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Biblio - Bibliographie IAL
Bibliographie IAL

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Accueil > Références bibliographiques

biblio

2009


  • Arnoult, D, Carneiro, L, Tattoli, I & Girardin, SE 2009, « The role of mitochondria in cellular defense against microbial infection », Semin Immunol, vol. 21, no. 4, p. 223-32, viewed sans date, .
    Résumé : Mitochondria have been long recognized for their key role in the modulation of cell death pathways. Thus, it is therefore not surprising that this organelle represents a recurrent target for pathogenic microbes, aiming to manipulate the fate of the infected host cell. More recently, mitochondria have been shown to serve as a crucial platform for innate immune signaling, as illustrated by the identification of MAVS (also known as IPS-1, VISA and Cardif), NLRX1 and STING as mitochondrial proteins. This review discusses the tight interplay between microbial infection, innate immune signaling and mitochondria.
    Mots-clés : Animals Bacterial Infections/*immunology/metabolism/pathology Cell Death Humans Immunity, Innate Mitochondria/*immunology/metabolism Signal Transduction Virus Diseases/*immunology/metabolism/pathology.

  • Arnoult, D, Soares, F, Tattoli, I, Castanier, C, Philpott, DJ & Girardin, SE 2009, « An N-terminal addressing sequence targets NLRX1 to the mitochondrial matrix », J Cell Sci, vol. 122, no. Pt 17, p. 3161-8, viewed sans date, .
    Résumé : NLRX1 is the only member of the Nod-like receptor (NLR) family that is targeted to the mitochondria, and its overexpression induces the generation of reactive oxygen species (ROS), thus impacting on NFkappaB- and JNK-dependent signaling cascades. In addition, NLRX1 has been shown to interact with MAVS (also known as IPS-1, VISA and Cardif) at the mitochondrial outer membrane and to modulate antiviral responses. Here we report that NLRX1 has a functional leader sequence and fully translocates to the mitochondrial matrix via a mechanism requiring the mitochondrial inner-membrane potential, DeltaPsim. Importantly, we failed to detect NLRX1 at the mitochondrial outer membrane. We also show that the leader sequence of NLRX1 is removed, which generates a mature protein lacking the first 39 amino acids through a maturation process that is common for mitochondrial-matrix proteins. Finally, we identified UQCRC2, a matrix-facing protein of the respiratory chain complex III, as an NLRX1-interacting molecule, thus providing a molecular basis for the role of NLRX1 in ROS generation. These results provide the first identification of a protein belonging to the NLR family that is targeted to the mitochondrial matrix.
    Mots-clés : Amino Acid Motifs HeLa Cells Humans Membrane Potential, Mitochondrial Mitochondrial Membranes/chemistry/*metabolism Mitochondrial Proteins/*chemistry/genetics/*metabolism Protein Sorting Signals Protein Transport.
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  • Bahri, R, Naji, A, Menier, C, Charpentier, B, Carosella, ED, Rouas-Freiss, N & Durrbach, A 2009, « Dendritic cells secrete the immunosuppressive HLA-G molecule upon CTLA4-Ig treatment: implication in human renal transplant acceptance », J Immunol, vol. 183, no. 11, p. 7054-62, viewed sans date, .
    Résumé : CTLA4-Ig (Belatacept) is a new recombinant molecule that interferes with the signal of T lymphocyte activation and prevents acute rejection after renal transplantation. HLA-G acts as a naturally tolerogenic molecule in humans. In this study, we analyzed whether HLA-G contributes to CTLA4-Ig-mediated graft acceptance. Our results demonstrate that patients treated with CTLA4-Ig displayed significantly higher soluble HLA-G (sHLA-G) plasma concentrations (72 +/- 14 ng/ml) than patients treated with calcineurin inhibitors (5 +/- 1 ng/ml) or healthy donors (5 +/- 5 ng/ml). Notably, sHLA-G purified from plasma of CTLA4-Ig-treated patients was biologically active as it inhibited allogeneic T cell proliferation in vitro. Dendritic cells (DC) were identified as one of the cellular sources of sHLA-G in CTLA4-Ig-treated patients. Supporting this observation, we showed that DC generated in vitro in presence of CTLA4-Ig released sHLA-G in response to allostimulation. These CTLA4-Ig-treated DC acted as tolerogenic APC through sHLA-G secretion as they suppressed T cell alloproliferation, which could be restored by using a neutralizing anti-HLA-G Ab. These data define a novel pathway by which CTLA4-Ig immunomodulates allogenic response through posttranscriptional regulation of HLA-G expression in DC. CTLA4-Ig-mediated HLA-G release appears as a critical factor in T cell alloresponse inhibition, thereby contributing to the immunosuppressive effect and graft acceptance.
    Mots-clés : Adult Blotting, Post-Transcriptional Reverse Transcriptase Polymerase Chain Reaction.

  • Barau, C, Blouin, P, Creput, C, Taburet, AM, Durrbach, A & Furlan, V 2009, « Effect of coadministered HIV-protease inhibitors on tacrolimus and sirolimus blood concentrations in a kidney transplant recipient », Fundam Clin Pharmacol, vol. 23, no. 4, p. 423-5, viewed sans date, .
    Résumé : A patient with human immunodeficiency virus infection and end-stage renal disease received a renal transplant. At the time of surgery, the patient was on quadruple antiretroviral therapy (lamivudine, zidovudine, and amprenavir/ritonavir). Immunosuppression was initiated with basiliximab, corticosteroid, mycophenolate mofetil, and a single 0.5 mg dose of tacrolimus. In the following days, an increase in tacrolimus concentration was observed with a peak of 37 ng/mL. Tacrolimus half-life was 6.5 days and tacrolimus maintenance dose was 0.5 mg every 4 days. Eleven months later, the patient had developed Kaposi sarcoma. Tacrolimus was replaced by sirolimus (first dose 1 mg), and the patient was stabilized with 1.5 mg of sirolimus once a week. Increased tacrolimus half-life and increased dose interval of sirolimus and tacrolimus were due to CYP3A4/5 and/or P-glycoprotein inhibition by protease inhibitors. Close monitoring is required in the management of tacrolimus and sirolimus dosing regimens when combined with ritonavir boosted HIV-1 protease inhibitors.
    Mots-clés : Chronic/therapy Kidney Transplantation Male Middle Aged Sarcoma, Drug Interactions HIV Infections/complications/drug therapy HIV Protease Inhibitors/*pharmacology/therapeutic use Half-Life Humans Immunosuppressive Agents/*pharmacokinetics/therapeutic use Kidney Failure, Kaposi/drug therapy/etiology Sirolimus/*pharmacokinetics/therapeutic use Tacrolimus/*pharmacokinetics/therapeutic use.

  • Barau, C, Frangie, C, Goujard, C, Tribut, O, Parant, F, Taburet, AM, Durrbach, A & Furlan, V 2009, « Falsely elevated whole blood tacrolimus concentrations due to interference in an affinity column-mediated immunoassay method on Xpand dimension », Ther Drug Monit, vol. 31, no. 2, p. 267-8, viewed sans date, .
    Résumé : The whole blood concentration of tacrolimus is required for therapeutic drug monitoring of this immunosuppressive drug. Abnormal tacrolimus levels affect its efficacy or toxicity, leading to changes in its dosage. Here, we report analytical interference in the affinity column-mediated immunoassay tacrolimus method on the Xpand autoanalyzer in a kidney transplant human immunodeficiency virus-infected patient. Tacrolimus concentrations obtained by affinity column-mediated immunoassay are 3- to 7-fold higher than measurements with the enzyme multiplied immunoassay technique assay. The cause of this interference remains unknown. However, it would be necessary to identify this type of interference to measure tacrolimus concentration with another method to avoid analytical error, which may lead to a poor clinical outcome.
    Mots-clés : *Kidney, Adult, Agents/*blood, C/physiopathology, drug, False, Hepatitis, HIV, Humans, Immunoassay, Immunosuppressive, Infections/physiopathology, Male, Monitoring, Positive, Reactions, Tacrolimus/*blood, Transplantation.

  • Basille, C, Frydman, R, El Aly, A, Hesters, L, Fanchin, R, Tachdjian, G, Steffann, J, LeLorc'h, M & Achour-Frydman, N 2009, « Preimplantation genetic diagnosis: state of the art », Eur J Obstet Gynecol Reprod Biol, vol. 145, no. 1, p. 9-13, viewed sans date, .
    Résumé : Preimplantation genetic diagnosis (PGD) is used to analyze embryos genetically before their transfer into the uterus. It was developed first in England in 1990, as part of progress in reproductive medicine, genetic and molecular biology. PGD offers couples at risk the chance to have an unaffected child, without facing termination of pregnancy. Embryos are obtained by in vitro fertilization with intracytoplasmic sperm injection (ICSI), and are biopsied mostly on day 3; blastocyst biopsy is mentioned as a possible alternative. The genetic analysis is performed on one or two blastomeres, by fluorescent in situ hybridization (FISH) for cytogenetic diagnosis, or polymerase chain reaction (PCR) for molecular diagnosis. Genetic analysis of the first or second polar body can be used to study maternal genetic contribution. Only unaffected embryos are transferred into the uterus. To improve the accuracy of the diagnosis, new technologies are emerging, with comparative genomic hybridization (CGH) and microarrays. In Europe, depending on national regulations, PGD is either prohibited, or allowed, or practiced in the absence of recommendations. The indications are chromosomal abnormalities, X-linked diseases or single gene disorders. The number of disorders being tested increases. In Europe, data collection from the year 2004 reports that globally 69.6% of cycles lead to embryo transfer and implantation rate is 17%. European results from the year 2004 show a clinical pregnancy rate of 18% per oocyte retrieval and 25% per embryo transfer, leading to 528 babies born. The cohort studies concerning the paediatric follow-up of PGD babies show developmental outcomes similar to children conceived after IVF-ICSI. Recent advances include human leucocyte antigen (HLA) typing for PGD embryos, when an elder sibling is affected with a genetic disorder and needs stem cell transplantation. The HLA-matched offspring resulting can give cord blood at birth. Preimplantation genetic screening (PGS) consists in euploid embryo selection; it could be used for advanced maternal age, repeated implantation failure, single embryo transfer or idiopathic recurrent pregnancy loss. These applications are controversial. PGD for inherited cancer predispositions is discussed and social sexing remains prohibited in Europe. PGD requires a close collaboration between obstetricians, fertility specialists, IVF laboratory and human geneticists. It needs intensive effort, expensive techniques and is demanding for the patients, but it offers tremendous opportunity for couples whose previous child has exhibited genetic abnormalities. The debate on certain indications is ongoing.
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  • Battaglia, S, Benzoubir, N, Ghigna, MR, Guettier, C, Brechot, C & Bourgeade, MF 2009, « [Epithelial-mesenchymal transition and hepatocellular carcinoma] », Ann Pathol, vol. 29 Spec No 1, p. S65-6.
    Résumé : Battaglia, Serena; Benzoubir, Nassima; Ghigna, Maria-Rosa; Guettier, Catherine; Brechot, Christian; Bourgeade, Marie-Francoise; Review; France; Ann Pathol. 2009 Nov;29 Spec No 1:S65-6. doi: 10.1016/j.annpat.2009.07.042. Epub 2009 Oct 6.
    Mots-clés : Cadherins/metabolism Capsid Proteins/physiology Carcinoma.
  • Battaglia, S, Benzoubir, N, Nobilet, S, Charneau, P, Samuel, D, Zignego, AL, Atfi, A, Brechot, C & Bourgeade, MF 2009, « Liver cancer-derived hepatitis C virus core proteins shift TGF-beta responses from tumor suppression to epithelial-mesenchymal transition », PLoS One, vol. 4, no. 2, p. e4355.
    Résumé : BACKGROUND: Chronic hepatitis C virus (HCV) infection and associated liver cirrhosis represent a major risk factor for hepatocellular carcinoma (HCC) development. TGF-beta is an important driver of liver fibrogenesis and cancer; however, its actual impact in human cancer progression is still poorly known. The aim of this study was to investigate the role of HCC-derived HCV core natural variants on cancer progression through their impact on TGF-beta signaling. PRINCIPAL FINDINGS: We provide evidence that HCC-derived core protein expression in primary human or mouse hepatocyte alleviates TGF-beta responses in terms or growth inhibition or apoptosis. Instead, in these hepatocytes TGF-beta was still able to induce an epithelial to mesenchymal transition (EMT), a process that contributes to the promotion of cell invasion and metastasis. Moreover, we demonstrate that different thresholds of Smad3 activation dictate the TGF-beta responses in hepatic cells and that HCV core protein, by decreasing Smad3 activation, may switch TGF-beta growth inhibitory effects to tumor promoting responses. CONCLUSION/SIGNIFICANCE: Our data illustrate the capacity of hepatocytes to develop EMT and plasticity under TGF-beta, emphasize the role of HCV core protein in the dynamic of these effects and provide evidence for a paradigm whereby a viral protein implicated in oncogenesis is capable to shift TGF-beta responses from cytostatic effects to EMT development.
    Mots-clés : Animals Cell Death/drug effects Cell Line.
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  • Benyamina, A, Saffroy, R, Blecha, L, Pham, P, Karila, L, Debuire, B, Lemoine, A & Reynaud, M 2009, « Association between MTHFR 677C-T polymorphism and alcohol dependence according to Lesch and Babor typology », Addict Biol, vol. 14, no. 4, p. 503-5, viewed sans date, .
    Résumé : Prior studies have associated 677C-T Methylenetetrahydrofolate reductase (MTHFR) gene polymorphism with decreased enzymatic activity and modified homocysteine regulation. This study determines and compares MTHFR 677C-T distribution and examines its consequences on homocysteine metabolism and alcohol dependence in alcoholic patients classified according to the Babor and Lesch typologies. MTHFR TT genotype was more prevalent in AD patients with milder alcohol dependence (Babor type A) and with Lesch type 3, associated with depression. MTHFR TT was also associated with hyperhomocysteinemia. Determining MTHFR 677C-T genotype, folate and vitamin B12 levels could assist physicians in identifying type 3 patients and improve addictions management.
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  • Bidere, N 2009, « [Role of CK1alpha in adaptive immunity and lymphomagenesis] », Med Sci (Paris), vol. 25, no. 5, p. 454-6, viewed sans date, .
    Résumé : Bidere, Nicolas fre Research Support, Non-U.S. Gov't France 2009/06/02 09:00 Med Sci (Paris). 2009 May;25(5):454-6. doi: 10.1051/medsci/2009255454.
    Mots-clés : Adaptor Proteins, Cellular/*physiology Jurkat Cells Lymphocytes/immunology/metabolism Lymphoma, Diffuse/*enzymology/etiology NF-kappa B/physiology Neoplasm Proteins/*physiology Wnt Proteins/physiology, Large B-Cell, Neoplastic Guanylate Cyclase/physiology Humans Immunity, Signal Transducing/physiology Antigens/immunology CARD Signaling Adaptor Proteins/physiology Casein Kinase Ialpha/*physiology Caspases/physiology *Cell Transformation.

  • Bidere, N, Ngo, VN, Lee, J, Collins, C, Zheng, L, Wan, F, Davis, RE, Lenz, G, Anderson, DE, Arnoult, D, Vazquez, A, Sakai, K, Zhang, J, Meng, Z, Veenstra, TD, Staudt, LM & Lenardo, MJ 2009, « Casein kinase 1alpha governs antigen-receptor-induced NF-kappaB activation and human lymphoma cell survival », Nature, vol. 458, no. 7234, p. 92-6, viewed sans date, .
    Résumé : The transcription factor NF-kappaB is required for lymphocyte activation and proliferation as well as the survival of certain lymphoma types. Antigen receptor stimulation assembles an NF-kappaB activating platform containing the scaffold protein CARMA1 (also called CARD11), the adaptor BCL10 and the paracaspase MALT1 (the CBM complex), linked to the inhibitor of NF-kappaB kinase complex, but signal transduction is not fully understood. We conducted parallel screens involving a mass spectrometry analysis of CARMA1 binding partners and an RNA interference screen for growth inhibition of the CBM-dependent 'activated B-cell-like' (ABC) subtype of diffuse large B-cell lymphoma (DLBCL). Here we report that both screens identified casein kinase 1alpha (CK1alpha) as a bifunctional regulator of NF-kappaB. CK1alpha dynamically associates with the CBM complex on T-cell-receptor (TCR) engagement to participate in cytokine production and lymphocyte proliferation. However, CK1alpha kinase activity has a contrasting role by subsequently promoting the phosphorylation and inactivation of CARMA1. CK1alpha has thus a dual 'gating' function which first promotes and then terminates receptor-induced NF-kappaB. ABC DLBCL cells required CK1alpha for constitutive NF-kappaB activity, indicating that CK1alpha functions as a conditionally essential malignancy gene-a member of a new class of potential cancer therapeutic targets.
    Mots-clés : Adaptor Proteins, Antigen/*metabolism Signal Transduction, Cultured Feedback, Diffuse/enzymology/*metabolism/*pathology NF-kappa B/*metabolism Neoplasm Proteins/metabolism Protein Binding Receptors, Large B-Cell, Physiological Guanylate Cyclase/metabolism Humans I-kappa B Kinase/metabolism Jurkat Cells Lymphoma, Signal Transducing/metabolism CARD Signaling Adaptor Proteins/metabolism Casein Kinases/*metabolism Caspases/metabolism Cell Proliferation Cell Survival Cells.
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  • Bonhomme-Faivre, L, Picard, V, Saliba, F, Abbara, C, Fodil, M, Chaunoy, M & Farinotti, R 2009, « Effect of the ABCB1 3435C>T polymorphism on tacrolimus concentrations and dosage requirements in liver transplant recipients », Am J Health Syst Pharm, vol. 66, no. 18, p. 1645-51.
    Résumé : PURPOSE: The effect of ABCB1 3435C>T on tacrolimus concentrations in liver transplant recipients was studied. Tacrolimus is a substrate for P-glycoprotein, the product of the ABCB1 gene. To determine whether the ABCB1 single-nucleotide polymorphism (SNP) 3435C>T was associated with variation in the tacrolimus concentration:dose ratio (C:D) in 42 liver transplant recipients during three months after transplantation. METHODS: Forty-two Caucasian patients who underwent an orthotopic liver transplantation from cadaveric donors received a basic immunosuppressive regimen containing tacrolimus and corticosteroids; mycophenolate mofetil was added in 18 cases. The SNP 3435C>T in exon 26 was investigated by MboI restriction-enzyme digestion, leading to the identification of CC, TT, or CT status at nucleotide 3435. Results obtained for the three genotypes were compared for each of three values: daily weight-adjusted tacrolimus dose, blood trough tacrolimus concentration, and C:D. RESULTS: The wild-type genotype (3435CC) was observed in 10 patients (24%); 23 patients (55%) were heterozygous (3435CT) and 9 patients (21%) were homozygous for the mutation (3435TT). One to three days after liver transplantation, the mean +/- S.D. C:D was significantly higher in subjects homozygous for the mutation compared with subjects with the wild-type allele (236 +/- 119 ng . kg/mL . mg versus 104 +/- 74 ng . kg/mL . mg, respectively; p = 0.0167). Subjects with the heterozygous allele had an intermediate mean +/- S.D. C:D (131 +/- 108 ng . kg/mL . mg). One or three months after transplantation, no significant difference in the tacrolimus C:D was evident among the three groups. CONCLUSION: The ABCB1 3435C>T polymorphism influenced the tacrolimus C:D in the first days after liver transplantation.
    Mots-clés : Female Genotype Humans Immunosuppressive Agents/administration & dosage/ pharmacokinetics Liver Transplantation Male Middle Aged Multidrug Resistance-Associated Proteins/ genetics Polymerase Chain Reaction Polymorphism, Single Nucleotide Tacrolimus/administration & dosage/ pharmacokinetics.

  • Bouchahda, M, Adam, R, Giacchetti, S, Castaing, D, Brezault-Bonnet, C, Hauteville, D, Innominato, PF, Focan, C, Machover, D & Lévi, F 2009, « Rescue chemotherapy using multidrug chronomodulated hepatic arterial infusion for patients with heavily pretreated metastatic colorectal cancer », Cancer, vol. 115, no. 21, p. 4990-9, viewed sans date, .
    Résumé : BACKGROUND: : Hepatic arterial infusion (HAI) chemotherapy delivers a high concentration of drugs both to liver metastases and to healthy liver with specific, limiting, hepatobiliary toxicities. Relevant detoxification and cellular proliferation pathways are controlled by the molecular circadian clock in normal liver but not in advanced tumors. In this article, the authors report their experience with chronomodulated HAI chemotherapy as rescue therapy in heavily pretreated patients who had metastatic colorectal cancer. METHODS: : Data from all consecutive patients with colorectal cancer liver metastases who received HAI with chronomodulated, multidrug chemotherapy regimens in the authors' center after failure on standard chemotherapy were reviewed for efficacy and safety. RESULTS: : Twenty-nine patients were treated, including 76% with liver metastasis only and 24% with liver and lung metastases. Seventy-five percent of patients had received > or =3 chemotherapy lines, including intravenous, chronomodulated chemotherapy in 59% of patients. Patients received a median of 4 HAI courses (range, 1-9 courses). The most frequent grade (according to National Cancer Institute of Canada Common Toxicity Criteria [version 3]) 3 and 4 nonhematologic toxicities were vomiting, diarrhea, abdominal pain, and fatigue. No severe hematologic or hepatic toxicities and no chemical cholangitis were reported. An objective tumor response was observed in 10 patients (34.5%), including 4 patients who subsequently underwent R0 or R1 hepatic resection. The median progression-free survival and overall survival were 4.5 months (95% confidence limits, 2.4-6.5 months) and 18 months (95% confidence limits, 5.8-30.2 months), respectively. CONCLUSIONS: : HAI chronomodulated chemotherapy had well tolerated activity in selected, heavily pretreated patients, and the authors believe it deserves to be assessed prospectively in clinical trials among patients who have less advanced disease. Cancer 2009. (c) 2009 American Cancer Society.
    Mots-clés : Adult Aged Antineoplastic Combined Chemotherapy Protocols/ administration & dosage/adverse effects Chemotherapy, Cancer, Intra-Arterial Liver Neoplasms/ drug therapy/secondary Male Middle Aged Retreatment Retrospective Studies, Regional Perfusion Circadian Rhythm Colorectal Neoplasms/ drug therapy/pathology Female Hepatic Artery Humans Infusions.
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    <p>19637365</p>
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    <p>19637365</p>
  • Burra, P, Senzolo, M, Masier, A, Prestele, H, Jones, R, Samuel, D & Villamil, F 2009, « Factors influencing renal function after liver transplantation. Results from the MOST, an international observational study », Dig Liver Dis, vol. 41, no. 5, p. 350-6.
    Résumé : INTRODUCTION: Renal failure, both acute and chronic, is a common complication after liver transplantation and can seriously jeopardise long-term outcome. Given organ shortage it should be essential to determine which patients will experience progressive and severe renal dysfunction after liver transplantation (LT). AIM: To correlate pre-transplant renal function and risk factors for renal failure after liver transplantation with occurrence of renal failure at 1 and 5 years after LT, with particular attention to hepatitis C virus (HCV) infection. METHODS: Data from patients enrolled in the liver section of Neoral MOST (Multinational Observational Study in Transplantation) study were used for the analysis. HCV status, pre-transplant serum creatinine level, recipient gender, recipient age, pre-transplant arterial hypertension, pre-transplant diabetes mellitus, pre-transplant antiviral therapy, the time of the transplant (before or after 2000) and immunosuppressive regimen were collected for each patient. Post-transplant occurrence of renal failure at 1 and 5 years was defined as a GFR<60 mL/min/1.73 m(2) (Stage III of the National Kidney Foundation). RESULTS: Data from 1948 patients enrolled in the study were considered. Glomerular filtration rate (GFR) was evaluated in 406 patients at 1 year and in 233 patients at 5 years after LT. The prevalence of HCV infection was 35% in the former and 37% in the latter. The median GFR was 70 mL/min/1.73 m(2) after 1 year and 69 mL/min after 5 years, significantly lower in HCV-positive (HCV+) than in HCV-negative (HCV-) patients both 1 and 5 years after LT (p<0.001). GFR before transplant correlated with GFR at 1 month, 1 and 3 years (p<0.0001 for all correlations). Multivariate analysis confirmed HCV status, pre-LT serum creatinine levels and recipient gender as significant predictors of 1-year GFR (p<0.001 for all three). Further analysis of the effect of recipient gender indicated that the only significant risk factor observed in both male and female patients was HCV positivity. Only 1-year GFR was an independent predictor of 5-year GFR (p<0.001). HCV+ status, cyclosporine (CsA) exposure, antiviral therapy and diabetes mellitus had no significant influence on 5-year GFR. CONCLUSIONS: HCV status and pre-LT serum creatinine levels were independent predictors of renal function a year after LT, together with GFR before transplant. The negative impact of HCV positivity on renal function was not confirmed in the long term, whereas the prognostic influence of an abnormal renal function in the early post-transplant period was more persistent.
    Mots-clés : &, Adult, Age, Aged, Agents/therapeutic, Antiviral, C/drug, Comorbidity, data, Diabetes, Donors/statistics, epidemiology, Factors, Failure/drug, Female, Filtration, Follow-Up, Glomerular, Graft, Hepatitis, Humans, Hypertension/epidemiology, Immunosuppressive, Insufficiency/diagnosis/, Liver, Male, Mellitus/epidemiology, Middle, numerical, Outcome, Prospective, Rate, Rejection/epidemiology, Renal, Retrospective, Risk, statistics, Studies, therapy/epidemiology, therapy/surgery, Tissue, Transplantation/, Treatment, use, Young.

  • Calmus, Y & Durrbach, A 2009, « Everolimus de novo in liver transplantation », Gastroenterol Clin Biol, vol. 33 Suppl 4, p. S247-52, viewed sans date, .
    Résumé : The safety and tolerability of everolimus has been evaluated in a randomized, phase II trial, comparing 3 doses of everolimus to a placebo, in association with cyclosporine and corticosteroids, after liver transplantation. There were no significant differences between groups in the rates of the composite end point (graft failure, biopsy-proven acute rejection, graft loss, death, or loss to follow-up) or its individual components. Although there were lower rates of treated acute rejection and mortality with the higher dosages (2 and 4 mg/day), these did not reach statistical significance. Interestingly, freedom from rejection correlated with trough blood levels of everolimus: patients with levels of 3 ng/mL or less had rejection rates 3-fold higher than patients with levels exceeding 3 ng/mL. All graft losses and most deaths were associated with typical posttransplant complications, not with study medication and not due to hepatic artery thrombosis. There were no clear dose-related differences among groups for hematology parameters. After transplantation, renal function declined to a similar extent in all 4 groups. The overall incidence of infection was comparable between groups (61-77%). Although the interpretation of the results of this trial is hampered by the small sample sizes of patient groups (about 30 in each group) and the high dropout rates (about 50%), this study suggests that everolimus is an effective immunosuppressive agent with an acceptable patient tolerance and safety profile after liver transplantation.
    Mots-clés : Cyclosporine/administration & dosage Dose-Response Relationship.

  • Cao, F-F, Xu, L-M, Peng, B, Xie, Q-H, Uzan, G & Zhang, D-H 2009, « A routinely applicable way for using FCM in cell enumeration with CFSE-labeled CellBeads as internal standard », Cytometry A, vol. 75, no. 12, p. 975-8, viewed sans date, .
    Note Note
    <p>19821513</p>
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  • Castaing, D, Vibert, E, Ricca, L, Azoulay, D, Adam, R & Gayet, B 2009, « Oncologic results of laparoscopic versus open hepatectomy for colorectal liver metastases in two specialized centers », Ann Surg, vol. 250, no. 5, p. 849-55, viewed sans date, .
    Résumé : OBJECTIVE: Compare oncologic results of laparoscopic versus open hepatectomy for resection of colorectal metastases to the liver. SUMMARY AND BACKGROUND DATA: Open hepatectomy (OH) is the current standard of care for the management of colorectal liver metastases. Although the feasibility of laparoscopic hepatectomy (LH) has been established, only select centers have used this technique as their primary modality. At present there is no study comparing the oncologic outcomes for colorectal liver metastases patients undergoing LH versus OH. METHODS: Two groups composed of 60 patients each were obtained from 2 specialized liver units performing either OH or LH as their primary modality. Cohorts of 215 LH cases and 1783 OH were used to establish the study population. Patients were compared on an intention to treat basis using 9 preoperative prognostic criteria obtained from LiverMetSurvey. These included sex, age, primary tumor localization, number of tumors, diameter of tumor, distribution of metastases, presence of extrahepatic disease, initial respectability, and the use of prehepatectomy chemotherapy. Overall survival and disease-free survival were compared between OH and LH for a follow-up of 36 months. RESULTS: The median follow-up for the LH group is 30 months and 33 months for the OH group (P = 0.75). One-, 3-, and 5-year patient survival for LH was 97%, 82%, and 64% and 97%, 70%, and 56% in the OH group, respectively (P = 0.32). One-, 3-, and 5-year disease-free survival was 70%, 47%, and 35% and 70%, 40%, and 27% (P = 0.32), respectively for the 2 groups. CONCLUSION: In a highly specialized center, first line application of laparoscopic liver resection in selected patients can provide comparable oncologic results to treatment with open liver resection for patients with colorectal liver metastases.
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    <p>19801934</p>
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  • Charrin, S, le Naour, F, Silvie, O, Milhiet, P-E, Boucheix, C & Rubinstein, E 2009, « Lateral organization of membrane proteins: tetraspanins spin their web », Biochem J, vol. 420, no. 2, p. 133-54, viewed sans date, .
    Résumé : Despite high expression levels at the plasma membrane or in intracellular vesicles, tetraspanins remain among the most mysterious transmembrane molecules 20 years after their discovery. Several genetic studies in mammals and invertebrates have demonstrated key physiological roles for some of these tetraspanins, in particular in the immune response, sperm-egg fusion, photoreceptor function and the normal function of certain epithelia. Other studies have highlighted their ability to modulate cell migration and metastasis formation. Their role in the propagation of infectious agents has drawn recent attention, with evidence for HIV budding in tetraspanin-enriched plasma membrane domains. Infection of hepatocytic cells by two major pathogens, the hepatitis C virus and the malaria parasite, also requires the tetraspanin CD81. The function of tetraspanins is thought to be linked to their ability to associate with one another and a wealth of other integral proteins, thereby building up an interacting network or 'tetraspanin web'. On the basis of the biochemical dissection of the tetraspanin web and recent analysis of the dynamics of some of its constituents, we propose that tetraspanins tightly regulate transient interactions between a variety of molecules and as such favour the efficient assembly of specialized structures upon proper stimulation.
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    <p>19426143</p>
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  • Charrin, S, Yalaoui, S, Bartosch, B, Cocquerel, L, Franetich, J-F, Boucheix, C, Mazier, D, Rubinstein, E & Silvie, O 2009, « The Ig domain protein CD9P-1 down-regulates CD81 ability to support Plasmodium yoelii infection », J Biol Chem, vol. 284, no. 46, p. 31572-8, viewed sans date, .
    Résumé : Invasion of hepatocytes by Plasmodium sporozoites is a prerequisite for establishment of a malaria natural infection. The molecular mechanisms underlying sporozoite invasion are largely unknown. We have previously reported that CD81 is required on hepatocytes for infection by Plasmodium falciparum and Plasmodium yoelii sporozoites. CD81 belongs to the tetraspanin superfamily of transmembrane proteins. By interacting with each other and with other transmembrane proteins, tetraspanins may play a role in the lateral organization of membrane proteins. In this study, we investigated the role of the two major molecular partners of CD81 in hepatocytic cells, CD9P-1/EWI-F and EWI-2, two transmembrane proteins belonging to a novel subfamily of immunoglobulin proteins. We show that CD9P-1 silencing increases the host cell susceptibility to P. yoelii sporozoite infection, whereas EWI-2 knock-down has no effect. Conversely, overexpression of CD9P-1 but not EWI-2 partially inhibits infection. Using CD81 and CD9P-1 chimeric molecules, we demonstrate the role of transmembrane regions in CD81-CD9P-1 interactions. Importantly, a CD9P-1 chimera that no longer associates with CD81 does not affect infection. Based on these data, we conclude that CD9P-1 acts as a negative regulator of P. yoelii infection by interacting with CD81 and regulating its function.
    Note Note
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  • Chiappini, F, Teicher, E, Saffroy, R, Debuire, B, Vittecoq, D & Lemoine, A 2009, « Relationship between polymerase gamma (POLG) polymorphisms and antiretroviral therapy-induced lipodystrophy in HIV-1 infected patients: a case-control study », Curr HIV Res, vol. 7, no. 2, p. 244-53, viewed sans date, .
    Résumé : Nucleoside Reverse Transcriptase Inhibitors (NRTIs) used for the treatment of HIV-1 inhibit the replication of mitochondrial DNA (mtDNA), which may contribute to severe mitochondrial toxicity including lipodystrophy, through the inhibition of polymerase gamma (POLG). Polymorphisms of POLG could explain the variation in mitochondrial toxicity in HIV-1-infected patients. We explored the relationship between selected polymorphisms of POLG and lipodystrophy related to NRTIs. We studied single nucleotide polymorphisms (SNP) at three amino acid residues (R1142, E1143 and R1146) and the CAG repeats of POLG in a case-control study including HIV-1 treated patients with lipodystrophy (n=69) and 2 controls (without lipodystrophy) per case matched by age, race and sex (n=138). Compared with matched controls, the polymorphisms in E1143 were significantly more frequent in case patients with lipodystrophy (aOR=4.7; p=0.048), and this was associated with a significant decrease of mtDNA in PBMC. In addition, among the parameters tested, the conditional logistic regression showed that the lipodystrophy has a strong link with E1143 polymorphisms, associated with D4T treatment (aOR=9.29, p=0.002). In conclusion, patients harbouring the changes of E1143 in the catalytic site of POLG exhibit a 4-fold increased risk to develop lipodystrophy than HIV-1 treated patients who do not have changes in E1143 and this risk can increase if the patient presenting the SNP received D4T. These could be due to decreased content of mtDNA in PBMC in these patients. Therefore, the toxicity of NRTIs leading to lipodystrophy in some HIV-1 infected patients could be explained in part by the occurrence of POLG polymorphisms.
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    <p>19275594</p>
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    <p>19275594</p>

  • Chok, MK, Ferlicot, S, Conti, M, Almolki, A, Durrbach, A, Loric, S, Benoit, G, Droupy, S & Eschwege, P 2009, « Renoprotective potency of heme oxygenase-1 induction in rat renal ischemia-reperfusion », Inflamm Allergy Drug Targets, vol. 8, no. 4, p. 252-9, viewed sans date, .
    Résumé : PURPOSE: Renal injury caused by ischemia-reperfusion (IR) can lead to acute renal failure or delayed graft function. Renal ischemia-reperfusion (RIR) induces inflammatory disorders via activation of arachidonic acid metabolism into prostaglandin E(2) (PGE(2)). Two inducible enzymes, COX-2 and microsomal prostaglandin E synthase (mPGES), regulate PGE(2) production. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme activated during cellular stress. Overexpression of HO-1 is beneficial in transplantation models including antigen-independent IR injury, acute and chronic allograft rejection. MATERIALS AND METHODS: We investigated the effect of HO-1 induction on the COX pathway, antioxidant enzyme activities, malondialdehyde (MDA) levels, and apoptosis in rat kidneys subjected to 45 min ischemia and 1 h or 24 h reperfusion. Rats were injected intraperitoneally with either: 50 mg/kg hemin (HO-1 inducer groups: H1, H2); 50 micromol/kg ZnPP (HO-1 inhibitor groups: Hz1, Hz2); or 0.9% saline (control groups: r1, r2). Sham animals (Sh) did not undergo RIR. RESULTS: Serum creatinine increased significantly after RIR (r vs Sh; p <0.05). Hemin treatment induced a significant decrease in serum creatinine after RIR (H vs r; p <0.05) whereas ZnPP treatment significantly increased serum creatinine levels (Sh vs Hz; p <0.05). Hemin reduced the severity of acute tubular necrosis and significantly reduced COX-2 and mPGES expression (p <0.05). Hemin did not alter depleted antioxidant enzyme activity but did decrease levels of MDA (p <0.05). Hemin also reduced caspase-3 expression. CONCLUSIONS: HO-1 decreased the degree and severity of tubular damage after IR, probably by attenuating the cytotoxic effects of inflammatory infiltrates and apoptosis.
    Mots-clés : Sprague-Dawley Reperfusion Injury/blood/drug therapy/*enzymology/pathology.

  • Chomel, J-C, Sorel, N, Bonnet, M-L, Bertrand, A, Brizard, F, Saulnier, P-J, Roy, L, Guilhot, F & Turhan, AG 2009, « Quantitative monitoring of the T315I mutation in patients with chronic myeloid leukemia (CML) », Leuk Res, vol. 33, no. 4, p. 551-5, viewed sans date, .
    Résumé : Tyrosine kinase inhibitors (TKIs) have dramatically improved the treatment of chronic myeloid leukemia (CML). However, resistances are occasionally observed, mainly due to mutations within the BCR-ABL kinase domain. The T315I substitution confers complete resistance to TKIs commonly used in clinical practice. In the present study, we used an allele-specific quantitative-RT-PCR to perform a molecular follow-up of BCR-ABL transcripts harboring the T315I mutation. We retrospectively quantified BCR-ABL315I mRNA in five patients who acquired the T315I mutation. Our results highlight the relevance of allele-specific Q-RT-PCR experiments for the monitoring of mutated BCR-ABL transcripts and suggest that the kinetics of emergence of T315I mutant mRNA is influenced by the stage of the disease and the presence of previous BCR-ABL kinase domain mutations.
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  • Claudinon, J, Gonnord, P, Beslard, E, Marchetti, M, Mitchell, K, Boularan, C, Johannes, L, Eid, P & Lamaze, C 2009, « Palmitoylation of interferon-alpha (IFN-alpha) receptor subunit IFNAR1 is required for the activation of Stat1 and Stat2 by IFN-alpha », J Biol Chem, vol. 284, no. 36, p. 24328-40, viewed sans date, .
    Résumé : Type I interferons (IFNs) bind IFNAR receptors and activate Jak kinases and Stat transcription factors to stimulate the transcription of genes downstream from IFN-stimulated response elements. In this study, we analyze the role of protein palmitoylation, a reversible post-translational lipid modification, in the functional properties of IFNAR. We report that pharmacological inhibition of protein palmitoylation results in severe defects of IFN receptor endocytosis and signaling. We generated mutants of the IFNAR1 subunit of the type I IFN receptor, in which each or both of the two cysteines present in the cytoplasmic domain are replaced by alanines. We show that cysteine 463 of IFNAR1, the more proximal of the two cytoplasmic cysteines, is palmitoylated. A thorough microscopic and biochemical analysis of the palmitoylation-deficient IFNAR1 mutant revealed that IFNAR1 palmitoylation is not required for receptor endocytosis, intracellular distribution, or stability at the cell surface. However, the lack of IFNAR1 palmitoylation affects selectively the activation of Stat2, which results in a lack of efficient Stat1 activation and nuclear translocation and IFN-alpha-activated gene transcription. Thus, receptor palmitoylation is a previously undescribed mechanism of regulating signaling activity by type I IFNs in the Jak/Stat pathway.
    Mots-clés : Active Transport, Cell Nucleus/drug effects/genetics Amino Acid Substitution Animals Antiviral Agents/*pharmacology Cell Line Cell Nucleus/genetics/metabolism Endocytosis/drug effects/genetics Humans Interferon-alpha/*pharmacology Mice Mutation, Interferon alpha-beta/genetics/*metabolism STAT1 Transcription Factor/genetics/*metabolism STAT2 Transcription Factor/genetics/*metabolism Signal Transduction/drug effects, Missense Palmitic Acid/*metabolism Protein Processing, Post-Translational/*drug effects/genetics Protein Structure, Tertiary/genetics Receptor.
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  • Colmant, C, Brisset, S, Tachdjian, G, Gautier, V, Ftouki, M, Laroudie, M, Druart, L, Frydman, R & Picone, O 2009, « Interstitial deletion 6p22.3-p24.3 characterized by CGH array in a foetus with multiple malformations », Prenat Diagn, vol. 29, no. 9, p. 908-10, viewed sans date, .
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  • Conti, M, Moutereau, S, Esmilaire, L, Desbene, C, Lallali, K, Devanlay, M, Durrbach, A, Manivet, P, Eschwege, P & Loric, S 2009, « Should kidney tubular markers be adjusted for urine creatinine? The example of urinary cystatin C », Clin Chem Lab Med, vol. 47, no. 12, p. 1553-6, viewed sans date, .
    Résumé : BACKGROUND: Evaluation of specific urinary markers with respect to urine creatinine (uCreat) is common. However, as uCreat is a function of both glomerular filtration and tubular secretion, using uCreat for specific tubular markers, suggests that glomerular function is normal, and there is no tubular secretion. Thus, adjusting values of any tubular marker to uCreat, especially in patients with acute or even moderate chronic renal failure, can be misleading. METHODS: Using urine cystatin-C (uCST3) as a model tubular marker for following 120 kidney graft recipients daily, we evaluated the utility of either uCST3 alone or the uCST3/uCreat ratio to detect tubular damage. All positive kidney biopsies were always associated with a uCST3>0.18 mg/L. RESULTS: Using the uCST3/uCreat ratio, discrepancies regarding biopsy status were observed in nine patients (4 false positive, 5 false negative results). In two patients, variability of uCreat appeared to be the most important factor causing inconsistent uCST3/uCreat ratios. With a negative predictive value (NPV) of 85.7%, uCST3/uCreat can lead to errors in clinical interpretation. These errors can be avoided when estimates of tubular damage are based on uCST3 concentrations alone (NPV=100%). CONCLUSIONS: We recommend using the uCST3 value to evaluate the extent of renal tubular damage. Indeed, our conflicting results on uCST3/uCreat can be extended to every marker of tubular function. Evaluating a urine marker specific for renal tubular damage to a second urine marker that is itself strongly dependent upon glomerular or other renal or non-renal conditions, impairs its clinical relevance and may lead to incorrect interpretations. Correction with uCreat can be performed only in pure glomerulopathy, when specific markers of glomerular function are measured (i.e., urinary albumin). In all other cases of renal diseases, such correction is inappropriate and should be avoided. Clin Chem Lab Med 2009;47:1553-6.
    Mots-clés : Biological, C/*urine, Creatinine/*urine, Cystatin, Detection, Humans, Kidney, Limit, Markers/*urine, of, Tubules/*metabolism.

  • Coppo, P, Dusanter-Fourt, I, Vainchenker, W & Turhan, AG 2009, « BCR-ABL induces opposite phenotypes in murine ES cells according to STAT3 activation levels », Cell Signal, vol. 21, no. 1, p. 52-60, viewed sans date, .
    Résumé : The mechanisms by which p210-BCR-ABL determines hematopoietic stem cells fate remain poorly understood. To better understand the behavior of BCR-ABL in pluripotent stem cells, we previously developed a murine embryonic stem (ES) cell model transformed by p210-BCR-ABL and reported that BCR-ABL activates STAT3, a major protein involved in ES cells self-renewal, which leads specifically to inhibition of ES cells differentiation. We show here that BCR-ABL either inhibits differentiation or, unexpectedly, induces a rapid commitment to differentiation of murine ES cells, according to the intracellular levels of activated STAT3. We show that inhibition of endogenous STAT3 activation with an inducible STAT3 protein with dominant-negative activity (STAT3F) results in an early, rapid and complete differentiation of BCR-ABL-expressing ES cells, whereas control ES cells retain a more undifferentiated phenotype. This phenomenon could be totally abrogated by PD98059, a specific MEK1 inhibitor, suggesting the involvement of mitogen-activated protein kinase (MAP-Kinase)/ERK1/2 pathway, which was found constitutively phosphorylated in BCR-ABL-expressing cells. In addition, BCR-ABL-expressing ES cells harboring low levels of activated STAT3 committed more rapidly through hematopoietic differentiation, since embryoid bodies (EBs) derived from these cells were able to generate numerous hematopoietic progenitors 2 days early. Moreover, BCR-ABL-expressing ES cells cultured first with low levels of activated STAT3 before EBs derivation displayed a more rapid loss of pluripotency than controls and failed to generate hematopoietic progenitors. This phenomenon was partially abrogated when ES cells were first exposed to PD98059 or to the tyrosine kinase inhibitor imatinib mesylate. From this predictive model, we suggest that variations of the activation levels in BCR-ABL substrates such as STAT3 may represent "instructive" secondary cooperating events involved in the transformation of the leukemic cell phenotype during the course of CML.
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  • Couturier, E, Roque-Afonso, AM, Letort, MJ, Dussaix, E, Vaillant, V & de Valk, H 2009, « Cluster of cases of hepatitis A with a travel history to Egypt, September-November 2008, France », Euro Surveill, vol. 14, no. 3.
    Résumé : Since September 2008, 26 cases of hepatitis A with a history of travel to Egypt have been reported in France. Investigations indicate that a common source of contamination linked to Nile river cruises is the most likely explanation of the increase in the number of cases reported in France as well as in several other European Union countries.
    Mots-clés : &, A/, Analysis, Assessment/, Cluster, data, disease, epidemiology, Factors, France/epidemiology, Hepatitis, Humans, Incidence, methods, numerical, Outbreaks/, Population, Risk, statistics, Surveillance, Travel/.
  • Couzigou, C, Seang, S, Morand-Joubert, L, Roque-Afonso, AM, Escaut, L & Vittecoq, D 2009, « Efficacy of etravirine for treatment of acute HIV meningoencephalitis », Clin Infect Dis, vol. 48, no. 6, p. e62-5.
    Résumé : We describe a patient with human immunodeficiency virus (HIV) and hepatitis C virus coinfection who experienced recurrent episodes of acute HIV meningoencephalitis. The addition of etravirine to the therapeutic regimen completely resolved symptoms, and HIV was no longer detected in cerebrospinal spinal fluid specimens. Etravirine has a satisfactory safety profile and, in this case, was a durable alternative therapy for HIV meningoencephalitis.
    Mots-clés : &, Adult, Agents/, Anti-HIV, C/complications, Cerebrospinal, complications/, drug, Female, Fluid/virology, Hepatitis, HIV, HIV/isolation, Humans, Infections/, Meningoencephalitis/, Outcome, purification, Pyridazines/, therapeutic, Therapy, Treatment, use.
  • Covic, A, Abramowicz, D, Bruchfeld, A, Leroux-Roels, G, Samuel, D, van Biesen, W, Zoccali, C, Zoulim, F & Vanholder, R 2009, « Endorsement of the Kidney Disease Improving Global Outcomes (KDIGO) hepatitis C guidelines: a European Renal Best Practice (ERBP) position statement », Nephrol Dial Transplant, vol. 24, no. 3, p. 719-27.
    Résumé : Covic, Adrian; Abramowicz, Daniel; Bruchfeld, Annette; Leroux-Roels, Geert; Samuel, Didier; van Biesen, Wim; Zoccali, Carmine; Zoulim, Fabien; Vanholder, Raymond; ERA-EDTA ERBP Advisory Board; England; Nephrol Dial Transplant. 2009 Mar;24(3):719-27. doi: 10.1093/ndt/gfn608. Epub 2009 Feb 8.
    Mots-clés : &, as, C/, complications/, control/, Cooperation, Diseases/, Europe, Guidelines, Hepatitis, Humans, International, Kidney, Practice, prevention, Therapy, Topic, virology.
  • Dagher, I, Nguyen, TH, Groyer-Picard, MT, Lainas, P, Mainot, S, Guettier, C, Pariente, D, Franco, D & Weber, A 2009, « Efficient hepatocyte engraftment and long-term transgene expression after reversible portal embolization in nonhuman primates », Hepatology, vol. 49, no. 3, p. 950-9.
    Résumé : The feasibility of ex vivo gene therapy as an alternative to liver transplantation for the treatment of liver metabolic diseases needs to be analyzed in large animal models. This approach requires appropriate gene transfer vectors and effective hepatocyte engraftment. Lentiviral vectors have the ability to transduce nondividing differentiated cells, such as hepatocytes, and portal vein occlusion increases hepatocyte engraftment. We investigated whether reversible portal vein embolization combined with ex vivo lentivirus-mediated gene transfer is an effective approach for successful hepatocyte engraftment in nonhuman primates and whether the transgene remains expressed in the long term in transplanted hepatocytes in situ. Simian hepatocytes were isolated after left lobe resection, and the left and right anterior portal branches of animals were embolized with absorbable material. Isolated hepatocytes were labeled with Hoechst dye or transduced in suspension with lentiviruses expressing green fluorescent protein under the control of the human apolipoprotein A-II promoter and transplanted via the inferior mesenteric vein. The whole procedure was well tolerated. The embolized liver was revascularized within 2 weeks. The volume of nonembolized liver increased from 38.7% +/- 0.8% before embolization to 55.9% +/- 1% after embolization and hepatocytes significantly proliferated (10.5% +/- 0.4% on day 3 after embolization). Liver repopulation after transplantation with Hoechst-labeled hepatocytes was 7.4% +/- 1.2%. Liver repopulation was 2.1% +/- 0.2% with transduced hepatocytes, a proportion similar to that obtained with Hoechst-labeled cells, given that the mean transduction efficacy of simian hepatocyte population was 34%. Transgene expression persisted at 16 weeks after transplantation. Conclusion: We have developed a new approach to improve hepatocyte engraftment and to express a transgene in the long term in nonhuman primates. This strategy could be suitable for clinical applications.
    Mots-clés : Animal Portal Vein/surgery Transgenes/genetics, Animals Apolipoprotein A-II/genetics/ metabolism Cell Proliferation Cell Transplantation/ methods Embolization, Therapeutic/ methods Gene Expression Regulation Genetic Therapy Hepatocytes/ metabolism/pathology/ transplantation Humans Lentivirus/genetics Liver/metabolism/pathology/surgery Liver Regeneration/physiology Macaca mulatta Models.


  • de Haas, RJ, Rahy Martin, AC, Wicherts, DA, Azoulay, D, Castaing, D & Adam, R 2009, « Long-term outcome in patients with adrenal metastases following resection of colorectal liver metastases », Br J Surg, vol. 96, no. 8, p. 935-40, viewed sans date, .
    Résumé : BACKGROUND: The prognostic significance of adrenal metastases (AMs) in patients with colorectal liver metastases (CLMs) remains unknown. The aim of this study was to determine the influence of AMs on long-term outcome and the role of adrenalectomy in patients with CLMs. METHODS: All patients resected for CLMs who developed AMs at a single institution between 1992 and 2006 were included in the study. Their long-term outcome was compared with that of all other patients resected for CLMs but without AMs. RESULTS: Hepatectomy was performed in 796 patients, of whom 14 (1.8 per cent) developed AMs, a median of 28 months after initial diagnosis of CLMs; the remaining 782 patients (98.2 per cent) had no AMs. All 14 patients had chemotherapy, and ten went on to adrenalectomy. Median survival after diagnosis of CLMs was 50 months in patients with AMs versus 68 months in those without (P = 0.020). After diagnosis of AMs, median survival was 23 months, whether or not adrenalectomy was performed. CONCLUSION: The development of AMs after liver resection for colorectal cancer deposits carries a poor prognosis, and adrenalectomy is probably not warranted.
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  • De Simone, P, Metselaar, HJ, Fischer, L, Dumortier, J, Boudjema, K, Hardwigsen, J, Rostaing, L, De Carlis, L, Saliba, F & Nevens, F 2009, « Conversion from a calcineurin inhibitor to everolimus therapy in maintenance liver transplant recipients: a prospective, randomized, multicenter trial », Liver Transpl, vol. 15, no. 10, p. 1262-9.
    Résumé : Calcineurin inhibitors (CNIs) contribute to renal dysfunction following liver transplantation. This prospective, randomized, multicenter, 6-month study (with an additional 6 months of follow-up) evaluated whether everolimus with CNI reduction or discontinuation would improve renal function in maintenance liver transplant recipients experiencing CNI-related renal impairment. Patients started everolimus therapy with CNI reduction or discontinuation (n = 72) or continued receiving standard-exposure CNI (n = 73). At month 6, 80% of the patients who had converted to everolimus had discontinued the CNI. The mean change in creatinine clearance (CrCl) from baseline to month 6 was similar between groups (everolimus, 1.0 +/- 10.2 mL/minute; controls, 2.3 +/- 7.8 mL/minute; P = 0.46), so the primary study endpoint (8 mL/minute difference in the change in CrCl) was not achieved. Among patients who continued everolimus according to the protocol, the mean increase in CrCl was 2.1 (n = 53) and 3.8 mL/minute (n = 38) at months 6 and 12, respectively, versus 2.4 (n = 68) and 3.5 mL/minute in controls (n = 51). The high frequency of CNI dose reductions in controls (77% of the patients) and the relatively long mean time post-transplant (>3 years) likely contributed to the small difference in CrCl. Biopsy-proven acute rejection occurred in 1.4% of the patients in each group, with no graft losses. Study drug discontinuation was higher in everolimus-treated patients, and adverse events were more frequent. These data demonstrate that everolimus allows for discontinuation or a major reduction of CNI exposure in liver allograft recipients suffering CNI-related renal dysfunction without a loss of efficacy. Trials targeting earlier conversion post-transplantation are required to confirm the efficacy and safety of everolimus for improving renal function after liver transplantation.
    Mots-clés : &, Adolescent, Adult, Aged, Agents/therapeutic, analogs, antagonists, Biopsy, Calcineurin/, derivatives/therapeutic, Diseases/, Female, Graft, Humans, Immunosuppressive, inhibitors, Liver, Male, methods, Middle, Outcome, Prospective, Rejection, Sirolimus/, Studies, Survival, Therapy, Transplantation/, Treatment, use.

  • Delgado, J-P, Vanneaux, V, Branger, J, Touboul, T, Sentilhes, L, Mainot, S, Lainas, P, Leclerc, P, Uzan, G, Mahieu-Caputo, D & Weber, A 2009, « The role of HGF on invasive properties and repopulation potential of human fetal hepatic progenitor cells », Exp Cell Res, vol. 315, no. 19, p. 3396-405, viewed sans date, .
    Résumé : The success of hepatocyte transplantation has been limited by the low efficiency of transplanted cell integration into liver parenchyma. Human fetal hepatic progenitor cells (hepatoblasts) engraft more effectively than adult hepatocytes in mouse livers. However, the signals required for their integration are not yet fully understood. We investigated the role of HGF on the migration and invasive ability of human hepatic progenitors in vitro and in vivo. Hepatoblasts were isolated from the livers of human fetuses between 10 and 12 weeks of gestation. Their invasive ability was assessed in the presence or absence of HGF. These cells were also transplanted into immunodeficient mice and analyzed by immunohistochemistry. In contrast to TNF-alpha, HGF increased the motogenesis and invasiveness of hepatoblasts, but not of human adult hepatocytes, via phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. The invasive ability of human hepatoblasts correlated with the expression and secretion of matrix metalloproteinases (MMPs). Hepatoblasts stimulated with HGF prior transplantation into newborn mice migrated from the portal area into the hepatic parenchyma. Conclusions: In contrast to adult hepatocytes, hepatoblasts display invasive ability that can be modulated by HGF in vitro and in vivo.
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  • Demange, C, Ferrand, N, Prunier, C, Bourgeade, MF & Atfi, A 2009, « A model of partnership co-opted by the homeodomain protein TGIF and the Itch/AIP4 ubiquitin ligase for effective execution of TNF-alpha cytotoxicity », Mol Cell, vol. 36, no. 6, p. 1073-85.
    Résumé : The homeodomain protein TGIF functions as a negative regulator of multiple classes of transcription factors. Here we report on the characterization of TGIF as an essential component of the tumor necrosis factor alpha (TNF-alpha) cytotoxic program. This proapoptotic role of TGIF does not appear to rely on transcriptional modulation but instead is executed in conjunction with Itch/AIP4, an E3 ubiquitin ligase operating in TNF-alpha-induced apoptosis through its ability to target the caspase antagonist cFlip(L) for degradation. Notably, we found that activation of TNF-alpha signaling induced the association of TGIF with Itch/AIP4, resulting in increased accessibility of cFlip(L) for association and ubiquitination by Itch/AIP4. Moreover, we show that Itch/AIP4 can also stabilize the TGIF protein in response to TNF-alpha by triggering its monoubiquitination at lysine 259, thereby revealing the existence of a functional network that can evolve into a positive feedback loop for ensuring effective execution of the TNF-alpha apoptotic signaling.
    Mots-clés : Animals CASP8 and FADD-Like Apoptosis Regulating Protein/genetics/metabolism Cell Death/ drug effects Cell Line Homeodomain Proteins/genetics/metabolism/ pharmacology Humans Lysine/metabolism Mice Mice, Knockout Repressor Proteins/genetics/metabolism/ pharmacology Signal Transduction/physiology Ubiquitin-Protein Ligases/genetics/ metabolism Ubiquitination.

  • Deng, Q, Mancini-Bourgine, M, Zhang, X, Cumont, MC, Zhu, R, Lone, YC & Michel, ML 2009, « Hepatitis B virus as a gene delivery vector activating foreign antigenic T cell response that abrogates viral expression in mouse models », Hepatology, vol. 50, no. 5, p. 1380-91, viewed sans date, .
    Résumé : Chronic hepatitis B virus (HBV) infection is characterized by functionally impaired T cell responses. To ensure active immunotherapy, the immune response must be switched from exhausted T cells to functional effectors that can attain the liver and cure the viral infection. We thus designed a recombinant HBV (rHBV) containing a modified viral core gene that specifically delivers a foreign antigenic polyepitope to the liver. This recombinant virus could only be self-maintained in hepatocytes already infected by HBV through capsid complementation. A strong foreign epitope-specific T cell response was first primed in the periphery by way of DNA immunization in human leukocyte antigen (HLA)-A2/DR1 transgenic mice. After the hydrodynamic (hyd.) injection of rHBV, expression of the foreign antigenic polyepitope in hepatocytes attracted/reactivated a vigorous T cell response in situ. Most liver-infiltrating CD8(+) T cells proved to be functional effectors. Following DNA priming and hyd. injection, the rHBV-based expression of hepatitis B surface antigen (HBsAg) in mouse liver was almost completely inhibited without causing major liver injury. Studies in HBsAg/HLA-A2/DR1 transgenic mice further validated our approach. CONCLUSION: For the first time, HBV was used as a gene delivery vector, which strongly triggered functional T cell response and subsequently controlled the viral expression in the liver of surrogate mouse models for HBV infection. It might represent an innovative and promising strategy of active immunotherapy during HBV persistent infection. This concept could even be more generally extended to other chronic viral diseases.
    Mots-clés : Active Liver/immunology/pathology/virology Mice Mice, Animal Epitopes/genetics Female Gene Expression Regulation, Animals Antigens/*metabolism Disease Models, Chronic/genetics/immunology/pathology Immunotherapy, Transgenic T-Lymphocytes/*immunology/pathology Virus Replication/physiology, Viral/*physiology *Gene Transfer Techniques Genetic Vectors/*genetics HLA-A2 Antigen/genetics/metabolism HLA-DR1 Antigen/genetics/metabolism Hepatitis B Surface Antigens/genetics/metabolism Hepatitis B virus/*genetics/physiology Hepatitis C.
  • Desbois, D, Roque-Afonso, AM, Lebraud, P & Dussaix, E 2009, « Use of dried serum spots for serological and molecular detection of hepatitis a virus », J Clin Microbiol, vol. 47, no. 5, p. 1536-42.
    Résumé : We assessed the feasibility of using dried serum spots (DSS) for the serological and molecular diagnosis of hepatitis A virus (HAV) infection. Sixty-eight sera spotted onto filter papers (Whatman International Ltd., United Kingdom) were used for detection of total anti-HAV antibodies, and 64 sera were used for detection of immunoglobulin M antibody to HAV. DSS were stored at 4 degrees C, room temperature, and 37 degrees C for 1, 2, and 4 weeks. Sensitivity and specificity of the serological assays were 100% regardless of temperature and storage duration. To assess the stability of HAV RNA, we performed qualitative and quantitative reverse transcription-PCRs (RT-PCRs) with human plasma spiked with serial dilutions of cultured HAV spotted on Flinders Technology Associates filter paper cards (Whatman International Ltd.). Filter papers were stored at room temperature and processed for RT-PCR assays. No reduction of viral load was observed after 5, 15, and 30 days of storage. The approximately 10-fold reduction of sensitivity from DSS was attributable to a smaller sample input in DSS samples. This method was further evaluated using 35 frozen sera. HAV RNA amplification showed 100% specificity and 92.3% sensitivity, and sequence analysis from DSS and sera provided identical results. HAV RNA can be accurately recovered from DSS for molecular epidemiology purposes, and we confirm the reliability of blotted samples in the serological diagnosis of HAV infection. The DSS method facilitates storage and shipment of samples from routine laboratories to reference centers for further investigations and large epidemiological studies.
    Mots-clés : Desiccation Great Britain Hepatitis A/ diagnosis Hepatitis A Antibodies/ blood Hepatitis A virus/ isolation & purification Humans Molecular Sequence Data Phylogeny RNA, DNA Sequence Homology Serum/ virology Specimen Handling/ methods, Viral/genetics Reverse Transcriptase Polymerase Chain Reaction Sensitivity and Specificity Sequence Analysis.
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  • Desterke, C, Bilhou-Nabera, C, Guerton, B, Tonetti, C, Clay, D, Pierre-Louis, O, Vannucchi, AM, Gisslinger, H, Bordessoule, D, Hasselbalch, HC, Lazar, V, Vainchenker, W, Bennaceur-Griscelli, A, Giraudier, S & Bousse-Kerdiles, MC 2009, « FLT3-Mediated MAPK Activation Participates in the Control of Megakaryopoiesis in Primary Myelofibrosis », Blood, vol. 114, no. 22, p. 398-398, viewed sans date, .


  • Domart, M-C, Esposti, DD, Sebagh, M, Olaya, N, Harper, F, Pierron, G, Franc, B, Tanabe, KK, Debuire, B, Azoulay, D, Brenner, C & Lemoine, A 2009, « Concurrent induction of necrosis, apoptosis, and autophagy in ischemic preconditioned human livers formerly treated by chemotherapy », J Hepatol, vol. 51, no. 5, p. 881-9, viewed sans date, .
    Résumé : BACKGROUND/AIMS: Liver pathology induced by chemotherapy (steatosis or vascular injury) is known to increase the liver's sensitivity to ischemia/ reperfusion (I/R) injury, thereby increasing morbidity and mortality after liver resection. Our aim was to assess whether ischemic preconditioning (IP) reduces I/R injury to livers with chemotherapy-induced pathology. METHODS: We analyzed a series of livers from patients treated with chemotherapy for colorectal cancer who underwent IP (n=30) or not (n=31) before hepatectomy. All but one of the livers exhibited chemotherapy-induced steatosis and/ or peliosis before the I/R insult. RESULTS: Necrosis was less frequent (p=0.038) in livers with IP than in the others. IP had no influence on apoptosis as assessed by terminal transferase uridyl nick-end labeling (TUNEL) assay or caspase-3, -8 and -9 expression. IP induced a twofold increase in B-cell leukemia/ lymphoma 2 (Bcl-2; p<0.05), which was localized to hepatocytes of centrolobular and peliotic areas and colocalized with the autophagy protein beclin-1 in livers with IP, suggesting their coordinated role in autophagy. Increased expression of the phosphorylated Bcl-2 was observed in preconditioned livers and was associated with a decreased immunoprecipitation of beclin-1 and the increased expression of light chain 3 type II (LC3-II). The increased number of autophagic vacuoles seen by electron microscopy confirmed an association of autophagy in chemotherapy-injured livers following IP. However, the differences in protein expression were not reflected in postresection liver-injury tests or measure of patient morbidity. CONCLUSIONS: IP is associated with a reduction in necrosis of hepatocytes already damaged by chemotherapy and an activation of autophagy. Bcl-2 and beclin-1 could be major targets in the regulation of cell death during I/R injury.
    Mots-clés : &, Aged, Apoptosis, Autophagy, Blood, c-bcl-2/metabolism, Colorectal, control, Female, Humans, Injury/prevention, Ischemic, Liver, Liver/, Male, Membrane, Middle, Necrosis, Neoplasms/drug, pathology, Preconditioning, Proteins, Proteins/metabolism, Proto-Oncogene, Regulatory, Reperfusion, supply/injuries/metabolism/, Therapy, therapy/secondary/surgery.
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  • Douay, L, Lapillonne, H & Turhan, AG 2009, « Stem cells–a source of adult red blood cells for transfusion purposes: present and future », Crit Care Clin, vol. 25, no. 2, p. 383-98, Table of Contents, viewed sans date, .
    Résumé : We have sufficient knowledge of the biology of hematopoietic stem cells to hope that we might generate human red blood cells in the laboratory. It may soon be possible to produce enough to transfuse "cultured" red blood cells to manufacture human red blood cells from hematopoietic stem cells for transfusion purposes. This article describes progress and the challenges that remain in the search for in vitro generated red blood cells that can be efficiently manufactured in high volumes and given to any recipient.
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  • Duchet-Niedziolka, P, Launay, O, Coutsinos, Z, Ajana, F, Arlet, P, Barrou, B, Beytout, J, Bouchaud, O, Brouqui, P, Buzyn, A, Chidiac, C, Couderc, LJ, Debord, T, Dellamonica, P, Dhote, R, Duboust, A, Durrbach, A, Fain, O, Fior, R, Godeau, B, Goujard, C, Hachulla, E, Marchou, B, Mariette, X, May, T, Meyer, O, Milpied, N, Morlat, P, Pouchot, J, Tattevin, P, Viard, JP, Lortholary, O, Hanslik, T & Gevaccim, 2009, « Vaccination in adults with auto-immune disease and/or drug related immune deficiency: results of the GEVACCIM Delphi survey », Vaccine, vol. 27, no. 10, p. 1523-9, viewed sans date, .
    Résumé : INTRODUCTION: There are insufficient data regarding the efficacy and safety of vaccination in patients with auto-immune disease (AID) and/or drug-related immune deficiency (DRID). The objective of this study was to obtain professional agreement on vaccine practices in these patients. METHODS: A Delphi survey was carried out with physicians recognised for their expertise in vaccinology and/or the caring for adult patients with AID and/or DRID. For each proposed vaccination practice, the experts' opinion and level of agreement were evaluated. RESULTS: The proposals relating to patients with AID specified: the absence of risk of AID relapse following vaccination; the possibility of administering live virus vaccines (LVV) to patients not receiving immunosuppressants; the pertinence of determining protective antibody titre before vaccination; the absence of need for specific monitoring following the vaccination. The proposals relating to patients with DRID specified that a 3-6 month delay is needed between the end of these treatments and the vaccination with LVV. There is no contraindication to administering LVV in patients receiving systemic corticosteroids prescribed for less than two weeks, regardless of their dose, or at a daily dose not exceeding 10mg of prednisone, if this involves prolonged treatment. Out of 14 proposals, the level of agreement between the experts was "very good" for eleven, and "good" for the remaining three. CONCLUSION: Proposals for vaccine practices in patients with AID and/or DRID should aid with decision-making in daily medical practice and provide better vaccine coverage for these patients.
    Mots-clés : &, Adrenal, Adult, Agents/adverse, Antineoplastic, Autoimmune, Cortex, Deficiency, Diseases/*immunology/*therapy, effects, effects/*methods/utilization, Expert, Factor-alpha/antagonists, Hormones/adverse, Humans, Immunologic, Immunosuppression/adverse, Immunosuppressive, induced/*immunology/*therapy, inhibitors, Necrosis, Questionnaires, Syndromes/chemically, Testimony, Tumor, Vaccination/*adverse.
  • Duclos-Vallee, JC, Roche, B & Samuel, D 2009, « [Liver transplantation in patients with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus] », Presse Med, vol. 38, no. 9, p. 1281-9.
    Résumé : The current 5-year survival rate after liver transplantation for hepatitis B virus HBV-related liver disease is excellent (85 %) because of excellent prophylaxis against HBV reinfection, obtained by the combination of antiviral therapy before transplantation and both anti-HBs immunoglobulin and antiviral therapy afterwards. End-stage liver disease due to hepatitis C virus (HCV) is a major indication for liver transplantation. Results are not as good (65%) because HCV reinfection after transplantation is almost impossible to prevent, and it impairs patient and graft survival. Combination therapy with pegylated interferon and ribavirin must be administered at an early stage of HCV recurrence on the graft. Liver transplantation is feasible for HIV-infected patients. Results are excellent for HIV/HBV coinfected patients (100%). In HIV/HCV coinfected patients, however, the recurrence of HCV infection is more severe than in patients with HCV alone and survival thus lower. Very early anti-HCV therapy must be discussed.
    Mots-clés : &, Agents/therapeutic, Algorithms, Antiviral, as, B/drug, C/drug, Cirrhosis/surgery/virology, complications/drug, control, control/, Guidelines, Hepatitis, HIV, Humans, Immunoglobulins/therapeutic, Infections/, Liver, Practice, Rate, Recurrence/prevention, surgery, Survival, Therapy, therapy/prevention, Topic, Transplantation/mortality, use.
  • Duclos-Vallee, JC & Sebagh, M 2009, « Recurrence of autoimmune disease, primary sclerosing cholangitis, primary biliary cirrhosis, and autoimmune hepatitis after liver transplantation », Liver Transpl, vol. 15 Suppl 2, p. S25-34.
    Résumé : 1. Recurrence of primary sclerosing cholangitis. a Five percent of liver transplants are performed because of end-stage liver disease secondary to primary sclerosing cholangitis. b Recurrent disease affects 10% to 27% of recipients. c Diagnostic criteria of recurrence include the following: A confirmed diagnosis of primary sclerosing cholangitis before liver transplantation. A cholangiogram showing nonanastomotic biliary strictures with beading and irregularity occurring 90 days after transplantation. Liver biopsy revealing fibrous cholangitis and/or fibro-obliterative lesions of large bile ducts. d The data argue for an association between recurrent primary sclerosing cholangitis and rejection and steroid therapy. 2. Recurrence of primary biliary cirrhosis. a Overall recurrence rates can reach 50%. b The gold standard for diagnosis is histological, with bile duct destruction by granulomas indicated by a florid lesion. c Anti-mitochondrial antibody is not a reliable marker of recurrence. d Recurrence does not affect long-term patient or graft survival. 3. Recurrence of autoimmune hepatitis. a Recurrence affects approximately 25% of liver allografts during the first 5 years after liver transplantation and more than 50% after 10 years of follow-up. b Diagnostic criteria of recurrence must include a combination of biochemical changes, (elevated serum aminotransferases levels and hypergammaglobulinemia), histological features of autoimmune hepatitis, and steroid dependency. c Immunosuppressive therapy should be pursued even if liver test results are normal.
    Mots-clés : Autoimmune/ pathology/surgery Humans Liver Cirrhosis, Biliary/ pathology/surgery Liver Transplantation Postoperative Complications/pathology/surgery Recurrence Risk Factors, Cholangitis, Sclerosing/ pathology/surgery Hepatitis.

  • Duluc, D, Tan, F, Scotet, M, Blanchard, S, Fremaux, I, Garo, E, Horvat, B, Eid, P, Delneste, Y & Jeannin, P 2009, « PolyI:C plus IL-2 or IL-12 induce IFN-gamma production by human NK cells via autocrine IFN-beta », Eur J Immunol, vol. 39, no. 10, p. 2877-84, viewed sans date, .
    Résumé : NK lymphocytes and type I IFN (IFN-alpha/beta) are major actors of the innate anti-viral response that also influence adaptive immune responses. We evaluated type I IFN production by human NK cells in response to polyI:C, a potent type I IFN-inducing TLR3 agonist. PolyI:C plus IL-2/IL-12 induced IFN-beta (but not IFN-alpha) mRNA expression and protein production by highly pure human NK cells and by the human NK cell line NK92. Neutralizing anti-IFNAR1 or anti-IFN-beta Ab prevented the production of IFN-gamma induced by polyI:C plus IL-2/IL-12. Similarly, IFN-gamma production induced by polyI:C plus IL-12 was reduced in NK cells isolated from IFNAR1(-/-) compared with WT mice. The ability of polyI:C plus IL-12 to induce IFN-gamma production was related to an increase of TLR3, Mda5 and IFNAR expression and by an increase of STAT1 and STAT4 phosphorylation. Collectively, these data demonstrate that NK cells, in response to polyI:C plus IL-2/IL-12, produce IFN-beta that induce, in an autocrine manner, the production of IFN-gamma and thereby highlight that NK cells may control the outcome of protective or injurious immune responses through type I IFN secretion.
    Mots-clés : Animals Antibodies/immunology/pharmacology Autocrine Communication/*immunology Cell Line Cells, Cultured DEAD-box RNA Helicases/genetics Gene Expression/drug effects/genetics Humans Interferon-beta/genetics/immunology/*metabolism/pharmacology Interferon-gamma/genetics/*metabolism Interleukin-12/*pharmacology Interleukin-2/*pharmacology Killer Cells, Inbred Strains Mice, Interferon alpha-beta/genetics/immunology Receptors, Interleukin-12/genetics STAT1 Transcription Factor/metabolism STAT4 Transcription Factor/metabolism Toll-Like Receptor 3/genetics, Knockout Phosphorylation/drug effects Poly I-C/*pharmacology Receptor, Natural/drug effects/*metabolism Kinetics Mice Mice.

  • Durelli, L, Conti, L, Clerico, M, Boselli, D, Contessa, G, Ripellino, P, Ferrero, B, Eid, P & Novelli, F 2009, « T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta », Ann Neurol, vol. 65, no. 5, p. 499-509, viewed sans date, .
    Résumé : OBJECTIVE: T-helper 1 (Th1) and Th17 lymphocytes are involved in experimental autoimmune encephalomyelitis, the model of multiple sclerosis (MS). We characterized the Th1/Th17 cell populations in peripheral blood (PB), their interferon (IFN) receptor expression sensitivity to IFN-beta in MS patients. METHODS: In 30 untreated patients with active MS (AMS) and 32 with inactive MS (IMS), and in 22 healthy subjects, we measured intracellular cytokine expression, interleukin-17-producing myelin basic protein-stimulated PB lymphocytes, surface IFN type I receptor chain1 (IFN-alphaR1) expression, IFN-beta-dependent signal transducer and activator of transcription 1 (STAT1) phosphorylation, and apoptosis of anti-CD3 monoclonal antibody-stimulated PB lymphocytes. RESULTS: Th17 cell percentage increased around sevenfold in AMS compared with IMS or healthy subjects, but there was no change in Th1 cells. Th17 cells in AMS were myelin basic protein specific. The longitudinal follow-up of 18 MS patients shifting between AMS and IMS showed that the percentage of Th17 but not Th1 cells always increased in AMS. IFN-alphaR1 expression, IFN-beta-induced STAT1 activation, and apoptosis were significantly greater in Th17 than Th1 cells. IFN-alphaR1 expression and IFN-beta-dependent STAT1 activation progressively increased in vitro with a highly significant positive correlation only in developing Th17 but not in Th0 or Th1 cells. INTERPRETATION: Evidence that an expansion of peripheral Th17 cells, a Th subset that can infiltrate brain parenchyma and damage cells, is associated with disease activity in MS. The greater IFN-alphaR1 level expressed by Th17 compared with Th1 cells might make them a selective target for IFN-beta therapy.
    Mots-clés : Adult Annexin A5/metabolism Antigens, Helper-Inducer/cytology/*drug effects/*metabolism Time Factors, Interferon alpha-beta/metabolism T-Lymphocytes, Mononuclear/pathology Male Multiple Sclerosis/blood/*pathology Receptor.
  • Eyraud, V, Chazouilleres, O, Ballot, E, Corpechot, C, Poupon, R & Johanet, C 2009, « Significance of antibodies to soluble liver antigen/liver pancreas: a large French study », Liver Int, vol. 29, no. 6, p. 857-64.
    Résumé : BACKGROUND: Antibodies to soluble liver antigen (SLA)/liver pancreas (LP) are generally considered as highly specific diagnostic markers of type 1 auto-immune hepatitis (AIH-1), and are particularly useful in patients without conventional antibodies. However, the presence of anti-SLA/LP in type 2 auto-immune hepatitis (AIH-2), primary sclerosing cholangitis (PSC) and hepatitis C has recently been reported. The aim was thus to describe the characteristics of anti-SLA/LP-positive patients in the largest series reported to date. METHODS: Sera were selected from the period between 1998 and 2005, based on the presence of antibodies to SLA/LP detected by two methods. The clinical status of patients was determined from their medical records. RESULTS: Eighty-one anti-SLA/LP-positive patients with available clinical data were included: 89% (72/81) had a diagnosis of AIH-1, including 10 (12%) associated with cholestatic diseases (primary biliary cirrhosis in seven cases and PSC in three cases). Six patients (7%) suffered from another liver disease: hepatitis C (n=3) and drug-induced hepatitis (n=3). No specific diagnosis was made in three patients. CONCLUSIONS: Antibodies to SLA/LP are of a major diagnostic value for AIH-1, including paediatric forms and overlap syndromes with cholestatic diseases, but are not found in association with anti-liver/kidney/microsome type 1 or antibodies to liver cytosol type 1. They are rarely present in other liver diseases such as hepatitis C and drug-induced hepatitis.
    Mots-clés : Antibodies/blood/ immunology Autoantigens/ immunology Bile Duct Diseases/ diagnosis/immunology Biological Markers/ blood Blotting, Autoimmune/ diagnosis/immunology Humans Retrospective Studies, Polyacrylamide Gel Enzyme-Linked Immunosorbent Assay France Hepatitis, Western Electrophoresis.

  • Figueroa-Romero, C, Iniguez-Lluhi, JA, Stadler, J, Chang, CR, Arnoult, D, Keller, PJ, Hong, Y, Blackstone, C & Feldman, EL 2009, « SUMOylation of the mitochondrial fission protein Drp1 occurs at multiple nonconsensus sites within the B domain and is linked to its activity cycle », FASEB J, vol. 23, no. 11, p. 3917-27, viewed sans date, .
    Résumé : Dynamin-related protein (Drp) 1 is a key regulator of mitochondrial fission and is composed of GTP-binding, Middle, insert B, and C-terminal GTPase effector (GED) domains. Drp1 associates with mitochondrial fission sites and promotes membrane constriction through its intrinsic GTPase activity. The mechanisms that regulate Drp1 activity remain poorly understood but are likely to involve reversible post-translational modifications, such as conjugation of small ubiquitin-like modifier (SUMO) proteins. Through a detailed analysis, we find that Drp1 interacts with the SUMO-conjugating enzyme Ubc9 via multiple regions and demonstrate that Drp1 is a direct target of SUMO modification by all three SUMO isoforms. While Drp1 does not harbor consensus SUMOylation sequences, our analysis identified2 clusters of lysine residues within the B domain that serve as noncanonical conjugation sites. Although initial analysis indicates that mitochondrial recruitment of ectopically expressed Drp1 in response to staurosporine is unaffected by loss of SUMOylation, we find that Drp1 SUMOylation is enhanced in the context of the K38A mutation. This dominant-negative mutant, which is deficient in GTP binding and hydrolysis, does not associate with mitochondria and prevents normal mitochondrial fission. This finding suggests that SUMOylation of Drp1 is linked to its activity cycle and is influenced by Drp1 localization.
    Mots-clés : Acylation Cells, Cultured GTP Phosphohydrolases/*metabolism Humans Microtubule-Associated Proteins/*metabolism Mitochondrial Proteins/*metabolism Protein Processing, Post-Translational Protein Structure, Tertiary Small Ubiquitin-Related Modifier Proteins/*metabolism Ubiquitin-Conjugating Enzymes/*metabolism.
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  • Filali, M, Frydman, N, Belot, MP, Hesters, L, Gaudin, F, Tachdjian, G, Emilie, D, Frydman, R & Machelon, V 2009, « Oocyte in-vitro maturation: BCL2 mRNA content in cumulus cells reflects oocyte competency », Reprod Biomed Online, vol. 19 Suppl 4, p. 4309, viewed sans date, .
    Résumé : BCL2-associated X protein (BAX) and B-cell leukaemia/lymphoma gene-2 (BCL2), which are, respectively, pro- and anti-apoptotic proteins of the BCL2 gene family, participate in the mitochondria-dependent apoptosis pathway. A correlation between low incidence of apoptosis in cumulus cells and oocyte maturation has previously been suggested in ovarian stimulation. However, little is known in unprimed ovaries. These authors have investigated whether BAX and BCL2 expression in cumulus cells affects the competency of in-vitro matured oocytes. We have studied 100 cumulus-oocyte-complexes (COC) recovered from unprimed ovaries of 13 women diagnosed with polycystic ovary syndrome (PCOS) and undergoing in-vitro maturation (IVM) with their informed consent. COC were matured for 24 h in a specific maturation medium and the cumulus was stripped from the oocyte. BAX and BCL2 mRNA content was measured in each COC using real-time polymerase chain reaction. We found that BCL2 mRNA expression was significantly higher in cumulus cells associated with mature oocytes than those associated with immature oocytes while BAX mRNA concentrations did not vary in cumulus cells. Regarding fertilization, higher BCL2 mRNA content was found in cumulus cells enclosing fertilized oocytes (0.140 versus 0.075; P = 0.03). These results suggest that BCL2 expression is strongly associated with the ability of oocytes to complete nuclear maturation and to be fertilized.
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    <p>20034411</p>

  • Filipski, E & Lévi, F 2009, « Circadian disruption in experimental cancer processes », Integr Cancer Ther, vol. 8, no. 4, p. 298-302, viewed sans date, .
    Résumé : The circadian timing system (CTS) coordinated by the suprachiasmatic nuclei (SCN) of the hypothalamus regulates daily rhythms of behavior, physiology, as well as cellular metabolism and proliferation. Altered circadian rhythms predict for poor survival in cancer patients. An increased incidence of several cancers has been reported in flight attendants and in shift workers. To explore the contribution of the CTS to tumor growth, we developed experimental models of disrupted or enhanced circadian coordination through stereotaxic destruction of the SCN, modifications of photoperiodic or feeding synchronizers and/or the administration of pharmacologic agents. SCN ablation or exposure to experimental chronic jetlag (CJL, consisting of an 8-hour advance of the light-dark cycle every 2 days) caused alterations in circadian physiology and significantly accelerated tumor growth. CJL suppressed or altered the rhythms of clock gene and cell cycle gene expression in mouse liver. It increased p53 and decreased c-Myc expression, a result in line with the promotion of diethylnitrosamine -initiated hepatocarcinogenesis in jet-lagged mice. The accelerating effect of CJL on tumor growth was counterbalanced by the regular timing of food access over the 24-h. Meal timing prevented the circadian disruption produced by CJL and slowed down tumor growth. In synchronized mice, meal timing reinforced host circadian coordination, phase-shifted the transcriptional rhythms of clock genes in the liver of tumor-bearing mice and slowed down cancer progression. These results support the role of the CTS in cancer progression and call for the development of therapeutic strategies aimed at preventing or treating circadian clock dysfunctions.
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    <p>20042408</p>
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  • Filipski, E, Subramanian, P, Carrière, J, Guettier, C, Barbason, H & Lévi, F 2009, « Circadian disruption accelerates liver carcinogenesis in mice », Mutat Res, vol. 680, no. 1-2, p. 95-105, viewed sans date, .
    Résumé : BACKGROUND: The circadian timing system rhythmically controls behavior, physiology, cellular proliferation and xenobiotic metabolism over the 24-h period. The suprachiasmatic nuclei in the hypothalamus coordinate the molecular clocks in most mammalian cells through an array of circadian physiological rhythms including rest-activity, body temperature, feeding patterns and hormonal secretions. As a result, shift work that involves circadian disruption is probably carcinogenic in humans. In experimental models, chronic jet-lag (CJL) suppresses rest-activity and body temperature rhythms and accelerates growth of two transplantable tumors in mice. CJL also suppresses or significantly alters the expression rhythms of clock genes in liver and tumors. Circadian clock disruption from CJL downregulates p53 and upregulates c-Myc, thus favoring cellular proliferation. Here, we investigate the role of CJL as a tumor promoter in mice exposed to the hepatic carcinogen, diethylnitrosamine (DEN). METHODS: In experiment 1 (Exp 1), the dose-dependent carcinogenicity of chronic intraperitoneal (i.p.) administration of DEN was explored in mice. In Exp 2, mice received DEN at 10 mg/kg/day (cumulative dose: 243 mg/kg), then were randomized to remain in a photoperiodic regimen where 12 h of light alternates with 12 h of darkness (LD 12:12) or to be submitted to CJL (8-h advance of light onset every 2 days). Rest-activity and body temperature were monitored. Serum liver enzymes were determined repeatedly. Mice were sacrificed and examined for neoplastic lesions at 10 months. RESULTS: In Exp 1, DEN produced liver cancers in all the mice receiving 10 mg/kg/day. In Exp 2, mice on CJL had increased mean plasma levels of aspartate aminotransferase and more liver tumors as compared to LD mice at approximately 10 months (p = 0.005 and 0.028, respectively). The mean diameter of the largest liver tumor was twice as large in CJL vs LD mice (8.5 vs 4.4 mm, p = 0.027). In LD, a single histologic tumor type per liver was observed. In CJL, up to four different types were associated in the same liver (hepatocellular- or cholangio-carcinomas, sarcomas or mixed tumors). DEN itself markedly disrupted the circadian rhythms in rest-activity and body temperature in all the mice. DEN-induced disruption was prolonged for >or= 3 months by CJL exposure. CONCLUSIONS: The association of circadian disruption with chronic DEN exposure suggests that circadian clocks actively control the mechanisms of liver carcinogenesis in mice. Persistent circadian coordination may further be critical for slowing down and/or reverting cancer development after carcinogen exposure.
    Mots-clés : Alanine Transaminase/blood Animals Aspartate Aminotransferases/blood Bile Duct Neoplasms/chemically induced/pathology Bile Ducts, Drug Injections, Hepatocellular/chemically induced/pathology Cholangiocarcinoma/chemically induced/pathology Circadian Rhythm/ drug effects Diethylnitrosamine/administration & dosage/ toxicity Dose-Response Relationship, Intrahepatic/drug effects/pathology Body Weight/drug effects Carcinogens/administration & dosage/ toxicity Carcinoma, Intraperitoneal Liver/drug effects/pathology Liver Neoplasms/blood/ chemically induced/pathology Male Mice Neoplasms, Multiple Primary/chemically induced/pathology Sarcoma/chemically induced/pathology Time Factors.
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    <p>19833225</p>
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  • Frydman, N, Féraud, O, Bas, C, Amit, M, Frydman, R, Bennaceur-Griscelli, A & Tachdjian, G 2009, « Characterization of human PGD blastocysts with unbalanced chromosomal translocations and human embryonic stem cell line derivation? », Reprod Biomed Online, vol. 19 Suppl 4, p. 4199, viewed sans date, .
    Résumé : Novel embryonic stem cell lines derived from embryos carrying structural chromosomal abnormalities obtained after preimplantation genetic diagnosis (PGD) are of interest to study in terms of the influence of abnormalities on further development. A total of 22 unbalanced blastocysts obtained after PGD were analysed for structural chromosomal defects. Morphological description and chromosomal status of these blastocysts was established and they were used to derive human embryonic stem cell (ESC) lines. An outgrowth of cells was observed for six blastocysts (6/22; 27%). For two blastocysts, the exact morphology was unknown since they were at early stage, and for four blastocysts, the inner cell mass was clearly visible. Fifteen blastocysts carried an unbalanced chromosomal defect linked to a reciprocal translocation, resulting in a positive outgrowth of cells for five blastocysts. One human ESC line was obtained from a blastocyst carrying a partial chromosome-21 monosomy and a partial chromosome-1 trisomy. Six blastocysts carried an unbalanced chromosomal defect linked to a Robertsonian translocation, and one showed a positive outgrowth of cells. One blastocyst carried an unbalanced chromosomal defect linked to an insertion and no outgrowth was observed. The efficiency of deriving human ESC lines with constitutional chromosomal disorders was low and probably depends on the initial morphological aspect of the blastocysts and/or the type of the chromosomal disorders.
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    <p>20034412</p>
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