Biblio

Francoz, C, Belghiti, J, Castaing, D, Chazouilleres, O, Duclos-Vallee, JC, Duvoux, C, Lerut, J, Le Treut, YP, Moreau, R, Mandot, A, Pageaux, G, Samuel, D, Thabut, D, Valla, D & Durand, F 2011, « Model for end-stage liver disease exceptions in the context of the French model for end-stage liver disease score-based liver allocation system », Liver Transpl, vol. 17, no. 10, p. 1137-51.

Résumé : Model for End-Stage Liver Disease (MELD) score-based allocation systems have been adopted by most countries in Europe and North America. Indeed, the MELD score is a robust marker of early mortality for patients with cirrhosis. Except for extreme values, high pretransplant MELD scores do not significantly affect posttransplant survival. The MELD score can be used to optimize the allocation of allografts according to a sickest first policy. Most often, patients with small hepatocellular carcinomas (HCCs) and low MELD scores receive extra points, which allow them appropriate access to transplantation comparable to the access of patients with advanced cirrhosis and high MELD scores. In addition to patients with advanced cirrhosis and HCC, patients with a number of relatively uncommon conditions have low MELD scores and a poor prognosis in the short term without transplantation but derive excellent benefits from transplantation. These conditions, which correspond to the so-called MELD score exceptions, justify the allocation of a specific score for appropriate access to transplantation. Here we report the conclusions of the French consensus meeting. The goals of this meeting were (1) to identify which conditions merit MELD score exceptions, (2) to list the criteria needed for defining each of these conditions, and (3) to define a reasonable time interval for organ allocation for each MELD exception in the general context of organ shortages. MELD exceptions were discussed in an attempt to reconcile the concepts of transparency, equity, justice, and utility.

Mots-clés : &, and, as, Assessment, Conferences, Consensus, Decision, Development, diagnosis/mortality/, Disease/, Distribution, Donors/, effects/mortality, End, Factors, France, Health, Humans, Indicators, Lists, Liver, Organ, Outcome, Patient, Procurement, Risk, Selection, Stage, Status, supply, Support, surgery, Techniques, Time, Tissue, Topic, Transplantation/adverse, Treatment, Waiting.

Galan-Moya, EM, Le Guelte, A, Lima Fernandes, E, Thirant, C, Dwyer, J, Bidere, N, Couraud, PO, Scott, MG, Junier, MP, Chneiweiss, H & Gavard, J 2011, « Secreted factors from brain endothelial cells maintain glioblastoma stem-like cell expansion through the mTOR pathway », EMBO Rep, vol. 12, no. 5, p. 470-6, viewed sans date, .

Résumé : Glioma stem-cells are associated with the brain vasculature. However, the way in which this vascular niche regulates stem-cell renewal and fate remains unclear. Here, we show that factors emanating from brain endothelial cells positively control the expansion of long-term glioblastoma stem-like cells. We find that both pharmacological inhibition of and RNA interference with the mammalian target of rapamycin (mTOR) pathway reduce their spheroid growth. Conversely, the endothelial secretome is sufficient to promote this mTOR-dependent survival. Thus, interfering with endothelial signals might present opportunities to identify treatments that selectively target malignant stem-cell niches.

Mots-clés : Blotting, Fluorescence Pyridines/pharmacology Pyrimidines/pharmacology RNA Interference RNA, Small Interfering/genetics Signal Transduction/*physiology Sirolimus/pharmacology Stem Cells/physiology/*secretion TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/*metabolism Transfection, Western Brain/blood supply/*cytology Endothelial Cells/*secretion Flow Cytometry Furans/pharmacology Glioblastoma/*physiopathology Humans Microscopy.

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Gallot, C, Grout, L, Roque-Afonso, AM, Couturier, E, Carrillo-Santisteve, P, Pouey, J, Letort, MJ, Hoppe, S, Capdepon, P, Saint-Martin, S, De Valk, H & Vaillant, V 2011, « Hepatitis A associated with semidried tomatoes, France, 2010 », Emerg Infect Dis, vol. 17, no. 3, p. 566-7.

Résumé : Gallot, Celine; Grout, Lise; Roque-Afonso, Anne Marie; Couturier, Elisabeth; Carrillo-Santisteve, Paloma; Pouey, Jerome; Letort, Marie Jose; Hoppe, Stephanie; Capdepon, Pascal; Saint-Martin, Sylvie; De Valk, Henriette; Vaillant, Veronique; Letter; United States; Emerg Infect Dis. 2011 Mar;17(3):566-7. doi: 10.3201/eid1703.101479.

Mots-clés : A, A/, Adolescent, Adult, Aged, Case-Control, Child, disease, Diseases/epidemiology/virology, epidemiology/transmission/virology, esculentum/, Female, Foodborne, France, genetics, Hepatitis, Humans, Lycopersicon, Male, Middle, Outbreaks, Studies, virology, virus/classification/, Young.

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Gane, EJ, Wang, Y, Liaw, YF, Hou, J, Thongsawat, S, Wan, M, Moon, YM, Jia, J, Chao, YC, Niu, J, Leung, N, Samuel, D, Hsu, CW, Bao, W, Lopez, P & Avila, C 2011, « Efficacy and safety of prolonged 3-year telbivudine treatment in patients with chronic hepatitis B », Liver Int, vol. 31, no. 5, p. 676-84.

Résumé : BACKGROUND: In the GLOBE trial, telbivudine demonstrated superior efficacy to lamivudine at 2 years in patients with chronic hepatitis B (CHB). Aims: To investigate the long-term efficacy and safety of telbivudine in the telbivudine-treated cohort from the GLOBE trial. METHODS: Virological and biochemical responses were assessed in 213 HBeAg-positive and 186 HBeAg-negative CHB patients who continued telbivudine treatment for 3 years. RESULTS: Undetectable hepatitis B virus DNA and HBeAg seroconversions were achieved by 77 and 37% of HBeAg-positive patients respectively. Cumulative HBeAg seroconversion rate was 46%. HBeAg seroconversion was sustained at 52 weeks off therapy in 84% of the patients enrolled in the off-treatment follow-up arm of the study. Undetectable viraemia and normal alanine aminotransferase (ALT) levels at 3 years were achieved by 85 and 83% of HBeAg-negative patients respectively. Genotypic resistance rates for the study population who continued therapy during the third year were 11.3 in HBeAg-positive and 6.5% in HBeAg-negative patients. Patients with undetectable viraemia at treatment week 24 had optimal outcomes at 3 years. In the HBeAg-positive population, cumulative HBeAg seroconversion occurred in 58%. Resistance rates for HBeAg-positive and HBeAg-negative patients were 3.6 and 6.2% respectively. The telbivudine safety profile during prolonged therapy was similar to that in the GLOBE trial. CONCLUSIONS: Three years of telbivudine treatment yielded high rates of viral suppression and ALT normalization with a favourable safety profile. High rates of HBeAg seroconversion were achieved with prolonged telbivudine therapy and were sustained in the majority of patients over 52 weeks off therapy.

Mots-clés : Adolescent Adult Aged Alanine Transaminase/blood Antiviral Agents/ administration & dosage/adverse effects Biological Markers/blood DNA, Chronic/diagnosis/ drug therapy Humans Male Middle Aged Nucleosides/ administration & dosage/adverse effects Pyrimidinones/ administration & dosage/adverse effects Time Factors Treatment Outcome Viral Load Young Adult, Viral/blood Drug Administration Schedule Drug Resistance, Viral/genetics Female Hepatitis B Surface Antigens/blood Hepatitis B e Antigens/blood Hepatitis B virus/immunology Hepatitis B.

Ghillani, P, Andre, C, Toly, C, Rouquette, AM, Bengoufa, D, Nicaise, P, Goulvestre, C, Gleizes, A, Dragon-Durey, MA, Alyanakian, MA, Chretien, P, Chollet-Martin, S, Musset, L, Weill, B & Johanet, C 2011, « Clinical significance of anti-Ro52 (TRIM21) antibodies non-associated with anti-SSA 60kDa antibodies: results of a multicentric study », Autoimmun Rev, vol. 10, no. 9, p. 509-13.

Résumé : Ro52 antigen has recently been identified as TRIM21 protein, but the clinical significance of anti-Ro52/TRIM21 antibodies remains controversial. The aim of this multicentric study was to investigate the significance of anti-Ro52 antibodies without anti-SSA/Ro60 antibodies in various connective diseases. Sera were selected by each laboratory using its own method (ELISA, immunodot or Luminex technology), and then performed with ANA Screen BioPlex reagent (BIO-RAD). Among the 247 screened sera, 155/247 (63%) were confirmed as anti-Ro52 positive and anti-SSA/Ro60 negative. These sera were analyzed for the detection of other antibodies in relation with clinical settings. Isolated anti-Ro52 antibodies were detected in 89/155 (57%) sera. For the remaining sera (66/155), the main antibodies associations were Sm/SmRNP or Chromatin (n=38; 57%), Jo1 (n=17; 26%) and CenpB (n=9; 14%). Clinical data from the 155 patients showed high prevalence in autoimmune diseases (73%) including myositis or dermatomyositis (n=30), lupus (n=23); Sjogren and/or sicca syndrome (n=27); CREST or Systemic sclerosis (n=11) and autoimmune hepatitis (n=11). We found that pulmonary manifestations were often associated with the presence of anti-Ro52 antibodies (n=34, 22%), in addition with anti-tRNA synthetases, anti-SRP or anti-Ku antibodies (18/34) or isolated in half of cases (16/34). Separate detection of anti-Ro52 antibodies might be useful in related antisynthetase syndrome diagnosis. The presence of anti-Ro52 antibodies should probably precede development of autoimmune disease and must induce sequential follow-up of positive patients, particularly in interstitial lung disease progression.

Mots-clés : 80 and over Antibodies/ blood/immunology Autoantibodies/blood/immunology Autoimmune Diseases/ blood/immunology Female Humans Lung Diseases/ blood/immunology Male Middle Aged Ribonucleoproteins/immunology Young Adult, Adolescent Adult Aged Aged.

Giron-Michel, J, Azzi, S, Khawam, K, Caignard, A, Devocelle, A, Perrier, A, Chouaib, S, Eid, P & Azzarone, B 2011, « Interleukin-15 is a major regulator of the cell-microenvironment interactions in human renal cancer », Bull Cancer, vol. 98, no. 5, p. 32-9, viewed sans date, .

Résumé : Primary human epithelial renal cells of normal (HRE), paratumoral (pTEC) and tumoral (RCC) origin display important differences, concerning the expression and biological effects of the IL-15/IL-15R system that deeply influences the evolution of the tumour microenvironment. A major distinguishing feature is represented in RCC and pTEC by the loss of the gammac chain leading to the assembly of a IL-15Ralphabeta heterodimer that in response to physiologic concentrations of IL-15 initiates the process of their epithelial-mesenchymal transition (EMT). In contrast, this treatment in HRE cells, which display the IL-15Ralphabetagammac heterotrimer, causes opposite effects inhibiting their drift towards EMT. Thus, IL-15 at physiologic concentrations displays novel functions acting as a major regulator of renal epithelial homeostasis. As second distinguishing feature, RCC and pTEC but not HRE cells express a trans-membrane-bound IL-15 (tmb-IL-15) able to deliver a reverse signal in response to the soluble IL-15Ralpha chain inducing their EMT. In conclusion, comparison of primary normal (HRE) to primary pathological cells (pTEC and RCC) highlights two major issues: (1) IL-15 is a major regulator of epithelial homeostasis; (2) "apparently normal" pTEC cells, could contribute to organize a generalized "pre-neoplastic" environment committed to favour tumour progression.

Mots-clés : Cadherins/metabolism Carcinoma.

Giuliani, M, Fleury, M, Vernochet, A, Ketroussi, F, Clay, D, Azzarone, B, Lataillade, JJ & Durrbach, A 2011, « Long-lasting inhibitory effects of fetal liver mesenchymal stem cells on T-lymphocyte proliferation », PLoS One, vol. 6, no. 5, p. e19988, viewed sans date, .

Résumé : Human bone marrow mesenchymal stem cells (BM-MSC) are multipotent progenitor cells that have transient immunomodulatory properties on Natural Killer (NK) cells, Dendritic Cells (DC), and T cells. This study compared the use of MSC isolated from bone marrow and fetal liver (FL-MSC) to determine which displayed the most efficient immunosuppressive effects on T cell activation. Although both types of MSC exhibit similar phenotype profile, FL-MSC displays a much more extended in vitro life-span and immunomodulatory properties. When co-cultured with CD3/CD28-stimulated T cells, both BM-MSC and FL-MSC affected T cell proliferation by inhibiting their entry into the cell cycle, by inducing the down-regulation of phospho-retinoblastoma (pRb), cyclins A and D1, as well as up-regulating p27(kip1) expression. The T cell inhibition by MSC was not due to the soluble HLA-G5 isoform, but to the surface expression of HLA-G1, as shown by the need of cell-cell contact and by the use of neutralizing anti-HLA-G antibodies. To note, in a HLA-G-mediated fashion, MSC facilitated the expansion of a CD4(low)/CD8(low) T subset that had decreased secretion of IFN-γ, and an induced secretion of the immunomodulatory cytokine IL-10. Because of their longer lasting in vitro immunosuppressive properties, mainly mediated by HLA-G, and their more efficient induction of IL-10 production and T cell apoptosis, fetal liver MSC could be considered a new tool for MSC therapy to prevent allograft rejection.

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Giuliani, M, Oudrhiri, N, Noman, ZM, Vernochet, A, Chouaib, S, Azzarone, B, Durrbach, A & Bennaceur-Griscelli, A 2011, « Human mesenchymal stem cells derived from induced pluripotent stem cells down-regulate NK-cell cytolytic machinery », Blood, vol. 118, no. 12, p. 3254-62, viewed sans date, .

Résumé : A major issue in immunosuppressive biotherapy is the use of mesenchymal stem cells (MSCs) that harbor regulatory capacity. However, currently used bone marrow-derived MSCs (BM-MSCs) are short-lived and cannot assure long lasting immunoregulatory function both in vitro and in vivo. Consequently, we have generated MSCs from human induced pluripotent stem (IPS-MSCs) cells that share similar properties with embryonic stem cells (ES-MSCs). Herein, we compared the immunoregulatory properties of ES/IPS-MSCs with those of BM-MSCs and showed, for the first time, that IPS-derived MSCs display remarkable inhibition of NK-cell proliferation and cytolytic function in a similar way to ES-MSCs. Both MSCs disrupt NK-cell cytolytic machinery in the same fashion that BM-MSCs, by down-regulating the expression of different activation markers and ERK1/2 signaling, leading to an impairment to form immunologic synapses with target cells and, therefore, secretion of cytotoxic granules. In addition, they are more resistant than adult BM-MSCs to preactivated NK cells. IPS-MSCs could represent an attractive alternative source of immunoregulatory cells, and their capacity to impair NK-cell cytotoxicity constitutes a complex mechanism to prevent allograft rejection.

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Grimbert, P, Audard, V, Diet, C, Matignon, M, Plonquet, A, Mansour, H, Desvaux, D, Durrbach, A, Cohen, JL & Lang, P 2011, « T-cell phenotype in protocol renal biopsy from transplant recipients treated with belatacept-mediated co-stimulatory blockade », Nephrol Dial Transplant, vol. 26, no. 3, p. 1087-93, viewed sans date, .

Résumé : BACKGROUND: Belatacept is thought to disrupt the interaction between CD80/86 and CD28, thus preventing T-cell activation by blocking the co-stimulatory second signal. However, the consequences on the T-cell profile in human renal transplant cases have not been determined. METHODS: In this study, we analysed intra-graft levels of the mRNAs for Treg (FOXP3), cytotoxic CD8 T cells (Granzyme B), Th1 (INFgamma, Tbet), Th2 (GATA3) and Th17 (RORgammat and IL-17) in protocol biopsies obtained 12 months after renal transplantation in recipients treated with Belatacept or calcineurin inhibitor (CNI). RESULTS: Only the intra-graft abundance of FOXP3 mRNA was significantly lower (P < 0.001) in the Belatacept group than the CNI group. Conclusions. These results are in agreement with in vitro data suggesting that CD28 is a major co-stimulatory signal of both Tregs development and peripheral homeostasis but contrast with clinical trials showing a better 1-year graft function and a lower incidence of chronic allograft nephropathy in patients receiving Belatacept than patients treated with CNI. They suggest that immune benefits induced by Belatacept are not mediated by Treg expansion and that FOXP3 is not by itself a prognostic marker of long-term graft function in a non-inflammatory context. These results have to be, however, considered as preliminary since the size of our study population is limited.

Mots-clés : Antigens, CD28/immunology Antigens, CD80/immunology Antigens, CD86/immunology Biopsy Clinical Trials, Messenger/genetics Reverse Transcriptase Polymerase Chain Reaction Risk Factors Survival Rate T-Lymphocytes, Phase II as Topic Clinical Trials, Regulatory/*drug effects/immunology Th1 Cells/immunology Th2 Cells/immunology Transplantation Tolerance/*drug effects/immunology.

Groheux, D, Giacchetti, S, Espié, M, Rubello, D, Moretti, J-luc & Hindié, E 2011, « Early monitoring of response to neoadjuvant chemotherapy in breast cancer with 18F-FDG PET/CT: defining a clinical aim », Eur J Nucl Med Mol Imaging, vol. 38, no. 3, p. 419-25, viewed sans date, .

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Groheux, D, Giacchetti, S, Espié, M, Vercellino, L, Hamy, A-S, Delord, M, Berenger, N, Toubert, M-E, Misset, J-L & Hindié, E 2011, « The yield of 18F-FDG PET/CT in patients with clinical stage IIA, IIB, or IIIA breast cancer: a prospective study », J Nucl Med, vol. 52, no. 10, p. 1526-34, viewed sans date, .

Résumé : UNLABELLED: The purpose of this study was to prospectively evaluate the role of (18)F-FDG PET/CT in patients with stage IIA, IIB, or IIIA breast cancer. METHODS: During 56 mo, 131 consecutive patients with large (>2 cm) breast cancer and clinical stage IIA, IIB, or IIIA (based on clinical examination, mammography, breast MRI, and ultrasonography) underwent (18)F-FDG PET/CT. The nuclear physician was unaware of the results of any other procedure (bone scan, chest radiography, liver ultrasound, or thoracoabdominal CT scan). RESULTS: Of the 131 examined patients, 36 had clinical stage IIA (34 T2N0 and 2 T1N1), 48 stage IIB (20 T3N0 and 28 T2N1), and 47 stage IIIA (29 T3N1, 9 T2N2, and 9 T3N2). (18)F-FDG PET/CT modified staging for 5.6% of stage IIA patients, for 14.6% of stage IIB patients, and for 27.6% of stage IIIA patients. However, within stage IIIA, the yield was specifically high among the 18 patients with N2 disease (56% stage modification). When considering stage IIB and primary operable IIIA (T3N1) together, the yield of (18)F-FDG PET/CT was 13% (10/77); extraaxillary regional lymph nodes were detected in 5 and distant metastases in 7 patients. In this series, (18)F-FDG PET/CT outperformed bone scanning, with only 1 misclassification versus 8 for bone scanning (P = 0.036). CONCLUSION: (18)F-FDG PET/CT provided useful information in 13% of patients with clinical T3N0, T2N1, or T3N1 disease. The yield was more modest in patients with stage IIA. The high yield in the case of N2 disease demonstrates that stage IIIA comprises 2 quite distinct groups of patients.

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Groheux, D, Giacchetti, S, Moretti, J-L, Porcher, R, Espié, M, Lehmann-Che, J, de Roquancourt, A, Hamy, A-S, Cuvier, C, Vercellino, L & Hindié, E 2011, « Correlation of high 18F-FDG uptake to clinical, pathological and biological prognostic factors in breast cancer », Eur J Nucl Med Mol Imaging, vol. 38, no. 3, p. 426-35, viewed sans date, .

Résumé : PURPOSE: The aim of this study was to determine the impact of the main clinicopathological and biological prognostic factors of breast cancer on (18)F-fluorodeoxyglucose (FDG) uptake. Only women with tumours larger than 20 mm (T2-T4) were included in order to minimize bias of partial volume effect. METHODS: In this prospective study, 132 consecutive women received FDG PET/CT imaging before starting neoadjuvant chemotherapy. Maximum standardized uptake values (SUV(max)) were compared to tumour characteristics as assessed on core biopsy. RESULTS: There was no influence of T and N stage on SUV. Invasive ductal carcinoma showed higher SUV than lobular carcinoma. However, the highest uptake was found for metaplastic tumours, representing 5% of patients in this series. Several biological features usually considered as bad prognostic factors were associated with an increase in FDG uptake: the median of SUV(max) was 9.7 for grade 3 tumours vs 4.8 for the lower grades (p < 0.0001); negativity for oestrogen receptors (ER) was associated with higher SUV (ER+ SUV = 5.5; ER- SUV = 7.6; p = 0.003); triple-negative tumours (oestrogen and progesterone receptor negative, no overexpression of c-erbB-2) had an SUV of 9.2 vs 5.8 for all others (p = 0005); p53 mutated tumours also had significantly higher SUV (7.8 vs 5.0; p < 0.0001). Overexpression of c-erbB-2 had no effect on the SUV value. CONCLUSION: Knowledge of the factors influencing uptake is important when interpreting FDG PET/CT scans. Also, findings that FDG uptake is highest in those patients with poor prognostic features (high grade, hormone receptor negativity, triple negativity, metaplastic tumours) is helpful to determine who are the best candidates for baseline staging.

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Grynberg, M, Chevalier, N, Mesner, A, Rocher, L, Prisant, N, Madoux, S, Feyereisen, E, Ferlicot, S, Fanchin, R, Frydman, R, Frydman, N & Izard, V 2011, « [Non-obstructive azoospermia: option of the testicular sperm extraction performed on the day of oocyte retrieval] », J Gynecol Obstet Biol Reprod (Paris), vol. 40, no. 2, p. 130-6, viewed sans date, .

Résumé : OBJECTIVE: Analyzing the results and validating the procedure of testicular sperm extraction (TESE) performed on the day of oocyte retrieval in non obstructive azoospermia (NOA) patients. PATIENTS AND METHODS: Sixty TESE were performed on the day of oocyte retrieval (dOR), in 52 NOA men. Patients were sorted into three groups according to the results of the surgical procedure: 1: sperm recovery with possible sperm freezing (n=20); 2: sperm recovery without freezing (n=27); 3: "negative" biopsy (n=13). ICSI outcomes in the two groups with sperm recovery were compared to those of ICSI performed with frozen-thawed sperm obtained from TESE performed (n=13). RESULTS: The rate of positive sperm retrieval was 78%. While the overall clinical pregnancy rate was 50%, no difference in the fertilization, implantation and clinical pregnancy rates was found in the two groups with positive sperm retrieval as compared to frozen-thawed sperm group. Twelve pregnancies were obtained in patients without further sperm cryopreservation. CONCLUSION: After TESE in NOA men, cryopreserved sperm produced comparable results with freshly obtained sperm. However, TESE performed on dOR can offer the opportunity, in patients with rare sperm that might not survive freeze-thaw, to have a possible fresh embryo transfer. Couples should be counselled regarding the possibility of oocyte retrieval without sperm for ICSI.

Mots-clés : Assisted Semen Preservation Sperm Injections, Azoospermia/*complications/genetics Cryopreservation Embryo Transfer Female Humans Infertility, Intracytoplasmic *Spermatozoa Testis/*cytology Tissue and Organ Harvesting/*methods, Male/etiology/*therapy Male Oocytes Pregnancy *Reproductive Techniques.

Guet, L, Desbois, D, Roque-Afonso, AM, Germain, JM & Merle, V 2011, « Investigation of a severe nosocomial outbreak of hepatitis A among healthcare workers and adult patients », J Hosp Infect, vol. 78, no. 1, p. 70-1.

Résumé : Guet, L; Desbois, D; Roque-Afonso, A M; Germain, J M; Merle, V; Letter; England; J Hosp Infect. 2011 May;78(1):70-1. doi: 10.1016/j.jhin.2010.11.010. Epub 2011 Jan 31.

Mots-clés : Viral/genetics/isolation & purification Reverse Transcriptase Polymerase Chain Reaction.

He, B, Zhang, YH, Richardson, MM, Zhang, JS, Rubinstein, E & Zhang, XA 2011, « Differential functions of phospholipid binding and palmitoylation of tumour suppressor EWI2/PGRL », Biochem J, vol. 437, no. 3, p. 399-411, viewed sans date, .

Résumé : The tumour suppressor EWI2 associates with tetraspanins and regulates tumour cell movement and proliferation. The short cytoplasmic domain of EWI2 is positively charged; five out of the ten residues of this domain are basic. In the present study we demonstrated that the EWI2 cytoplasmic tail interacts specifically with negatively charged PIPs (phosphatidylinositol phosphates), but not with other membrane lipids. The PIPs that interact with EWI2 cytoplasmic tail include PtdIns5P, PtdIns4P, PtdIns3P, PtdIns(3,5)P(2) and PtdIns(3,4)P2. The binding affinity of PIPs to the EWI2 tail, however, is not solely based on charge because PtdIns5P, PtdIns4P and PtdIns3P have a higher affinity to EWI2 than PtdIns(3,5)P(2) and PtdIns(3,4)P(2) do. Mutation of either of two basic residue clusters in the EWI2 cytoplasmic tail abolishes PIP binding, and PIP binding is also determined by the position of basic residues in the EWI2 cytoplasmic tail. In addition, EWI2 is constitutively palmitoylated at the cytoplasmic cysteine residues located at the N-terminal of those basic residues. The PIP interaction is not required for, but appears to regulate, the palmitoylation, whereas palmitoylation is neither required for nor regulates the PIP interaction. Functionally, the PIP interaction regulates the stability of EWI2 proteins, whereas palmitoylation is needed for tetraspanin-EWI2 association and EWI2-dependent inhibition of cell migration and lamellipodia formation. For cell-cell adhesion and cell proliferation, the PIP interaction functions in opposition to the palmitoylation. In conclusion, the EWI2 cytoplasmic tail actively engages with the cell membrane via PIP binding and palmitoylation, which play differential roles in EWI2 functions.

Mots-clés : Tertiary.

Hoti, E, Salloum, C & Azoulay, D 2011, « Hepatic resection with in situ hypothermic perfusion is superior to other resection techniques », Dig Surg, vol. 28, no. 2, p. 94-9, viewed sans date, .

Résumé : Through the years, liver resection and bleeding control techniques have progressively evolved. However, for liver tumors located unfavorably, the standard techniques are not suitable due to either failure to control the bleeding or to liver ischemia induced by prolonged interruption of perfusion. In this regard, total vascular exclusion (TVE) with in situ hypothermic perfusion is advantageous as it protects the parenchyma, achieves better vascular control and enables difficult vascular reconstructions or reimplantations. The advantages of this procedure described as early as 1960s by Fortner were also confirmed by our team in a subsequent report. We showed that TVE with in situ hypothermic perfusion is superior to TVE alone if used for more than 60 min in complex resections with or without vascular reconstruction. Other techniques (ex situ liver resection developed by Pichlmayr and ante situm liver resection by Hannoun) have been described; however, they have not been widely accepted due to a high rate of complications. In this article, we report our operative technique as well as discuss some important operative points.

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Ichai, P & Samuel, D 2011, « Epidemiology of liver failure », Clin Res Hepatol Gastroenterol, vol. 35, no. 10, p. 610-7.

Résumé : The etiology of fulminant hepatitis varies in different countries and at different times. The main causes of fulminant hepatitis are viruses, paracetamol, drugs (other than paracetamol), poisons and 15-30% remained of undetermined origin. The prevalence of these etiologies varies according to the geographic region and has changed over the past 10 years. Paracetamol has now overtaken viruses (particularly hepatitis B virus) as the leading cause of fulminant hepatitis. Establishing the cause of fulminant hepatitis is an important step in the management of acute liver failure, so that specific therapy can be initiated and any contraindications to liver transplantation be eliminated.

Mots-clés : Acute/ epidemiology/ etiology, Humans Liver Failure.

Innominato, PF, Giacchetti, S, Moreau, T, Smaaland, R, Focan, C, Bjarnason, GA, Garufi, C, Iacobelli, S, Tampellini, M, Tumolo, S, Carvalho, C, Karaboué, A, Lévi, F & Group, ARTBCIC 2011, « Prediction of survival by neutropenia according to delivery schedule of oxaliplatin-5-Fluorouracil-leucovorin for metastatic colorectal cancer in a randomized international trial (EORTC 05963) », Chronobiol Int, vol. 28, no. 7, p. 586-600, viewed sans date, .

Résumé : Circadian clocks control cellular proliferation and drug metabolism over the 24 h. However, circadian chronomodulated chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (chronoFLO4) offered no survival benefit as compared with the non-time-stipulated FOLFOX2, in an international randomized trial involving patients with previously untreated metastatic colorectal cancer (EORTC 05963). The authors hypothesized that treatment near maximum tolerated dose could disrupt circadian clocks thus impairing the efficacy of chronoFLO4 but not of FOLFOX2. Patients with available data (N = 556) were categorized into three subgroups according to the worst grade (G) of neutropenia experienced during treatment. Distinct multivariate models with time-dependent covariates were constructed for each treatment schedule. Neutropenia incidence (all grades) was 33% on chronoFLO4 and 61% on FOLFOX2 (p < .0001), and G3-4 were 7% and 25%, respectively (p < .0001). Neutropenia was significantly more frequent in women than men on either schedule (FOLFOX2, p = .003; chronoFLO4, p = .04). Median survival was 20.7 mo in patients with G3-4 neutropenia versus 12.5 mo in neutropenia-free patients on FOLFOX2 (p < .0001). Corresponding figures were 13.7 and 19.4 mo, respectively, on chronoFLO4 (p = .36). Multivariate analysis confirmed occurrence of severe neutropenia independently predicted for better overall survival on FOLFOX2 (HR = 0.56; p = .015), and worse survival on chronoFLO4 (HR = 1.77, p = .06), with a significant interaction test (p < .0001). Prediction of better survival in neutropenic patients on FOLFOX2 supports the administration of conventional chemotherapy near maximum tolerated dose. The opposite trend shown here for chronoFLO4 supports the novel concept of jointly optimized hematologic tolerability and efficacy through personalized circadian-timed therapy.

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Jain, M, Venkatraman, G, Moniaux, N, Kaur, S, Kumar, S, Chakraborty, S, Varshney, GC & Batra, SK 2011, « Monoclonal antibodies recognizing the non-tandem repeat regions of the human mucin MUC4 in pancreatic cancer », PLoS One, vol. 6, no. 8, p. e23344.

Résumé : The MUC4 mucin is a high molecular weight, membrane-bound, and highly glycosylated protein. It is a multi-domain protein that is putatively cleaved into a large mucin-like subunit (MUC4alpha) and a C-terminal growth-factor like subunit (MUC4beta). MUC4 plays critical roles in physiological and pathological conditions and is aberrantly overexpressed in several cancers, including those of the pancreas, cervix, breast and lung. It is also a potential biomarker for the diagnosis, prognosis and progression of several malignancies. Further, MUC4 plays diverse functional roles in cancer initiation and progression as evident from its involvement in oncogenic transformation, proliferation, inhibition of apoptosis, motility and invasion, and resistance to chemotherapy in human cancer cells. We have previously generated a monoclonal antibody 8G7, which is directed against the TR region of MUC4, and has been extensively used to study the expression of MUC4 in several malignancies. Here, we describe the generation of anti-MUC4 antibodies directed against the non-TR regions of MUC4. Recombinant glutathione-S-transferase (GST)-fused MUC4alpha fragments, both upstream (MUC4alpha-N-Ter) and downstream (MUC4alpha-C-Ter) of the TR domain, were used as immunogens to immunize BALB/c mice. Following cell fusion, hybridomas were screened using the aforementioned recombinant proteins ad lysates from human pancreatic cell lines. Three anti MUC4alpha-N-Ter and one anti-MUC4alpha-C-Ter antibodies were characterized by several inmmunoassays including enzyme-linked immunosorbent assay (ELISA), immunoblotting, immunofluorescene, flow cytometry and immunoprecipitation using MUC4 expressing human pancreatic cancer cell lines. The antibodies also reacted with the MUC4 in human pancreatic tumor sections in immunohistochemical analysis. The new domain-specific anti-MUC4 antibodies will serve as important reagents to study the structure-function relationship of MUC4 domains and for the development of MUC4-based diagnostics and therapeutics.

Mots-clés : Animals Antibodies, Monoclonal/ immunology Cell Line.

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Johanet, C & Ballot, E 2011, « Significance of autoantibodies to soluble liver antigen (SLA) in autoimmune hepatitis », Immuno-analyse et biologie spécialisée, vol. 26, no. 3, p. 118-124.

Résumé : Antibody detection plays an important role in diagnosis and classification of autoimmune hepatitis. Antibodies to soluble liver antigen are considered to be a specific marker of type 1 autoimmune hepatitis. Their detection is of interest in patients who are negative for conventional markers of the disease (antinuclear antibodies and anti-smooth muscle antibodies reacting specifically against actin cables). Actually, these antibodies allow us to reclassify as type 1 autoimmune hepatitis, 15 to 20% of hepatitis regarded as cryptogenic. The pronostic value of antibodies to soluble liver antigen has seldom been studied and is controversial. They might be used to evaluate the risk of relapse of the inflammatory process after corticosteroid therapy and to recurrence of autoimmune hepatitis after orthotopic liver transplantation.

Joyon, N, Francois, H, Guettier, C & Ferlicot, S 2011, « [A rare cause of renal graft dysfunction] », Ann Pathol, vol. 31, no. 2, p. 116-8, viewed sans date, .

Résumé : Joyon, Natacha Francois, Helene Guettier, Catherine Ferlicot, Sophie fre Case Reports France 2011/05/24 06:00 Ann Pathol. 2011 Apr;31(2):116-8. doi: 10.1016/j.annpat.2011.02.003. Epub 2011 Apr 1.

Mots-clés : Acute Disease Adenoviridae Infections/*complications Female Graft Rejection/*virology Humans *Kidney Transplantation Middle Aged Nephritis, Interstitial/*complications/*virology.

Kamar, N, Garrouste, C, Haagsma, EB, Garrigue, V, Pischke, S, Chauvet, C, Dumortier, J, Cannesson, A, Cassuto-Viguier, E, Thervet, E, Conti, F, Lebray, P, Dalton, HR, Santella, R, Kanaan, N, Essig, M, Mousson, C, Radenne, S, Roque-Afonso, AM, Izopet, J & Rostaing, L 2011, « Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants », Gastroenterology, vol. 140, no. 5, p. 1481-9.

Résumé : BACKGROUND & AIMS: Hepatitis E virus (HEV) infection can cause chronic hepatitis in recipients of solid organ transplants. However, the factors that contribute to chronic infection and the outcomes of these patients are incompletely understood. We performed a retrospective analysis of data from 17 centers from Europe and the United States that described the progression, outcomes, and factors associated with development of chronic HEV infection in recipients of transplanted solid organs. METHODS: We studied data from 85 recipients of solid organ transplants who were infected with HEV. Chronic HEV infection was defined by the persistent increases in levels of liver enzymes and polymerase chain reaction evidence of HEV in the serum and/or stool for at least 6 months. RESULTS: Fifty-six patients (65.9%) developed chronic hepatitis. Univariate analysis associated liver transplant, shorter times since transplant, lower levels of liver enzymes and serum creatinine, lower platelet counts, and tacrolimus-based immunosuppressive therapy (rather than cyclosporin A) with chronic hepatitis. On multivariate analysis, the independent predictive factors associated with chronic HEV infection were the use of tacrolimus rather than cyclosporin A (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.49-1.97; P = .004) and a low platelet count at the time of diagnosis with HEV infection (OR, 1.02; 95% CI, 1.001-1.1; P = .04). Of patients with chronic hepatitis, 18 (32.1%) achieved viral clearance after the dose of immunosuppressive therapy was reduced. No HEV reactivation was observed after HEV clearance. CONCLUSIONS: HEV infection causes chronic hepatitis in more than 60% of recipients of solid organ transplants. Tacrolimus therapy is the main predictive factor for chronic hepatitis. Dose reductions of immunosuppressive therapy resulted in viral clearance in more than 30% of patients.

Mots-clés : Adult Aged Europe/epidemiology Female Follow-Up Studies Hepatitis E/ virology Hepatitis E virus/ genetics Hepatitis, Chronic/epidemiology/ virology Humans Incidence Male Middle Aged Organ Transplantation Polymerase Chain Reaction RNA, Viral/ genetics Retrospective Studies United States/epidemiology Young Adult.

Ketroussi, F, Giuliani, M, Bahri, R, Azzarone, B, Charpentier, B & Durrbach, A 2011, « Lymphocyte cell-cycle inhibition by HLA-G is mediated by phosphatase SHP-2 and acts on the mTOR pathway », PLoS One, vol. 6, no. 8, p. e22776, viewed sans date, .

Résumé : Human leukocyte antigen G (HLA-G) is involved in regulating T-cell responses through its interaction with inhibitory receptors belonging to the immunoglobulin-like transcript family (ILT). In this context, we investigated the pathways involved in the control of cell-cycle entry of T cells following HLA-G interaction with its inhibitory receptor. We show that HLA-G acts through its interaction with the LILRB1 receptor expressed on T lymphocytes. Both HLA-G and LILRB1 antibodies block the inhibitory effect of HLA-G and restore T-cell proliferation. The interaction of HLA-G with T lymphocytes is associated with phosphorylation of SHP-2 phosphatase, but not SHP-1. In addition, in activated T cells, their incubation with HLA-G is not associated with a decrease in the TCR or CD28 downstream pathways, but is associated with dephosphorylation of the mTOR molecule and p70S6K. In contrast, Akt, which acts upstream of mTOR, is not affected by HLA-G. The inhibition of SHP-2 by NSC-87877(5 microM), a chemical inhibitor of SHP-2, or the use of siRNA, abrogates dephosphorylation of mTOR and impairs the overexpression of p27(kip) in the presence of HLA-G. Together, these results indicate that HLA-G is associated with activation of phosphatase SHP-2, which inhibits the mTOR pathway and favors the inhibition of the cell-cycle entry of human-activated T cells.

Mots-clés : 70-kDa/metabolism Signal Transduction/*drug effects T-Lymphocytes/*cytology/drug effects/*enzymology TOR Serine-Threonine Kinases/*metabolism Time Factors Transcription, Antigen, Antigens, CD/metabolism Blotting, Genetic/drug effects, Immunologic/metabolism Ribosomal Protein S6 Kinases, Non-Receptor Type 11/*metabolism Proto-Oncogene Proteins c-akt/metabolism RNA, Small Interfering/metabolism Receptors, T-Cell/metabolism Receptors, Tumor Cell Proliferation/drug effects HLA-G Antigens/*pharmacology Humans Immunoprecipitation Interleukin-2/pharmacology Lymphocyte Activation/drug effects Muromonab-CD3/pharmacology Phosphorylation/drug effects Protein Tyrosine Phosphatase, Western Cell Cycle/*drug effects Cell Line.

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Laperche, S, Bouchardeau, F, Andre-Garnier, E, Thibault, V, Roque-Afonso, AM, Trimoulet, P, Colimon, R, Duverlie, G, Leguillou-Guillemette, H, Lunel, F, Bouvier-Alias, M, Pawlotsky, JM, Henquell, C, Schvoerer, E, Stoll-Keller, F, Chaix, ML, Branger, M, Gaudy-Graffin, C, Rosenberg, AR, Pozzetto, B, Vallet, S, Baazia, Y, Izopet, J & Lefrere, JJ 2011, « Interpretation of real-time PCR results for hepatitis C virus RNA when viral load is below quantification limits », J Clin Microbiol, vol. 49, no. 3, p. 1113-5.

Résumé : Hepatitis C virus RNA quantification results obtained in 18 laboratories using real-time PCR methods with 10 negative samples and 22 sample dilutions (viral loads of 0.5 to 500 IU/ml) showed a score of correct results of up to 93.5%. However, 55.6% of the laboratories did not follow the recommendations for the interpretation of their results, leading to ambiguous conclusions.

Mots-clés : Decision Support Techniques Hepacivirus/ isolation & purification Humans RNA, Viral/blood Reverse Transcriptase Polymerase Chain Reaction/ methods/ standards Viral Load/ methods Virology/ methods/ standards.

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Lavergne, M, Vanneaux, V, Delmau, C, Gluckman, E, Rodde-Astier, I, Larghero, J & Uzan, G 2011, « Cord blood-circulating endothelial progenitors for treatment of vascular diseases », Cell Prolif, vol. 44 Suppl 1, p. 44-7, viewed sans date, .

Résumé : Adult peripheral blood (PB) endothelial progenitor cells (EPC) are produced in the bone marrow and are able to integrate vascular structures in sites of neoangiogenesis. EPCs thus represent a potential therapeutic tool for ischaemic diseases. However, use of autologous EPCs in cell therapy is limited by their rarity in adult PB. Cord blood (CB) contains more EPCs than PB, and they are functional after expansion. They form primary colonies that give rise to secondary colonies, each yielding more than 10(7) cells after few passages. The number of endothelial cells obtained from one unit of CB is compatible with potential clinical application. EPC colonies can be securely produced, expanded and cryopreserved in close culture devices and endothelial cells produced in these conditions are functional as shown in different in vitro and in vivo assays. As CB EPC-derived endothelial cells would be allogeneic to patients, it would be of interest to prepare them from ready-existing CB banks. We show that not all frozen CB units from a CB bank are able to generate EPC colonies in culture, and when they do so, number of colonies is lower than that obtained with fresh CB units. However, endothelial cells derived from frozen CB have the same phenotypical and functional properties than those derived from fresh CB. This indicates that CB cryopreservation should be improved to preserve integrity of stem cells other than haematopoietic ones. Feasibility of using CB for clinical applications will be validated in porcine models of ischaemia.

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Leclerc, T, Thepenier, C, Jault, P, Bey, E, Peltzer, J, Trouillas, M, Duhamel, P, Bargues, L, Prat, M, Bonderriter, M & Lataillade, J-J 2011, « Cell therapy of burns », Cell Prolif, vol. 44 Suppl 1, p. 48-54, viewed sans date, .

Résumé : Severe burns remain a life-threatening local and general inflammatory condition often with serious sequelae, despite remarkable progress in their treatment over the past three decades. Cultured epidermal autografts, the first and still most up-to-date cell therapy for burns, plays a key role in that progress, but drawbacks to this need to be reduced by using cultured dermal-epidermal substitutes. This review focuses on what could be, in our view, the next major breakthrough in cell therapy of burns - use of mesenchymal stromal cells (MSCs). After summarizing current knowledge, including our own clinical experience with MSCs in the pioneering field of cell therapy of radiation-induced burns, we discuss the strong rationale supporting potential interest in MSCs in treatment of thermal burns, including limited but promising pre-clinical and clinical data in wound healing and acute inflammatory conditions other than burns. Practical options for future therapeutic applications of MSCs for burns treatment, are finally considered.

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Lehmann-Che, J, Amira-Bouhidel, F, Turpin, E, Antoine, M, Soliman, H, Legres, L, Bocquet, C, Bernoud, R, Flandre, E, Varna, M, de Roquancourt, A, Plassa, L-F, Giacchetti, S, Espié, M, de Bazelaire, C, Cahen-Doidy, L, Bourstyn, E, Janin, A, de Thé, H & Bertheau, P 2011, « Immunohistochemical and molecular analyses of HER2 status in breast cancers are highly concordant and complementary approaches », Br J Cancer, vol. 104, no. 11, p. 1739-46, viewed sans date, .

Résumé : BACKGROUND: Immunohistochemistry (IHC) and fluorescent in situ hybridisation (FISH) are currently the most commonly used methods to assess HER2 status. PCR-based assays allow quantitative determination of HER2 amplification (Q-PCR) or overexpression (Q-RT-PCR), but are not routinely used. We evaluated the relevance of Q-RT-PCR for HER2 status determination. METHODS: We compared IHC and Q-RT-PCR in 466 breast tumours. In discordant or equivocal cases, five additional methods (IHC with two other antibodies, FISH, silver in situ hybridisation (SISH) and Q-PCR) were combined to determine HER2 status. Two cases with HER2 intra-tumour heterogeneity were further explored by allelic profiles analysis and HUMARA clonality determination after microdissection. RESULTS: We observed 97.3% concordance between Q-RT-PCR and non-equivocal IHC. Twelve out of 466 cases (3%) revealed discordances between the two methods. The power of Q-RT-PCR to predict HER2 status (defined by seven methods) was similar to that of IHC. Although rare, some discordances between techniques might be due to HER2 intra-tumour heterogeneity and we report two examples, one tumour containing two distinct clones, another tumour consisting of HER2 amplified and non-amplified subclones. CONCLUSION: Q-RT-PCR and IHC are highly concordant methods for HER2 status assessment, and Q-RT-PCR allows a highly reliable quantitative assessment and could be a useful adjunct to IHC.

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Levesque, E, Hoti, E, Azoulay, D, Adam, R, Samuel, D, Castaing, D & Saliba, F 2011, « Non-invasive ICG-clearance: a useful tool for the management of hepatic artery thrombosis following liver transplantation », Clin Transplant, vol. 25, no. 2, p. 297-301, viewed sans date, .

Résumé : BACKGROUND: The clinical presentation of hepatic artery thrombosis (HAT) post-liver transplantation (LT) varies considerably. Doppler ultrasonography (Doppler US) is the first line investigation, with a diagnostic sensitivity for HAT as high as 92%. Because indocyanine green (ICG) elimination from the blood depends among other factors on the hepatic blood flow, we hypothesized that plasma disappearance rate of indocyanine green (PDR-ICG) can be influenced by the flow in the hepatic artery. Thus, we evaluated the role of PDR-ICG measurement in HAT diagnosis in post-LT patients. PATIENTS AND METHODS: Fourteen liver transplant patients with no visible flow in the hepatic artery (Doppler US) were identified. Of the 14, seven patients had HAT confirmed by CT-angiography. The PDR-ICG measurement, an investigation routinely used in our center, was performed in all 14 patients. RESULTS: The PDR-ICG in patients with HAT was significantly lower than in patients without HAT (5.8 ± 4.3 vs. 23.8 ± 7.4%/min, p= 0.0009). In patients with HAT, after the revascularization, the PDR-ICG value increased (5.8 ± 4.3 vs. 15.6 ± 3.5%/min, p = 0.006). CONCLUSION: The ICG elimination may be an adjunct diagnostic tool in the management of patients with suspected HAT following LT.

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Levesque, E, Hoti, E, Jiabin, J, Dellamonica, J, Ichai, P, Saliba, F, Azoulay, D & Samuel, D 2011, « Respiratory impact of paracentesis in cirrhotic patients with acute lung injury », J Crit Care, vol. 26, no. 3, p. 257-61, viewed sans date, .

Résumé : INTRODUCTION: Ascites may contribute to the loss of lung volume and alter the gas exchange in cirrhotic patients with acute lung injury (ALI). AIM: The aim of the study was to evaluate the effects of paracentesis on respiratory parameters in ventilated cirrhotic patients with ALI. STUDY DESIGN: This was a prospective trial in an intensive care unit of a university hospital. PATIENTS AND METHODS: Thirty-one cirrhotic patients on mechanical ventilation (with ALI) requiring paracentesis were included in this study. Arterial blood gases, intraabdominal pressures, ventilator parameters, and lung volumes were measured before and after the ascitic drainage. RESULTS: Following paracentesis, the intraabdominal pressure decreased (24.1 ± 7.0 vs 12.3 ± 8.9 mm Hg, P < .0001) and the Pao(2)/Fio(2) improved significantly (190.0 ± 65.2 vs 284.9 ± 76.1 mm Hg, P < .0001), without hemodynamic disturbances. End-expiratory lung volume, markedly reduced before drainage, increased significantly following paracentesis (Δ end-expiratory lung volume: +463 ± 249 mL, P = .0009). No adverse effects related to the paracentesis were encountered. CONCLUSION: In contrast to ventilatory recruitment maneuvers, paracentesis is a simple and well-tolerated technique able to improve oxygenation and alveolar recruitment without the risk of the lung overdistension in severely hypoxemic cirrhotic patients.

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Levesque, E, Hoti, E, Khalfallah, M, Salloum, C, Ricca, L, Vibert, E & Azoulay, D 2011, « Impact of reversible cardiac arrest in the brain-dead organ donor on the outcome of adult liver transplantation », Liver Transpl, vol. 17, no. 10, p. 1159-66, viewed sans date, .

Résumé : Several donor and graft characteristics are associated with higher failure rates for deceased donor liver transplantation (LT). The influence of reversible cardiac arrest in the donor on these failure rates is unclear because of scarce and inconsistent data. The aim of this study was to determine whether reversible cardiac arrest in the donor could affect the early postoperative outcome of LT. From January 2008 to February 2010, 165 patients underwent LT, and they were retrospectively divided into 2 groups: a cardiac arrest group (34 patients who received grafts from donors who had experienced reversible cardiac arrest before organ procurement) and a control group (131 patients who received grafts from donors without a history of reversible cardiac arrest). The postoperative complications and the graft and recipient outcomes were prospectively recorded for all the patients. Graft failure was defined as death or the need for retransplantation within 90 days of LT. Donors in the cardiac arrest group displayed higher serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels than donors in the control group [AST: 104 (19-756) versus 42 IU/L (10-225 IU/L), P < 0.001; ALT: 73 (13-869) versus 29 IU/L (6-549 IU/L), P < 0.001]. However, no difference in the graft failure rates was found between the 2 groups (11.8% versus 8.4%, P = 0.51). The biological parameters 5 and 7 days after LT and the peak AST/ALT levels were similar for the 2 groups. Furthermore, the 2 groups had similar graft and patient survival rates at the 6-month mark (87% and 88%, respectively). In conclusion, our study shows that brief and reversible cardiac arrest in organ donors does not affect post-LT allograft survival and function, even though liver function test values are higher for these donors. However, the risk of using these grafts needs to be balanced against the potential benefits for the recipients.

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Lévi, F, Karaboué, A, Gorden, L, Innominato, PF, Saffroy, R, Giacchetti, S, Hauteville, D, Guettier, C, Adam, R & Bouchahda, M 2011, « Cetuximab and circadian chronomodulated chemotherapy as salvage treatment for metastatic colorectal cancer (mCRC): safety, efficacy and improved secondary surgical resectability », Cancer Chemother Pharmacol, vol. 67, no. 2, p. 339-48, viewed sans date, .

Résumé : BACKGROUND: Circadian rhythm disruption was linked to high serum levels of Transforming Growth Factor Receptor α, an Epidermal Growth Factor Receptor (EGFR) ligand and poor survival in patients with metastatic colorectal cancer (mCRC). We hypothesized that EGFR blockade with cetuximab would enhance the activity of chronotherapy as a result of improved circadian coordination. METHODS: All the patients with mCRC referred to our unit for progression on prior chemotherapy over a 30-month-period received weekly cetuximab and fortnightly chronotherapy. RESULTS: Fifty-six patients were treated with a median of six courses of fluoropyrimidine-based chemotherapy and irinotecan (61%), oxaliplatin (25%) or both (14%) after a median of three prior regimens. We found no EFGR amplification by FISH in the tumor of 27 consecutive patients. Acneiform rash and diarrhea were the most common toxicities. Objective response rate was 32.1% and positively correlated with rash grade (p = 0.025). None of the responders had K-Ras mutation in their tumor. Median progression-free and overall survival were 4.6 and 13.7 months, respectively. Complete macroscopic resections of metastases in liver, lung or other abdominopelvic sites were performed following tumor downstaging by the treatment regimen in 11 patients (21%), 8 of whom being alive at 3 years. These figures are twice as high as those reported for first-line combination of cetuximab with conventional chemotherapy or for third line chronotherapy. CONCLUSIONS: The addition of cetuximab to chronotherapy allowed safe and effective therapeutic control of metastases, including their complete resection, despite previous failure of several treatment regimens.

Mots-clés : 80 and over Antibodies, Adult Aged Aged, Epidermal Growth Factor/genetics/metabolism Salvage Therapy/adverse effects/ methods Survival Rate Treatment Outcome, ras/genetics Humans Leucovorin/administration & dosage Male Middle Aged Neoplasm Metastasis/drug therapy/therapy Organoplatinum Compounds/administration & dosage Prognosis Receptor.

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Lin, H, Flamant, S & Jiang, X 2011, « IDENTIFICATION OF MICRORNA EXPRESSION CHANGES IN CHRONIC MYELOID LEUKEMIA CELLS IN RESPONSE TO IMATINIB », Experimental Hematology, vol. 39, no. 8, p. S90-S91, viewed sans date, <<Go to ISI>://WOS:000293801700150>.

Résumé : Lin, H. Flamant, S. Jiang, X. 1

Mascarell, L, Saint-Lu, N, Moussu, H, Zimmer, A, Louise, A, Lone, Y, Ladant, D, Leclerc, C, Tourdot, S, Van Overtvelt, L & Moingeon, P 2011, « Oral macrophage-like cells play a key role in tolerance induction following sublingual immunotherapy of asthmatic mice », Mucosal Immunol, vol. 4, no. 6, p. 638-47, viewed sans date, .

Résumé : Sublingual allergen-specific immunotherapy (SLIT) is a safe and efficacious treatment for type 1 respiratory allergies. Herein, we investigated the key subset(s) of antigen-presenting cells (APCs) involved in antigen/allergen capture and tolerance induction during SLIT. Following sublingual administration, fluorochrome-labeled ovalbumin (OVA) is predominantly captured by oral CD11b(+)CD11c(-) cells that migrate to cervical lymph nodes (CLNs) and present the antigen to naive CD4(+) T cells. Conditional depletion with diphtheria toxin of CD11b(+), but not CD11c(+) cells, in oral tissues impairs CD4(+) T-cell priming in CLNs. In mice with established asthma to OVA, specific targeting of the antigen to oral CD11b(+) cells using the adenylate cyclase vector system reduces airway hyperresponsiveness (AHR), eosinophil recruitment in bronchoalveolar lavages (BALs), and specific Th2 responses in CLNs and lungs. Oral CD11b(+)CD11c(-) cells resemble tolerogenic macrophages found in the lamina propria (LP) of the small intestine in that they express the mannose receptor CD206, as well as class-2 retinaldehyde dehydrogenase (RALDH2), and they support the differentiation of interferon-gamma/interleukin-10 (IFNgamma/IL-10)-producing Foxp3(+) CD4(+) regulatory T cells. Thus, among the various APC subsets present in oral tissues of mice, macrophage-like cells play a key role in tolerance induction following SLIT.

Mots-clés : Administration, Animal Forkhead Transcription Factors/metabolism Humans Immune Tolerance Macrophages/immunology/*metabolism/pathology Mice Mice, Cultured Cytokines/secretion *Desensitization, Immunologic Disease Models, Inbred BALB C Mice, Regulatory/immunology/*metabolism/pathology, Sublingual Allergens/administration & dosage Animals Antigen Presentation Asthma/chemically induced/drug therapy/*immunology/physiopathology Cells, Transgenic Mouth Mucosa/pathology Ovalbumin/administration & dosage T-Lymphocyte Subsets/immunology/*metabolism/pathology T-Lymphocytes.

Masson-Lecomte, A, Rocher, L, Ferlicot, S, Benoit, G & Droupy, S 2011, « High-flow priapism due to a malignant glomus tumor (glomangiosarcoma) of the corpus cavernosum », J Sex Med, vol. 8, no. 12, p. 3518-22, viewed sans date, .

Résumé : INTRODUCTION: The major cause of non-ischemic high-flow priapism is post-traumatic vascular injury leading to an arterio-lacunar fistula. However, rare causes such as tumors may induce priapism. This is the first report of a malignant glomus tumor localized in the corpora cavernosa. AIM: The aim of this case is to emphasize the importance of the initial management of priapism and to suggest new tracks on the tests to be performed when the usual exams are not sufficient. METHOD: We report the case of a hypervascular penile tumor responsible for high-flow priapism as the first clinical symptom of a metastatic glomus tumor. The persistent penile tumescence was initially considered to be a stuttering priapism and treated using an oral alpha-adrenergic as no provoking event nor fistula was found. After a 2-week reluctance, a penile magnetic resonance imaging (MRI) was performed. RESULTS: The MRI showed a hypervascular lesion at the proximal part of the right corpora. The lesion was considered as a fistula, and a selective embolization was performed. Two weeks after embolization, the patient came back to the emergency room because of syncopes and dyspnea. Examination by cardiac ultrasound and chest computed tomography revealed the presence of cardiac, pulmonary, and subcutaneous malignant glomus tumors (glomangiosarcoma). Patient received three lines of chemotherapy, and the penile tumor was surgically removed because of persistent erectile dysfunction and perineal pain. CONCLUSION: This case supports the use of corporal body blood gas analysis in difficult cases to discriminate high- and low-flow priapism and penile MRI when clinical history, physical examination, and aspiration are not contributory.

Mots-clés : *Penile, Adult, Erection, Glomus, Humans, Imaging, Magnetic, Male, Neoplasms/*complications/pathology/surgery, Penile, Penis/blood, Priapism/*etiology/pathology/surgery, Resonance, supply/*pathology, Tumor/*complications/pathology/surgery.

Mathurin, P, Moreno, C, Samuel, D, Dumortier, J, Salleron, J, Durand, F, Castel, H, Duhamel, A, Pageaux, GP, Leroy, V, Dharancy, S, Louvet, A, Boleslawski, E, Lucidi, V, Gustot, T, Francoz, C, Letoublon, C, Castaing, D, Belghiti, J, Donckier, V, Pruvot, FR & Duclos-Vallee, JC 2011, « Early liver transplantation for severe alcoholic hepatitis », N Engl J Med, vol. 365, no. 19, p. 1790-800.

Résumé : BACKGROUND: A 6-month abstinence from alcohol is usually required before patients with severe alcoholic hepatitis are considered for liver transplantation. Patients whose hepatitis is not responding to medical therapy have a 6-month survival rate of approximately 30%. Since most alcoholic hepatitis deaths occur within 2 months, early liver transplantation is attractive but controversial. METHODS: We selected patients from seven centers for early liver transplantation. The patients had no prior episodes of alcoholic hepatitis and had scores of 0.45 or higher according to the Lille model (which calculates scores ranging from 0 to 1, with a score >/= 0.45 indicating nonresponse to medical therapy and an increased risk of death in the absence of transplantation) or rapid worsening of liver function despite medical therapy. Selected patients also had supportive family members, no severe coexisting conditions, and a commitment to alcohol abstinence. Survival was compared between patients who underwent early liver transplantation and matched patients who did not. RESULTS: In all, 26 patients with severe alcoholic hepatitis at high risk of death (median Lille score, 0.88) were selected and placed on the list for a liver transplant within a median of 13 days after nonresponse to medical therapy. Fewer than 2% of patients admitted for an episode of severe alcoholic hepatitis were selected. The centers used 2.9% of available grafts for this indication. The cumulative 6-month survival rate (+/-SE) was higher among patients who received early transplantation than among those who did not (77 +/- 8% vs. 23 +/- 8%, P<0.001). This benefit of early transplantation was maintained through 2 years of follow-up (hazard ratio, 6.08; P = 0.004). Three patients resumed drinking alcohol: one at 720 days, one at 740 days, and one at 1140 days after transplantation. CONCLUSIONS: Early liver transplantation can improve survival in patients with a first episode of severe alcoholic hepatitis not responding to medical therapy. (Funded by Societe Nationale Francaise de Gastroenterologie.).

Mots-clés : Adult Alcoholism Case-Control Studies Female Follow-Up Studies Glucocorticoids/therapeutic use Hepatitis, Alcoholic/drug therapy/mortality/ surgery Humans Kaplan-Meier Estimate Liver Transplantation Male Middle Aged Patient Selection Proportional Hazards Models Recurrence Survival Rate Temperance Time Factors.

Meazza, R, Azzarone, B, Orengo, AM & Ferrini, S 2011, « Role of common-gamma chain cytokines in NK cell development and function: perspectives for immunotherapy », J Biomed Biotechnol, vol. 2011, p. 861920, viewed sans date, .

Résumé : NK cells are components of the innate immunity system and play an important role as a first-line defense mechanism against viral infections and in tumor immune surveillance. Their development and their functional activities are controlled by several factors among which cytokines sharing the usage of the common cytokine-receptor gamma chain play a pivotal role. In particular, IL-2, IL-7, IL-15, and IL-21 are the members of this family predominantly involved in NK cell biology. In this paper, we will address their role in NK cell ontogeny, regulation of functional activities, development of specialized cell subsets, and acquisition of memory-like functions. Finally, the potential application of these cytokines as recombinant molecules to NK cell-based immunotherapy approaches will be discussed.

Mots-clés : Cellular/immunology *Immunotherapy Interferon-gamma/immunology Interleukin Receptor Common gamma Subunit/*immunology Interleukin-15/immunology Interleukin-2/immunology Interleukin-7/immunology Interleukins/*immunology Killer Cells, Humans Immunity, Natural/*immunology Neoplasms/immunology/*therapy.

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Moise, L, Matta, C, Hanna, C, Pilorge, S, Ferme, C, Durrbach, A & Ribrag, V 2011, « Methotrexate- and/or cytarabine-based chemotherapy may be effective and safe in solid-organ transplant recipients with primary central nervous system lymphomas », Leuk Lymphoma, vol. 52, no. 3, p. 521-4, viewed sans date, .

Résumé : Moise, Laura Matta, Clemence Hanna, Colette Pilorge, Sylvain Ferme, Christophe Durrbach, Antoine Ribrag, Vincent eng Controlled Clinical Trial Letter England 2010/12/08 06:00 Leuk Lymphoma. 2011 Mar;52(3):521-4. doi: 10.3109/10428194.2010.536601. Epub 2010 Dec 6.

Mots-clés : Adult Aged Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use Central Nervous System Neoplasms/*drug therapy/mortality/pathology Cytarabine/*administration & dosage/adverse effects Dose-Response Relationship.

Moniaux, N & Faivre, J 2011, « Key role of sinusoidal endothelial cells in the triggering of liver regeneration », J Hepatol, vol. 55, no. 2, p. 488-90.

Résumé : Moniaux, Nicolas; Faivre, Jamila; Comment; England; J Hepatol. 2011 Aug;55(2):488-90. doi: 10.1016/j.jhep.2011.02.005. Epub 2011 Feb 22.

Moniaux, N & Faivre, J 2011, « A reengineered liver for transplantation », J Hepatol, vol. 54, no. 2, p. 386-7.

Résumé : Moniaux, Nicolas; Faivre, Jamila; Comment; England; J Hepatol. 2011 Feb;54(2):386-7. doi: 10.1016/j.jhep.2010.07.053. Epub 2010 Nov 10.

Moniaux, N, Song, H, Darnaud, M, Garbin, K, Gigou, M, Mitchell, C, Samuel, D, Jamot, L, Amouyal, P, Amouyal, G, Brechot, C & Faivre, J 2011, « Human hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein cures fas-induced acute liver failure in mice by attenuating free-radical damage in injured livers », Hepatology, vol. 53, no. 2, p. 618-27.

Résumé : Acute liver failure (ALF) is a rare syndrome with a difficult clinical management and a high mortality rate. During ALF, several molecular pathways governing oxidative stress and apoptosis are activated to induce massive tissue injury and suppress cell proliferation. There are few anti-ALF drug candidates, among which is the C-type lectin Reg3alpha, or human hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP), which displayed promising properties for tissue regeneration and protection against cellular stress in transgenic mice. We report on substantial preclinical and clinical advances in the development of a recombinant (rc) full-length human HIP/PAP protein as an anti-ALF drug. The curative effects and mechanisms of action of rcHIP/PAP were investigated in murine Fas-induced ALF. Primary hepatocytes were cultured with cytotoxic doses of tumor necrosis factor alpha/actinomycin-D, transforming growth factor beta, agonistic Fas antibody or hydrogen peroxide, and various concentrations of rcHIP/PAP. Cell viability, proliferation index, apoptosis, and oxidation were monitored. We found that rcHIP/PAP significantly improved survival in Fas-intoxicated mice in a dose-dependent and time-dependent manner, with optimum effects when it was injected at advanced stages of ALF. Primary hepatocytes were efficiently protected against multiple cell death signals by rcHIP/PAP. This survival benefit was linked to a depletion of oxidized biomolecules in injured liver cells due to a strong reactive oxygen species scavenging activity of rcHIP/PAP. Clinically, an escalating dose phase 1 trial demonstrated a good tolerability and pharmacokinetic profile of rcHIP/PAP in healthy subjects. CONCLUSION: The rcHIP/PAP protein exhibited significant curative properties against ALF in mice. It is a free-radical scavenger that targets a broad spectrum of death effectors and favors liver regeneration. The good safety profile of rcHIP/PAP during a phase 1 trial encourages evaluation of its efficacy in patients with ALF.

Mots-clés : Acute/ chemically induced/ drug therapy/metabolism Male Mice Mice, Adolescent Adult Animals Antigens, Animal Dose-Response Relationship, Biological/pharmacokinetics/pharmacology/ therapeutic use Young Adult, C-Type/ therapeutic use Lipid Peroxidation/drug effects Liver Failure, CD95/ adverse effects Antigens, Cultured Disease Models, Drug Double-Blind Method Drug-Induced Liver Injury/ drug therapy/ metabolism Free Radical Scavengers/pharmacokinetics/pharmacology/therapeutic use Free Radicals/ metabolism Hepatocytes/drug effects/metabolism/pathology Humans Lectins, Inbred C57BL Mice, Neoplasm/pharmacology/ therapeutic use Apoptosis/drug effects Cell Proliferation/drug effects Cells, Transgenic Middle Aged Recombinant Proteins/pharmacokinetics/pharmacology/therapeutic use Time Factors Tumor Markers.

Montpellier, C, Tews, BA, Poitrimole, J, Rocha-Perugini, V, D'Arienzo, V, Potel, J, Zhang, XA, Rubinstein, E, Dubuisson, J & Cocquerel, L 2011, « Interacting regions of CD81 and two of its partners, EWI-2 and EWI-2wint, and their effect on hepatitis C virus infection », J Biol Chem, vol. 286, no. 16, p. 13954-65, viewed sans date, .

Résumé : CD81 is a tetraspanin protein that is involved in several essential cellular functions, as well as in the hepatitis C virus (HCV) infection. CD81 interacts with a high stoichiometry with its partner proteins EWI-2, EWI-2wint, and EWI-F. These latter proteins modify the functions of CD81 and can thereby potentially inhibit infection or modulate cell migration. Here, we characterized the cleavage of EWI-2 leading to the production of EWI-2wint, which has been shown to inhibit HCV infection. We determined the regions of EWI-2/EWI-2wint and CD81 that are important for their interaction and their functionality. More precisely, we identified a glycine zipper motif in the transmembrane domain of EWI-2/EWI-2wint that is essential for the interaction with CD81. In addition, we found that palmitoylation on two juxtamembranous cysteines in the cytosolic tail of EWI-2/EWI-2wint is required for their interaction with CD81 as well as with CD9, another tetraspanin. Thus, we have shown that palmitoylation of a tetraspanin partner protein can influence the interaction with a tetraspanin. We therefore propose that palmitoylation not only of tetraspanins, but also of their partner proteins is important in regulating the composition of complexes in tetraspanin networks. Finally, we identified the regions in CD81 that are necessary for its functionality in HCV entry and we demonstrated that EWI-2wint needs to interact with CD81 to exert its inhibitory effect on HCV infection.

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Naveau, A, Lataillade, J-J, Fournier, BP, Couty, L, Prat, M, Ferre, FC, Gourven, M, Durand, E, Coulomb, B, Lafont, A & Gogly, B 2011, « Phenotypic study of human gingival fibroblasts in a medium enriched with platelet lysate », J Periodontol, vol. 82, no. 4, p. 632-41, viewed sans date, .

Résumé : BACKGROUND: The modulation abilities of gingival fibroblasts open new therapeutic strategies for the treatment of vascular diseases (e.g., aneurism) and irradiation burns. Culture media are classically supplemented with animal sera to provide nutriments. Unfortunately, because of their potential for interspecies transmission of microorganisms, these media are not used for cells destined for human transplantation. This preliminary phenotypic study aims to test a serum-free (SF) culture medium for human gingival fibroblasts (hGF) supplemented with human platelet lysates (PLs) for rapid cell expansion. METHODS: An SF medium was first elaborated to compete with hGF proliferation in a reference medium containing 10% fetal bovine serum (BSmedium). Adhesion, proliferation, and doubling kinetics were run in the presence of PLs (SF+PL). Cytoskeletal proteins were analyzed and chromosomal abnormalities were evaluated by karyotype analyses. The SF+PL influence on secretion of molecules implied in tissue remodeling (i.e., matrix metalloproteinases [MMPs], their tissue inhibitors [TIMPs], and several growth factors) was studied. RESULTS: SF+PL increased the proliferation rate 1.5-fold in a week compared to BSmedium. Cytoskeleton protein expression was similar in BSmedium and in SF+PL. Chromosomal abnormalities were rare in SF+PL. MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, TIMP-1, and the growth factors interleukin-1β and -4 and transforming growth factor-β1 secretions were stable during the experiment. TIMP-2 and interleukin-6 were slightly decreased in SF+PL compared to BSmedium. CONCLUSION: While waiting confirmation from a proteomic approach, this SF culture medium could allow a secured faster hGF proliferation adapted for human cell transplant therapy.

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Negrini, S, Giuliani, M, Durali, D, Chouaib, S & Azzarone, B 2011, « Membrane-bound IL-15 stimulation on peripheral blood natural kiler progenitors leads to the generation of an adherent subset co-expressing dendritic cells and natural kiler functional markers », Haematologica, vol. 96, no. 5, p. 762-6, viewed sans date, .

Résumé : Human peripheral blood natural killer progenitors represent a flexible, heterogeneous population whose phenotype and function are controlled by their membrane-bound IL-15. Indeed, reciprocal membrane-bond IL-15 trans-presentation commits these cells into NK differentiation, while membrane-bound IL-15 stimulation with its soluble ligand (sIL-15Ralpha) triggers a reverse signal (pERK1/2 and pFAK) that modifies the developmental program of at least two subsets of PB-NKPs. This treatment generates: i) the expansion of an immature NK subset growing in suspension; ii) the appearance of an unprecedented adherent non-proliferative subset with a dendritic morphology co-expressing marker, cytokines and functions typical of myeloid dendritic cells (CD1a(+)/BDCA1(+)/IL-12(+)) and NK cells (CD3-/NKp46(+)/ CD56(+)/IFNgamma(+)). The generation of these putative NK/DCs is associated to the rapid inhibition of negative regulators of myelopoiesis (the transcription factors STAT6 and GATA-3) followed by the transient upregulation of inducers of myeloid development, such as the transcription factors (PU.1, GATA-1) and the anti-apoptotic molecule (MCL-1).

Mots-clés : Blotting, Interleukin-15/immunology/metabolism Reverse Transcriptase Polymerase Chain Reaction STAT6 Transcription Factor/immunology/metabolism Signal Transduction/drug effects/immunology Stem Cell Factor/pharmacology, Mixed Membrane Proteins/*immunology/metabolism Myeloid Cells/immunology/metabolism Proto-Oncogene Proteins c-bcl-2/genetics/immunology/metabolism Receptors, Natural/*immunology/metabolism Lymphocyte Culture Test, Western Cell Adhesion/immunology Cell Differentiation/drug effects/immunology Cells.

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Okyar, A, Piccolo, E, Ahowesso, C, Filipski, E, Hossard, V, Guettier, C, La Sorda, R, Tinari, N, Iacobelli, S & Lévi, F 2011, « Strain- and sex-dependent circadian changes in abcc2 transporter expression: implications for irinotecan chronotolerance in mouse ileum », PLoS One, vol. 6, no. 6, p. e20393, viewed sans date, .

Résumé : BACKGROUND: ATP-binding cassette transporter abcc2 is involved in the cellular efflux of irinotecan. The drug is toxic for mouse ileum, where abcc2 is highly expressed. Here, we investigate whether circadian changes in local abcc2 expression participate in the circadian rhythm of irinotecan toxicity for ileum mucosa, and further assess whether genetic background or sex modify this relation. METHODOLOGY/PRINCIPAL FINDINGS: Ileum mucosa was obtained every 3-4 h for 24 h in male and female B6D2F(1) and B6CBAF(1) mice synchronized with light from Zeitgeber Time (ZT)0 to ZT12 alternating with 12 h of darkness. Irinotecan (50 mg/kg i.v. daily for 4 days) was administered at the sex- and strain-specific times corresponding to least (ZT11-15) or largest drug-induced body weight loss (ZT23-03-07). Abcc2 expression was determined with qRT-PCR for mRNA and with immunohistochemistry and confocal microscopy for protein. Histopathologic lesions were graded in ileum tissues obtained 2, 4 or 6 days after treatment. Two- to six-fold circadian changes were demonstrated for mRNA and protein mean expressions of abcc2 in mouse ileum (p<0.05). ZT12 corresponded to high mRNA and protein expressions, with circadian waveforms differing according to genetic background and sex. The proportion of mice spared from ileum lesions varied three-fold according to irinotecan timing, with best tolerability at ZT11-15 (p = 0.00003). Irinotecan was also best tolerated in males (p = 0.05) and in B6CBAF(1) (p = 0.0006). CONCLUSIONS/SIGNIFICANCE: Strain- and sex-dependent circadian patterns in abcc2 expressions displayed robust relations with the chronotolerance of ileum mucosa for irinotecan. This finding has strong potential implications for improving the intestinal tolerability of anticancer drugs through circadian delivery.

Mots-clés : Messenger/genetics/metabolism Sex Characteristics Species Specificity.

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Oughlis, S, Lessim, S, Changotade, S, Bollotte, F, Poirier, F, Helary, G, Lataillade, JJ, Migonney, V & Lutomski, D 2011, « Development of proteomic tools to study protein adsorption on a biomaterial, titanium grafted with poly(sodium styrene sulfonate) », J Chromatogr B Analyt Technol Biomed Life Sci, vol. 879, no. 31, p. 3681-7, viewed sans date, .

Résumé : It is known that protein adsorption is the initial interaction between implanted biomaterials and biological environment. Generally, a complex protein layer will be formed on material surfaces within a few minutes and the composition of this layer at the interface determines the biological response to the implanted material, and therefore the long-term compatibility of the biomaterial. Despite different techniques exist to observe protein adsorption on biomaterials, none of them led to the identification of adsorbed proteins. In this paper, we report a chromatographic technique coupled to proteomics to analyse and identify proteins from complex biological samples adsorbed on biomaterial surfaces. This approach is based on (1) elaboration of the chromatographic support containing the biomaterial (2) a chromatography step involving adsorption of proteins on the biomaterial (3) the high-resolution separation of eluted proteins by 2-DE gel and (4) the identification of proteins by mass spectrometry. Experiments were performed with proteins from platelets rich plasma (PRP) adsorbed on a biomaterial which consist in titanium bioactivated with PolyNaSS. Our results show that chromatographic approach combined to 2-DE gels and mass spectrometry provides a powerful tool for the analysis and identification of proteins adsorbed on various surfaces.

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Payen, JL, Muscari, F, Vibert, E, Ernst, O & Pelletier, G 2011, « [Biliary lithiasis] », Presse Med, vol. 40, no. 6, p. 567-80.

Résumé : No treatment is recommended for silent gallstones. The diagnosis of acute cholecystitis is based on clinical and biological signs and on abdominal sonography. Early laparoscopic cholecystectomy is the treatment of choice, except in case of severe (grade III) cholecystitis where a percutaneous cholecystostomy associated with antibiotic therapy is recommended. The diagnostic accuracy of abdominal sonography for the diagnosis of common bile duct stones is poor. A second-line MR cholangiopancreatography or an endoscopic sonography is often needed to confirm the diagnosis. The treatment of acute cholangitis is based on both antibiotic therapy and biliary drainage. Results of the treatment of common bile duct stone with either laparoscopic surgery or with the combined endoscopic sphincterotomy plus laparoscopic cholecystectomy are comparable when performed by well-trained practitionners. The choice of the method should be based on the locally available treatment.

Mots-clés : Anti-Bacterial Agents/therapeutic use Biological Markers Cholangiopancreatography, Biological/metabolism Predictive Value of Tests Pregnancy Pregnancy Complications/diagnosis/ultrasonography Prevalence Risk Factors Sphincterotomy, Endoscopic, Endoscopic Retrograde Cholangiopancreatography, Magnetic Resonance Cholangitis/complications/diagnosis/drug therapy/surgery Cholecystectomy/methods Cholecystectomy.

Peck-Radosavljevic, M, Boletis, J, Besisik, F, Ferraz, ML, Alric, L, Samuel, D, Messinger, D, Tietz, A & Cheinquer, H 2011, « Low-dose peginterferon alfa-2a is safe and produces a sustained virologic response in patients with chronic hepatitis C and end-stage renal disease », Clin Gastroenterol Hepatol, vol. 9, no. 3, p. 242-8.

Résumé : BACKGROUND & AIMS: Chronic hepatitis C increases mortality of patients with end-stage renal disease (ESRD). Ribavirin is not recommended for patients with renal dysfunction; peginterferon monotherapy is the most appropriate treatment for chronic hepatitis C in such patients. We evaluated the efficacy and safety of 2 dosages of peginterferon alfa-2a (40 kDa) in patients with chronic hepatitis C and ESRD on hemodialysis. METHODS: We performed a randomized, multicenter, open-label clinical study of 85 patients with chronic hepatitis C and ESRD who were receiving hemodialysis at specialist outpatient hepatology clinics. Patients were treated with subcutaneous peginterferon alfa-2a (40 kDa) at dosages of 135 or 90 mug/wk for 48 weeks. RESULTS: The incidences of overall sustained virologic responses (SVRs) (undetectable hepatitis C virus [HCV] RNA [<50 IU/mL] after 24 weeks of untreated follow-up) were 39.5% (15/38) in the 135 mug/wk group and 34.9% (15/43) in the 90 mug/wk group (odds ratio, 1.22; 95% confidence interval, 0.49-3.06; P = .67). Among patients with undetectable HCV RNA at week 12, 60.9% (14/23) of those in the 135 mug/wk group and 87.5% (14/16) of those in the 90 mug/wk group achieved an SVR. Therapy was well-tolerated with no new safety concerns. The most common adverse events (>10% of patients in at least 1 treatment group) included conditions associated with ESRD (anemia and hypertension) and with interferon treatment. CONCLUSIONS: Forty-eight weeks of treatment with low-dose peginterferon alfa-2a (40 kDa) is safe and produces an SVR in 35%-40% of patients with chronic hepatitis C and ESRD on hemodialysis.

Mots-clés : Adult Female Hepatitis C, Chronic/ complications/ drug therapy Humans Immunologic Factors/ administration & dosage/adverse effects Injections, Chronic/ diagnosis/ drug therapy Male Middle Aged Polyethylene Glycols/ administration & dosage/adverse effects Recombinant Proteins Renal Dialysis Treatment Outcome, Subcutaneous Interferon-alpha/ administration & dosage/adverse effects Kidney Failure.

Pere, H, Montier, Y, Bayry, J, Quintin-Colonna, F, Merillon, N, Dransart, E, Badoual, C, Gey, A, Ravel, P, Marcheteau, E, Batteux, F, Sandoval, F, Adotevi, O, Chiu, C, Garcia, S, Tanchot, C, Lone, YC, Ferreira, LC, Nelson, BH, Hanahan, D, Fridman, WH, Johannes, L & Tartour, E 2011, « A CCR4 antagonist combined with vaccines induces antigen-specific CD8+ T cells and tumor immunity against self antigens », Blood, vol. 118, no. 18, p. 4853-62, viewed sans date, .

Résumé : Regulatory T cells (Tregs) may impede cancer vaccine efficacy in hematologic malignancies and cancer. CCR4 antagonists, an emergent class of Treg inhibitor, have been shown to block recruitment of Tregs mediated by CCL22 and CCL17. Our aim was to demonstrate the ability of a CCR4 antagonist (a small chemical molecule identified in silico) when combined with vaccines to break peripheral tolerance controlled by Tregs, a prerequisite for the induction of CD8(+) T cells against self Ags. Immunization of transgenic or normal mice expressing tumor-associated self Ags (Her2/neu, OVA, gp100) with a CCR4 antagonist combined with various vaccines led to the induction of effector CD8(+) T cells and partial inhibition of tumor growth expressing self Ags in both prophylactic and therapeutic settings. The CCR4 antagonist was more efficient than cyclophosphamide to elicit anti-self CD8(+) T cells. We also showed that the population of Tregs expressing CCR4 corresponded to memory (CD44(high)) and activated (ICOS(+)) Tregs, an important population to be targeted to modulate Treg activity. CCR4 antagonist represents a competitive class of Treg inhibitor able to induce functional anti-self CD8(+) T cells and tumor growth inhibition when combined with vaccines. High expression of CCR4 on human Tregs also supports the clinical development of this strategy.

Mots-clés : Animal Female Humans Immunologic Factors/administration & dosage Mice Mice, Animals Antigens, CCR4/*antagonists & inhibitors T-Cell Antigen Receptor Specificity/drug effects/immunology Tumor Escape/*drug effects/immunology, Inbred C57BL Mice, Neoplasm/immunology Antineoplastic Agents/administration & dosage Autoantigens/drug effects/*immunology CD8-Positive T-Lymphocytes/*drug effects/immunology Cancer Vaccines/*administration & dosage Combined Modality Therapy Disease Models, Transgenic Neoplasms/genetics/immunology/pathology/*therapy Receptors.

Perier, A, Fregni, G, Wittnebel, S, Gad, S, Allard, M, Gervois, N, Escudier, B, Azzarone, B & Caignard, A 2011, « Mutations of the von Hippel-Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma », Oncogene, vol. 30, no. 23, p. 2622-32, viewed sans date, .

Résumé : The tumor suppressor gene von Hippel-Lindau (VHL) is involved in the development of sporadic clear-cell renal cell carcinoma (RCC). VHL interferes with angiogenesis and also controls cell adhesion and invasion. Therapies that target VHL-controlled genes are currently being evaluated in RCC patients. RCC is a immunogenic tumor and treatment with interleukin-2 (IL2) or interferon (IFN)-alpha results in regression in some patients. We used two renal tumor cell lines (RCC6 and RCC4) carrying VHL loss-of-function mutations to investigate the role of mutant VHL in susceptibility to natural killer (NK) cell-mediated lysis. The RCC6 and RCC4 cell lines were transfected with the wild-type gene to restore the function of VHL. The presence of the gene in RCC cells downregulated hypoxia-inducible factor (HIF)-1alpha and subsequently decreased vascular endothelial growth factor (VEGF) production. Relative to control transfectants and parental cells, pVHL-transfected cell lines activated resting and IL2-activated NK cells less strongly, as assessed by IFNgamma secretion, NK degranulation and cell lysis. NKG2A, a human leukocyte antigen (HLA)-I-specific inhibitory NK receptor, controls the lysis of tumor targets. We show that HLA-I expression in RCC-pVHL cells is stronger than that in parental and controls cells, although the expression of activating receptor NK ligands remains unchanged. Blocking NKG2A/HLA-I interactions substantially increased lysis of RCC-pVHL, but had little effect on the lysis of VHL-mutated RCC cell lines. In addition, in response to IFNalpha, the exponential growth of RCC-pVHL was inhibited more than that of RCC-pE cells, indicating that VHL mutations may be involved in IFNalpha resistance. These results indicate that a decreased expression of HLA-I molecules in mutated VHL renal tumor cells sensitizes them to NK-mediated lysis. These results suggest that combined immunotherapy with anti-angiogenic drugs may be beneficial for patients with mutated VHL.

Mots-clés : alpha Subunit/genetics/immunology/metabolism Interferon-alpha/pharmacology Interferon-gamma/immunology/metabolism Kidney Neoplasms/genetics/immunology/pathology Killer Cells, Blotting, Immunologic/*genetics/immunology Genetic Complementation Test Histocompatibility Antigens Class I/metabolism Humans Hypoxia-Inducible Factor 1, Natural/immunology/*metabolism *Mutation NK Cell Lectin-Like Receptor Subfamily C/metabolism RNA Interference Transfection Vascular Endothelial Growth Factor A/immunology/metabolism Von Hippel-Lindau Tumor Suppressor Protein/*genetics/metabolism, Renal Cell/genetics/immunology/pathology Cell Hypoxia Cell Line, Tumor Cell Proliferation/drug effects Cytotoxicity, Western Carcinoma.

Ples, R, Mechai, F, Champiat, B, Droupy, S, Huerre, M, Guettier, C & Ferlicot, S 2011, « [Pseudotumoral toxoplasmic cystitis revealing acquired immunodeficiency syndrome] », Ann Pathol, vol. 31, no. 1, p. 46-9, viewed sans date, .

Résumé : A case of bladder toxoplasmosis in a 57-year-old male Caucasian patient was diagnosed with difficulty due to misleading clinical presentation. The patient presented with pollakiuria and urination burning. Imagery showed pseudotumoral thickening of the vesicle wall. Previously unknown status of HIV infection was found positive through the diagnosis of bladder toxoplasmosis. The patient died rapidly from neurological complications. This is the second published case in which bladder toxoplasmosis reveals an HIV infection.

Mots-clés : Cerebral/diagnosis/etiology.

Recherche bibliographique scientifique

2011