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Biblio - Bibliographie IAL
Bibliographie IAL

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Recherche bibliographique scientifique

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Accueil > Références bibliographiques

biblio

2011

  • Arumugam, M, Raes, J, Pelletier, E, Le Paslier, D, Yamada, T, Mende, DR, Fernandes, GR, Tap, J, Bruls, T, Batto, JM, Bertalan, M, Borruel, N, Casellas, F, Fernandez, L, Gautier, L, Hansen, T, Hattori, M, Hayashi, T, Kleerebezem, M, Kurokawa, K, Leclerc, M, Levenez, F, Manichanh, C, Nielsen, HB, Nielsen, T, Pons, N, Poulain, J, Qin, J, Sicheritz-Ponten, T, Tims, S, Torrents, D, Ugarte, E, Zoetendal, EG, Wang, J, Guarner, F, Pedersen, O, de Vos, WM, Brunak, S, Dore, J, Antolin, M, Artiguenave, F, Blottiere, HM, Almeida, M, Brechot, C, Cara, C, Chervaux, C, Cultrone, A, Delorme, C, Denariaz, G, Dervyn, R, Foerstner, KU, Friss, C, van de Guchte, M, Guedon, E, Haimet, F, Huber, W, van Hylckama-Vlieg, J, Jamet, A, Juste, C, Kaci, G, Knol, J, Lakhdari, O, Layec, S, Le Roux, K, Maguin, E, Merieux, A, Melo Minardi, R, M'Rini, C, Muller, J, Oozeer, R, Parkhill, J, Renault, P, Rescigno, M, Sanchez, N, Sunagawa, S, Torrejon, A, Turner, K, Vandemeulebrouck, G, Varela, E, Winogradsky, Y, Zeller, G, Weissenbach, J, Ehrlich, SD & Bork, P 2011, « Enterotypes of the human gut microbiome », Nature, vol. 473, no. 7346, p. 174-80.
    Résumé : Our knowledge of species and functional composition of the human gut microbiome is rapidly increasing, but it is still based on very few cohorts and little is known about variation across the world. By combining 22 newly sequenced faecal metagenomes of individuals from four countries with previously published data sets, here we identify three robust clusters (referred to as enterotypes hereafter) that are not nation or continent specific. We also confirmed the enterotypes in two published, larger cohorts, indicating that intestinal microbiota variation is generally stratified, not continuous. This indicates further the existence of a limited number of well-balanced host-microbial symbiotic states that might respond differently to diet and drug intake. The enterotypes are mostly driven by species composition, but abundant molecular functions are not necessarily provided by abundant species, highlighting the importance of a functional analysis to understand microbial communities. Although individual host properties such as body mass index, age, or gender cannot explain the observed enterotypes, data-driven marker genes or functional modules can be identified for each of these host properties. For example, twelve genes significantly correlate with age and three functional modules with the body mass index, hinting at a diagnostic potential of microbial markers.
    Mots-clés : Bacteria/, Bacterial, Biodiversity, Biological, classification/genetics, Europe, Feces/microbiology, Female, Humans, Intestines/, Male, Markers/analysis, Metagenome, Metagenomics, microbiology, Phylogeny, Techniques, Typing.


  • Avouac, J, Cagnard, N, Distler, JH, Schoindre, Y, Ruiz, B, Couraud, PO, Uzan, G, Boileau, C, Chiocchia, G & Allanore, Y 2011, « Insights into the pathogenesis of systemic sclerosis based on the gene expression profile of progenitor-derived endothelial cells », Arthritis Rheum, vol. 63, no. 11, p. 3552-62, viewed sans date, .
    Résumé : OBJECTIVE: To determine the gene expression profile of endothelial cells derived from the endothelial progenitor cells (EPCs) of patients with systemic sclerosis (SSc). METHODS: Microarray experiments were performed on Affymetrix GeneChip Human Exon 1.0 ST Arrays in unstimulated and hypoxia-stimulated EPC-derived cells from patients with SSc and control subjects. Followup of the raised hypotheses was performed ex vivo by immunohistochemical analysis of skin tissue. RESULTS: Signals from 92 probe sets and 188 probe sets were different in unstimulated and hypoxia-stimulated cells, respectively, from patients with SSc compared with controls. Within the largest groups of genes related to cell-cell interaction and vascular remodeling, down-regulation of tumor necrosis factor ligand superfamily member 10 (TNFSF10) and homeobox A9 (HOX-A9) was confirmed by real-time polymerase chain reaction and Western blots in EPC-derived cells and by immunohistochemistry in SSc skin tissue. Signals from 221 and 307 probe sets were different in unstimulated and hypoxia-stimulated cells, respectively, from patients with diffuse cutaneous SSc compared with patients with limited cutaneous SSc. Within the largest group of genes related to the inflammatory response, differential expression of TNFα-induced protein 3 and prostaglandin-endoperoxide synthase 2 was observed in EPC-derived cells and skin tissue from patients with SSc. CONCLUSION: Our data revealed important gene expression changes in EPC-derived endothelial cells from patients with SSc, characterized by a proadhesive, proinflammatory, and activated phenotype. Differential expression in lesional SSc skin tissue of new targets, such as TNF family members and HOX-A9, may contribute to the pathogenesis of SSc and deserves more in-depth exploration.


  • Azoulay, D, Bhangui, P, Andreani, P, Salloum, C, Karam, V, Hoti, E, Pascal, G, Adam, R, Samuel, D, Ichai, P, Saliba, F & Castaing, D 2011, « Short- and long-term donor morbidity in right lobe living donor liver transplantation: 91 consecutive cases in a European Center », Am J Transplant, vol. 11, no. 1, p. 101-10, viewed sans date, .
    Résumé : The lack of use of a common grading system in reporting morbidity impedes estimation of the true risk to a right lobe living donor (RLLD). We report outcomes in 91 consecutive RLLD's using the validated 5-tier Clavien grading and a quality of life (QOL) questionnaire. The median follow-up was 79 months. The donors were predominantly female (66%), 22 (24%) received autologous blood transfusions. Fifty-three complications occurred in 43 donors (47% morbidity), 19 (37%) were ≥ Grade III, biliary fistula (14%) was the most common. There was no donor mortality. Two intraoperative complications could not be graded and two disfiguring complications in female donors were graded as minor. Two subgroups (first 46 vs. later 45 donors) were compared to study the presence if any, of a learning curve. The later 45 donors had lesser autologous transfusions, lesser rehospitalization and no reoperation and a reduction in the proportion of ≥ Grade III (major) complications (24% vs. 50%; p = 0.06). In the long term, donors expressed an overall sense of well being, but some sequelae of surgery do restrain their current lifestyle. Our results warn against lackadaisical vigilance once RLLD hepatectomy becomes routine.
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  • Azzi, S, Bruno, S, Giron-Michel, J, Clay, D, Devocelle, A, Croce, M, Ferrini, S, Chouaib, S, Vazquez, A, Charpentier, B, Camussi, G, Azzarone, B & Eid, P 2011, « Differentiation therapy: targeting human renal cancer stem cells with interleukin 15 », J Natl Cancer Inst, vol. 103, no. 24, p. 1884-98, viewed sans date, .
    Résumé : BACKGROUND: Many renal cancer patients experience disease recurrence after immunotherapy or combined treatments due to persistence of cancer stem cells (CSCs). The identification of reliable inducers of CSC differentiation may facilitate the development of efficient strategies for eliminating CSCs. We investigated whether interleukin 15 (IL-15), a regulator of kidney homeostasis, induces the differentiation of CD105-positive (CD105(+)) CSCs from human renal cancers. METHODS: CD105(+) CSCs were cultured to preserve their stem cell properties and treated with recombinant human IL-15 (rhIL-15) to evaluate their ability to differentiate, to acquire sensitivity to chemotherapeutic drugs, and to form spheroids in vitro and tumors in vivo. Expression of stem cell and epithelial markers were studied by flow cytometry, immunocytochemistry, and immunoblotting. Identification of a CSC side population fraction and its sensitivity to chemotherapy drugs and expression of ATP-binding cassette (ABC) transporters and aldehyde dehydrogenase (ALDH) activities were determined by flow cytometry. Spheroid formation was determined in limiting dilution assay. Xenograft tumors were generated in severe combined immunodeficient mice (n = 12-18 mice per group). All statistical tests were two-sided. RESULTS: CD105(+) CSCs treated with rhIL-15 at 10 pg/mL differentiated into cells expressing epithelial markers. rhIL-15 induced epithelial differentiation of all CD105(+) CSCs subsets and blocked CSC self-renewal (sphere-forming ability) and their tumorigenic properties in severe combined immunodeficient mice. Vinblastine and paclitaxel induced statistically significant higher levels of apoptosis in rhIL-15-differentiated epithelial cells compared with CD105(+) CSCs (mean percentage of apoptotic cells, vinblastine: 33% vs 16.5%, difference = 16.5%, 95% confidence interval = 12.25% to 20.74%, P = .0025; paclitaxel: 35% vs 11.6%, difference = 23.4%, 95% confidence interval = 22.5% to 24.24%, P = .0015). The higher sensitivity of rhIL-15-differentiated epithelial cells to chemotherapeutic drugs was associated with loss of detoxifying mechanisms such as ALDH and ABC transporter activities. CONCLUSION: IL-15 directs the epithelial differentiation of renal CSCs and meets the criteria for a treatment strategy: CSC pool depletion and generation of differentiated nontumorigenic cells that are sensitive to chemotherapeutic agents.
    Mots-clés : ATP-Binding Cassette Transporters/metabolism Aldehyde Dehydrogenase/metabolism Animals Antigens, CD/*metabolism Antineoplastic Agents/*pharmacology/therapeutic use Carcinoma, Cell Surface/*metabolism Recurrence/prevention & control STAT5 Transcription Factor/drug effects/metabolism Transplantation, Heterologous, Local/*prevention & control Neoplastic Stem Cells/*drug effects/metabolism Receptors, Neoplastic Humans Immunoblotting Immunohistochemistry Interleukin-15/*pharmacology/therapeutic use Kidney Neoplasms/*drug therapy Mice Mice, Renal Cell/*drug therapy Cell Differentiation/drug effects Cell Proliferation/drug effects Enzyme-Linked Immunosorbent Assay Flow Cytometry Gene Expression Regulation, SCID Neoplasm Recurrence.

  • Bagag, A, Giuliani, A, Canon, F, Refregiers, M & Le Naour, F 2011, « Separation of peptides from detergents using ion mobility spectrometry », Rapid Commun Mass Spectrom, vol. 25, no. 22, p. 3436-40.
    Résumé : Mass spectrometry (MS) has dramatically evolved in the last two decades and has been the driving force of the spectacular expansion of proteomics during this period. However, the very poor compatibility of MS with detergents is still a technical obstacle in some studies, in particular on membrane proteins. Indeed, the high hydrophobicity of membrane proteins necessitates the use of detergents for their extraction and solubilization. Here, we address the analytical potential of high-field asymmetric waveform ion mobility spectrometry (FAIMS) for separating peptides from detergents. The study was focused on peptides from the human integral membrane protein CD9. A tryptic peptide was mixed with the non-ionic detergents Triton X-100 or beta-D-dodecyl maltoside (DDM) as well as with the ionic detergents sodium dodecyl sulfate (SDS) or sodium deoxycholate (SDC). Although electrospray ionization (ESI) alone led to a total suppression of the peptide ion signal on mass spectra with only detection of the detergents, use of FAIMS allowed separation and clear identification of the peptide with any of the detergents studied. The detection and identification of the target compound in the presence of an excess of detergents are then feasible. FAIMS should prove especially useful in the structural and proteomic analysis of membrane proteins.
    Mots-clés : Antigens.

  • Ballesta, A, Dulong, S, Abbara, C, Cohen, B, Okyar, A, Clairambault, J & Levi, F 2011, « A combined experimental and mathematical approach for molecular-based optimization of irinotecan circadian delivery », PLoS Comput Biol, vol. 7, no. 9, p. e1002143, viewed sans date, .
    Résumé : Circadian timing largely modifies efficacy and toxicity of many anticancer drugs. Recent findings suggest that optimal circadian delivery patterns depend on the patient genetic background. We present here a combined experimental and mathematical approach for the design of chronomodulated administration schedules tailored to the patient molecular profile. As a proof of concept we optimized exposure of Caco-2 colon cancer cells to irinotecan (CPT11), a cytotoxic drug approved for the treatment of colorectal cancer. CPT11 was bioactivated into SN38 and its efflux was mediated by ATP-Binding-Cassette (ABC) transporters in Caco-2 cells. After cell synchronization with a serum shock defining Circadian Time (CT) 0, circadian rhythms with a period of 26 h 50 (SD 63 min) were observed in the mRNA expression of clock genes REV-ERBα, PER2, BMAL1, the drug target topoisomerase 1 (TOP1), the activation enzyme carboxylesterase 2 (CES2), the deactivation enzyme UDP-glucuronosyltransferase 1, polypeptide A1 (UGT1A1), and efflux transporters ABCB1, ABCC1, ABCC2 and ABCG2. DNA-bound TOP1 protein amount in presence of CPT11, a marker of the drug PD, also displayed circadian variations. A mathematical model of CPT11 molecular pharmacokinetics-pharmacodynamics (PK-PD) was designed and fitted to experimental data. It predicted that CPT11 bioactivation was the main determinant of CPT11 PD circadian rhythm. We then adopted the therapeutics strategy of maximizing efficacy in non-synchronized cells, considered as cancer cells, under a constraint of maximum toxicity in synchronized cells, representing healthy ones. We considered exposure schemes in the form of an initial concentration of CPT11 given at a particular CT, over a duration ranging from 1 to 27 h. For any dose of CPT11, optimal exposure durations varied from 3h40 to 7h10. Optimal schemes started between CT2h10 and CT2h30, a time interval corresponding to 1h30 to 1h50 before the nadir of CPT11 bioactivation rhythm in healthy cells.
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  • Bargues, L, Prat, M, Leclerc, T, Bey, E & Lataillade, J-J 2011, « [Present and future of cell therapy in burns] », Pathol Biol (Paris), vol. 59, no. 3, p. e49-56, viewed sans date, .
    Résumé : Severe burned patients need definitive and efficient wound coverage. Outcome of massive burns has been improved by using cultured epithelial autografts (CEA). Despite fragility, percentages of success take, cost of treatment and long-term tendency to contracture, this surgical technique has been developed in few burn centres. First improvements were to combine CEA and dermis-like substitute. Cultured skin substitutes provide earlier skin closure and satisfying functional result. These methods have been used successfully in massive burns. Second improvement was to allow skin regeneration by using epidermal stem cells. Stem cells have capacity to differentiate into keratinocytes, to promote wound repair and to regenerate skin appendages. Human mesenchymal stem cells contribute to wound healing and were evaluated in cutaneous radiation syndrome. Skin regeneration and tissue engineering methods remain a complex challenge and offer the possibility of new treatment for injured and burned patients.
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  • Beaudreuil, S, Krivine, A, Hebibi, H, Ducot, B, Mazet, AA, Taouffik, Y, Seidowsky, A, Jacquet, A, Lorenzo, HK, Charpentier, B, Francois, H & Durrbach, A 2011, « Efficacy and safety of the H1N1 monovalent vaccine in renal-transplant recipients and dialysis patients », Hum Vaccin, vol. 7, no. 8, p. 868-73, viewed sans date, .
    Résumé : BACKGROUND: The (H1N)1v influenza virus infection emerged in 2009 as a serious disease in targeted populations. Herein, we report on the tolerability and efficacy of (anti-H1N1)v vaccination in dialysis and transplant patients. METHODS: 18 renal-transplant recipients (RTR) and 19 dialysis patients (DP) [12 patients treated with peritoneal dialysis (PDP), 7 patients treated with haemodialysis (HDP)] were enrolled. DPs received one monovalent H1N1 adjuvanted-vaccine injection, and RTRs received two unadjuvanted vaccine injections within a 21-day period. Serologic response was defined as a haemagglutination inhibition titre of > 40 (seroprotection) and/or at least a four-fold increase in antibody titre from baseline (seroconversion). RESULTS: Seroprotection rate after vaccination was greater in DPs than RTRs (p = 0.007), as was seroconversion (p = 0.001). Serologic response was similar in PDPs and HDPs. CONCLUSIONS: Serologic response was satisfactory in DPs, whichever dialysis mode (DPD or HDP). It was low in RTRs as compared to DPs.
    Mots-clés : 80 and over Antibodies, Adjuvants, H1N1 Subtype/*immunology *Influenza Vaccines/administration & dosage/adverse effects/immunology Influenza, Human/*immunology/*prevention & control *Kidney Transplantation Male Middle Aged *Renal Dialysis Vaccination, Immunologic Adult Aged Aged, Viral/blood Female Hemagglutination Inhibition Tests Humans Influenza A Virus.
  • Berthier-Vergnes, O, Kharbili, ME, de la Fouchardiere, A, Pointecouteau, T, Verrando, P, Wierinckx, A, Lachuer, J, Le Naour, F & Lamartine, J 2011, « Gene expression profiles of human melanoma cells with different invasive potential reveal TSPAN8 as a novel mediator of invasion », Br J Cancer, vol. 104, no. 1, p. 155-65.
    Résumé : BACKGROUND: Metastatic melanoma requires early detection, being treatment resistant. However, the earliest events of melanoma metastasis, and especially of dermal invasion, remain ill defined. RESULTS AND METHODS: Gene expression profiles of two clonal subpopulations, selected from the same human melanoma cell line, but differing in ability to cross the dermal-epidermal junction in skin reconstructs, were compared by oligonucleotide microarray. Of 26 496 cDNA probes, 461 were differentially expressed (>2-fold; P< 0.001), only 71 genes being upregulated in invasive cells. Among them, TSPAN8, a tetraspanin not yet described in melanoma, was upregulated at mRNA and protein levels in melanoma cells from the invasive clone, as assessed by RT-PCR, flow cytometry and western blot analysis. Interestingly, TSPAN8 was the only tetraspanin in which overexpression correlated with invasive phenotype. Flow cytometry of well-defined melanoma cell lines confirmed that TSPAN8 was exclusively expressed by invasive, but not non-invasive melanoma cells or normal melanocytes. Immunohistochemistry revealed that TSPAN8 was expressed by melanoma cells in primary melanomas and metastases, but not epidermal cells in healthy skin. The functional role of TSPAN8 was demonstrated by silencing endogenous TSPAN8 with siRNA, reducing invasive outgrowth from tumour spheroids within matrigel without affecting cell proliferation or survival. CONCLUSION: TSPAN8 expression may enable melanoma cells to cross the cutaneous basement membrane, leading to dermal invasion and progression to metastasis. TSPAN8 could be a promising target in early detection and treatment of melanoma.
    Mots-clés : Antigens, Biological/ genetics/metabolism, Cellular/metabolism/pathology Tetraspanins Tumor Cells, Cultured Tumor Markers, Messenger/genetics RNA, Neoplasm/genetics/ metabolism Apoptosis Blotting, Small Interfering/genetics Reverse Transcriptase Polymerase Chain Reaction Skin Neoplasms/genetics/ metabolism/ pathology Spheroids.
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  • Bhangui, P, Lim, C, Salloum, C, Andreani, P, Sebbagh, M, Hoti, E, Ichai, P, Saliba, F, Adam, R, Castaing, D & Azoulay, D 2011, « Caval inflow to the graft for liver transplantation in patients with diffuse portal vein thrombosis: a 12-year experience », Ann Surg, vol. 254, no. 6, p. 1008-16, viewed sans date, .
    Résumé : OBJECTIVE: To analyze the short- and long-term results of cavoportal anastomosis (CPA) and renoportal anastomosis (RPA) in 20 consecutive liver transplantation (LT) candidates with diffuse portal vein thrombosis (PVT). SUMMARY BACKGROUND DATA: Caval inflow to the graft (CIG) by CPA or RPA has been the most commonly used salvage technique to overcome the absolute contraindication for LT in case of diffuse PVT. METHODS: From 1996 to 2009, 3 patients (15%) underwent CPA and 17 patients (85%) had an RPA during LT. In addition to routine follow-up, patients were specifically evaluated for signs of portal hypertension (PHT) and for patency of the anastomoses. The follow-up ranged from 3 months to 12 years (median of 4.5 years). RESULTS: : Caval inflow to the graft was feasible in all attempted cases. In the short term (<6 months), 35% of patients had residual PHT-related complications (massive ascites and variceal bleeding). These resolved spontaneously or with endoscopic management. Three deaths occurred; none was related to PHT or shunt thrombosis. In the long term (>6 months), 1 death occurred because of recurrent variceal bleeding after RPA thrombosis. At last follow-up, all living patients [n = 13 (65%)] had normal liver function, no signs of PHT and patent anastomoses. There were no retransplantations. Graft and patient survival at 1, 3, and 5 years were 83%, 75%, and 60%, respectively. CONCLUSIONS: Caval inflow to the graft is an efficacious salvage technique with satisfactory long-term results, considering the spontaneous outcome in patients denied LT because of diffuse PVT. Adequate preoperative management of PHT and its associated complications is vital in obtaining good results. In the long term, residual PHT resolves and the liver function returns to normal.
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  • Bhangui, P, Vibert, E, Majno, P, Salloum, C, Andreani, P, Zocrato, J, Ichai, P, Saliba, F, Adam, R, Castaing, D & Azoulay, D 2011, « Intention-to-treat analysis of liver transplantation for hepatocellular carcinoma: living versus deceased donor transplantation », Hepatology, vol. 53, no. 5, p. 1570-9, viewed sans date, .
    Résumé : UNLABELLED: For patients who have cirrhosis with hepatocellular carcinoma (HCC), living donor liver transplantation (LDLT) reduces waiting time and dropout rates. We performed a comparative intention-to-treat analysis of recurrence rates and survival outcomes after LDLT and deceased donor liver transplantation (DDLT) in HCC patients. Our study included 183 consecutive patients with HCC who were listed for liver transplantation over a 9-year period at our institution. Tumor recurrence was the primary endpoint. At listing, patient and tumor characteristics were comparable in the two groups (LDLT, n = 36; DDLT, n = 147). Twenty-seven (18.4%) patients dropped out, all from the DDLT waiting list, mainly due to tumor progression (19/27 [70%] patients). The mean waiting time was shorter in the LDLT group (2.6 months versus 7.9 months; P = 0.001). The recurrence rates in the two groups were similar (12.9% and 12.7%, P = 0.78), and there was a trend toward a longer time to recurrence after LDLT (38 ± 27 months versus 16 ± 13 months, P = 0.06). Tumors exceeding the University of California, San Francisco (UCSF) criteria, tumor grade, and microvascular invasion were independent predictive factors for recurrence. On an intention-to-treat basis, the overall survival (OS) in the two groups was comparable. Patients beyond the Milan and UCSF criteria showed a trend toward worse outcomes with LDLT compared with DDLT (P = 0.06). CONCLUSION: The recurrence and survival outcomes after LDLT and DDLT were comparable on an intent-to-treat analysis. Shorter waiting time preventing dropouts is an additional advantage with LDLT. LDLT for HCC patients beyond validated criteria should be proposed with caution.
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  • Biet, F, Gendt, L, Anton, E, Ballot, E, Hugot, JP & Johanet, C 2011, « Serum antibodies to Mycobacterium avium subspecies paratuberculosis combined with anti-Saccharomyces cerevisiae antibodies in Crohn's disease patients: prevalence and diagnostic role », Dig Dis Sci, vol. 56, no. 6, p. 1794-800.
    Résumé : BACKGROUND: Because Mycobacterium avium subspecies paratuberculosis (MAP), the etiologic agent of Johne's disease in ruminant, has been identified in the mucosal layer and deeper bowel wall in CD patients, the seroactivity against MAP may define a distinct subset of patients requiring individual treatment. The aim of this study was to assess the performance of anti-MAP antibodies in the diagnostic strategy for CD. METHODS: Two hundred seventy-two individuals were included: 81 with CD, 36 with ulcerative colitis, 35 with coeliac diseases and 120 healthy blood donors. Anti-MAP were detected by ELISA using a purified protein derivative from MAP. Anti-Saccharomyces cerevisiae antibodies (ASCA) were detected by indirect immunofluorescence. RESULTS: The sensitivity and specificity of anti-MAP and ASCA for CD diagnosis were similar (sensitivity: 0.33 +/- 0.10 and 0.31 +/- 0.10; specificity: 0.96 +/- 0.03 and 0.98 +/- 0.02, respectively). A combination of these two tests enabled an increase in sensitivity (0.53 +/- 0.10), although specificity remained unchanged (0.95 +/- 0.04). No correlation was found between anti-MAP positivity and clinical features such as age at onset and the duration of CD, disease location, or intestinal complications. Conversely, extra-intestinal manifestations of CD were statistically associated with a positivity of anti-MAP (48% vs. 24%, P = 0.028), mostly with respect to arthritis (44.5% vs. 13%, P < 0.002). Interestingly, anti-MAP and ASCA were also found in an active form of coeliac disease. CONCLUSION: Our results suggest a complementary role of ASCA and anti-MAP for CD diagnosis and a possible common role of bacteria in small intestinal mucosal damage in CD and coeliac disease.
    Mots-clés : Adolescent Adult Aged Antibodies, Bacterial/ blood Antibodies, Fungal/ blood Biological Markers Child Child, Preschool Colitis.


  • Bollée, G, Flamant, M, Schordan, S, Fligny, C, Rumpel, E, Milon, M, Schordan, E, Sabaa, N, Vandermeersch, S, Galaup, A, Rodenas, A, Casal, I, Sunnarborg, SW, Salant, DJ, Kopp, JB, Threadgill, DW, Quaggin, SE, Dussaule, J-C, Germain, S, Mesnard, L, Endlich, K, Boucheix, C, Belenfant, X, Callard, P, Endlich, N & Tharaux, P-L 2011, « Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis », Nat Med, vol. 17, no. 10, p. 1242-50, viewed sans date, .
    Résumé : Rapidly progressive glomerulonephritis (RPGN) is a life-threatening clinical syndrome and a morphological manifestation of severe glomerular injury that is marked by a proliferative histological pattern ('crescents') with accumulation of T cells and macrophages and proliferation of intrinsic glomerular cells. We show de novo induction of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in intrinsic glomerular epithelial cells (podocytes) from both mice and humans with RPGN. HB-EGF induction increases phosphorylation of the epidermal growth factor receptor (EGFR, also known as ErbB1) in mice with RPGN. In HB-EGF-deficient mice, EGFR activation in glomeruli is absent and the course of RPGN is improved. Autocrine HB-EGF induces a phenotypic switch in podocytes in vitro. Conditional deletion of the Egfr gene from podocytes of mice alleviates the severity of RPGN. Likewise, pharmacological blockade of EGFR also improves the course of RPGN, even when started 4 d after the induction of experimental RPGN. This suggests that targeting the HB-EGF-EGFR pathway could also be beneficial in treatment of human RPGN.
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  • Bouchahda, M, Lévi, F, Adam, R & Rougier, P 2011, « Modern insights into hepatic arterial infusion for liver metastases from colorectal cancer », Eur J Cancer, vol. 47, no. 18, p. 2681-90, viewed sans date, .
    Résumé : Hepatic arterial infusion (HAI) selectively achieves high drug exposure of liver metastases from colorectal cancer. Such pharmacologic advantage has doubled the response rate of liver metastases on fluoropyrimidines (FP) delivered as HAI rather than intravenously, in a meta-analysis of randomised clinical trials (RCT). However, the improvement in antitumour efficacy did not consistently translate into any significant survival advantage across all randomised studies. However, the results of this meta-analysis should be cautiously interpreted due to the heterogeneity of the studies, inadequate study designs, obsolete therapy and high rate of early treatment discontinuation due to HAI technical failures or hepato-biliary toxicity. Most studies actually were performed before year 2000 and did not integrate the considerable progresses accomplished in the management of CRC, such as multidrug regimens instead of single agent FP and secondary resection of metastases, a major contributing factor for prolonged survival. Furthermore, the systemic exposure of patients given HAI was low without concomitant IV therapy, facilitating extra-hepatic relapses. The role of HAI in liver metastases from CRC should, therefore, be revisited, using modern multidisciplinary therapeutic approaches and appropriate study designs. Recommendations for the design of future RCTs exploring HAI are provided.
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  • Bouchahda, M, Macarulla, T, Liedo, G, Lévi, F, Elez, ME, Paule, B, Karaboué, A, Artru, P, Tabernero, J, Machover, D, Innominato, P, Goldschmidt, E, Bonnet, D, Ducreux, M, Castagne, V & Guimbaud, R 2011, « Feasibility of cetuximab given with a simplified schedule every 2 weeks in advanced colorectal cancer: a multicenter, retrospective analysis », Med Oncol, vol. 28 Suppl 1, p. S253-8, viewed sans date, .
    Résumé : Cetuximab was approved using a weekly schedule, alone or in combination with chemotherapy (CT). However, many CT regimens in metastatic colorectal cancer (CRC) are delivered every 2 weeks (q2wks). Preliminary data suggested that a simplified schedule using cetuximab q2wks, 500 mg/m² would be equivalent to the standard weekly administration. Medical data of all patients with advanced CRC who received cetuximab q2wks were retrospectively collected and checked for consistency by an independent monitor in 4 European centers. Ninety-one patients were treated between 2005 and 2007 when the K-RAS mutational status of tumors was not determined routinely. They received a median of 4 (0-5) previous drugs, including previous weekly cetuximab in 38.5% of patients. Cetuximab q2wks was associated with an irinotecan-based regimen in 85.7% of patients. The median number of cetuximab administrations was 6 (1-23). Skin toxicity was observed in 68.2% of evaluable patients (grade 3 in 15%). Only one grade 1 allergy was reported. In the 84 patients beyond first-line therapy, response rate was 29.3%. The median progression-free survival was 3.0 months (range 2.2-3.8), and median overall survival was 9.0 months (range 6.2-11.8). Cetuximab q2wks appears safe and effective in heavily pretreated patients and convenient in combination with q2wks CT schedules.
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  • Boudjema, K, Camus, C, Saliba, F, Calmus, Y, Salame, E, Pageaux, G, Ducerf, C, Duvoux, C, Mouchel, C, Renault, A, Compagnon, P, Lorho, R & Bellissant, E 2011, « Reduced-dose tacrolimus with mycophenolate mofetil vs. standard-dose tacrolimus in liver transplantation: a randomized study », Am J Transplant, vol. 11, no. 5, p. 965-76.
    Résumé : We conducted a multicenter randomized study in liver transplantation to compare standard-dose tacrolimus to reduced-dose tacrolimus with mycophenolate mofetil to reduce the occurrence of tacrolimus side effects. Two primary outcomes (censored criteria) were monitored during 48 weeks post-transplantation: occurrence of renal dysfunction or arterial hypertension or diabetes (evaluating benefit) and occurrence of acute graft rejection (evaluating risk). Interim analyses were performed every 40 patients to stop the study in the case of increased risk of graft rejection. One hundred and ninety-five patients (control: 100; experimental: 95) had been included when the study was stopped. Acute graft rejection occurred in 46 (46%) and 28 (30%) patients in control and experimental groups, respectively (HR = 0.59; 95% CI: [0.37-0.94]; p = 0.024). Renal dysfunction or arterial hypertension or diabetes occurred in 80 (80%) and 61 (64%) patients in control and experimental groups, respectively (HR = 0.68; 95% CI: [0.49-0.95]; p = 0.021). Renal dysfunction occurred in 42 (42%) and 23 (24%) patients in control and experimental groups, respectively (HR = 0.49; 95% CI: [0.29-0.81]; p = 0.004). Leucopoenia (p = 0.001), thrombocytopenia (p = 0.017) and diarrhea (p = 0.002) occurred more frequently in the experimental group. Reduced-dose tacrolimus with mycophenolate mofetil reduces the occurrence of renal dysfunction and the risk of graft rejection. This immunosuppressive regimen could replace full-dose tacrolimus in adult liver transplantation.
    Mots-clés : Adult Diabetes Complications/immunology Diarrhea/chemically induced Dose-Response Relationship.

  • Bouquet, F, Ousset, M, Biard, D, Fallone, F, Dauvillier, S, Frit, P, Salles, B & Muller, C 2011, « A DNA-dependent stress response involving DNA-PK occurs in hypoxic cells and contributes to cellular adaptation to hypoxia », Journal of Cell Science, vol. 124, no. 11, p. 1943-1951, viewed sans date, <<Go to ISI>://WOS:000290617800018>.
    Résumé : DNA-dependent protein kinase (DNA-PK) is involved in DNA double-strand break (DSB) signalling and repair. We report that DNA-PK is activated by mild hypoxia conditions (0.1-1% O(2)) as shown by (1) its autophosphorylation on Ser2056, and (2) its mobilisation from a soluble nucleoplasmic compartment to a less extractable nuclear fraction. The recruitment of DNA-PK was not followed by activation and recruitment of the XRCC4-DNA-ligase-IV complex, suggesting that DSBs are not responsible for activation of DNA-PK. To unravel the mechanism of DNA-PK activation, we show that exposure of cells to trichostatin A, a histone deacetylase inhibitor, leads to DNA-PK autophosphorylation and relocalisation to DNA. Histone acetylation (mainly H3K14) is increased in hypoxic cells and treatment with anacardic acid, an inhibitor of histone acetyl transferase, prevented both histone modifications and DNA-PK activation in hypoxic conditions. Importantly, in using either silenced DNA-PK cells or cells exposed to a specific DNA-PK inhibitor (NU7026), we demonstrated that hypoxic DNA-PK activation positively regulates the key transcription factor HIF-1 and one subsequent target gene, GLUT1. Our results show that hypoxia initiates chromatin modification and consequently DNA-PK activation, which positively regulate cellular oxygen-sensing and oxygen-signalling pathways.

  • Bourgeois, EA, Levescot, A, Diem, S, Chauvineau, A, Berges, H, Milpied, P, Lehuen, A, Damotte, D, Gombert, JM, Schneider, E, Girard, JP, Gourdy, P & Herbelin, A 2011, « A natural protective function of invariant NKT cells in a mouse model of innate-cell-driven lung inflammation », European Journal of Immunology, vol. 41, no. 2, p. 299-305, viewed sans date, <<Go to ISI>://WOS:000287159600007>.
    Résumé : Activation of invariant natural killer T (iNKT) cells by treatment with their alpha-galactosyl ceramide ligand provides therapeutic benefits in several immune inflammatory settings. Given the artificial nature of this stimulation, the natural regulatory functions of iNKT remain uncertain. Addressing this issue in a mouse model of innate-cell-driven lung inflammation induced by the cytokine/alarmin IL-33 that targets iNKT cells, we found that eosinophil and neutrophil recruitment was markedly increased in treated iNKT cell-deficient (J alpha 18 KO) mice, as was the local production of eotaxin and keratinocyte chemoattractant chemokines. By contrast, lung inflammation decreased after adoptive transfer of iNKT cells, which restored the WT inflammatory response in J alpha 18 KO mice. Finally, we established that this natural anti-inflammatory function of iNKT cells depends on their IFN-gamma production and on endogenous IL-12. Our study provides the first evidence of a protective role of iNKT cells during lung inflammation that does not require pharmacological TCR engagement.
  • Bruneel, A, Wendum, D, Labas, V, Mulner-Lorillon, O, Vinh, J, Bosselut, N, Ballot, E, Baudin, B, Housset, C, Dabernat, S, Lacombe, ML & Boissan, M 2011, « Proteomic analysis of NME1/NDPK A null mouse liver: evidence for a post-translational regulation of annexin IV and EF-1Balpha », Naunyn Schmiedebergs Arch Pharmacol, vol. 384, no. 4-5, p. 407-19.
    Résumé : NME/NDPK family proteins are involved in the control of intracellular nucleotide homeostasis as well as in both physiological and pathological cellular processes, such as proliferation, differentiation, development, apoptosis, and metastasis dissemination, through mechanisms still largely unknown. One family member, NME1/NDPK-A, is a metastasis suppressor, yet the primary physiological functions of this protein are still missing. The purpose of this study was to identify new NME1/NDPK-A-dependent biological functions and pathways regulated by this gene in the liver. We analyzed the proteomes of wild-type and transgenic NME1-null mouse livers by combining two-dimensional gel electrophoresis and mass spectrometry (matrix-assisted laser desorption/ionization time of flight and liquid chromatography-tandem mass spectrometry). We found that the levels of three proteins, namely, phenylalanine hydroxylase, annexin IV, and elongation factor 1 Balpha (EF-1Balpha), were strongly reduced in the cytosolic fraction of NME1(-/-) mouse livers when compared to the wild type. This was confirmed by immunoblotting analysis. No concomitant reduction in the corresponding messenger RNAs or of total protein level was observed, however, suggesting that NME1 controls annexin IV and EF-1Balpha amounts by post-translational mechanisms. NME1 deletion induced a change in the subcellular location of annexin IV in hepatocytes resulting in enrichment of this protein at the plasma membrane. We also observed a redistribution of EF-1Balpha in NME1(-/-) hepatocytes to an intracytoplasmic compartment that colocalized with a marker of the reticulum endoplasmic. Finally, we found reduced expression of annexin IV coincident with decreased NME1 expression in a panel of different carcinoma cell lines. Taken together, our data suggest for the first time that NME1 might regulate the subcellular trafficking of annexin IV and EF-1Balpha. The potential role of these proteins in metastatic dissemination is discussed.
    Mots-clés : Animals Annexin A4/genetics/ metabolism Blotting, Gel, Knockout NM23 Nucleoside Diphosphate Kinases/genetics/ physiology Peptide Elongation Factor 1/ genetics/ metabolism Protein Processing, Mass, Matrix-Assisted Laser Desorption-Ionization Tandem Mass Spectrometry, Post-Translational Protein Transport Proteomics Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Spectrometry, Tumor Cytosol/enzymology/metabolism Electrophoresis, Two-Dimensional Endoplasmic Reticulum/enzymology/metabolism Humans Liver/ enzymology/metabolism Male Mice Mice, Western Cell Line.

  • Canet, E, Osman, D, Lambert, J, Guitton, C, Heng, AE, Argaud, L, Klouche, K, Mourad, G, Legendre, C, Timsit, JF, Rondeau, E, Hourmant, M, Durrbach, A, Glotz, D, Souweine, B, Schlemmer, B & Azoulay, E 2011, « Acute respiratory failure in kidney transplant recipients: a multicenter study », Crit Care, vol. 15, no. 2, p. R91, viewed sans date, .
    Résumé : INTRODUCTION: Data on pulmonary complications in renal transplant recipients are scarce. The aim of this study was to evaluate acute respiratory failure (ARF) in renal transplant recipients. METHODS: We conducted a retrospective observational study in nine transplant centers of consecutive kidney transplant recipients admitted to the intensive care unit (ICU) for ARF from 2000 to 2008. RESULTS: Of 6,819 kidney transplant recipients, 452 (6.6%) required ICU admission, including 200 admitted for ARF. Fifteen (7.5%) of these patients had combined kidney-pancreas transplantations. The most common causes of ARF were bacterial pneumonia (35.5%), cardiogenic pulmonary edema (24.5%) and extrapulmonary acute respiratory distress syndrome (ARDS) (15.5%). Pneumocystis pneumonia occurred in 11.5% of patients. Mechanical ventilation was used in 93 patients (46.5%), vasopressors were used in 82 patients (41%) and dialysis was administered in 104 patients (52%). Both the in-hospital and 90-day mortality rates were 22.5%. Among the 155 day 90 survivors, 115 patients (74.2%) were dialysis-free, including 75 patients (65.2%) who recovered prior renal function. Factors independently associated with in-hospital mortality were shock at admission (odds ratio (OR) 8.70, 95% confidence interval (95% CI) 3.25 to 23.29), opportunistic fungal infection (OR 7.08, 95% CI 2.32 to 21.60) and bacterial infection (OR 2.53, 95% CI 1.07 to 5.96). Five factors were independently associated with day 90 dialysis-free survival: renal Sequential Organ Failure Assessment (SOFA) score on day 1 (OR 0.68/SOFA point, 95% CI 0.52 to 0.88), bacterial infection (OR 0.43, 95% CI 0.21 to 0.90), three or four quadrants involved on chest X-ray (OR 0.44, 95% CI 0.21 to 0.91), time from hospital to ICU admission (OR 0.98/day, 95% CI 0.95 to 0.99) and oxygen flow at admission (OR 0.93/liter, 95% CI 0.86 to 0.99). CONCLUSIONS: In kidney transplant recipients, ARF is associated with high mortality and graft loss rates. Increased Pneumocystis and bacterial prophylaxis might improve these outcomes. Early ICU admission might prevent graft loss.
    Mots-clés : &, *Hospital, *Kidney, Acute, Aged, Care, data, disease, Female, Follow-Up, Graft, Humans, Insufficiency/*etiology/mortality, Intensive, Male, Middle, Mortality, numerical, Outcome, Rejection/*etiology, Respiratory, Retrospective, Studies, Transplantation, Treatment, Units/statistics.
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  • Carvalho, G, Poalas, K, Demian, C, Hatchi, E, Vazquez, A & Bidere, N 2011, « Participation of the cell polarity protein PALS1 to T-cell receptor-mediated NF-kappaB activation », PLoS One, vol. 6, no. 3, p. e18159, viewed sans date, .
    Résumé : BACKGROUND: Beside their established function in shaping cell architecture, some cell polarity proteins were proposed to participate to lymphocyte migration, homing, scanning, as well as activation following antigen receptor stimulation. Although PALS1 is a central component of the cell polarity network, its expression and function in lymphocytes remains unknown. Here we investigated whether PALS1 is present in T cells and whether it contributes to T Cell-Receptor (TCR)-mediated activation. METHODOLOGY/PRINCIPAL FINDINGS: By combining RT-PCR and immunoblot assays, we found that PALS1 is constitutively expressed in human T lymphocytes as well as in Jurkat T cells. siRNA-based knockdown of PALS1 hampered TCR-induced activation and optimal proliferation of lymphocyte. We further provide evidence that PALS1 depletion selectively hindered TCR-driven activation of the transcription factor NF-kappaB. CONCLUSIONS: The cell polarity protein PALS1 is expressed in T lymphocytes and participates to the optimal activation of NF-kappaB following TCR stimulation.
    Mots-clés : *Cell Polarity Cell Proliferation Humans Jurkat Cells Lymphocyte Activation/immunology Membrane Proteins/*metabolism NF-kappa B/*metabolism Nucleoside-Phosphate Kinase/*metabolism Receptors, Antigen, T-Cell/*metabolism Signal Transduction/immunology T-Lymphocytes/*cytology/*metabolism.
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  • Castaing, D, Vibert, E, Bhangui, P, Salloum, C, Smail, A, Adam, R & Azoulay, D 2011, « Results of percutaneous manoeuvres in biliary disease: the Paul Brousse experience », Surg Endosc, vol. 25, no. 6, p. 1858-65, viewed sans date, .
    Résumé : BACKGROUND: Percutaneous manoeuvres are alternatives to the endoscopic approach in the management of complex biliary disease. METHODS: We retrospectively reviewed our experience with 1,014 percutaneous interventions performed between 1980 and 2005 at a tertiary-level hepatobiliary centre. The main outcome measures were the success rate of percutaneous manoeuvres and the procedure-related morbidity and mortality. Eight hundred seventy-two patients who underwent 1,014 percutaneous procedures were divided into four groups according to the indication and goal of therapy: Group A: percutaneous manoeuvres aimed at improving the patient's general condition (worsened by severe jaundice, pruritus, or cholangitis); Group B: cancer patients receiving chemotherapy who required biliary drainage as jaundice was a contraindication for continuing chemotherapy; Group C: manoeuvres performed to confirm diagnosis of biliary obstruction; and Group D: manoeuvres performed with the goal of complete treatment of calculus disease. RESULTS: Interno-external drainage (526 procedures) was the most common intervention and dilatation the most frequently associated manoeuvre (456 procedures). Mean duration of biliary drainage was 159±152 days. Overall success rate (total+partial success) was 86%; the best and worst results were in Groups C (95% success) and A (70% success), respectively. The mortality rate was 7.5%; 29 (37%) deaths were procedure-related (cholangitis being the principal cause). End-stage malignancy was the major cause of mortality (58%). Procedure-related morbidity rate was 17%, and Group C (0%) and Group D (5%) patients had the least number of complications. CONCLUSIONS: In complex biliary disease, the percutaneous approach is a feasible and safe therapeutic option and should be added to the armamentarium of experienced hepatobiliary teams. A well-planned strategy consisting of repeated interventions, prolonged biliary drainage, and optimal antibiotic therapy are prerequisites for success with this approach.
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  • Castanier, C & Arnoult, D 2011, « Mitochondrial localization of viral proteins as a means to subvert host defense », Biochim Biophys Acta, vol. 1813, no. 4, p. 575-83, viewed sans date, .
    Résumé : Viruses have developed a battery of distinct strategies to overcome the very sophisticated defense mechanisms of the infected host. Throughout the process of pathogen-host co-evolution, viruses have therefore acquired the capability to prevent host cell apoptosis because elimination of infected cells via apoptosis is one of the most ancestral defense mechanism against infection. Conversely, induction of apoptosis may favor viral dissemination as a result of the dismantlement of the infected cells. Mitochondria have been long recognized for their key role in the modulation of apoptosis but more recently, mitochondria have been shown to serve as a crucial platform for innate immune signaling as illustrated by the identification of MAVS. Thus, it is therefore not surprising that this organelle represents a recurrent target for viruses, aiming to manipulate the fate of the infected host cell or to inhibit innate immune response. In this review, we highlight the viral proteins that are specifically targeted to the mitochondria to subvert host defense. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.
    Mots-clés : Animals Humans *Immunity, Innate Mitochondria/*metabolism/*virology Viral Proteins/*metabolism Viruses/*pathogenicity.

  • Charpentier, B, Beaudreuil, S, Francois, H, Jacquet, A & Durrbach, A 2011, « [History of medical progress in renal transplantation: a review of 3,000 consecutive kidney grafts at Bicetre-Kremlin, Bicetre University Hospital - France] », Bull Acad Natl Med, vol. 195, no. 2, p. 335-49; discussion 349-50, viewed sans date, .
    Résumé : Major medical progress has been made in the field of renal transplantation over the last 40 years, thanks to advances in areas such as metabolism, immunology, therapeutics, and pathology. This progress has been accompanied by important changes in French legislation that governs organ harvest and transplantation, as well as the institutions that regulate organ allocation. Patient and graft survival have both increased markedly, although long-term improvements have been somewhat offset by complications, including adverse effects of immunosuppression. On average recipients are older than in the past and some recipients are now dying from age-related comorbidities despite having functional grafts.
    Mots-clés : 20th Century History, 21st Century Hospitals, France History, University Humans Immunosuppressive Agents/therapeutic use Kidney Transplantation/*history/mortality/trends.

  • Charpentier, B, Beaudreuil, S, Francois, H, Jacquet, A & Durrbach, A 2011, « [Use of new non-nephrotoxic immunosuppressive drugs in kidney transplantation, especially after ischemia-reperfusion injury] », Bull Acad Natl Med, vol. 195, no. 4-5, p. 899-912; discussion 912, viewed sans date, .
    Résumé : Medium- and long-term renal graft survival depends on 4 main factors: the quality of the harvested graft, ischemia-reperfusion injury during harvesting and re-implantation, rejection, and the nephrotoxicity of certain drugs (especially immunosuppressants) used in this setting. The most nephrotoxic immunosuppressive drugs are the anticalcineurins (cyclosporine A and tacrolimus), a class discovered in the late 1970s and currently representing a basic component of all immunosuppressive protocols for solid organ graft recipients. The renal tubular and vascular toxicity of anticalcineurins is due to their immunosuppressive mechanism: they block the calcineurin pathway and thereby prevent transmission of the first signal from the T cell receptor to the nucleus, which normally triggers cytokine synthesis, New non-nephrotoxic immunosuppressants are therefore needed, especially for grafts of poor quality or subject to severe ischemia-reperfusion injury. Attention is turning to "old " molecules such as anti-thymocyte globulins, but exciting new immunosuppressants are now appearing. Alefacept is a fusion protein that binds to the immunological synapse-associated molecule CD2, which normally interacts with LFA-3. Belatacept, another fusion protein, blocks the T cell second signal CD 28-B7.1/B7.2. Finally, new chemical agents are being developed, such as sautrasporine, a tyrosine kinase inhibitor, and tofacitinib, a Jak inhibitor.
    Mots-clés : &, *Kidney, Agents/*therapeutic, control, Graft, Humans, immunology, Immunosuppressive, Injury/prevention, Rejection/*prevention, Reperfusion, Survival, Transplantation, use.


  • Charpentier, B & Durrbach, A 2011, « Transplantation: pre-emptive kidney transplantation–perfect, but when? », Nat Rev Nephrol, vol. 7, no. 10, p. 550-1, viewed sans date, .
    Résumé : Charpentier, Bernard Durrbach, Antoine eng England 2011/08/25 06:00 Nat Rev Nephrol. 2011 Aug 23;7(10):550-1. doi: 10.1038/nrneph.2011.111.
    Mots-clés : Chronic/physiopathology/*surgery *Kidney Transplantation/methods Living Donors Patient Selection Time, Decision Making Humans Kidney Failure.

  • Cheray, M, Petit, D, Forestier, L, Karayan-Tapon, L, Maftah, A, Jauberteau, MO, Battu, S, Gallet, FP & Lalloue, F 2011, « Glycosylation-related gene expression is linked to differentiation status in glioblastomas undifferentiated cells », Cancer Letters, vol. 312, no. 1, p. 24-32, viewed sans date, <<Go to ISI>://WOS:000296164900004>.
    Résumé : Glioblastoma Multiforme (GBM) is the most frequent malignant brain tumor with still poor prognosis. Tumor initiation, growth and recurrences might depend on Brain Tumor Stem Cells (BTSCs) which can promote tumor aggressiveness and potentially affords new therapeutic target. Recent works emphasized aberrant cell-surface glyco-conjugate expression in brain tumors suggesting that altered glycosylation is closely linked to cancer tumor metastasis and invasive process. Post-translational changes might play a key role in determining the fates of most aggressive and undifferentiated cells such as self-renewal, proliferation and differentiation. In order to characterize the glycosylation-related genes involved in differentiation status of the BTSCs, two glioblastoma cell lines. U87-MG and U251 have been cultured according to two conditions leading to undifferentiated floating cells or differentiated adherent cells. The expression level of 559 glycosylation related genes has been analyzed by Taqman Low Density Array (TLDA) analysis and allowed to isolate eight up-regulated genes specific of a subpopulation of undifferentiated cells. Protein expression has been confirmed. Among main selected genes, five are also over-expressed in the undifferentiated condition in primary cultures provided by three GBM freshly isolated from patient. This work suggests that new Glycosylation-related gene signature might improve the characterization of the most aggressive and undifferentiated cells and supports that in future, N-linked glycosylation might provide new target to develop therapeutic strategy for inhibiting tumor growth. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

  • Chomel, J-C, Bonnet, M-L, Sorel, N, Bertrand, A, Meunier, M-C, Fichelson, S, Melkus, M, Bennaceur-Griscelli, A, Guilhot, F & Turhan, AG 2011, « Leukemic stem cell persistence in chronic myeloid leukemia patients with sustained undetectable molecular residual disease », Blood, vol. 118, no. 13, p. 3657-60, viewed sans date, .
    Résumé : Sustained undetectable molecular residual disease (UMRD) is obtained in a minority of patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. It remains unclear whether these patients are definitively cured of their leukemia or whether leukemic stem cells (LSCs) persist in their BM. We have evaluated the presence of BCR-ABL-expressing marrow LSCs in 6 patients with chronic myeloid leukemia with sustained UMRD induced by IFN-α (n = 3), imatinib mesylate after IFN-α failure (n = 2), and dasatinib after imatinib intolerance (n = 1). Purified CD34(+) cells were used for clonogenic and long-term culture-initiating cell assays performed on classic or HOXB4-expressing MS-5 feeders. Using this strategy, we identified BCR-ABL-expressing LSCs in all patients. Interestingly, long-term culture-initiating cell assays with MS-5/HOXB4 stromal feeders increased detected numbers of LSCs in 3 patients. The relation between LSC persistency and a potential risk of disease relapse for patients with durable UMRD (on or off tyrosine kinase inhibitor therapy) warrants further investigation.
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  • Chomel, J-C & Turhan, AG 2011, « Chronic myeloid leukemia stem cells in the era of targeted therapies: resistance, persistence and long-term dormancy », Oncotarget, vol. 2, no. 9, p. 713-27, viewed sans date, .
    Résumé : Targeted therapies of chronic myeloid leukemia (CML) using tyrosine kinase inhibitors (TKI) have profoundly changed the natural history of the disease with a major impact on survival. Molecular monitoring with BCR-ABL quantification shows that a status of undetectable molecular residual disease (UMRD) is obtained in a significant minority of patients. However, it remains unclear whether these patients are definitively cured of their leukemia. Imatinib mesylate withdrawal trials have demonstrated the rapid appearance of the malignant clone in the majority of the patients whereas some patients remain in a state of UMRD. It has clearly been demonstrated that the most primitive stem cells are refractory to all TKIs used in clinical practice. In addition, long-term dormancy is one of the most fundamental characteristics of hematopoietic stem cells. In this context, we have recently undertaken a systematic analysis of the bone marrow stem cell compartment in several patients in durable UMRD. We have demonstrated the long-term persistence of a considerable amount of BCR-ABL-expressing stem cells, even in the absence of relapse. The phenomenon of long-term leukemic stem cell dormancy is of major importance in CML and one of the key questions in cancer biology in general. We discuss, here, the potential mechanisms, including intrinsic and microenvironmental factors, that control the response of leukemic stem cells (LSCs) to targeted therapies and potential novel strategies currently in progress with a curative intent. Moreover, we propose a molecular evaluation of the residual LSC compartment in selected patients in order to develop rational TKI-cessation strategies in CML.
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  • Cirodde, A, Leclerc, T, Jault, P, Duhamel, P, Lataillade, J-J & Bargues, L 2011, « Cultured epithelial autografts in massive burns: a single-center retrospective study with 63 patients », Burns, vol. 37, no. 6, p. 964-72, viewed sans date, .
    Résumé : UNLABELLED: Cultured epithelial autografts (CEAs) have long been used to tackle limited donor site availability and difficulty of permanent skin coverage in massive burns, but this approach still has limited documentation. METHODS: In this retrospective, single-center study, medical records of patients treated with CEAs in our burn center from 1991 until 2008 were analyzed in search of factors associated with outcome. RESULTS: Out of 68 patients, 63 records were analyzable. Patients were aged 29 [17-41.5] years (seven children). Total body surface area (TBSA) burned was 81±10%, of which 69±14% TBSA full thickness. CEAs were first applied after 45±34 days, on a surface of 32±14% TBSA. Success rate at take down was 65±19%, correlating only with young age (r(2)=0.18; p=0.0006). At discharge, CEAs covered 26±15% TBSA. Infections (4.3±2 per patient), most frequently of skin, often complicated the clinical course. Mortality was 16% (10 patients). In multivariate analysis, the number of infections was the only factor associated with mortality (OR=2.05 per single infection, 95%CI 1.03-4.07, p=0.04). CONCLUSION: Although complex and costly, CEAs can be used with reasonable success and satisfying survival results for the treatment of massive burns. In this study, favorable outcome was principally associated with young age and low number of infectious complications.
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  • Clairambault, J 2011, « Commitment of mathematicians in medicine: a personal experience, and generalisations », Acta Biotheor, vol. 59, no. 3-4, p. 201-11, viewed sans date, .
    Résumé : I will present here a personal point of view on the commitment of mathematicians in medicine. Starting from my personal experience, I will suggest generalisations including favourable signs and caveats to show how mathematicians can be welcome and helpful in medicine, both in a theoretical and in a practical way.
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  • Corruble, E, Barry, C, Varescon, I, Durrbach, A, Samuel, D, Lang, P, Castaing, D, Charpentier, B & Falissard, B 2011, « Report of depressive symptoms on waiting list and mortality after liver and kidney transplantation: a prospective cohort study », BMC Psychiatry, vol. 11, p. 182, viewed sans date, .
    Résumé : BACKGROUND: Little research has explored pre-transplantation psychological factors as predictors of outcome after liver or kidney transplantation. Our objective is to determine whether report of depressive symptoms on waiting list predicts outcome of liver and kidney transplantation. METHODS: Patients on waiting list for liver or kidney transplantation were classified for report or non-report of depressive symptoms on waiting list. 339 were transplanted 6 months later on average, and followed prospectively. The main outcome measures were graft failure and mortality 18 months post-transplantation. RESULTS: Among the 339 patients, 51.6% reported depressive symptoms on waiting list, 16.5% had a graft failure and 7.4% died post-transplantation.Report of depressive symptoms on waiting list predicted a 3 to 4-fold decreased risk of graft failure and mortality 18-months post-transplantation, independently from age, gender, current cigarette smoking, anxiety symptoms, main primary diagnosis, UNOS score, number of comorbid diagnoses and history of transplantation. Data were consistent for liver and kidney transplantations. Other baseline predictive factors were: for graft failure, the main primary diagnosis and a shorter length since this diagnosis, and for mortality, older age, male gender and the main primary diagnosis. CONCLUSION: Further studies are needed to understand the underlying mechanisms of the association between report of depressive symptoms on waiting list and decreased risk of graft failure and mortality after transplantation.
    Mots-clés : Adult, Aged, Cohort, Depression/mortality/*psychology, Diagnostic, Evaluation, Female, Humans, Kidney, Lists/*mortality, Liver, Male, Middle, Prospective, Self, Studies, Transplantation/mortality/*psychology, Waiting.
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  • Corruble, E, Barry, C, Varescon, I, Falissard, B, Castaing, D & Samuel, D 2011, « Depressive symptoms predict long-term mortality after liver transplantation », J Psychosom Res, vol. 71, no. 1, p. 32-7.
    Résumé : OBJECTIVE: Depressive symptoms are common after liver transplantation (LT). We studied whether depressive symptoms affect long-term survival after LT. METHODS: In a prospective cohort study, 134 liver transplant patients were assessed for depressive symptoms using the Beck Depression Inventory-short form (BDI), focusing on the 3 months post-LT score and on the score change from the waiting list period. They were followed up for long-term survival. The median duration of the follow-up period was 43 months post-LT. None of the 134 patients was lost to follow-up for survival. RESULTS: A total of 33.6% of the LT patients had mild to moderate depressive symptoms 3 months post-LT. Eighteen (13.4%) patients died during the follow-up. Using Cox proportional hazards analysis, depressive symptoms were significantly associated with mortality (hazard ratio [HR] 1.22, 95% confidence interval (CI) 1.07-1.40, P<.003), one more point in the BDI score being associated with a 17% increase in mortality risk. Other predictive factors of mortality were older age and hepatitis C virus with recurrence 3 months post-LT. Similarly, an increase in depressive symptoms between the waiting list and 3 months post-LT periods predicted mortality (HR 1.18, 95% CI 1.01-1.38, P=.03), especially for patients without depressive symptoms on waiting list (HR 1.56, 95% CI 1.16-2.12, P=.004). CONCLUSION: Depressive symptoms after LT and an increase in depressive symptoms between the waiting list and post-LT are associated with an increased risk of long-term mortality. Interventions that could reduce depressive symptoms could potentially decrease long-term mortality after LT.
    Mots-clés : Adult, Age, Aged, Depression/mortality/, Factors, Female, Hepacivirus, Humans, Liver, Male, Middle, mortality/, of, Predictive, Prognosis, Prospective, Psychiatric, psychology, Rating, Recurrence, Scales, Status, Studies, Tests, Transplantation/, Value.

  • Crema, A, Ledda, M, De Carlo, F, Fioretti, D, Rinaldi, M, Marchese, R, Sanchez, M, Giuliani, M, Arena, V, Durrbach, A, Brunetti, E, Haas, C, Ponzetto, A, Lisi, A & Carloni, G 2011, « Cord blood CD133 cells define an OV6-positive population that can be differentiated in vitro into engraftable bipotent hepatic progenitors », Stem Cells Dev, vol. 20, no. 11, p. 2009-21, viewed sans date, .
    Résumé : Cell therapy represents the most promising alternative strategy for end-stage liver diseases and hepatic progenitors are the best candidates. We have identified a reservoir of immature hepatic precursors within human cord blood, which can derive engraftable bipotent progenitors. We isolated a stem cell subset CD133+/CD34+/OV6(low) expressing a surface-marker profile consistent with that of fetal liver cells. Upon induction of hepatic commitment by a medium containing cytokines and factors involved in vivo oval-cell activation, a heterogeneous cell population displaying characteristics of functional oval-cell-like bipotent hepatic progenitors was obtained. The cells expressed markers of hepatocytes and cholangiocytes and were highly enriched in OV6, c-Met, c-Kit, and Thy-1. They also displayed liver functional activity as glycogen storage, urea production, albumin secretion, and inducible CyP2B6 activity. When injected into liver-damaged severe-combined immunodeficient mice, induced bipotent hepatic progenitors appropriately engrafted livers of recipient animals, where they formed clusters of human-derived cells expressing human leucocyte antigen-class I, Hep-Par1, and OV6 antigens. Human-specific albumin, alpha-fetoprotein, and cytokeratin 19 were also expressed. In transplanted animals, AST serum levels showed a significative reduction with regard to controls. This human model for in vitro progenitor-cell activation may provide a powerful tool for elucidating the pathways and synergies that regulate this complex process and can represent a valuable source, exploitable for liver cell-based therapies and regenerative medicine.
    Mots-clés : Acute/chemically induced/therapy Liver Regeneration Male Mice Mice, Alanine Transaminase/blood Animals Antigens, CD/*metabolism Antigens, CD34/metabolism Antigens, Cultured Fetal Blood/*cytology Gene Expression Glycoproteins/*metabolism Humans Keratin-19/metabolism Lipoproteins, Differentiation/*metabolism Aspartate Aminotransferases/blood Biological Markers/metabolism Cell Differentiation Cell Shape Cells, LDL/metabolism Liver/*cytology/metabolism Liver Failure, SCID Peptides/*metabolism Phenotype *Stem Cell Transplantation Stem Cells/*metabolism alpha-Fetoproteins/metabolism.

  • de Goer de Herve, MG, Durali, D, Dembele, B, Giuliani, M, Tran, TA, Azzarone, B, Eid, P, Tardieu, M, Delfraissy, JF & Taoufik, Y 2011, « Interferon-alpha triggers B cell effector 1 (Be1) commitment », PLoS One, vol. 6, no. 4, p. e19366, viewed sans date, .
    Résumé : B-cells can contribute to the pathogenesis of autoimmune diseases not only through auto-antibody secretion but also via cytokine production. Therapeutic depletion of B-cells influences the functions and maintenance of various T-cell subsets. The mechanisms governing the functional heterogeneity of B-cell subsets as cytokine-producing cells are poorly understood. B-cells can differentiate into two functionally polarized effectors, one (B-effector-1-cells) producing a Th-1-like cytokine pattern and the other (Be2) producing a Th-2-like pattern. IL-12 and IFN-gamma play a key role in Be1 polarization, but the initial trigger of Be1 commitment is unclear. Type-I-interferons are produced early in the immune response and prime several processes involved in innate and adaptive responses. Here, we report that IFN-alpha triggers a signaling cascade in resting human naive B-cells, involving STAT4 and T-bet, two key IFN-gamma gene imprinting factors. IFN-alpha primed naive B-cells for IFN-gamma production and increased IFN-gamma gene responsiveness to IL-12. IFN-gamma continues this polarization by re-inducing T-bet and up-regulating IL-12Rbeta2 expression. IFN-alpha and IFN-gamma therefore pave the way for the action of IL-12. These results point to a coordinated action of IFN-alpha, IFN-gamma and IL-12 in Be1 polarization of naive B-cells, and may provide new insights into the mechanisms by which type-I-interferons favor autoimmunity.
    Mots-clés : Autoimmunity B-Lymphocytes/*cytology/immunology Cell Differentiation Cell Separation Cytokines/metabolism Dimerization *Gene Expression Regulation Humans Interferon Type I/metabolism Interferon-alpha/*metabolism Microscopy, Confocal/methods Phenotype STAT4 Transcription Factor/metabolism T-Lymphocytes/immunology Th2 Cells/cytology.
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  • de Haas, RJ, Wicherts, DA, Andreani, P, Pascal, G, Saliba, F, Ichai, P, Adam, R, Castaing, D & Azoulay, D 2011, « Impact of expanding criteria for resectability of colorectal metastases on short- and long-term outcomes after hepatic resection », Ann Surg, vol. 253, no. 6, p. 1069-79, viewed sans date, .
    Résumé : BACKGROUND: An expansion of resectability criteria of colorectal liver metastases (CLM) is justified provided "acceptable" short-term and long-term outcomes. The aim of the present study was to ascertain this paradigm in an era of modern liver surgery. METHODS: All consecutive patients who underwent hepatic resection for CLM at our institute between 1990 and 2010 were included in the study. Ninety-day mortality and morbidity rates were determined in the total study population and in 2 separate time periods (group I: 1990-2000; group II: 2000-2010). Similarly, overall and progression-free survival rates were determined. Independent predictors of postoperative morbidity were identified at multivariate analysis. RESULTS: Between 1990 and 2010, 1394 hepatectomies were performed in 1028 patients. Overall perioperative mortality and postoperative morbidity rates were 1.3% and 33%, respectively. Although patients in group II were older, had more often comorbid illnesses, and presented with more extensive liver disease, similar perioperative mortality rates were observed (1.1% in group I and 1.4% in group II; P = 0.53). A trend toward a higher morbidity rate was observed in group II (34% vs 31% in group I; P = 0.16). Independent predictors of postoperative morbidity were: treatment between 2000 and 2010, total hepatic ischemia time of 60 minutes or more, maximum size of CLM of 30 mm or more at histopathology, and presence of abnormalities in the nontumoral liver parenchyma. Although a trend toward lower overall survival was observed in patients with significant postoperative complications, no significant differences were observed in long-term outcomes between both treatment periods. CONCLUSION: After an aggressive multidisciplinary treatment of CLM, acceptable overall mortality and morbidity rates were observed. Perioperative mortality rates did not differ according to treatment period; however, more recently operated patients experienced more postoperative complications. These favorable short-term outcomes, without worsening of long-term outcomes, justify an expansion of the criteria for resectability in this patient category.
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  • Decaens, T, Roudot-Thoraval, F, Badran, H, Wolf, P, Durand, F, Adam, R, Boillot, O, Vanlemmens, C, Gugenheim, J, Dharancy, S, Bernard, P-H, Boudjema, K, Calmus, Y, Hardwigsen, J, Ducerf, C, Pageaux, GP, Hilleret, M-N, Chazouillères, O, Cherqui, D, Mallat, A & Duvoux, C 2011, « Impact of tumour differentiation to select patients before liver transplantation for hepatocellular carcinoma », Liver Int, vol. 31, no. 6, p. 792-801, viewed sans date, .
    Résumé : AIM: To generate a new score with improved accuracy compared with Milan criteria to select patients. PATIENTS: The training cohort comprised 373 patients transplanted for hepatocellular carcinoma (HCC) between 1988 and 1998 (cohort 1). An algorithm was derived from the analysis of patient data by the proportional hazard Cox regression model. The area under the receiver operating characteristic (AUROC) was used to determine a cut-off value. The validation cohort comprised 140 patients transplanted between 1999 and 2001 (cohort 2). RESULTS: Multivariate analysis identified three predictors of 5-year tumour-free survival: tumour differentiation (P=0.02), diameter (P<0.0001) and number of nodules (P=0.04). A cut-off value of 4 was derived from the AUROC of the final score. Five-year tumour-free survival was 60.2 ± 3.1% in patients with as score <4 and 36.4 ± 4.7% in individuals with a score ≥4, P<0.0001. In the validation cohort, 5-year tumour-free survival was 82.8 ± 3.6% (score <4) and 50.0 ± 10.7% (score ≥4), P=0.0003. In patients with a score <4, there was no significant difference in 5-year tumour-free survival between Milan+ and Milan- patients, either in cohort 1 or 2. Five-year tumour-free survival of Milan- patients was significantly better in individuals with a score <4 compared with those with a score ≥4, both in cohort 1 (61.5 ± 9.1 vs 31.4 ± 4.6%, P=0.009) and in cohort 2 (P=0.02). CONCLUSION: A novel score taking into account tumour differentiation shows higher accuracy than Milan criteria in predicting 5-year tumour-free survival following liver transplantation for HCC. Prospective studies should validate these findings.
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  • Degli Esposti, D, Sebagh, M, Pham, P, Reffas, M, Poüs, C, Brenner, C, Azoulay, D & Lemoine, A 2011, « Ischemic preconditioning induces autophagy and limits necrosis in human recipients of fatty liver grafts, decreasing the incidence of rejection episodes », Cell Death Dis, vol. 2, p. e111, viewed sans date, .
    Résumé : Whether ischemic preconditioning (IP) reduces ischemia/reperfusion (I/R) injury in human normal and fatty livers remains controversial. We compared two independent groups of liver donor transplants with versus without steatosis to evaluate IP consequences. Liver donors with (n=22) or without (n=28) steatosis either did or did not undergo IP before graft retrieval. Clinical data from the recipients, as well as histological and immunohistological characteristics of post-reperfusion biopsies were analyzed. Incidence of post-reperfusion necrosis was increased (10/10 versus 9/14, respectively; P<0.05) and the clinical outcome of recipients was worse for non-IP steatotic liver grafts compared with non-IP non-steatotic grafts. IP significantly lowered the transaminase values only in patients receiving a non-steatotic liver. An increased expression of beclin-1 and LC3, two pro-autophagic proteins, tended to decrease the incidence of necrosis (P=0.067) in IP steatotic livers compared with non-IP steatotic group. IP decreased the incidence of acute and chronic rejection episodes in steatotic livers (2/12 versus 6/10; P=0.07 and 2/12 versus 7/10; P<0.05, respectively), but not in non-steatotic livers. Thus, IP may induce autophagy in human steatotic liver grafts and reduce rejection in their recipients.
    Mots-clés : Adult, Aged, Autophagy, Donors, epidemiology/pathology/physiopathology, Fatty, Female, Graft, Humans, Incidence, Injury/, Ischemic, Liver, Liver/, Male, Middle, Necrosis, pathology/physiopathology/, Preconditioning, Rejection/, Reperfusion, surgery, Tissue, Transplantation.
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  • Desbois, D, Couturier, E, Graube, A, Letort, MJ, Dussaix, E & Roque-Afonso, AM 2011, « [Genetic diversity of a rare hepatitis A virus genotype] », Pathol Biol (Paris), vol. 59, no. 1, p. 57-65.
    Résumé : PURPOSE OF THE STUDY: Very few is known on genotype II hepatitis A virus (HAV) since it is rarely isolated. From 2002 to 2007, the French observatory of HAV identified six sub-genotype IIA strains of which one from a patient having travelled to West Africa. To investigate the possible African origin of sub-genotype IIA, we determined its prevalence among French travellers in 2008 and characterised its genetic variability. PATIENTS AND METHODS: The 2008 mandatory notification records were screened for travel to Africa. Viral genotype was determined on the nucleotide sequencing of the VP1/2A junction region. The P1 region coding for capsid proteins was used to compare the genetic diversity of IIA isolates to those of other genotypes. RESULTS: In 2008, five out of 54 patients returning from West Africa were infected by IIA strains and an additional "autochthonous" case was identified. Two more African cases were identified in 2009. A total of 14 IIA isolates (eight African and six "autochthonous") were analysed. Nucleotide and amino-acid variability of IIA sequences was lower than that of the other genotypes. Phylogenetic analysis revealed the clustering of two "autochthonous" cases with African isolates whereas the other ones belonged to a different lineage. CONCLUSION: Most IIA strains isolated in France are imported by travellers returning from West Africa. However, the unexplained contamination mode of some "autochthonous" cases suggests another geographical origin to discover or a French reservoir to explore.
    Mots-clés : Adolescent Adult Africa, Amino Acid Travel Viral Structural Proteins/genetics Young Adult, Viral/ genetics Sequence Alignment Sequence Homology, Western Amino Acid Sequence Child Female France Genetic Variation Genotype Hepatitis A/ virology Hepatitis A virus/classification/ genetics Humans Male Middle Aged Molecular Sequence Data Phylogeny RNA.

  • Deschaseaux, F, Delgado, D, Pistoia, V, Giuliani, M, Morandi, F & Durrbach, A 2011, « HLA-G in organ transplantation: towards clinical applications », Cell Mol Life Sci, vol. 68, no. 3, p. 397-404, viewed sans date, .
    Résumé : HLA-G plays a particular role during pregnancy in which its expression at the feto-maternal barrier participates into the tolerance of the allogenic foetus. HLA-G has also been demonstrated to be expressed in some transplanted patients, suggesting that it regulates the allogenic response. In vitro data indicate that HLA-G modulates NK cells, T cells, and DC maturation through its interactions with various inhibitory receptors. In this paper, we will review the data reporting the HLA-G involvement of HLA-G in human organ transplantation, then factors that can modulate HLA-G, and finally the use of HLA-G as a therapeutic tool in organ transplantation.
    Mots-clés : Antigens, Antigens/genetics/*immunology/*therapeutic, Class, Expression, Gene, Histocompatibility, HLA, HLA-G, Humans, I/genetics/*immunology/*therapeutic, Organ, Regulation, Transplantation, use.

  • Desterke, C, Bilhou-Nabéra, C, Guerton, B, Martinaud, C, Tonetti, C, Clay, D, Guglielmelli, P, Vannucchi, A, Bordessoule, D, Hasselbalch, H, Dupriez, B, Benzoubir, N, Bourgeade, M-F, Pierre-Louis, O, Lazar, V, Vainchenker, W, Bennaceur-Griscelli, A, Gisslinger, H, Giraudier, S, Le Bousse-Kerdilès, M-C, Disorders, FI of M, INSERM, F & Myelofibrosis, EEUMNETN on 2011, « FLT3-mediated p38-MAPK activation participates in the control of megakaryopoiesis in primary myelofibrosis », Cancer Res, vol. 71, no. 8, p. 2901-15, viewed sans date, .
    Résumé : Primary myelofibrosis (PMF) is characterized by increased number of hematopoietic progenitors and a dysmegakaryopoiesis which supports the stromal reaction defining this disease. We showed that increased ligand (FL) levels in plasma, hematopoietic progenitors, and stromal cells from PMF patients were associated with upregulation of the cognate Flt3 receptor on megakaryocytic (MK) cells. This connection prompted us to study a functional role for the FL/Flt3 couple in PMF dysmegakaryopoiesis, as a route to reveal insights into pathobiology and therapy in this disease. Analysis of PMF CD34(+) and MK cell transcriptomes revealed deregulation of the mitogen-activated protein kinase (MAPK) pathway along with Flt3 expression. In PMF patients, a higher proportion of circulating Flt3(+)CD34(+)CD41(+) cells exhibited an increased MAPK effector phosphorylation independently of Jak2(V617F) mutation. Activation of FL/Flt3 axis in PMF MK cell cultures, in response to FL, induced activation of the p38-MAPK cascade, which is known to be involved in inflammation, also increasing expression of its target genes (NFATC4, p53, AP-1, IL-8). Inhibiting Flt3 or MAPK or especially p38 by chemical, antibody, or silencing strategies restored megakaryopoiesis and reduced phosphorylation of Flt3 and p38 pathway effectors, confirming the involvement of Flt3 in PMF dysmegakaryopoiesis via p38 activation. In addition, in contrast to healthy donors, MK cells derived from PMF CD34(+) cells exhibited an FL-induced migration that could be reversed by p38 inhibition. Taken together, our results implicate the FL/Flt3 ligand-receptor complex in PMF dysmegakaryopoiesis through persistent p38-MAPK activation, with implications for therapeutic prospects to correct altered megakaryopoiesis in an inflammatory context.
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  • Doignon, I, Julien, B, Serriere-Lanneau, V, Garcin, I, Alonso, G, Nicou, A, Monnet, F, Gigou, M, Humbert, L, Rainteau, D, Azoulay, D, Castaing, D, Gillon, MC, Samuel, D, Duclos-Vallee, JC & Tordjmann, T 2011, « Immediate neuroendocrine signaling after partial hepatectomy through acute portal hyperpressure and cholestasis », J Hepatol, vol. 54, no. 3, p. 481-8.
    Résumé : BACKGROUND & AIMS: Early neuroendocrine pathways contribute to liver regeneration after partial hepatectomy (PH). We investigated one of these pathways involving acute cholestasis, immediate portal hyperpressure, and arginine vasopressin (AVP) secretion. METHODS: Surgical procedure (PH, Portal vein stenosis (PVS), bile duct ligation (BDL), spinal cord lesion (SCL)) and treatments (capsaicin, bile acids (BA), oleanolic acid (OA)) were performed on rats and/or wild type or TGR5 (GPBAR1) knock-out mice. In these models, the activation of AVP-secreting supraoptic nuclei (SON) was analyzed, as well as plasma BA, AVP, and portal vein pressure (PVP). Plasma BA, AVP, and PVP were also determined in human living donors for liver transplantation. RESULTS: Acute cholestasis (mimicked by BDL or BA injection) as well as portal hyperpressure (mimicked by PVS) independently activated SON and AVP secretion. BA accumulated in the brain after PH or BDL, and TGR5 was expressed in SON. SON activation was mimicked by the TGR5 agonist OA and inhibited in TGR5 KO mice after BDL. An afferent nerve pathway also contributed to post-PH AVP secretion, as capsaicin treatment or SCL resulted in a weaker SON activation after PH. CONCLUSIONS: After PH in rodents, acute cholestasis and portal hypertension, via the nervous and endocrine routes, stimulate the secretion of AVP that may protect the liver against shear stress and bile acids overload. Data in living donors suggest that this pathway may also operate in humans.
    Mots-clés : Adult Animals Arginine Vasopressin/physiology Bile Acids and Salts/physiology Blood Pressure/physiology Cholestasis/physiopathology Female Hepatectomy Humans Hypertension, Animal Neurosecretory Systems/ physiology Portal System/physiology Rats Rats, G-Protein-Coupled/deficiency/genetics/physiology Signal Transduction Supraoptic Nucleus/physiology, Inbred C57BL Mice, Knockout Models, Portal/physiopathology Liver Regeneration/ physiology Male Mice Mice, Wistar Receptors.

  • Dominguez, C, Karayan-Tapon, L, Desurmont, T, Gibelin, H, Crespin, S, Fromont, G, Levillain, P, Bouche, G, Cantereau, A, Mesnil, M & Kraimps, JL 2011, « Altered Expression of the Gap Junction Protein Connexin43 Is Associated with Papillary Thyroid Carcinomas When Compared with Other Noncancer Pathologies of the Thyroid », Thyroid, vol. 21, no. 10, p. 1057-1066, viewed sans date, <<Go to ISI>://WOS:000295157800004>.
    Résumé : Background: Gap junctions are membrane structures composed of connexins (Cx) that allow diffusion of small molecules between cells. They are involved in tissue homeostasis, and various organ dysfunctions have been associated with gap junction defects. To verify their possible involvement in thyroid pathologies, the expression of connexin43 (Cx43), the major Cx in the human thyroid, was evaluated in a variety of diseases including cancer. Methods: There were 122 samples from various thyroid pathologies that were collected to analyze the presence of Cx43 by immunofluorescence. Through confocal microscopy, different patterns of Cx43 localization were identified as normal (membrane) or abnormal (cytoplasmic or lack of detection). The analysis of Cx43 expression was further performed by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry in a subset of 25 papillary carcinomas and compared with nontumoral thyroid tissues. Results: The presence of Cx43 was commonly altered in thyroid cancer, as abnormal Cx43 staining was detected in 94.1% of cancer, 47.4% of adenomas, 45.7% of multinodular goiter, 16.7% of Graves' disease, and 25% of thyroiditis. In papillary carcinoma samples, the deregulation of Cx43 expression was mostly the consequence of a decrease of Cx43 mRNA (68% of cases) when compared with normal tissue. When Cx43 mRNA was not downregulated (32% of cases), both loss of membrane staining and aberrant cytoplasmic distribution of the protein were observed. Conclusions: These results show that aberrations of Cx43 expression are associated with thyroid papillary carcinoma.
  • Duclos-Vallee, JC 2011, « [Recurrence of hepatitis B and C after liver transplantation] », Rev Prat, vol. 61, no. 1, p. 61-4.
    Résumé : Duclos-Vallee, Jean-Charles; France; Rev Prat. 2011 Jan;61(1):61-4.
    Mots-clés : Antiviral Agents/ therapeutic use Carcinoma, Hepatocellular/surgery/virology Hepatitis B/ prevention & control Hepatitis C/ prevention & control Humans Liver Cirrhosis/surgery/virology Liver Neoplasms/surgery/virology Liver Transplantation Recurrence/prevention & control.
  • Duclos-Vallee, JC, Falissard, B & Samuel, D 2011, « Liver transplant outcomes in HIV-infected patients: a systematic review and meta-analysis with a synthetic cohort », AIDS, vol. 25, no. 13, p. 1675-6.
    Résumé : Duclos-Vallee, Jean-Charles; Falissard, Bruno; Samuel, Didier; Comment; Letter; England; AIDS. 2011 Aug 24;25(13):1675-6. doi: 10.1097/QAD.0b013e3283498346.
    Mots-clés : C/, Hepatitis, HIV, Humans, immunology, Infections/, Liver, Transplantation/.
  • Duclos-Vallee, JC, Ichai, P & Samuel, D 2011, « Autoimmune acute liver failure », Hepatology, vol. 54, no. 1, p. 372-3; author reply 373.
    Résumé : Duclos-Vallee, Jean-Charles; Ichai, Philippe; Samuel, Didier; Comment; Letter; United States; Hepatology. 2011 Jul;54(1):372-3; author reply 373. doi: 10.1002/hep.24337. Epub 2011 May 2.
    Mots-clés : Acute/diagnosis/drug therapy/ pathology Necrosis, Adrenal Cortex Hormones/adverse effects/therapeutic use Autoimmune Diseases/diagnosis/drug therapy/ pathology Biopsy Humans Liver/ pathology Liver Failure.

  • Edlich, F, Banerjee, S, Suzuki, M, Cleland, MM, Arnoult, D, Wang, C, Neutzner, A, Tjandra, N & Youle, RJ 2011, « Bcl-x(L) retrotranslocates Bax from the mitochondria into the cytosol », Cell, vol. 145, no. 1, p. 104-16, viewed sans date, .
    Résumé : The Bcl-2 family member Bax translocates from the cytosol to mitochondria, where it oligomerizes and permeabilizes the mitochondrial outer membrane to promote apoptosis. Bax activity is counteracted by prosurvival Bcl-2 proteins, but how they inhibit Bax remains controversial because they neither colocalize nor form stable complexes with Bax. We constrained Bax in its native cytosolic conformation within cells using intramolecular disulfide tethers. Bax tethers disrupt interaction with Bcl-x(L) in detergents and cell-free MOMP activity but unexpectedly induce Bax accumulation on mitochondria. Fluorescence loss in photobleaching (FLIP) reveals constant retrotranslocation of WT Bax, but not tethered Bax, from the mitochondria into the cytoplasm of healthy cells. Bax retrotranslocation depends on prosurvival Bcl-2 family proteins, and inhibition of retrotranslocation correlates with Bax accumulation on the mitochondria. We propose that Bcl-x(L) inhibits and maintains Bax in the cytosol by constant retrotranslocation of mitochondrial Bax.
    Mots-clés : Apoptosis Cell Line, Tumor Cytosol/*metabolism Humans Mitochondria/*metabolism Protein Conformation Protein Folding Protein Transport bcl-2-Associated X Protein/chemistry/*metabolism bcl-X Protein/*metabolism.
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  • Fallani, M, Amarri, S, Uusijarvi, A, Adam, R, Khanna, S, Aguilera, M, Gil, A, Vieites, JM, Norin, E, Young, D, Scott, JA, Doré, J, Edwards, CA & team, INFABIO 2011, « Determinants of the human infant intestinal microbiota after the introduction of first complementary foods in infant samples from five European centres », Microbiology, vol. 157, no. Pt 5, p. 1385-92, viewed sans date, .
    Résumé : Although it is well established that early infant feeding has a major influence on the establishment of the gut microbiota, very little is understood about how the introduction of first solid food influences the colonization process. This study aimed to determine the impact of weaning on the faecal microbiota composition of infants from five European countries (Sweden, Scotland, Germany, Italy and Spain) which have different lifestyle characteristics and infant feeding practices. Faecal samples were collected from 605 infants approximately 4 weeks after the introduction of first solid foods and the results were compared with the same infants before weaning (6 weeks of age) to investigate the association with determining factors such as geographical origin, mode of delivery, previous feeding method and age of weaning. Samples were analysed by fluorescence in situ hybridization and flow cytometry using a panel of 10 rRNA targeted group- and species-specific oligonucleotide probes. The genus Bifidobacterium (36.5 % average proportion of total detectable bacteria), Clostridium coccoides group (14 %) and Bacteroides (13.6 %) were predominant after weaning. Similar to pre-weaning, northern European countries were associated with a higher proportion of bifidobacteria in the infant gut microbiota while higher levels of Bacteroides and lactobacilli characterized southern European countries. As before weaning, the initial feeding method influenced the Clostridium leptum group and Clostridium difficile+Clostridium perfringens species, and bifidobacteria still dominated the faeces of initially breast-fed infants. Formula-fed babies presented significantly higher proportions of Bacteroides and the C. coccoides group. The mode of birth influenced changes in the proportions of bacteroides and atopobium. Although there were significant differences in the mean weaning age between countries, this was not related to the populations of bifidobacteria or bacteroides. Thus, although the faecal microbiota of infants after first complementary foods was different to that before weaning commenced, many of the initial influences on microbiota composition were still evident.
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  • Farges, O, Fuks, D, Boleslawski, E, Le Treut, YP, Castaing, D, Laurent, A, Ducerf, C, Rivoire, M, Bachellier, P, Chiche, L, Nuzzo, G & Regimbeau, JM 2011, « Influence of surgical margins on outcome in patients with intrahepatic cholangiocarcinoma: a multicenter study by the AFC-IHCC-2009 study group », Ann Surg, vol. 254, no. 5, p. 824-29; discussion 830.
    Résumé : OBJECTIVE: Define the optimal surgical margin in patients undergoing surgery for intrahepatic cholangiocarcinoma (IHCC). BACKGROUND DATA: Surgery is the most effective treatment for IHCC. However, the influence of R1 resection on outcome is controversial and that of margin width has not been evaluated. METHODS: We studied 212 patients undergoing curative resection of mass-forming-type IHCC. The respective influences on survival of resection status (R0 vs R1), surgical margin width, pTNM stage, and the latter's components were evaluated. RESULTS: Incidence of R1 resection was 24%. Overall, R1 resection was not an independent predictor of survival [odds ratio (OR) 1.2 (0.7-2.1)] in contrast to the pTNM stage [OR 2.10 (1.2-3.5)]. In the 78 pN+ patients, survival was similar after R0 and R1 resections (median: 18 vs 13 months, respectively, P = 0.1). In the 134 pN0 patients, R1 resection was an independent predictor of poor survival [OR 9.6 (4.5-20.4)], as was the presence of satellite nodules [OR 1.9 (1.1-3.2)]. In the 116 pN0 patients with R0 resections, median survival was correlated with margin width (</=1 mm: 15 months; 2-4 mm: 36 months; 5-9 mm: 57 month; >/=10 mm: 64 month, P < 0.001) and a margin >5 mm was an independent predictor of survival [OR 2.22 (1.59-3.09)]. CONCLUSION: Patients undergoing surgery for IHCC are at high risk of R1 resections. In pN0 patients, R1 resection is the strongest independent predictor of poor outcome and a margin of at least 5 mm should be created. The survival benefits of resection in pN+ patients and R1 resection in general are very low.
    Mots-clés : Aged Bile Duct Neoplasms/drug therapy/mortality/ pathology/ surgery Bile Ducts, Intrahepatic Biliary Tract Surgical Procedures Cholangiocarcinoma/drug therapy/mortality/ pathology/ surgery Female Humans Male Neoplasm Invasiveness Neoplasm Staging Retrospective Studies Treatment Outcome.
  • Fischer, L, Trunecka, P, Gridelli, B, Roy, A, Vitale, A, Valdivieso, A, Varo, E, Seehofer, D, Lynch, S, Samuel, D, Ericzon, BG, Boudjema, K, Karpf, C & Undre, N 2011, « Pharmacokinetics for once-daily versus twice-daily tacrolimus formulations in de novo liver transplantation: a randomized, open-label trial », Liver Transpl, vol. 17, no. 2, p. 167-77.
    Résumé : Tacrolimus, a cornerstone immunosuppressant, is available as a twice-daily formulation (tacrolimus bid). A once-daily prolonged-release formulation (tacrolimus qd) has been developed. This 6-week, randomized, phase 2, multicenter, open-label, prospective trial in primary liver transplant recipients investigated and compared the pharmacokinetics (PK) of tacrolimus for qd and bid formulations. All patients received tacrolimus-based immunosuppression (tacrolimus qd, n = 67; bid, n = 62). PK data were available for 77 patients (tacrolimus qd, n = 45; bid, n = 32). Tacrolimus area under the curve (AUC) from 0 to 24 hours (AUC(0-24) ) at equivalent doses was approximately 50% lower for tacrolimus qd than for bid on day 1 (146 versus 264 ng . h/mL, respectively), but by day 14 was comparable between treatments (324 and 287 ng . h/mL, respectively) with higher tacrolimus qd doses. There was a strong correlation between AUC(0-24) and concentration at 24 hours for tacrolimus qd and bid (r = 0.92 and r = 0.76, respectively). Furthermore, the relationship between these 2 parameters (ie, the slope of the line) was also similar for the 2 formulations. Efficacy endpoints were comparable for both formulations at 6 weeks with no marked differences in incidence, nature, or severity of adverse events between treatments (although the study was not powered to draw efficacy conclusions). These results suggest that targeting the same trough levels will achieve similar total AUC over 24 hours for both tacrolimus qd and tacrolimus bid in de novo liver transplant recipients.
    Mots-clés : Administration, Oral Adult Aged Area Under Curve Australia Canada Delayed-Action Preparations Drug Administration Schedule Drug Therapy.

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