p and miR-199b-5p (3-fold median change) after two weeks of imatinib therapy. A significant correlation (P<0.05) between the Sokal score and pre-treatment miR-142-3p levels was noted. Expression changes in the same miRNAs were consistently found in an additional cohort of chronic myeloid leukemia patients, as compared to healthy subjects. Peripheral blood cells from chronic phase and blast crisis patients displayed a 30-fold lower expression of miR-150 compared to normal samples, which is of particular interest since c-Myb, a known target of miR-150, was recently shown to be necessary for Bcr-Abl-mediated transformation. Conclusions We found that imatinib treatment of chronic myeloid leukemia patients rapidly normalizes the characteristic miRNA expression profile, suggesting that miRNAs may serve as a novel clinically useful biomarker in this disease.

  • Fleury, M, Petit-Cocault, L, Clay, D & Souyri, M 2010, « Mpl receptor defect leads to earlier appearance of hematopoietic cells/hematopoietic stem cells in the Aorta-Gonad-Mesonephros region, with increased apoptosis », The International Journal of Developmental Biology, vol. 54, no. 6-7, p. 1067-1074.
    Résumé : In a previous study, we underlined the functional role of the TPO receptor, Mpl, in the establishment of definitive mouse hematopoiesis, by demonstrating that the lack of Mpl led to a delayed production of definitive hematopoietic cells in the aorta-gonad-mesonephros (AGM) region, and resulted in the production of hematopoietic stem cells (HSCs) with an impaired activity at E11.5. In order to more accurately estimate the role of Mpl during generation of HSCs in the aorta, we performed an analysis of these AGMs at the time of the first HSC emergence (E10.5). Our results indicated that while Mpl-/- AGMs were found to contain more hematopoietic cells (HC) than C57Bl6 AGMs at E10.5, a defect in the expansion process of the HC/HSCs was detected in explant cultures of these AGMs, likely due to an increased apoptosis of these cells. To determine the molecular mechanisms by which invalidation of Mpl receptor affects the temporal distribution and expansion of HC/HSCs in the AGM, a study of the transcription level of of Mpl target genes was conducted. Expression of Runx1, a master transcription factor for the formation of hematopoietic progenitor (HP) cells and HSCs from the vasculature, as well as expression of Meis1 and HoxB4, known to play a role in self-renewal and expansion of HSCs, were found to be down regulated in E10.5 Mpl-/- AGMs. Our data indicate that Mpl is an active player during the first steps of definitive hematopoiesis establishment through direct regulation of the expression of transcription factors or genes important for the self-renewal, proliferation and apoptosis of HSCs.
    Mots-clés : Animals, Antigens, CD34, Antigens, CD45, Aorta, Apoptosis, Cell Count, Cell Proliferation, Core Binding Factor Alpha 2 Subunit, Embryo, Mammalian, Female, Flow Cytometry, Gene Expression Regulation, Developmental, Gonads, Hematopoietic Stem Cells, Hematopoietic System, Male, Mesonephros, Mice, Mice, Inbred C57BL, Mice, Knockout, Proto-Oncogene Proteins c-bcl-2, Receptors, Thrombopoietin, Reverse Transcriptase Polymerase Chain Reaction, Tissue Culture Techniques.

  • Fournier, BPJ, Ferre, FC, Couty, L, Lataillade, J-J, Gourven, M, Naveau, A, Coulomb, B, Lafont, A & Gogly, B 2010, « Multipotent progenitor cells in gingival connective tissue », Tissue Eng Part A, vol. 16, no. 9, p. 2891-9, viewed sans date, .
    Résumé : The gum has an exceptional capacity for healing. To examine the basis for this property and explore the potential of conferring it to organs with inferior healing capacity, we sought the presence of progenitor cells in gingival connective tissue. Colony-forming units of fibroblast-enriched cells from gingival fibroblast cultures were assessed for expression of membrane markers of mesenchymal stem cells; capacity to differentiate into osteoblasts, chondroblasts, and adipocytes; and engraftment efficiency after in vivo transfer. On the basis of their ability to differentiate into several lineages, proliferate from single cells, induce calcium deposits, and secrete collagen in vivo after transfer on hydroxyapatite carriers, we suggest that this population represents gingival multipotent progenitor cells. The discovery of progenitor cells in gingival connective tissue may help improve our understanding of how the wounded gum is capable of almost perfect healing and opens the prospect of cellular therapy for wound healing using readily available cells at limited risk to the patient.
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  • Fourquet, S, Guerois, R, Biard, D & Toledano, MB 2010, « Activation of NRF2 by Nitrosative Agents and H(2)O(2) Involves KEAP1 Disulfide Formation », Journal of Biological Chemistry, vol. 285, no. 11, p. 8463-8471, viewed sans date, <<Go to ISI>://WOS:000275413800061>.
    Résumé : The NRF2 transcription factor regulates a major environmental and oxidative stress response. NRF2 is itself negatively regulated by KEAP1, the adaptor of a Cul3-ubiquitin ligase complex that marks NRF2 for proteasomal degradation by ubiquitination. Electrophilic compounds activate NRF2 primarily by inhibiting KEAP1-dependent NRF2 degradation, through alkylation of specific cysteines. We have examined the impact on KEAP1 of reactive oxygen and nitrogen species, which are also NRF2 inducers. We found that in untreated cells, a fraction of KEAP1 carried a long range disulfide linking Cys(226) and Cys(613). Exposing cells to hydrogen peroxide, to the nitric oxide donor spermine NONOate, to hypochlorous acid, or to S-nitrosocysteine further increased this disulfide and promoted formation of a disulfide linking two KEAP1 molecules via Cys(151). None of these oxidants, except S-nitrocysteine, caused KEAP1 S-nitrosylation. A cysteine mutant preventing KEAP1 intermolecular disulfide formation also prevented NRF2 stabilization in response to oxidants, whereas those preventing intramolecular disulfide formation were functionally silent. Further, simultaneously inactivating the thioredoxin and glutathione pathways led both to major constitutive KEAP1 oxidation and NRF2 stabilization. We propose that KEAP1 intermolecular disulfide formation via Cys(151) underlies the activation of NRF2 by reactive oxygen and nitrogen species.

  • Franceschi, S, Lise, M, Clifford, GM, Rickenbach, M, Levi, F, Maspoli, M, Bouchardy, C, Dehler, S, Jundt, G, Ess, S, Bordoni, A, Konzelmann, I, Frick, H, Dal Maso, L, Elzi, L, Furrer, H, Calmy, A, Cavassini, M, Ledergerber, B, Keiser, O & Study, SHIVC 2010, « Changing patterns of cancer incidence in the early- and late-HAART periods: the Swiss HIV Cohort Study », Br J Cancer, vol. 103, no. 3, p. 416-22, viewed sans date, .
    Résumé : BACKGROUND: The advent of highly active antiretroviral therapy (HAART) in 1996 led to a decrease in the incidence of Kaposi's sarcoma (KS) and non-Hodgkin's lymphoma (NHL), but not of other cancers, among people with HIV or AIDS (PWHA). It also led to marked increases in their life expectancy. METHODS: We conducted a record-linkage study between the Swiss HIV Cohort Study and nine Swiss cantonal cancer registries. In total, 9429 PWHA provided 20,615, 17,690, and 15,410 person-years in the pre-, early-, and late-HAART periods, respectively. Standardised incidence ratios in PWHA vs the general population, as well as age-standardised, and age-specific incidence rates were computed for different periods. RESULTS: Incidence of KS and NHL decreased by several fold between the pre- and early-HAART periods, and additionally declined from the early- to the late-HAART period. Incidence of cancers of the anus, liver, non-melanomatous skin, and Hodgkin's lymphoma increased in the early- compared with the pre-HAART period, but not during the late-HAART period. The incidence of all non-AIDS-defining cancers (NADCs) combined was similar in all periods, and approximately double that in the general population. CONCLUSIONS: Increases in the incidence of selected NADCs after the introduction of HAART were largely accounted for by the ageing of PWHA.
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  • Fromont, G 2010, « Reliability of intraoperative pathology consultation for urologic malignancy », Progres En Urologie, vol. 20, no. 4, p. F127-F130, viewed sans date, <<Go to ISI>://WOS:000285525300005>.
    Résumé : The intraoperative pathology consultation is indicated if the findings have an impact on the surgical procedure. In urological oncology, pathologists can be requested to evaluate the nature of the tumor, to determine the metastatic status of lymph node resections or to assess the surgical margins. The identification of the benign nature of a tumor on frozen sections can allow organ sparing surgery, but must be limited to some cases of renal and testicular lesions. Intraoperative examination of pelvic lymph nodes detects metastasis with a low incidence and a weak reliability to diagnose micrometastasis. The surgical margin status after partial nephrectomy do not have to be assess on tumor bed biopsies, but on the whole surgical specimen, and a macroscopic exam is most of time sufficient. Intraoperative evaluation of the margin status after radical prostatectomy is a difficult exam that needs a well-trained pathologist and that must be limited to posterolateral areas in case of nerve bundle preservation.


  • Gallerne, C, Touat, Z, Chen, ZX, Martel, C, Mayola, E, Sharaf el dein, O, Buron, N, Le Bras, M, Jacotot, E, Borgne-Sanchez, A, Lemoine, A, Lemaire, C, Pervaiz, S & Brenner, C 2010, « The fourth isoform of the adenine nucleotide translocator inhibits mitochondrial apoptosis in cancer cells », Int J Biochem Cell Biol, vol. 42, no. 5, p. 623-9, viewed sans date, .
    Résumé : The adenine nucleotide translocator (ANT) is a mitochondrial bi-functional protein, which catalyzes the exchange of ADP and ATP between cytosol and mitochondria and participates in many models of mitochondrial apoptosis. The human adenine nucleotide translocator sub-family is composed of four isoforms, namely ANT1-4, encoded by four nuclear genes, whose expression is highly regulated. Previous studies have revealed that ANT1 and 3 induce mitochondrial apoptosis, whereas ANT2 is anti-apoptotic. However, the role of the recently identified isoform ANT4 in the apoptotic pathway has not yet been elucidated. Here, we investigated the effects of stable heterologous expression of the ANT4 on proliferation, mitochondrial respiration and cell death in human cancer cells, using ANT3 as a control of pro-apoptotic isoform. As expected, ANT3 enhanced mitochondria-mediated apoptosis in response to lonidamine, a mitochondriotoxic chemotherapeutic drug, and staurosporine, a protein kinase inhibitor. Our results also indicate that the pro-apoptotic effect of ANT3 was accompanied by decreased rate of cell proliferation, alteration in the mitochondrial network topology, and decreased reactive oxygen species production. Of note, we demonstrate for the first time that ANT4 enhanced cell growth without impacting mitochondrial network or respiration. Moreover, ANT4 differentially regulated the intracellular levels of hydrogen peroxide without affecting superoxide anion levels. Finally, stable ANT4 overexpression protected cancer cells from lonidamine and staurosporine apoptosis in a manner independent of Bcl-2 expression. These data highlight a hitherto undefined cytoprotective activity of ANT4, and provide a novel dichotomy in the human ANT isoform sub-family with ANT1 and 3 isoforms functioning as pro-apoptotic while ANT2 and 4 isoforms render cells resistant to death inducing stimuli.
    Mots-clés : ATP Translocases/biosynthesis/blood/genetics/*physiology Oxidative Phosphorylation Protein Kinase Inhibitors/pharmacology Proto-Oncogene Proteins c-bcl-2/metabolism Staurosporine/pharmacology Superoxides/analysis.

  • Gao, DY, Jin, GD, Yao, BL, Zhang, DH, Gu, LL, Lu, ZM, Gong, Q, Lone, YC, Deng, Q & Zhang, XX 2010, « Characterization of the specific CD4+ T cell response against the F protein during chronic hepatitis C virus infection », PLoS One, vol. 5, no. 12, p. e14237, viewed sans date, .
    Résumé : BACKGROUND: The hepatitis C virus (HCV) Alternate Reading Frame Protein (ARFP or F protein) presents a double-frame shift product of the HCV core gene. We and others have previously reported that the specific antibodies against the F protein could be raised in the sera of HCV chronically infected patients. However, the specific CD4(+) T cell responses against the F protein during HCV infection and the pathological implications remained unclear. In the current study, we screened the MHC class II-presenting epitopes of the F protein through HLA-transgenic mouse models and eventually validated the specific CD4(+) T cell responses in HCV chronically infected patients. METHODOLOGY: DNA vaccination in HLA-DR1 and-DP4 transgenic mouse models, proliferation assay to test the F protein specific T cell response, genotyping of Chronic HCV patients and testing the F-peptide stimulated T cell response in the peripheral blood mononuclear cell (PBMC) by in vitro expansion and interferon (IFN)- gamma intracellular staining. PRINCIPAL FINDINGS: At least three peptides within HCV F protein were identified as HLA-DR or HLA-DP4 presenting epitopes by the proliferation assays in mouse models. Further study with human PBMCs evidenced the specific CD4(+) T cell responses against HCV F protein as well in patients chronically infected with HCV. CONCLUSION: The current study provided the evidence for the first time that HCV F protein could elicit specific CD4(+) T cell response, which may provide an insight into the immunopathogenesis during HCV chronic infection.
    Mots-clés : Amino Acid Sequence Animals CD4-Positive T-Lymphocytes/*metabolism Epitopes/chemistry HLA Antigens/metabolism Hepacivirus/*metabolism Hepatitis C/*virology Humans Interferon-gamma/metabolism Leukocytes, Mononuclear/metabolism Mice Mice, Transgenic Molecular Sequence Data Spleen/cytology Viral Fusion Proteins/*metabolism.
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  • Gonzales, E, Julien, B, Serriere-Lanneau, V, Nicou, A, Doignon, I, Lagoudakis, L, Garcin, I, Azoulay, D, Duclos-Vallee, JC, Castaing, D, Samuel, D, Hernandez-Garcia, A, Awad, SS, Combettes, L, Thevananther, S & Tordjmann, T 2010, « ATP release after partial hepatectomy regulates liver regeneration in the rat », J Hepatol, vol. 52, no. 1, p. 54-62.
    Résumé : BACKGROUND & AIMS: Paracrine interactions are critical to liver physiology, particularly during regeneration, although physiological involvement of extracellular ATP, a crucial intercellular messenger, remains unclear. The physiological release of ATP into extracellular milieu and its impact on regeneration after partial hepatectomy were investigated in this study. METHODS: Hepatic ATP release after hepatectomy was examined in the rat and in human living donors for liver transplantation. Quinacrine was used for in vivo staining of ATP-enriched compartments in rat liver sections and isolated hepatocytes. Rats were treated with an antagonist for purinergic receptors (Phosphate-6-azo(benzene-2,4-disulfonic acid), PPADS), and liver regeneration after hepatectomy was analyzed. RESULTS: A robust and transient ATP release due to acute portal hyperpressure was observed immediately after hepatectomy in rats and humans. Clodronate liposomal pre-treatment partly inhibited ATP release in rats. Quinacrine-stained vesicles, co-labeled with a lysosomal marker in liver sections and isolated hepatocytes, were predominantly detected in periportal areas. These vesicles significantly disappeared after hepatectomy, in parallel with a decrease in liver ATP content. PPADS treatment inhibited hepatocyte cell cycle progression after hepatectomy, as revealed by a reduction in bromodeoxyuridine incorporation, phosphorylated histone 3 immunostaining, cyclin D1 and A expression and immediate early gene induction. CONCLUSION: Extracellular ATP is released immediately after hepatectomy from hepatocytes and Kupffer cells under mechanical stress and promotes liver regeneration in the rat. We suggest that in hepatocytes, ATP is released from a lysosomal compartment. Finally, observations made in living donors suggest that purinergic signalling could be critical for human liver regeneration.
    Mots-clés : Animal Purinergic P2 Receptor Antagonists Pyridoxal Phosphate/analogs & derivatives/pharmacology Rats Rats, Mechanical Tissue Donors, Purinergic P2/metabolism Stress, Sprague-Dawley Receptors.
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