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Biblio - Bibliographie IAL
Bibliographie IAL

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Recherche bibliographique scientifique

Moteur de recherche scientifique en Médecine, Biologie et Sciences

Accueil > Références bibliographiques

biblio

2013

  • Xia, T, Levy, L, Levillayer, F, Jia, B, Li, G, Neuveut, C, Buendia, MA, Lan, K & Wei, Y 2013, « The four and a half LIM-only protein 2 (FHL2) activates transforming growth factor beta (TGF-beta) signaling by regulating ubiquitination of the E3 ligase Arkadia », J Biol Chem, vol. 288, no. 3, p. 1785-94.
    Résumé : Arkadia is a RING-based ubiquitin ligase that positively regulates TGF-beta signaling by targeting several pathway components for ubiquitination and degradation. However, little is known about the mechanisms controlling Arkadia activity. Here we show that the LIM-only protein FHL2 binds and synergistically cooperates with Arkadia to activate Smad3/Smad4-dependent transcription. Knockdown of FHL2 by RNA interference decreases Arkadia level and restricts the amplitude of Arkadia-induced TGF-beta target gene responses. We found that Arkadia is ubiquitinated via K63- and K27-linked polyubiquitination. A single mutation at the RING domain that abolishes the E3 activity diminishes Arkadia ubiquitination, indicating that this modification partly involves autocatalytic process. Mutation of seven lysines at the C-terminal region of Arkadia severely impairs ubiquitination through the K27 but not the K63 linkage and slows down the turnover of Arkadia, suggesting that K27-linked polyubiquitination might promote proteolysis-dependent regulation of Arkadia. We show that FHL2 increases the half-life of Arkadia through inhibition of ubiquitin chain assembly on the protein, which provides a molecular basis for functional cooperation between Arkadia and FHL2 in enhancing TGF-beta signaling. Our study uncovers a novel regulatory mechanism of Arkadia by ubiquitination and identifies FHL2 as important regulator of Arkadia ubiquitination and TGF-beta signal transduction.
    Mots-clés : Animals Binding Sites Cell Line, Reporter Half-Life Humans LIM-Homeodomain Proteins/ genetics/metabolism Luciferases Mice Muscle Proteins/ genetics/metabolism Mutation Nuclear Proteins/ genetics/metabolism Protein Binding Protein Structure, Tertiary Signal Transduction Transcription Factors/ genetics/metabolism Transfection Transforming Growth Factor beta/ genetics/metabolism Ubiquitin/ genetics/metabolism Ubiquitin-Protein Ligases/ genetics/metabolism Ubiquitination, Tumor Fibroblasts/cytology/metabolism Gene Expression Regulation Genes.
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  • Yang, G, Si-Tayeb, K, Corbineau, S, Vernet, R, Gayon, R, Dianat, N, Martinet, C, Clay, D, Goulinet-Mainot, S, Tachdjian, G, Tachdjian, G, Burks, D, Vallier, L, Bouillé, P, Dubart-Kupperschmitt, A & Weber, A 2013, « Integration-deficient lentivectors: an effective strategy to purify and differentiate human embryonic stem cell-derived hepatic progenitors », BMC biology, vol. 11, p. 86.
    Résumé : BACKGROUND: Human pluripotent stem cells (hPSCs) hold great promise for applications in regenerative medicine. However, the safety of cell therapy using differentiated hPSC derivatives must be improved through methods that will permit the transplantation of homogenous populations of a specific cell type. To date, purification of progenitors and mature cells generated from either embryonic or induced pluripotent stem cells remains challenging with use of conventional methods. RESULTS: We used lentivectors encoding green fluorescent protein (GFP) driven by the liver-specific apoliprotein A-II (APOA-II) promoter to purify human hepatic progenitors. We evaluated both integrating and integration-defective lentivectors in combination with an HIV integrase inhibitor. A human embryonic stem cell line was differentiated into hepatic progenitors using a chemically defined protocol. Subsequently, cells were transduced and sorted at day 16 of differentiation to obtain a cell population enriched in hepatic progenitor cells. After sorting, more than 99% of these APOA-II-GFP-positive cells expressed hepatoblast markers such as α-fetoprotein and cytokeratin 19. When further cultured for 16 days, these cells underwent differentiation into more mature cells and exhibited hepatocyte properties such as albumin secretion. Moreover, they were devoid of vector DNA integration. CONCLUSIONS: We have developed an effective strategy to purify human hepatic cells from cultures of differentiating hPSCs, producing a novel tool that could be used not only for cell therapy but also for in vitro applications such as drug screening. The present strategy should also be suitable for the purification of a broad range of cell types derived from either pluripotent or adult stem cells.
    Mots-clés : Apolipoprotein A-II, Biological Markers, Cell Differentiation, Cell Line, Cell Separation, Cytochrome P-450 CYP3A, DNA, Viral, Embryonic Stem Cells, Flow Cytometry, Genes, Reporter, Genetic Vectors, Green Fluorescent Proteins, Hepatocytes, Humans, Lentivirus, Liver, Organ Specificity, Promoter Regions, Genetic, Transduction, Genetic, Virus Integration.
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  • Zona, L, Lupberger, J, Sidahmed-Adrar, N, Thumann, C, Harris, HJ, Barnes, A, Florentin, J, Tawar, RG, Xiao, F, Turek, M, Durand, SC, Duong, FH, Heim, MH, Cosset, FL, Hirsch, I, Samuel, D, Brino, L, Zeisel, MB, Le Naour, F, McKeating, JA & Baumert, TF 2013, « HRas signal transduction promotes hepatitis C virus cell entry by triggering assembly of the host tetraspanin receptor complex », Cell Host Microbe, vol. 13, no. 3, p. 302-13.
    Résumé : Hepatitis C virus (HCV) entry is dependent on coreceptor complex formation between the tetraspanin superfamily member CD81 and the tight junction protein claudin-1 (CLDN1) on the host cell membrane. The receptor tyrosine kinase EGFR acts as a cofactor for HCV entry by promoting CD81-CLDN1 complex formation via unknown mechanisms. We identify the GTPase HRas, activated downstream of EGFR signaling, as a key host signal transducer for EGFR-mediated HCV entry. Proteomic analysis revealed that HRas associates with tetraspanin CD81, CLDN1, and the previously unrecognized HCV entry cofactors integrin beta1 and Ras-related protein Rap2B in hepatocyte membranes. HRas signaling is required for lateral membrane diffusion of CD81, which enables tetraspanin receptor complex assembly. HRas was also found to be relevant for entry of other viruses, including influenza. Our data demonstrate that viruses exploit HRas signaling for cellular entry by compartmentalization of entry factors and receptor trafficking.

  • Zuber, J, Grimbert, P, Blancho, G, Thaunat, O, Durrbach, A, Baron, C & Lebranchu, Y 2013, « Prognostic significance of graft Foxp3 expression in renal transplant recipients: a critical review and attempt to reconcile discrepancies », Nephrol Dial Transplant, vol. 28, no. 5, p. 1100-11, viewed sans date, .
    Résumé : A large body of evidence has been accumulated from experimental models in the past decade to support the critical role of Foxp3-expressing regulatory T cells (Tregs) in the suppression of alloimmune responses. This has prompted transplant clinicians to investigate whether Foxp3 analysis might be used as an immunodiagnostic tool for better assessment of the significance of graft infiltrate and to predict its impact on graft outcome. However, conflicting results have emerged from these studies and may have generated more confusion than clarification. Foxp3 expression has been antagonistically correlated with either good or poor prognosis. We discuss here how methodological issues and specific clinical settings may have accounted for the discrepancies between the results of these studies. Depending on many factors, including the techniques used, the method of sampling normalization, the extent of intra-graft inflammation, the immunosuppressive regimen and the depletion or repletion of T lymphocyte compartment, the significance of Foxp3 expression may vary. We propose here the conditions to be fulfilled in order to use Foxp3 analysis as a relevant biomarker for graft outcome assessment. Far from challenging the key role of Tregs in dampening alloimmune responses, this review highlights the need for technical harmonization and standards.

2012


  • Abdelmalek, MF, Humar, A, Stickel, F, Andreone, P, Pascher, A, Barroso, E, Neff, GW, Ranjan, D, Toselli, LT, Gane, EJ, Scarola, J, Alberts, RG, Maller, ES & Lo, CM 2012, « Sirolimus conversion regimen versus continued calcineurin inhibitors in liver allograft recipients: a randomized trial », Am J Transplant, vol. 12, no. 3, p. 694-705, viewed sans date, .
    Résumé : A large prospective, open-label, randomized trial evaluated conversion from calcineurin inhibitor (CNI)- to sirolimus (SRL)-based immunosuppression for preservation of renal function in liver transplantation patients. Eligible patients received liver allografts 6-144 months previously and maintenance immunosuppression with CNI (cyclosporine or tacrolimus) since early posttransplantation. In total, 607 patients were randomized (2:1) to abrupt conversion (<24 h) from CNI to SRL (n = 393) or CNI continuation for up to 6 years (n = 214). Between-group changes in baseline-adjusted mean Cockcroft-Gault GFR at month 12 (primary efficacy end point) were not significant. The primary safety end point, noninferiority of cumulative rate of graft loss or death at 12 months, was not met (6.6% vs. 5.6% in the SRL and CNI groups, respectively). Rates of death at 12 months were not significantly different, and no true graft losses (e.g. liver transplantation) were observed during the 12-month period. At 52 weeks, SRL conversion was associated with higher rates of biopsy-confirmed acute rejection (p = 0.02) and discontinuations (p < 0.001), primarily for adverse events. Adverse events were consistent with known safety profiles. In conclusion, liver transplantation patients showed no demonstrable benefit 1 year after conversion from CNI- to SRL-based immunosuppression.

  • Adam, R 2012, « Selective hepatic vascular exclusion versus Pringle manoeuvre in liver resection for tumours encroaching on major hepatic veins (Br J Surg 2012; 99: 973-977) », Br J Surg, vol. 99, no. 7, p. 978, viewed sans date, .
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  • Adam, R, Karam, V, Delvart, V, O'Grady, J, Mirza, D, Klempnauer, J, Castaing, D, Neuhaus, P, Jamieson, N, Salizzoni, M, Pollard, S, Lerut, J, Paul, A, Garcia-Valdecasas, JC, Rodriguez, FS & Burroughs, A 2012, « Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR) », J Hepatol, vol. 57, no. 3, p. 675-88.
    Résumé : Adam, Rene; Karam, Vincent; Delvart, Valerie; O'Grady, John; Mirza, Darius; Klempnauer, Jurgen; Castaing, Denis; Neuhaus, Peter; Jamieson, Neville; Salizzoni, Mauro; Pollard, Stephen; Lerut, Jan; Paul, Andreas; Garcia-Valdecasas, Juan Carlos; Rodriguez, Fernando San Juan; Burroughs, Andrew; All contributing centers (www.eltr.org); European Liver and Intestine Transplant Association (ELITA); Research Support, Non-U.S. Gov't; England; J Hepatol. 2012 Sep;57(3):675-88. doi: 10.1016/j.jhep.2012.04.015. Epub 2012 May 16.
    Mots-clés : 80 and over Alcoholism/complications Biliary Atresia/surgery Carcinoma, Acute/surgery Liver Neoplasms/ surgery Liver Transplantation/mortality/ statistics & numerical data/ trends Male Middle Aged Registries/ statistics & numerical data Survival Rate Young Adult, Adolescent Adult Aged Aged, Hepatocellular/ surgery Child Child, Preschool Cholangitis, Sclerosing/surgery Europe Female Hepatitis B/complications Hepatitis C/complications Humans Infant Liver Cirrhosis/etiology/ surgery Liver Failure.
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  • Adam, R, Bhangui, P, Vibert, E, Azoulay, D, Pelletier, G, Duclos-Vallée, J-C, Samuel, D, Guettier, C & Castaing, D 2012, « Resection or transplantation for early hepatocellular carcinoma in a cirrhotic liver: does size define the best oncological strategy? », Ann Surg, vol. 256, no. 6, p. 883-91, viewed sans date, .
    Résumé : BACKGROUND: Resection and liver transplantation (LT) are the only curative options for hepatocellular carcinoma in cirrhotic patients (HCC-cirr). OBJECTIVE: We tried to define the best primary intention-to-treat strategy in patients undergoing either resection or LT for early single HCC-cirr (≤5 cm). METHODS: From 1990 to 2010, 198 patients with early HCC-cirr underwent either resection (group R, n = 97) or LT (group T, n = 101) as the primary procedure. Our policy was to prioritize Childs A patients with peripheral lesions for resection rather than LT. Patient and tumor characteristics, and outcomes (recurrence-free survival [RFS] and overall survival [OS]), were studied. RESULTS: A longer diagnosis-to-surgery interval, more Child Pugh B/C patients, and more tumor nodules (on histopathological examination) were found in group T patients. The postoperative mortality (4.1% vs 3.0%, P = 0.72) and rate of major complications (19.1% vs 24.7%, P = 0.35) were similar in groups R and T, respectively, whereas tumor recurrence was higher in group R (62% vs 10% in group T, P < 0.0001). The 5-year OS (75% vs 52%, P = 0.0008) and RFS (72% vs 20%, P < 0.0001) were better in group T; similarly, more patients were disease free at last follow-up (27% vs 62%, P < 0.0001). Resection as the surgical procedure, tumor diameter 3 cm or more on histology, and microvascular tumor invasion were poor prognostic factors for OS and RFS. Including dropout patients from LT list in the analysis, the outcomes in group T were still better (70% and 61% vs 51% and 36% at 5 and 10 years, P = 0.01). CONCLUSIONS: On an intention-to-treat basis, LT is associated with the best survival outcomes in patients with early HCC-cirr. Resection may achieve comparable OS in patients with single HCC-cirr of size smaller than 3 cm; however, the RFS still remains lower than that in patients of group T. This study could serve as a guide for HCC-cirr patients who are candidates for either resection or LT.
    Mots-clés : Carcinoma.
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  • Adam, R, De Gramont, A, Figueras, J, Guthrie, A, Kokudo, N, Kunstlinger, F, Loyer, E, Poston, G, Rougier, P, Rubbia-Brandt, L, Sobrero, A, Tabernero, J, Teh, C, Van Cutsem, E & group, J-NV of the EGOSLIM 2012, « The oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary international consensus », Oncologist, vol. 17, no. 10, p. 1225-39, viewed sans date, .
    Résumé : An international panel of multidisciplinary experts convened to develop recommendations for the management of patients with liver metastases from colorectal cancer (CRC). The aim was to address the main issues facing the CRC hepatobiliary multidisciplinary team (MDT) when managing such patients and to standardize the treatment patients receive in different centers. Based on current evidence, the group agreed on a number of issues including the following: (a) the primary aim of treatment is achieving a long disease-free survival (DFS) interval following resection; (b) assessment of resectability should be performed with high-quality cross-sectional imaging, staging the liver with magnetic resonance imaging and/or abdominal computed tomography (CT), depending on local expertise, staging extrahepatic disease with thoracic and pelvic CT, and, in selected cases, fluorodeoxyglucose positron emission tomography with ultrasound (preferably contrast-enhanced ultrasound) for intraoperative staging; (c) optimal first-line chemotherapy-doublet or triplet chemotherapy regimens combined with targeted therapy-is advisable in potentially resectable patients; (d) in this situation, at least four courses of first-line chemotherapy should be given, with assessment of tumor response every 2 months; (e) response assessed by the Response Evaluation Criteria in Solid Tumors (conventional chemotherapy) or nonsize-based morphological changes (antiangiogenic agents) is clearly correlated with outcome; no imaging technique is currently able to accurately diagnose complete pathological response but high-quality imaging is crucial for patient management; (f) the duration of chemotherapy should be as short as possible and resection achieved as soon as technically possible in the absence of tumor progression; (g) the number of metastases or patient age should not be an absolute contraindication to surgery combined with chemotherapy; (h) for synchronous metastases, it is not advisable to undertake major hepatic surgery during surgery for removal of the primary CRC; the reverse surgical approach (liver first) produces as good an outcome as the conventional approach in selected cases; (i) for patients with resectable liver metastases from CRC, perioperative chemotherapy may be associated with a modestly better DFS outcome; and (j) whether initially resectable or unresectable, cure or at least a long survival duration is possible after complete resection of the metastases, and MDT treatment is essential for improving clinical and survival outcomes. The group proposed a new system to classify initial unresectability based on technical and oncological contraindications.
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  • Adams, D, Samuel, D & Slama, M 2012, « [Treatment of familial amyloid polyneuropathy] », Presse Med, vol. 41, no. 9 Pt 1, p. 793-806.
    Résumé : The treatment of familial amyloid polyneuropathies (FAP) is complex and requires a neurological and cardiological multidisciplinary coverage. It includes specific treatments to control the progression of the systemic amyloidogenesis, the symptomatic treatment of the peripheral and autonomic neuropathy (digestive, urinary, sexual, postural hypotension) and the treatment of organs severely involved by amyloidosis (heart, eyes, kidneys). First line specific treatment of met30 TTR-FAP is liver transplantation (LT) which allows to suppress the main source of mutant TTR, to stop the progression of the neuropathy in 70 % of cases at long-term (with an experience of 18 years) and to double the median survival. In case of severe renal or cardiac insufficiency, a double transplant kidney-liver or heart-liver can be discussed. The tafamidis (in temporary authorization of use in France) is a stabilizing medicine of the tetrameric TTR which showed in very early stages of met30 TTR-FAP short-term capacities to stop the progress of the peripheral neuropathy in 60 % of the cases versus 38 % with placebo. It should be proposed in case of contraindication of TH (age>70 years [20 % of the cases]), of very early stages (very low NIS-LL score), or for the period of wait of LT. Other innovative medicines issued from biopharmaceutical companies have been developed to block the hepatic production of both mutant and wild TTR which are noxious in the late forms NAH (>50 years old) (RNAi [RNA interference] therapeutics, AntiSens oligonucleotids), for removing the amyloid deposits (monoclonal antibody anti-SAP), or to slow down the formation of deposits of TTR and amyloidosis (combination of doxycycline-TUDCA). Clinical trials should be first addressed to the patients with a late onset of FAP or non-met30 TTR-FAP who are less responding to LT and patients with contraindications in the LT. Initial cardiac assessment and periodic cardiac investigations are important for the FAP according to the frequency of cardiac impairment which is responsible of high rate of mortality. Conduction disorders (atrio-ventricular blocks) require the implantation of a pacemaker in about one third of the cases during the evolution of the disease. A myocardial infiltration is detected in two third of the cases and is for a long time latent; it remains often limited to a diastolic dysfunction which can be responsible for hemodynamical difficulties during the LT; it evolves sometimes, late, towards a systolic dysfunction of bad prognosis. A combined liver-heart transplantation is proposed in cases of severe cardiac involvement which are contraindication to the LT only, essentially in forms "not met30". In every case of FAP, a regular cardiological follow-up is required for life, because of the progress of the cardiac involvement, which is not always stopped by the liver transplantation. The symptomatic treatments are indispensable to improve the quality of life of the patients: neurogenic pains, urinary disorders, liqueurs, sexual impotence, postural hypotension. The familial screening of the carriers of the TTR gene mutation and their regular follow-up by appropriate clinical examination and complementary investigations are major to detect early the onset of the disease to start as soon as possible specific therapy.
    Mots-clés : Amyloid/antagonists & inhibitors/genetics Amyloid Neuropathies, Familial/ therapy Arrhythmias, Small Interfering/therapeutic use.


  • Afdhal, NH, Giannini, EG, Tayyab, G, Mohsin, A, Lee, JW, Andriulli, A, Jeffers, L, McHutchison, J, Chen, PJ, Han, KH, Campbell, F, Hyde, D, Brainsky, A & Theodore, D 2012, « Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia », N Engl J Med, vol. 367, no. 8, p. 716-24, viewed sans date, .
    Résumé : BACKGROUND: Eltrombopag is an oral thrombopoietin-receptor agonist. This study evaluated the efficacy of eltrombopag for increasing platelet counts and reducing the need for platelet transfusions in patients with thrombocytopenia and chronic liver disease who are undergoing an elective invasive procedure. METHODS: We randomly assigned 292 patients with chronic liver disease of diverse causes and platelet counts of less than 50,000 per cubic millimeter to receive eltrombopag, at a dose of 75 mg daily, or placebo for 14 days before a planned elective invasive procedure that was performed within 5 days after the last dose. The primary end point was the avoidance of a platelet transfusion before, during, and up to 7 days after the procedure. A key secondary end point was the occurrence of bleeding (World Health Organization [WHO] grade 2 or higher) during this period. RESULTS: A platelet transfusion was avoided in 104 of 145 patients who received eltrombopag (72%) and in 28 of 147 who received placebo (19%) (P<0.001). No significant difference between the eltrombopag and placebo groups was observed in bleeding episodes of WHO grade 2 or higher, which were reported in 17% and 23% of patients, respectively. Thrombotic events of the portal venous system were observed in 6 patients who received eltrombopag, as compared with 1 who received placebo, resulting in the early termination of the study. The incidence and severity of other adverse events were similar in the eltrombopag and placebo groups. CONCLUSIONS: Eltrombopag reduced the need for platelet transfusions in patients with chronic liver disease who were undergoing elective invasive procedures, but it was associated with an increased incidence of portal-vein thrombosis, as compared with placebo. (Funded by GlaxoSmithKline; ELEVATE ClinicalTrials.gov number, NCT00678587.).
  • Algalarrondo, V, Dinanian, S, Juin, C, Chemla, D, Bennani, SL, Sebag, C, Plante, V, Le Guludec, D, Samuel, D, Adams, D & Slama, MS 2012, « Prophylactic pacemaker implantation in familial amyloid polyneuropathy », Heart Rhythm, vol. 9, no. 7, p. 1069-75.
    Résumé : BACKGROUND: Familial amyloid polyneuropathy (FAP) is an autosomic dominant disease with a high rate of conduction disorders and increased risk of sudden death. Prophylactic cardiac pacing may be considered in asymptomatic patients with FAP. However, the potential benefits are unknown. OBJECTIVE: To document conduction disorders in a large series of FAP and the incidence of high-degree atrioventricular (AV) block in patients with prophylactic pacemaker (PM). METHODS: From January 1999 to January 2010, 262 patients with FAP were retrospectively evaluated. Prophylactic PM was implanted in patients with His-ventricular interval >/= 70 ms, His-ventricular interval >55 ms associated with a fascicular block, a first-degree AV block, or a Wenckebach anterograde point </= 100 beats/min. The spontaneous AV conduction was then analyzed by temporarily inhibiting the PM. RESULTS: As compared with patients with prophylactic PM (n = 100) and patients implanted given a class I/IIa indication (n = 18), the patients who did not require PM (n = 144) were younger and displayed less severe cardiac involvement. Follow-up after prophylactic PM implantation was analyzed in 95 of the 100 patients over 45 +/- 35 months, and a high-degree AV block was documented in 24 of the 95 patients (25%). The risk of high-degree AV block was higher in patients with first-degree AV block or Wenckebach anterograde point </= 100 beats/min (hazard ratio 3.5; 95% confidence interval 1.2-10) while microvoltage on surface electrocardiogram reduced the risk (hazard ratio 0.2; 95% confidence interval 0.1-0.7). CONCLUSION: In FAP with conduction disorders, prophylactic PM implantation prevented major cardiac events in 25% of the patients over a 45-month mean follow-up. It is suggested that prophylactic PM implantation prevented symptomatic bradycardia in these patients.
    Mots-clés : Adult Aged Amyloid Neuropathies, Artificial Death, Artificial Retrospective Studies, Cardiac Female Heart Conduction System/physiopathology Humans Male Middle Aged Pacemaker, Cardiac/ etiology/physiopathology Bradycardia/prevention & control Cardiac Pacing, Cardiac/ prevention & control Electrophysiologic Techniques, Familial/ complications Arrhythmias, Sudden.
  • Algalarrondo, V, Eliahou, L, Thierry, I, Bouzeman, A, Dasoveanu, M, Sebag, C, Moubarak, G, Le Guludec, D, Samuel, D, Adams, D, Dinanian, S & Slama, MS 2012, « Circadian rhythm of blood pressure reflects the severity of cardiac impairment in familial amyloid polyneuropathy », Arch Cardiovasc Dis, vol. 105, no. 5, p. 281-90.
    Résumé : BACKGROUND: Cardiac amyloidosis due to familial amyloid polyneuropathy (FAP) includes restrictive cardiomyopathy, thickened cardiac walls, conduction disorders and cardiac denervation. Impaired blood pressure variability has been documented in FAP related to the Val30Met mutation. AIMS: To document blood pressure variability in FAP patients with various mutation types and its relationship to the severity of cardiac involvement. METHODS: Blood pressure variability was analysed in 49 consecutive FAP patients and was compared with a matched control population. Cardiac evaluation included echocardiography, right heart catheterization, electrophysiological study, Holter electrocardiogram and metaiodobenzylguanidine (MIBG) scintigraphy. RESULTS: A non-dipping pattern was found in 80% of FAP patients and in 35% of control patients (P<0.0001); this was due to a significantly lower diurnal blood pressure in FAP patients (FAP group, 113 +/- 21 mmHg; control group, 124 +/- 8 mmHg; P<0.0001), whereas nocturnal blood pressures were similar. Among FAP patients, a non-dipping pattern was significantly associated with haemodynamic involvement, cardiac thickening or conduction disorders. These associations did not depend on the average blood pressure levels. Impaired blood pressure variability was more frequent and more pronounced in patients with multiple criteria for severe cardiac amyloidosis. CONCLUSION: Low blood pressure variability is common in cardiac amyloidosis due to FAP. A non-dipping pattern was more frequently observed in FAP patients with haemodynamic impairment, cardiac thickening or conduction disorders. It is suggested that impairment of circadian rhythm of blood pressure reflects the severity of cardiac amyloidosis due to FAP.
    Mots-clés : 3-Iodobenzylguanidine/diagnostic use Adult Aged Amyloid Neuropathies, Ambulatory Electrophysiologic Techniques, Cardiac Female France Humans Logistic Models Male Middle Aged Mutation Prealbumin/genetics Predictive Value of Tests Radiopharmaceuticals/diagnostic use Retrospective Studies Severity of Illness Index Time Factors, Familial/ complications/genetics/physiopathology Blood Pressure Cardiac Catheterization Cardiomyopathies/diagnosis/ etiology/physiopathology Circadian Rhythm Cross-Sectional Studies Echocardiography Electrocardiography.


  • Avouac, J, Meune, C, Ruiz, B, Couraud, PO, Uzan, G, Boileau, C, Kahan, A, Chiocchia, G & Allanore, Y 2012, « Angiogenic biomarkers predict the occurrence of digital ulcers in systemic sclerosis », Ann Rheum Dis, vol. 71, no. 3, p. 394-9, viewed sans date, .
    Résumé : OBJECTIVE: To evaluate the possible merit of endothelial markers for the prediction of ischaemic digital ulcers in patients with systemic sclerosis (SSc). METHODS: Circulating endothelial progenitor cells (EPC), circulating endothelial cells and serum levels of placental growth factor (PlGF), soluble vascular adhesion molecule and vascular endothelial growth factor were measured in a prospective cohort of 100 SSc patients. The primary outcome was the occurrence of one or more new ischaemic digital ulcers during a planned 3-year follow-up. RESULTS: After the follow-up period, 17 patients developed new digital ulcers. By multivariate analysis focused on biomarkers, high PlGF serum levels and low EPC counts were identified as predictors of the occurrence of at least one new digital ulcer. In a secondary model including biomarkers together with clinical SSc characteristics all predictors of digital ulcers defined by p≤0.1 in univariate analysis, high PlGF serum levels (HR 7.26, 95% CI 1.92 to 27.41) and a history of digital ulcers (HR 9.32, 95% CI 1.51 to 59.83) were identified as independent predictors of a new digital ulcer. In an alternative model excluding patients with a history of digital ulcers at baseline, high PlGF serum levels (HR 13.46, 95% CI 1.58 to 114.73) and low EPC counts (HR 7.95, 95% CI 2.09 to 30.09) remained predictive of new digital ulcer occurrence during follow-up. CONCLUSION: This study identified high PlGF serum levels and low circulating EPC counts as predictors of new digital ulcers in SSc. It highlights the critical role of angiogenesis in this vascular outcome. These markers may improve digital ulcer risk stratification and therefore allow earlier therapeutic intervention.
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  • Azoulay, D, Salloum, C, Samuel, D & Plante-Bordeneuve, V 2012, « Operative risks of domino liver transplantation for the FAP liver donor and the FAP liver recipient », Amyloid, vol. 19 Suppl 1, p. 73-4.
    Résumé : This study aimed at evaluating the operative risks of domino liver transplantation (LT). Two retrospective analyses were conducted (comparison of familial amyloid polyneuropathy (FAP) liver donors [61 patients] versus FAP nondonors [39 patients] and FAP liver recipients [61 patients] versus cadaveric liver recipients [61 patients]). First analysis showed a 60-day mortality of 6.6% for FAP donors and 7.7% for FAP nondonors (p = 1.0). Both groups had similar vascular and biliary complication rates. Both groups had similar 1- and 5-year patient and graft survival rates (83.4 % versus 87.2%, and 79.8 % versus 71.8%, p = 0.7) and (83.3% versus 87.2%, and 79.1% versus 71.8%, p = 0.7). The second analysis showed a 1.6% mortality for FAP liver recipients versus 3.2% of the control group (p = 1). Both groups had similar morbidity and technical complication rates (18.0% versus 13.1%, p = 0.45) and (0.18 versus 0.15, p = 0.65). Domino procedure doesn't add any risk to FAP donor or recipient. It increases the organ pool allowing transplantation of marginal recipients who otherwise are denied cadaveric LT.
    Mots-clés : Amyloid Neuropathies, Familial/ surgery Humans Liver Transplantation/ adverse effects Living Donors Retrospective Studies Transplantation.
  • Bailloud, R, Bertin, D, Roquelaure, B, Roman, C, Ballot, E, Johanet, C & Desplat-Jego, S 2012, « Anti-mitochondrial-2 antibodies (anti-PDC-E2): a marker for autoimmune hepatitis of children? », Clin Res Hepatol Gastroenterol, vol. 36, no. 4, p. e57-9.
    Résumé : In an 8-year-old boy with biochemical hepatic disorders, an histological examination of a liver biopsy showed a severe chronic hepatitis without cirrhosis. The biliary tract was normal and no toxic or infectious etiologies were found. Spontaneous improvement of the clinical status was observed in the following weeks but biochemical abnormalities were persistent and a second episode occurred 3 years after. Immunological studies showed anti-mitochondrial-2 antibodies (AMA-2) confirmed by an immunoblot performed with rat mitochondrial proteins resolved by two-dimensional electrophoresis. We described here the second case in the literature of paediatric autoimmune hepatitis associated with well documented AMA-2.
    Mots-clés : Autoantibodies/ blood Biological Markers/blood Child Hepatitis, Autoimmune/ blood/diagnosis/ immunology Humans Male Mitochondrial Proteins/ immunology.
  • Bertheau, P, Chabouis, A, Fabiani, B, Poullier, E, Daniel, C, Cucherousset, J, Bosq, J, Henin, D, Capron, F & Guettier, C 2012, « Telepathology with virtual slides », Med Sci (Paris), vol. 28, no. 11, p. 983-5.
    Résumé : Bertheau, Philippe; Chabouis, Agnes; Fabiani, Bettina; Poullier, Eric; Daniel, Christel; Cucherousset, Joel; Bosq, Jacques; Henin, Dominique; Capron, Frederique; Guettier, Catherine; France; Med Sci (Paris). 2012 Nov;28(11):983-5. doi: 10.1051/medsci/20122811018. Epub 2012 Nov 12.
    Mots-clés : Analog-Digital Conversion Forecasting Humans Image Processing, Clinical/instrumentation/ methods Photography/instrumentation/ methods Telepathology/instrumentation/ methods/organization & administration/trends User-Computer Interface, Computer-Assisted/instrumentation/ methods Information Services Microscopy/instrumentation/ methods Online Systems Pathology.

  • Bessede, T, Droupy, S, Hammoudi, Y, Bedretdinova, D, Durrbach, A, Charpentier, B & Benoit, G 2012, « Surgical prevention and management of vascular complications of kidney transplantation », Transpl Int, vol. 25, no. 9, p. 994-1001, viewed sans date, .
    Résumé : The main surgical changes in kidney procurement, preparation, and transplantation procedures occurred 20 years ago and were undertaken despite the inability to design randomized studies. The objective was to assess the evolution of vascular complications after kidney transplantation in a setting of surgical preventive measures in a historical series. A monocentric series of 3129 consecutive kidney transplantations performed over 3 decades was reviewed. The occurrence of arterial or venous thromboses, stenoses, and aneurysms was analyzed in relation with kidney procurement, preparation, and transplantation techniques. Vascular complications occurred in 13.5% of the recipients with a mean 3-year decrease in kidney graft function. The transplantation of a right kidney without renal vein extension, multiple renal arteries, ex vivo vascular repairs, and end-to-end arterial anastomoses were the unfavorable surgical vascular factors. It was possible to manage Transplant Renal Artery Stenosis (TRAS) nonsurgically in 80% of the cases. The prevention of vascular complications begins from the time of organ procurement by skilled surgeons. The aims of organ preparation are to evaluate the vascular risk, select the organs, and to simplify the anatomical constraints of vascular implantations. The three surgical steps of kidney transplantation are determinant in postoperative vascular complications and the duration of graft function.
    Mots-clés : Adult Aged Anastomosis.
  • Bioulac-Sage, P, Cubel, G, Taouji, S, Scoazec, JY, Leteurtre, E, Paradis, V, Sturm, N, Nhieu, JT, Wendum, D, Bancel, B, Ramos, J, Paraf, F, Saint Paul, MC, Michalak, S, Fabre, M, Guettier, C, Le Bail, B, Zucman-Rossi, J & Balabaud, C 2012, « Immunohistochemical markers on needle biopsies are helpful for the diagnosis of focal nodular hyperplasia and hepatocellular adenoma subtypes », Am J Surg Pathol, vol. 36, no. 11, p. 1691-9.
    Résumé : Phenotypic identification of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) subtypes using immunohistochemical markers has been developed from their molecular characteristics. Our objective was to evaluate the sensitivity of these markers in the definitive diagnosis of these lesions by core needle biopsies. A total of 239 needle biopsies paired with their surgical resection specimen (group A) or without an associated resection specimen (group B) were reviewed. Using a step-by-step algorithm after standard staining, appropriate immunostaining analyses were performed to determine the certainty of diagnosis of FNH, HNF1alpha-inactivated HCA, inflammatory HCA, beta-catenin-activated HCA, or unclassified HCA. The diagnosis of FNH was certain or probable on routine stains in 53% of needle biopsies of group A, whereas after glutamine synthetase staining, the diagnosis was certain in 86.7% as compared with 100% on the corresponding surgical specimen (P=0.04). In needle biopsies of group A, the diagnosis of HCA was certain on routine stains in 58.6% as compared with 94.3% on surgical specimens. After specific immunostaining, diagnosis was established on biopsies with 74.3% certainty, including all HCA subtypes, with similar distribution in surgical specimens. For each "certain diagnosis" paired diagnostic test (biopsy and surgical specimen), a positive correlation was observed (P<0.001). No significant difference was observed between groups A and B for FNH (P=0.714) or for HCA subtypes (P=0.750). Compared with surgical specimens, immunohistochemical analysis performed on biopsies allowed the discrimination of FNH from HCA and the identification of HCA subtypes with good performance.
    Mots-clés : Adenoma, Biological/ metabolism beta Catenin/metabolism, Large-Core Needle Diagnosis, Liver Cell/ diagnosis/metabolism/surgery Adult Algorithms Biopsy.
  • Buendia, MA, Bourre, L & Cairo, S 2012, « Myc target miRs and liver cancer: small molecules to get Myc sick », Gastroenterology, vol. 142, no. 2, p. 214-8.
    Résumé : Buendia, Marie-Annick; Bourre, Ludovic; Cairo, Stefano; Review; United States; Gastroenterology. 2012 Feb;142(2):214-8. doi: 10.1053/j.gastro.2011.12.023. Epub 2011 Dec 16.
    Mots-clés : Biological/genetics/ metabolism, Carcinoma, Hepatocellular/ genetics/metabolism/therapy Gene Expression Regulation, myc/ physiology Genetic Therapy Hepatoblastoma/ genetics/metabolism/therapy Humans Liver Neoplasms/ genetics/metabolism/therapy MicroRNAs/ metabolism/therapeutic use Proto-Oncogene Proteins c-myc/genetics/ metabolism Tumor Markers, Neoplastic Genes.


  • Bussolati, B, Dekel, B, Azzarone, B & Camussi, G 2012, « Human renal cancer stem cells », Cancer Lett, viewed sans date, .
    Résumé : Cancer stem cells (CSCs), isolated in renal carcinomas, exhibit tumor-initiating capabilities and pluripotency. No specific CSC markers have been identified so far; therefore, their characterization is mainly based on functional studies. As they are resistant to chemo and radio therapy, renal CSCs may have a relevant role in tumor establishment, progression, and recurrence. CSCs were also shown to contribute to intra-tumor vasculogenesis through an endothelial differentiation and to favor the generation of the pre-metastatic niche through the release of exosomes/microvesicles.
  • Cairo, S, Armengol, C & Buendia, MA 2012, « Activation of Wnt and Myc signaling in hepatoblastoma », Front Biosci (Elite Ed), vol. 4, p. 480-6.
    Résumé : Hepatoblastoma (HB) is the most common type of pediatric liver cancer. This tumor is thought to derive from hepatic progenitor cells that are arrested at various stages of liver development, as illustrated by a variety of histologic subtypes. Recent genomic studies have led to better understand the molecular pathogenesis of HB, to point out the crucial roles of the Wnt Myc signaling pathways in malignant transformation of liver progenitor cells. Molecular classification of HB based on genome-wide studies, as well as identification of reliable diagnostic prognostic markers, open the way to the development of new personalized targeted therapies for the management of aggressive lethal childhood tumors.
    Mots-clés : beta, c-myc/, Catenin/genetics/metabolism, Hepatoblastoma/, Humans, Liver, metabolism, Mutation, Neoplasms/, Proteins, Proteins/, Proto-Oncogene, Signal, Transduction, Wnt.
  • Cairo, S & Buendia, MA 2012, « How transient becomes stable: an epigenetic switch linking liver inflammation and tumorigenesis », J Hepatol, vol. 57, no. 4, p. 910-2.
    Résumé : Cairo, Stefano; Buendia, Marie Annick; Comment; Netherlands; J Hepatol. 2012 Oct;57(4):910-2. doi: 10.1016/j.jhep.2012.05.017. Epub 2012 Jun 2.
  • Calmus, Y, Duvoux, C, Pageaux, G, Wolf, P, Rostaing, L, Vanlemmens, C, Botta-Fridlund, D, Dharancy, S, Gugenheim, J, Durand, F, Neau-Cransac, M, Boillot, O, Chazouilleres, O, Samelson, L, Boudjema, K & Samuel, D 2012, « Treatment of recurrent HCV infection following liver transplantation: results of a multicenter, randomized, versus placebo, trial of ribavirin alone as maintenance therapy after one year of PegIFNalpha-2a plus ribavirin », J Hepatol, vol. 57, no. 3, p. 564-71.
    Résumé : BACKGROUND & AIMS: We aimed at determining the effect of maintenance therapy with ribavirin alone, after a year of combined peginterferon-alfa 2a (PegIFNalpha-2a) and ribavirin therapy, on viral response and liver histology after liver transplantation (LT). METHODS: Hundred and one patients with recurrent HCV and a minimum of stage 1 fibrosis (METAVIR scoring), 1-5years after LT, were enrolled. PegIFNalpha-2a and ribavirin were initiated at 90 mug/wk and 600 mg/d, respectively, then increased or adjusted as a function of tolerance. At 12 months, combination therapy was discontinued and patients were randomized to ribavirin or placebo for a further 12 months. Growth factor use was permitted. RESULTS: At 18 months, a sustained virological response (SVR) was obtained in 47.9% of patients in Per Protocol (PP) analysis, and was higher in patients with genotype 2 or 3 than in patients with genotype 1 or 4, in patients with genotypes 1+4 receiving ciclosporine than in those receiving tacrolimus, in patients with worse renal function, in those having received EPO, in patients with lower weight, and in those with lower viral load at 3 months. Using logistic regression, only the early viral response, recipient weight and renal function were independently associated with better SVR. SVR, viral load, activity, and fibrosis scores were similar, at M18 and M30, in patients randomized to ribavirin, or to placebo. CONCLUSIONS: A PP SVR was achieved in 47.9% of patients with established recurrent hepatitis C after LT. Maintenance therapy with ribavirin alone does not improve the virological response or the histological parameters.
    Mots-clés : Antiviral Agents/adverse effects/ therapeutic use Cyclosporine/therapeutic use Double-Blind Method Drug Therapy.

  • Castanier, C, Zemirli, N, Portier, A, Garcin, D, Bidere, N, Vazquez, A & Arnoult, D 2012, « MAVS ubiquitination by the E3 ligase TRIM25 and degradation by the proteasome is involved in type I interferon production after activation of the antiviral RIG-I-like receptors », BMC Biol, vol. 10, p. 44, viewed sans date, .
    Résumé : BACKGROUND: During a viral infection, the intracellular RIG-I-like receptors (RLRs) sense viral RNA and signal through the mitochondrial antiviral signaling adaptor MAVS (also known as IPS-1, Cardif and VISA) whose activation triggers a rapid production of type I interferons (IFN) and of pro-inflammatory cytokines through the transcription factors IRF3/IRF7 and NF-kappaB, respectively. While MAVS is essential for this signaling and known to operate through the scaffold protein NEMO and the protein kinase TBK1 that phosphorylates IRF3, its mechanism of action and regulation remain unclear. RESULTS: We report here that RLR activation triggers MAVS ubiquitination on lysine 7 and 10 by the E3 ubiquitin ligase TRIM25 and marks it for proteasomal degradation concomitantly with downstream signaling. Inhibition of this MAVS degradation with a proteasome inhibitor does not affect NF-kappaB signaling but it hampers IRF3 activation, and NEMO and TBK1, two essential mediators in type I IFN production, are retained at the mitochondria. CONCLUSIONS: These results suggest that MAVS functions as a recruitment platform that assembles a signaling complex involving NEMO and TBK1, and that the proteasome-mediated MAVS degradation is required to release the signaling complex into the cytosol, allowing IRF3 phosphorylation by TBK1.
    Mots-clés : Adaptor Proteins.
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  • Chantran, Y, Ballot, E & Johanet, C 2012, « Autoantibodies in autoimmune hepatitis: anti-asialoglycoprotein receptor (anti-ASGPR) antibodies », Clin Res Hepatol Gastroenterol, vol. 36, no. 5, p. 510-2.
    Résumé : Chantran, Yannick; Ballot, Eric; Johanet, Catherine; France; Clin Res Hepatol Gastroenterol. 2012 Oct;36(5):510-2. doi: 10.1016/j.clinre.2012.07.013. Epub 2012 Sep 6.
    Mots-clés : Asialoglycoprotein Receptor/ immunology Autoantibodies/ immunology Hepatitis, Autoimmune/ immunology Humans.

  • Chomel, J-C, Sorel, N, Guilhot, J, Guilhot, F & Turhan, AG 2012, « BCR-ABL expression in leukemic progenitors and primitive stem cells of patients with chronic myeloid leukemia », Blood, vol. 119, no. 12, p. 2964-5; author reply 2965-6, viewed sans date, .
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  • Clavien, PA, Lesurtel, M, Bossuyt, PM, Gores, GJ, Langer, B & Perrier, A 2012, « Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report », Lancet Oncol, vol. 13, no. 1, p. e11-22, viewed sans date, .
    Résumé : Although liver transplantation is a widely accepted treatment for hepatocellular carcinoma (HCC), much controversy remains and there is no generally accepted set of guidelines. An international consensus conference was held on Dec 2-4, 2010, in Zurich, Switzerland, with the aim of reviewing current practice regarding liver transplantation in patients with HCC and to develop internationally accepted statements and guidelines. The format of the conference was based on the Danish model. 19 working groups of experts prepared evidence-based reviews according to the Oxford classification, and drafted recommendations answering 19 specific questions. An independent jury of nine members was appointed to review these submissions and make final recommendations, after debates with the experts and audience at the conference. This report presents the final 37 statements and recommendations, covering assessment of candidates for liver transplantation, criteria for listing in cirrhotic and non-cirrhotic patients, role of tumour downstaging, management of patients on the waiting list, role of living donation, and post-transplant management.
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  • Clifford, GM, Lise, M, Franceschi, S, Egger, M, Bouchardy, C, Korol, D, Levi, F, Ess, S, Jundt, G, Wandeler, G, Fehr, J, Schmid, P, Battegay, M, Bernasconi, E, Cavassini, M, Calmy, A, Keiser, O, Schöni-Affolter, F & Study, SHIVC 2012, « Lung cancer in the Swiss HIV Cohort Study: role of smoking, immunodeficiency and pulmonary infection », Br J Cancer, vol. 106, no. 3, p. 447-52, viewed sans date, .
    Résumé : BACKGROUND: Immunodeficiency and AIDS-related pulmonary infections have been suggested as independent causes of lung cancer among HIV-infected persons, in addition to smoking. METHODS: A total of 68 lung cancers were identified in the Swiss HIV Cohort Study (SHCS) or through linkage with Swiss Cancer Registries (1985-2010), and were individually matched to 337 controls by centre, gender, HIV-transmission category, age and calendar period. Odds ratios (ORs) were estimated by conditional logistic regression. RESULTS: Overall, 96.2% of lung cancers and 72.9% of controls were ever smokers, confirming the high prevalence of smoking and its strong association with lung cancer (OR for current vs never=14.4, 95% confidence interval (95% CI): 3.36-62.1). No significant associations were observed between CD4+ cell count and lung cancer, neither when measured within 1 year (OR for <200 vs ≥500=1.21, 95% CI: 0.49-2.96) nor further back in time, before lung cancer diagnosis. Combined antiretroviral therapy was not significantly associated with lung cancer (OR for ever vs never=0.67, 95% CI: 0.29-1.52), and nor was a history of AIDS with (OR=0.49, 95% CI: 0.19-1.28) or without (OR=0.53, 95% CI: 0.24-1.18) pulmonary involvement. CONCLUSION: Lung cancer in the SHCS does not seem to be clearly associated with immunodeficiency or AIDS-related pulmonary disease, but seems to be attributable to heavy smoking.
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  • Coilly, A, Furlan, V, Roche, B, Barau, C, Noel, C, Bonhomme-Faivre, L, Antonini, TM, Roque-Afonso, AM, Samuel, D, Taburet, AM & Duclos-Vallee, JC 2012, « Practical management of boceprevir and immunosuppressive therapy in liver transplant recipients with hepatitis C virus recurrence », Antimicrob Agents Chemother, vol. 56, no. 11, p. 5728-34.
    Résumé : Hepatitis C virus (HCV) recurrence is the most important complication in HCV liver transplant patients. Boceprevir with pegylated interferon and ribavirin (PegIFN/RBV) enabled improvement in sustained virological response rates of patients with genotype 1 HCV. Boceprevir interacts with immunosuppressive therapy (IT) by inhibiting the cytochrome P450 3A enzyme. Our aim was to study interactions and assess the safety of boceprevir in the context of HCV recurrence. Boceprevir (800 mg three times a day) initiated after a 4-week lead-in phase was associated with cyclosporine (three patients), tacrolimus (two patients), and everolimus (one patient) in five liver transplant patients with genotype 1 HCV infection who experienced HCV recurrence. The mean follow-up period after HCV therapy was 14.8 +/- 3.1 weeks. Estimated oral clearances of IT decreased on average by 50%, requiring reduced dosing regimens. Anemia occurred in all patients, with a mean fall in hemoglobin levels between baseline and week 12 of 3.12 +/- 2.27 g/dl. All patients required administration of beta-erythropoietin (n = 5), three needed ribavirin dose reduction, and one needed a blood transfusion. A virological response was observed in all patients (mean HCV viral load [HVL] decrease at week 12, 6.64 +/- 0.35 log(10) IU/ml). These preliminary results in liver transplant patients with HCV recurrence demonstrate the feasibility and safety of coadministration of boceprevir and IT.
    Mots-clés : Aged Antiviral Agents/pharmacology/ therapeutic use Cyclosporine/pharmacology/therapeutic use Disease Management Drug Therapy, Combination Hepacivirus/ drug effects/growth & development Hepatitis C.
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  • Corpechot, C, Gaouar, F, Chretien, Y, Johanet, C, Chazouilleres, O & Poupon, R 2012, « Smoking as an independent risk factor of liver fibrosis in primary biliary cirrhosis », J Hepatol, vol. 56, no. 1, p. 218-24.
    Résumé : BACKGROUND & AIMS: Smoking has been identified as a potential predisposition factor for primary biliary cirrhosis (PBC). However, it remains unclear whether it is associated with more active and severe disease. Our aim was to assess the relationships between smoking and the severity of the elementary histological lesions, as well as the biochemical and immunological features of PBC. METHODS: Smoking history data were collected from 223 PBC patients using a standardized questionnaire. Histological data were available in 164 patients at presentation. Liver fibrosis and histological inflammatory activity were semi-quantified according to a METAVIR-based classification system. Odds ratios (OR) were assessed using a logistic regression analysis. RESULTS: Smoking history prior to diagnosis was reported in 58 patients (26%). Twenty-five patients (11%) were active smokers at diagnosis. Male gender (OR, 4.5), alcohol intake >20 g/d (OR, 4.2), and F3-F4 fibrosis stage (OR, 2.7), but not inflammatory grade, bile duct changes, biochemical or immunological features, were associated with smoking history. Smoking intensity was significantly higher in patients with F3-F4 stage (8.1+/-14.2 pack-years vs. 3.0+/-7.0 pack-years; p=0.01). Adjusted logistic regression identified smoking history and smoking intensity as independent risk factors of advanced fibrosis. Each pack-year of increase in smoking intensity was associated with a 5.0% (95% CI, 1.3-8.7%) increased likelihood of advanced fibrosis. CONCLUSIONS: Smoking increases, in a dose-dependent fashion, the risk of liver fibrosis in PBC without apparent increase in the histological inflammatory activity, bile duct lesions, biochemical, and immunological features of the disease. PBC patients should be strongly encouraged not to smoke.
    Mots-clés : Adult Aged Alcohol Drinking/adverse effects Cohort Studies Female Humans Liver Cirrhosis/ etiology/pathology Liver Cirrhosis, Biliary/ complications/immunology/pathology Male Middle Aged Risk Factors Smoking/ adverse effects.
  • Corruble, E, Barry, C, Varescon, I, Castaing, D, Samuel, D & Falissard, B 2012, « The Transplanted Organ Questionnaire: a validation study », J Psychosom Res, vol. 73, no. 4, p. 319-24.
    Résumé : OBJECTIVE: The transplanted organ is a key element of the recipient's daily life. But its representations are neither spontaneously expressed by patients, nor taken into account by transplantation professionals. Our objective was to assess specifically the transplanted organ representations in liver transplant recipients. METHODS: In a prospective cohort study, 134 liver transplanted (LT) patients were assessed using the Transplanted Organ Questionnaire (TOQ), a new specifically designed questionnaire, fulfilled 3, 6, 12, 24, and 36months post-LT. RESULTS: The TOQ comprised three dimensions, explaining 44% of the total variance: Donor (21.3%) measuring the recipients' concerns about the donor, Positive attitude towards the transplant (13.4%), and Psychological Rejection (9.3%), measuring a lack of incorporation of the transplant. These three dimensions have a high internal consistency (Cronbach alpha: 0.91, 0.76 and 0.56) and are stable over time. Older recipients had more concern about the Donor than younger ones. As compared to other medical primary diagnoses, viral hepatitis was associated with higher scores on the subscales Positive attitude towards the transplant and Psychological Rejection. Interestingly, Psychological rejection predicted increased long term risk of death (HR, 1.20; 95% CI, 1.01-1.44, P=.046) under multivariate Cox analyses, independently from other variables. CONCLUSION: The transplanted organ representations as specifically assessed by the Transplanted Organ Questionnaire (TOQ) are relevant in liver transplant recipients. Interventions based on the transplant representations after LT should be assessed in further studies. Indeed, preventing psychological rejection of the transplanted organ and facilitating its psychological incorporation may decrease long term mortality after LT.
    Mots-clés : Adult, Aged, Attitude, Female, Health, Humans, Liver, Male, Middle, of, Prospective, psychology, Questionnaires, Reproducibility, Results, Studies, to, Transplantation/.
  • Cougot, D, Allemand, E, Riviere, L, Benhenda, S, Duroure, K, Levillayer, F, Muchardt, C, Buendia, MA & Neuveut, C 2012, « Inhibition of PP1 phosphatase activity by HBx: a mechanism for the activation of hepatitis B virus transcription », Sci Signal, vol. 5, no. 205, p. ra1.
    Résumé : The regulatory protein HBx is essential for hepatitis B virus (HBV) replication in vivo and for transcription of the episomal HBV genome. We previously reported that in infected cells HBx activates genes targeted by the transcription factor CREB [cyclic adenosine monophosphate (cAMP) response element-binding protein]. cAMP induces phosphorylation and activation of CREB, and CREB inactivation is promoted by protein phosphatase 1 (PP1), which binds to CREB through histone deacetylase 1 (HDAC1). We showed that CREB was recruited to HBV DNA. Phosphorylation induced by cAMP had a longer half-life when CREB was bound to the episomal HBV genome compared to when it was bound to the promoter of a host target gene not regulated by HBx, suggesting that the virus has developed a mechanism to favor its own transcription. This mechanism required HBx, which interacted with and inhibited PP1 to extend the half-life of CREB phosphorylation. Silencing of PP1 rescued replication of an HBx-deficient HBV genome, suggesting that HBx enhances viral transcription in part by neutralizing PP1 activity. Our results illustrate a previously unknown mechanism of HBV transcriptional activation by HBx in which HBx interferes with the inactivation of CREB by the PP1 and HDAC1 complex.
    Mots-clés : Analysis of Variance Blotting, Biological Phosphorylation Protein Phosphatase 1/ antagonists & inhibitors RNA, Gel Cyclic AMP Response Element-Binding Protein/ metabolism DNA Primers/genetics DNA, Northern Chromatin Immunoprecipitation Chromatography, Small Interfering/genetics Real-Time Polymerase Chain Reaction Trans-Activators/ metabolism/physiology Transcriptional Activation/ physiology, Viral/metabolism Forskolin HEK293 Cells HeLa Cells Hepatitis B virus/ physiology Humans Models.

  • Croce, M, Orengo, AM, Azzarone, B & Ferrini, S 2012, « Immunotherapeutic applications of IL-15 », Immunotherapy, vol. 4, no. 9, p. 957-69, viewed sans date, .
    Résumé : IL-15 is a member of the IL-2 family of cytokines, which play a fundamental role in innate and adaptive immune responses. IL-15 has pleiotropic immune-enhancing activities, as it stimulates NK, T and NKT cell proliferation, survival and effector functions. In view of these properties, IL-15 is regarded as a good candidate for cancer immunotherapy. This possibility is reinforced by its low toxicity and efficacy in preclinical tumor models. The use of IL-15 to boost the immune response in HIV infection has also been proposed, although further studies are required to establish potential risks and benefits. Clinical trials of IL-15 have been initiated in cancer patients and in HIV vaccination and will elucidate the potential of IL-15-based immunotherapy. The purpose of this review is to provide an update on the potential applications of IL-15 in cancer immunotherapy and HIV infection.
    Mots-clés : Animals, as, Clinical, HIV, Humans, Immunotherapy, Infections/*drug, Interleukin-15/physiology/*therapeutic, Neoplasms/*drug, Therapy, Topic, Trials, use/toxicity.
  • Dannaoui, E, Desnos-Ollivier, M, Garcia-Hermoso, D, Grenouillet, F, Cassaing, S, Baixench, MT, Bretagne, S, Dromer, F & Lortholary, O 2012, « Candida spp. with acquired echinocandin resistance, France, 2004-2010 », Emerg Infect Dis, vol. 18, no. 1, p. 86-90.
    Résumé : We report 20 episodes of infection caused by acquired echinocandin-resistant Candida spp. harboring diverse and new Fksp mutations. For 12 patients, initial isolates (low MIC, wild-type Fksp sequence) and subsequent isolates (after caspofungin treatment, high MIC, mutated Fksp) were genetically related.
    Mots-clés : 80 and over Antifungal Agents/ pharmacology Candida/classification/ drug effects Candidiasis/ epidemiology/ microbiology Drug Resistance, Adolescent Adult Aged Aged, Fungal Echinocandins/ pharmacology Female France/epidemiology Humans Male Microbial Sensitivity Tests Middle Aged Young Adult.
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  • De Simone, P, Nevens, F, De Carlis, L, Metselaar, HJ, Beckebaum, S, Saliba, F, Jonas, S, Sudan, D, Fung, J, Fischer, L, Duvoux, C, Chavin, KD, Koneru, B, Huang, MA, Chapman, WC, Foltys, D, Witte, S, Jiang, H, Hexham, JM & Junge, G 2012, « Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial », Am J Transplant, vol. 12, no. 11, p. 3008-20.
    Résumé : In a prospective, multicenter, open-label study, de novo liver transplant patients were randomized at day 30+/-5 to (i) everolimus initiation with tacrolimus elimination (TAC Elimination) (ii) everolimus initiation with reduced-exposure tacrolimus (EVR+Reduced TAC) or (iii) standard-exposure tacrolimus (TAC Control). Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy-proven acute rejection (tBPAR). EVR+Reduced TAC was noninferior to TAC Control for the primary efficacy endpoint (tBPAR, graft loss or death at 12 months posttransplantation): 6.7% versus 9.7% (-3.0%; 95% CI -8.7, 2.6%; p<0.001 for noninferiority [12% margin]). tBPAR occurred in 2.9% of EVR+Reduced TAC patients versus 7.0% of TAC Controls (p = 0.035). The change in adjusted estimated GFR from randomization to month 12 was superior with EVR+Reduced TAC versus TAC Control (difference 8.50 mL/min/1.73 m(2) , 97.5% CI 3.74, 13.27 mL/min/1.73 m(2) , p<0.001 for superiority). Drug discontinuation for adverse events occurred in 25.7% of EVR+Reduced TAC and 14.1% of TAC Controls (relative risk 1.82, 95% CI 1.25, 2.66). Relative risk of serious infections between the EVR+Reduced TAC group versus TAC Controls was 1.76 (95% CI 1.03, 3.00). Everolimus facilitates early tacrolimus minimization with comparable efficacy and superior renal function, compared to a standard tacrolimus exposure regimen 12 months after liver transplantation.
    Mots-clés : Adolescent Adult Aged Confidence Intervals Cross-Over Studies Dose-Response Relationship.
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  • de Visscher, SA, Witjes, MJ, Kascakova, S, Sterenborg, HJ, Robinson, DJ, Roodenburg, JL & Amelink, A 2012, « In vivo quantification of photosensitizer concentration using fluorescence differential path-length spectroscopy: influence of photosensitizer formulation and tissue location », J Biomed Opt, vol. 17, no. 6, p. 067001.
    Résumé : In vivo measurement of photosensitizer concentrations may optimize clinical photodynamic therapy (PDT). Fluorescence differential path-length spectroscopy (FDPS) is a non-invasive optical technique that has been shown to accurately quantify the concentration of Foscan(R) in rat liver. As a next step towards clinical translation, the effect of two liposomal formulations of mTHPC, Fospeg(R) and Foslip(R), on FDPS response was investigated. Furthermore, FDPS was evaluated in target organs for head-and-neck PDT. Fifty-four healthy rats were intravenously injected with one of the three formulations of mTHPC at 0.15 mg kg(-1). FDPS was performed on liver, tongue, and lip. The mTHPC concentrations estimated using FDPS were correlated with the results of the subsequent harvested and chemically extracted organs. An excellent goodness of fit (R(2)) between FDPS and extraction was found for all formulations in the liver (R(2)=0.79). A much lower R(2) between FDPS and extraction was found in lip (R(2)=0.46) and tongue (R(2)=0.10). The lower performance in lip and in particular tongue was mainly attributed to the more layered anatomical structure, which influences scattering properties and photosensitizer distribution.
    Mots-clés : Adhesiveness Animals Light Lip/pathology Liposomes/chemistry Liver/pathology Male Mesoporphyrins/ chemistry Microscopy, Confocal/methods Nanoparticles/chemistry Photochemotherapy/ methods Photosensitizing Agents/ pharmacology Rats Rats, Fluorescence/ methods Tongue/pathology, Radiation Spectrometry, Wistar Regression Analysis Scattering.

  • Debiec, H, Hanoy, M, Francois, A, Guerrot, D, Ferlicot, S, Johanet, C, Aucouturier, P, Godin, M & Ronco, P 2012, « Recurrent membranous nephropathy in an allograft caused by IgG3kappa targeting the PLA2 receptor », J Am Soc Nephrol, vol. 23, no. 12, p. 1949-54, viewed sans date, .
    Résumé : Up to 80% of patients with idiopathic membranous nephropathy have non-complement-fixing IgG4 autoantibodies to the phospholipase A2 receptor (PLA2R). Membranous nephropathy recurs in approximately 40% of patients after kidney transplantation, but the mechanism is unknown. Here, we describe a patient with recurrent membranous nephropathy 13 days after kidney transplantation whose graft biopsy specimen showed granular staining for C3, C5b-9, C1q, and IgG3kappa; electron microscopy revealed subepithelial nonorganized deposits. A search for hematologic disorders was negative. Retrospective evaluation of a biopsy sample from the native kidney revealed a similar pattern: monotypic IgG3kappa deposits together with C3, C1q, and C5b-9. Glomerular deposits contained PLA2R in both the graft and the native kidney, suggesting that the recurrence was the result of circulating anti-PLA2R antibodies binding to PLA2R antigen expressed on donor podocytes. Confocal analysis of anti-PLA2R and antihuman IgG3 showed co-localization, and the patient had IgG3kappa-restricted circulating anti-PLA2R antibodies. Treatment with rituximab stabilized both proteinuria and serum creatinine, and circulating anti-PLA2R became undetectable. In summary, this case of recurrent membranous nephropathy in a graft suggests that circulating monoclonal anti-PLA2R IgG3kappa caused the disease and activated complement by the classic pathway.
    Mots-clés : Glomerulonephritis, Homologous/immunology, Membranous/*immunology Humans Immunoglobulin G/*physiology *Kidney Transplantation Male Middle Aged Postoperative Complications/*immunology Receptors, Phospholipase A2/*immunology Recurrence Transplantation.
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  • Degli Esposti, D, Hamelin, J, Bosselut, N, Saffroy, R, Sebagh, M, Pommier, A, Martel, C & Lemoine, A 2012, « Mitochondrial roles and cytoprotection in chronic liver injury », Biochem Res Int, vol. 2012, p. 387626, viewed sans date, .
    Résumé : The liver is one of the richest organs in terms of number and density of mitochondria. Most chronic liver diseases are associated with the accumulation of damaged mitochondria. Hepatic mitochondria have unique features compared to other organs' mitochondria, since they are the hub that integrates hepatic metabolism of carbohydrates, lipids and proteins. Mitochondria are also essential in hepatocyte survival as mediator of apoptosis and necrosis. Hepatocytes have developed different mechanisms to keep mitochondrial integrity or to prevent the effects of mitochondrial lesions, in particular regulating organelle biogenesis and degradation. In this paper, we will focus on the role of mitochondria in liver physiology, such as hepatic metabolism, reactive oxygen species homeostasis and cell survival. We will also focus on chronic liver pathologies, especially those linked to alcohol, virus, drugs or metabolic syndrome and we will discuss how mitochondria could provide a promising therapeutic target in these contexts.
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  • Degos, B, Daelman, L, Huberfeld, G, Meppiel, E, Rabier, D, Galanaud, D, Magis, AS, Lyon-Caen, O, Samuel, D & Sedel, F 2012, « Portosystemic shunts: an underdiagnosed but treatable cause of neurological and psychiatric disorders », J Neurol Sci, vol. 321, no. 1-2, p. 58-64.
    Résumé : Portosystemic shunts (PSS) remain an unrecognized cause of neurological or psychiatric disorders. Here we report 5 patients with neuropsychiatric presentations of PSS. Main presentations encompassed progressive Parkinsonism, organic psychosis, recurrent coma, recurrent delusion, cognitive decline and posterior cortical atrophy. None of our patients had a known history of liver disease and laboratory analyses of liver function were normal or only slightly perturbed. Only 16 similar cases of PSS revealed by neurological or psychiatric symptoms were found in the English literature. Clinical presentations were similar to our patients but asterixis, cerebellar symptoms and spastic paraparesis were noticed in some cases. EEG could be normal or could show non specific slow waves or even, rarely, triphasic slow waves. The most frequent and specific diagnostic features included hyperammonemia, abnormal brain magnetic resonance spectroscopy and visualization of the shunts by ultrasonography or abdominal imaging techniques. Therefore, in otherwise unexplained neuropsychiatric disturbances, ammonia should be routinely measured and, if elevated, a dedicated gastroenterologist or an expert radiologist should be consulted for potential PSS examination. Treatment of the shunts or of the hyperammonemia resulted in marked neurological or psychiatric improvement in all cases.
    Mots-clés : Adult Aged Electroencephalography Female Humans Hyperammonemia Magnetic Resonance Spectroscopy Male Mental Disorders/diagnosis/ etiology Middle Aged Nervous System Diseases/diagnosis/ etiology Portasystemic Shunt, Surgical/ adverse effects Ultrasonography Young Adult.
  • Denost, Q, Pontallier, A, Rault, A, Ewald, JA, Collet, D, Masson, B & Sa-Cunha, A 2012, « Wirsungostomy as a salvage procedure after pancreaticoduodenectomy », HPB (Oxford), vol. 14, no. 2, p. 82-6.
    Résumé : BACKGROUND: Mortality rates associated with postoperative peritonitis or haemorrhage secondary to pancreatic fistula (PF) after pancreaticoduodenectomy (PD) remain high. This study analysed the results of an alternative management strategy for these life-threatening complications. METHODS: All patients undergoing PD between January 2004 and April 2011 were identified. Patients who underwent further laparotomy for failure of the pancreatico-digestive anastomosis were identified. Since 2004, this problem has been managed by dismantling the pancreatico-digestive anastomosis and cannulating the pancreatic duct remnant with a thin polyethylene tube (Escat tube), which is then passed through the abdominal wall. Main outcome measures were mortality, morbidity and longterm outcome. RESULTS: From January 2004 to April 2011, 244 patients underwent a PD. Postoperatively, 21 (8.6%) patients required re-laparotomy to facilitate a wirsungostomy. Two patients were transferred from another hospital with life-threatening PF after PD. Causes of re-laparotomy were haemorrhage (n= 12), peritonitis (n= 4), septic shock (n= 4) and mesenteric ischaemia (n= 1). Of the 21 patients who underwent wirsungostomy, six patients subsequently died of liver failure (n= 3), refractory septic shock (n= 2) or mesenteric ischaemia (n= 1) and nine patients suffered complications. The median length of hospital stay was 42 days (range: 34-60 days). The polyethylene tube at the pancreatic duct was removed at a median of 4 months (range: 2-11 months). Three patients developed diabetes mellitus during follow-up. CONCLUSIONS: These data suggest that preservation of the pancreatic remnant with wirsungostomy has a role in the management of patients with uncontrolled haemorrhage or peritonitis after PF.
    Mots-clés : adverse, Aged, Catheterization, Digestive, Ducts/, effects, effects/mortality, Factors, Female, Fistula/etiology/mortality/, Hemorrhage/etiology/mortality/, Humans, Length, Male, Middle, Neoplasms/pathology/, of, Outcome, Pancreatic, Pancreaticoduodenectomy/, Peritonitis/etiology/mortality/, Postoperative, Reoperation, Retrospective, Salvage, Stay, Studies, surgery, System, Therapy/adverse, Time, Treatment.
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  • Domart, M-C, Benyamina, A, Lemoine, A, Bourgain, C, Blecha, L, Debuire, B, Reynaud, M & Saffroy, R 2012, « Association between a polymorphism in the promoter of a glutamate receptor subunit gene (GRIN2A) and alcoholism », Addict Biol, vol. 17, no. 4, p. 783-5, viewed sans date, .
    Résumé : A variable (GT)(n) repeat in the 5'-regulatory region of N-methyl-D-aspartate GRIN2A subtype has recently been identified and associated with psychiatric disorders. In this study, we examined the association of this polymorphism with alcohol dependence. Subject-control analysis included 206 alcohol-dependent and 168 control subjects. Average observed repeat numbers and genotype distributions were significantly different (P-value = 0.001) in alcohol-dependent subjects versus control subjects. Short alleles were significantly less frequent among alcohol-dependent subjects (odds ratio = 0.58, P-value = 7 × 10(-4)). These results could be replicated in an independent sample of 116 alcohol-dependent subjects. For the first time, a significant association was identified between this polymorphism and alcoholism.
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  • Dornier, E, Coumailleau, F, Ottavi, J-F, Moretti, J, Boucheix, C, Mauduit, P, Schweisguth, F & Rubinstein, E 2012, « TspanC8 tetraspanins regulate ADAM10/Kuzbanian trafficking and promote Notch activation in flies and mammals », J Cell Biol, vol. 199, no. 3, p. 481-96, viewed sans date, .
    Résumé : The metalloprotease ADAM10/Kuzbanian catalyzes the ligand-dependent ectodomain shedding of Notch receptors and activates Notch. Here, we show that the human tetraspanins of the evolutionary conserved TspanC8 subfamily (Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33) directly interact with ADAM10, regulate its exit from the endoplasmic reticulum, and that four of them regulate ADAM10 surface expression levels. In an independent RNAi screen in Drosophila, two TspanC8 genes were identified as Notch regulators. Functional analysis of the three Drosophila TspanC8 genes (Tsp3A, Tsp86D, and Tsp26D) indicated that these genes act redundantly to promote Notch signaling. During oogenesis, TspanC8 genes were up-regulated in border cells and regulated Kuzbanian distribution, Notch activity, and cell migration. Furthermore, the human TspanC8 tetraspanins Tspan5 and Tspan14 positively regulated ligand-induced ADAM10-dependent Notch1 signaling. We conclude that TspanC8 tetraspanins have a conserved function in the regulation of ADAM10 trafficking and activity, thereby positively regulating Notch receptor activation.
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  • Dosset, M, Godet, Y, Vauchy, C, Beziaud, L, Lone, YC, Sedlik, C, Liard, C, Levionnois, E, Clerc, B, Sandoval, F, Daguindau, E, Wain-Hobson, S, Tartour, E, Langlade-Demoyen, P, Borg, C & Adotevi, O 2012, « Universal cancer peptide-based therapeutic vaccine breaks tolerance against telomerase and eradicates established tumor », Clin Cancer Res, vol. 18, no. 22, p. 6284-95, viewed sans date, .
    Résumé : PURPOSE: To evaluate CD4(+) helper functions and antitumor effect of promiscuous universal cancer peptides (UCP) derived from telomerase reverse transcriptase (TERT). EXPERIMENTAL DESIGN: To evaluate the widespread immunogenicity of UCPs in humans, spontaneous T-cell responses against UCPs were measured in various types of cancers using T-cell proliferation and ELISPOT assays. The humanized HLA-DRB1*0101/HLA-A*0201 transgenic mice were used to study the CD4(+) helper effects of UCPs on antitumor CTL responses. UCP-based antitumor therapeutic vaccine was evaluated using HLA-A*0201-positive B16 melanoma that express TERT. RESULTS: The presence of a high number of UCP-specific CD4(+) T cells was found in the blood of patients with various types of cancer. These UCP-specific T cells mainly produce IFN-gamma and TNF-alpha. In HLA transgenic mice, UCP vaccinations induced high avidity CD4(+) T(H)1 cells and activated dendritic cells that produced interleukin-12. UCP-based vaccination breaks self-tolerance against TERT and enhances primary and memory CTL responses. Furthermore, the use of UCP strongly improves the efficacy of therapeutic vaccination against established B16-HLA-A*0201 melanoma and promotes tumor infiltration by TERT-specific CD8(+) T cells. CONCLUSIONS: Our results showed that UCP-based vaccinations strongly stimulate antitumor immune responses and could be used to design efficient immunotherapies in multiple types of cancers.
    Mots-clés : Animals CD4-Positive T-Lymphocytes/immunology/physiology CD8-Positive T-Lymphocytes/immunology/physiology Cancer Vaccines/*immunology Cell Line, Cytotoxic/immunology/physiology Telomerase/*immunology Th1 Cells/immunology/physiology Xenograft Model Antitumor Assays, Experimental/immunology/*therapy Mice Mice, Immunologic Dendritic Cells/immunology Humans Melanoma, Transgenic Peptide Fragments/*immunology T-Lymphocytes/*immunology T-Lymphocytes, Tumor Cell Proliferation Cytotoxicity.

  • Durand, F, Gines, P, Saliba, F & Fernandez, J 2012, « Reply to: "Encephalopathy or hepatic encephalopathy?": Management of critically-ill cirrhotic patients », J Hepatol, vol. 57, no. 4, p. 929-930, viewed sans date, .

  • Duvoux, C, Roudot-Thoraval, F, Decaens, T, Pessione, F, Badran, H, Piardi, T, Francoz, C, Compagnon, P, Vanlemmens, C, Dumortier, J, Dharancy, S, Gugenheim, J, Bernard, PH, Adam, R, Radenne, S, Muscari, F, Conti, F, Hardwigsen, J, Pageaux, GP, Chazouilleres, O, Salame, E, Hilleret, MN, Lebray, P, Abergel, A, Debette-Gratien, M, Kluger, MD, Mallat, A, Azoulay, D & Cherqui, D 2012, « Liver transplantation for hepatocellular carcinoma: a model including alpha-fetoprotein improves the performance of Milan criteria », Gastroenterology, vol. 143, no. 4, p. 986-94 e3; quiz e14-5, viewed sans date, .
    Résumé : BACKGROUND & AIMS: The aim of this study was to generate an improved prognostic model for predicting recurrence in liver transplant candidates with hepatocellular carcinoma (HCC). METHODS: Predictors of recurrence were tested by a Cox model analysis in a training cohort of 537 patients transplanted for HCC. A prognostic score was developed and validated in a national cohort of 435 patients followed up prospectively. RESULTS: alpha-Fetoprotein (AFP) independently predicted tumor recurrence and correlated with vascular invasion and differentiation. At a Cox score threshold of 0.7 (area under the receiver operating characteristic curve, 0.701; 95% confidence interval, 0.63-0.76; accuracy, 75.8%), a model combining log(10) AFP, tumor size, and number was highly predictive of tumor recurrence and death. By using a simplified version of the model, with untransformed AFP values, a cut-off value of 2 was identified. In the validation cohort, a score greater than 2 predicted a marked increase in 5-year risk of recurrence (50.6% +/- 10.2% vs 8.8% +/- 1.7%; P < .001) and decreased survival (47.5% +/- 8.1% vs 67.8% +/- 3.4%; P = .002) as compared with others. Among patients exceeding Milan criteria, a score of 2 or lower identified a subgroup of patients with AFP levels less than 100 ng/mL with a low 5-year risk of recurrence (14.4% +/- 5.3% vs 47.6% +/- 11.1%; P = .006). Among patients within Milan criteria, a score greater than 2 identified a subgroup of patients with AFP levels greater than 1000 ng/mL at high risk of recurrence (37.1% +/- 8.9% vs 13.3% +/- 2.0%; P < .001). Net reclassification improvement showed that predictability of the AFP model was superior to Milan criteria. CONCLUSIONS: Prediction of tumor recurrence is improved significantly by a model that incorporates AFP. We propose the adoption of new selection criteria for HCC transplant candidates, taking into account AFP.


  • Duvoux, C, Roudot-Thoraval, F, Decaens, T, Pessione, F, Badran, H, Piardi, T, Francoz, C, Compagnon, P, Vanlemmens, C, Dumortier, J, Dharancy, S, Gugenheim, J, Bernard, P-H, Adam, R, Radenne, S, Muscari, F, Conti, F, Hardwigsen, J, Pageaux, G-P, Chazouillères, O, Salame, E, Hilleret, M-N, Lebray, P, Abergel, A, Debette-Gratien, M, Kluger, MD, Mallat, A, Azoulay, D, Cherqui, D & Group, LTFS 2012, « Liver transplantation for hepatocellular carcinoma: a model including α-fetoprotein improves the performance of Milan criteria », Gastroenterology, vol. 143, no. 4, p. 986-94.e3; quiz e14-5, viewed sans date, .
    Résumé : BACKGROUND & AIMS: The aim of this study was to generate an improved prognostic model for predicting recurrence in liver transplant candidates with hepatocellular carcinoma (HCC). METHODS: Predictors of recurrence were tested by a Cox model analysis in a training cohort of 537 patients transplanted for HCC. A prognostic score was developed and validated in a national cohort of 435 patients followed up prospectively. RESULTS: α-Fetoprotein (AFP) independently predicted tumor recurrence and correlated with vascular invasion and differentiation. At a Cox score threshold of 0.7 (area under the receiver operating characteristic curve, 0.701; 95% confidence interval, 0.63-0.76; accuracy, 75.8%), a model combining log(10) AFP, tumor size, and number was highly predictive of tumor recurrence and death. By using a simplified version of the model, with untransformed AFP values, a cut-off value of 2 was identified. In the validation cohort, a score greater than 2 predicted a marked increase in 5-year risk of recurrence (50.6% ± 10.2% vs 8.8% ± 1.7%; P < .001) and decreased survival (47.5% ± 8.1% vs 67.8% ± 3.4%; P = .002) as compared with others. Among patients exceeding Milan criteria, a score of 2 or lower identified a subgroup of patients with AFP levels less than 100 ng/mL with a low 5-year risk of recurrence (14.4% ± 5.3% vs 47.6% ± 11.1%; P = .006). Among patients within Milan criteria, a score greater than 2 identified a subgroup of patients with AFP levels greater than 1000 ng/mL at high risk of recurrence (37.1% ± 8.9% vs 13.3% ± 2.0%; P < .001). Net reclassification improvement showed that predictability of the AFP model was superior to Milan criteria. CONCLUSIONS: Prediction of tumor recurrence is improved significantly by a model that incorporates AFP. We propose the adoption of new selection criteria for HCC transplant candidates, taking into account AFP.

  • Dwyer, J, Hebda, JK, Le Guelte, A, Galan-Moya, EM, Smith, SS, Azzi, S, Bidere, N & Gavard, J 2012, « Glioblastoma cell-secreted interleukin-8 induces brain endothelial cell permeability via CXCR2 », PLoS One, vol. 7, no. 9, p. e45562, viewed sans date, .
    Résumé : Glioblastoma constitutes the most aggressive and deadly of brain tumors. As yet, both conventional and molecular-based therapies have met with limited success in treatment of this cancer. Among other explanations, the heterogeneity of glioblastoma and the associated microenvironment contribute to its development, as well as resistance and recurrence in response to treatments. Increased vascularity suggests that tumor angiogenesis plays an important role in glioblastoma progression. However, the molecular crosstalk between endothelial and glioblastoma cells requires further investigation. To examine the effects of glioblastoma-derived signals on endothelial homeostasis, glioblastoma cell secretions were collected and used to treat brain endothelial cells. Here, we present evidence that the glioblastoma secretome provides pro-angiogenic signals sufficient to disrupt VE-cadherin-mediated cell-cell junctions and promote endothelial permeability in brain microvascular endothelial cells. An unbiased angiogenesis-specific antibody array screen identified the chemokine, interleukin-8, which was further demonstrated to function as a key factor involved in glioblastoma-induced permeability, mediated through its receptor CXCR2 on brain endothelia. This underappreciated interface between glioblastoma cells and associated endothelium may inspire the development of novel therapeutic strategies to induce tumor regression by preventing vascular permeability and inhibiting angiogenesis.
    Mots-clés : Brain Neoplasms/genetics/*metabolism *Capillary Permeability/drug effects Cell Line, Conditioned/pharmacology Endothelial Cells/drug effects/*metabolism Gene Expression Regulation, Interleukin-8B/genetics/*metabolism, Neoplastic Glioblastoma/genetics/*metabolism Humans Interleukin-8/pharmacology/*secretion Receptors, Tumor Culture Media.
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  • Faitot, F, Vibert, E, Salloum, C, Gorden, DL, Coscas, F, Adam, R & Castaing, D 2012, « Importance of conserving middle hepatic vein distal branches for homogeneous regeneration of the left liver after right hepatectomy », HPB (Oxford), vol. 14, no. 11, p. 746-53, viewed sans date, .
    Résumé : BACKGROUND: Liver regeneration enables repeat surgical procedures to achieve a potential cure in liver cancer patients. However, data regarding segmental regeneration and liver anatomy after liver resection are scarce. This study examined left liver regeneration after right hepatectomy and the impact of hepatic venous drainage on the regeneration of the paramedian sector (Couinaud's segment IV). METHODS: Twenty patients in whom right hepatectomy with conservation of the middle hepatic vein (MHV) on healthy liver had been performed were analysed for segmental volumes and vascular anatomy. Volumetric analysis of left liver segments and three-dimensional MHV reconstruction were conducted using pre- and postoperative computed tomography. The volumetric proportions represented by each segment within the left liver were compared and MHV anatomy was analysed to determine its potential role in the regeneration of left liver segments. RESULTS: After right hepatectomy, the proportion represented by segment IV within the left liver decreases by 13%, whereas the proportion represented by segments II and III increases by 15%. This heterogeneous regeneration is particularly observed in patients in whom a venous branch for segment IVb is sacrificed, leading to an altered outflow similar to that observed in MHV deprivation. The risk for venous branch deprivation in IVb is correlated to the depth of the bifurcation of the MHV in liver parenchyma. CONCLUSIONS: It is crucial to conserve the MHV in its distal part if homogeneous left liver regeneration after right hepatectomy that will allow potential repeat liver resection is to be achieved.
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  • Fallot, G, Halgand, B, Garnier, E, Branger, M, Gervais, A, Roque-Afonso, AM, Thiers, V, Billaud, E, Matheron, S, Samuel, D & Feray, C 2012, « Recombination of hepatitis B virus DNA in patients with HIV », Gut, vol. 61, no. 8, p. 1197-208.
    Résumé : INTRODUCTION: Hepatitis B is a major cause of death in patients with HIV who usually receive drugs active against hepatitis B virus (HBV). The variability of HBV DNA over time has been little studied. Recombination between different HBV genotypes has been described in many cross-sectional studies, but the frequency of intergenotypic and intragenotypic recombinations in individual patients is unknown. METHODS: 32 HIV-positive and 11 HIV-negative patients who remained HBV viraemic despite antiviral therapy for at least 1 year were studied. Genotyping was based on line probe assays and genotype-specific PCR. The variability of HBV DNA over time was examined with restriction length and single-strand conformational polymorphism (RFLP-SSCP). HBV DNA sequences obtained by cloning a 2800 bp PCR fragment were analysed for phylogenetic parameters (diversity and selection pressure) and recombination was detected with RDP3 software. RESULTS: Large fragments of HBV DNA could be amplified at two different time points in 33 patients. Marked quasi-species modifications occurred in 14 patients. In seven of these patients and in one patient with no change detectable by RFLP-SSCP, the 2800 bp fragment was cloned at two time points at least. In four (57%) of these seven patients, various intergenotypic or intragenotypic recombination events were detected between subvariants present in the initial quasi-species. Recombinant fragments mostly harboured antiviral resistance determinants and reflected a large increase in diversity and in positive selection pressure on the entire HBV quasi-species. CONCLUSIONS: In coinfected patients, HBV DNA recombination events are frequent during antiviral therapy, corresponding to increased positive selection pressure on the HBV quasi-species and to conservation of antiviral resistance mutations. In this population and at the individual level, recombination is a significant source of HBV genetic variability.
    Mots-clés : Adult Cross-Sectional Studies DNA, Genetic Young Adult.

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