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Biblio - Bibliographie IAL
Bibliographie IAL

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Recherche bibliographique scientifique

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Accueil > Références bibliographiques

biblio

2012

  • Fallot, G, Neuveut, C & Buendia, MA 2012, « Diverse roles of hepatitis B virus in liver cancer », Curr Opin Virol, vol. 2, no. 4, p. 467-73.
    Résumé : Hepatitis B virus (HBV) is a widespread human pathogen responsible for acute and chronic liver diseases. The hepatitis B burden is particularly heavy in endemic countries, where liver cirrhosis and hepatocellular carcinoma are leading causes of death. However, the oncogenic role of HBV remains enigmatic. As the virus has no cytopathic effect, liver damage is attributed to immune responses that induce inflammation, apoptosis and regeneration, fostering the accumulation of genetic and epigenetic alterations. In a more direct action, frequent integration of HBV DNA into host chromosomes may lead to insertional mutagenesis of cancer-related genes and chromosomal instability. HBV proteins, notably the HBx transactivator, participate as co-factors in oncogenesis. Better understanding of hepatitis B pathogenesis is mandatory for improving disease management.
    Mots-clés : Animals Carcinoma, Hepatocellular/genetics/metabolism/pathology/ virology Cell Transformation, Viral Gene Expression Regulation, Viral Hepatitis B virus/genetics/ physiology Humans Liver Neoplasms/genetics/metabolism/pathology/ virology Viral Proteins/genetics/metabolism Virus Integration.
  • Farges, O, Goutte, N, Bendersky, N & Falissard, B 2012, « Incidence and risks of liver resection: an all-inclusive French nationwide study », Ann Surg, vol. 256, no. 5, p. 697-704; discussion 704-5.
    Résumé : OBJECTIVE: To evaluate at a national level the incidence of liver resection, postoperative mortality, and variables that predict this outcome. BACKGROUND: Data on indications of and results of liver resection are mainly derived from high-volume centers. Nationwide data are lacking. METHODS: French health care databases were screened to identify all patients who had undergone elective hepatectomy between 2007 and 2010. The patients' age, address, associated conditions, indication and extent of hepatic (or extrahepatic) surgery and the hospital type, location, and hepatectomy caseload were retrieved. Logistic regression was used to measure the influence of these parameters on in-hospital and 90-day mortality rates. The model, created using patients operated on in 2007 and 2009, was tested in those operated on in 2008 and 2010. RESULTS: Overall, 28,708 hepatectomies were performed. The annual incidence (13.2 per 10 adult inhabitants) varied between regions, but the extremal quotient was limited to 2.2 because 15% of the operations took place outside the patients' home region. Hospitals performed a median of 4 resections per year but 53% of all resections were performed in institutions with a volume of more than 50 per year. Treatment for primary tumors and major resections correlated with hepatectomy caseload. In-hospital and 90-day mortality were 3.4% and 5.8%, respectively. The area under the receiver operating characteristic curve of the prognostic model was 0.78/0.77 in the training and validation sample. CONCLUSIONS: There were significant disparities in practice. In-hospital mortality underestimated true, postoperative mortality by more than 50%. The model created may be useful for more efficient regionalization of care and patient counseling.
    Mots-clés : 80 and over Female France/epidemiology Hepatectomy/ mortality/ statistics & numerical data Hospital Mortality Humans Incidence Liver Diseases/epidemiology/ surgery Logistic Models Male Middle Aged Risk Factors Survival Rate, Aged Aged.

  • Ferretti, L, Giuliani, M, Bessede, T, Qiu, X, Zhang, H, Alsaid, B, Durrbach, A, Giuliano, F, Benoit, G & Droupy, S 2012, « Tissue engineering for penile surgery: comparative study of noncellular and cell-seeded synthetic grafts for tunica albuginea replacement », J Sex Med, vol. 9, no. 2, p. 625-31, viewed sans date, .
    Résumé : INTRODUCTION: Surgical treatment outcomes in Peyronie's disease remain controversial because of high rates of recurrence. AIM: The aim of this study was to engineer in vitro a new type of tunica albuginea (TA) autologous graft obtained by culture of autologous fibroblast on a polyglycolic acid (PGA) scaffold. This engineering graft was compared with PGA with morphological and functional outcomes for TA replacement, 4 months after graft upon corpus cavernosum in a rat model. METHODS: Thirty-nine Sprague Dawley adult male rats were divided into four groups: (i) control group (C) with resection and resuture of a 5 mm long and 2 mm large piece of original TA; (ii) PGA scaffold group (P) with the same resection of TA and suture of PGA scaffold; (iii) autologous fibroblast-seeded on PGA scaffold graft after resection of the same piece of TA (F + P); and (iv) sham group for functional and histological comparison. MAIN OUTCOME MEASURE: The main outcome measure was assessment of graft size variation at 4 months and comparison between the three test groups. The secondary objective is assessment of erectile function by measuring erectile response to cavernous nerve electrical stimulation in each group. RESULTS: At 4 months, there was a significant difference in graft area retraction between the groups (P = 0.0081) with higher retraction in P group vs. in C or F + P groups. Erectile response to cavernous nerve stimulation significantly differed between the groups and was sham equivalent to C equivalent to F + P superior to P group. CONCLUSIONS: This study provides experimental evidence for the feasibility and the functionality of fibroblast-seeded scaffold compared with acellular graft for TA replacement.
    Mots-clés : Animals Fibroblasts/pathology/*transplantation Male Penile Erection/*physiology Penile Induration/*surgery Penis/*surgery Rats Rats, Autologous Treatment Outcome, Sprague-Dawley Tissue Engineering/*methods Transplantation.
  • Foucher, B, Johanet, C, Jego-Desplat, S, Sanmarco, M, Dubucquoi, S, Fily-Nalewajk, S, Olsson, NO, Lakomy, D, Escande, A, Chretien, P, Fortenfant, F, Chevailler, A, Andre, C, Goetz, J, Humbel, RL, Monier, JC, Sibilia, J, Taillefer, MF, Abreu, I & Fabien, N 2012, « Are immunoglobulin A anti-gliadin antibodies helpful in diagnosing coeliac disease in children younger than 2 years? », J Pediatr Gastroenterol Nutr, vol. 54, no. 1, p. 110-2.
    Résumé : The usefulness of immumoglobulin (Ig) A antibodies to gliadin (AGA-IgA) in addition to IgA anti-endomysium and tissue transglutaminase antibodies was evaluated in 4122 children younger than 2 years with a suspicion of coeliac disease (CD). Eight percent (312/4122) displayed IgA anti-endomysium and/or IgA anti-tissue transglutaminase, whereas 2.1% (85/4122) displayed only AGA-IgA. Clinical data were obtained for 62 of 85 children with isolated AGA-IgA, and 33 children underwent a duodenal biopsy. Histologically proven CD was established for 5 patients, whereas 57 children were diagnosed to experience other diseases. The systematic detection of AGA-IgA using native gliadin conferred no additional diagnostic benefit for the diagnosis of CD in children younger than 2 years of age, except for rare cases.
    Mots-clés : Anti-Idiotypic/ blood Biopsy Celiac Disease/ diagnosis/epidemiology/immunology Child, Antibodies, Preschool Duodenum/pathology Female Gliadin/ immunology Humans Immunoglobulin A/ blood Incidence Infant Male Transglutaminases/ immunology.
  • Germani, G, Theocharidou, E, Adam, R, Karam, V, Wendon, J, O'Grady, J, Burra, P, Senzolo, M, Mirza, D, Castaing, D, Klempnauer, J, Pollard, S, Paul, A, Belghiti, J, Tsochatzis, E & Burroughs, AK 2012, « Liver transplantation for acute liver failure in Europe: outcomes over 20 years from the ELTR database », J Hepatol, vol. 57, no. 2, p. 288-96.
    Résumé : BACKGROUND & AIMS: Liver transplantation for acute liver failure (ALF) still has a high early mortality. We evaluated changes during 20 years, and identified risk factors for poor outcome. METHODS: Donor, graft, and recipient variables from the European Liver Transplant Registry database (January 1988-June 2009), were analysed. Aetiologies and time periods were compared. Three and 12-month survival models were generated from separate training data sets, which were validated. A sub-analysis was performed for recipient older than 50 years. RESULTS: Four thousand nine hundred and three patients were evaluated. One, 5- and 10-year patient, and graft survival rates were 74%, 68%, 63%, and 63%, 57%, 50%, respectively. Survival was better in 2004-2009 compared to previous quinquennia (p<0.001), despite donors >60 years increased from 1.8% to 21%. A higher incidence of suicide or non-adherence occurred in paracetamol-related ALF (p<0.001). Death or graft loss were independently associated with male recipients (adjusted OR 1.25), recipient >50 years (1.26), incompatible ABO matching (1.93), donors >60 years (1.21), and reduced size graft (1.54). For both 3- and 12-month models, incompatible ABO matching, non-viral aetiology, reduced size graft, and non-UW preservation fluid were associated with increased mortality/graft loss, whereas male recipients and age >50 years were associated only at 12 months. Both models had reasonable discriminative ability with good calibration at 3 months. Recipients >50 years, combined with donors >60 years resulted in 57% mortality/graft loss within the first year. CONCLUSIONS: Survival after liver transplantation has improved despite increases in donor/recipient age. Recipients >50 years paired with donors >60 years had a very high mortality/graft loss within the first year.
    Mots-clés : Acute/ surgery Liver Transplantation/mortality Male Middle Aged Proportional Hazards Models Time Factors Tissue Donors Treatment Outcome, Adult Databases, Factual Europe Female Humans Liver Failure.

  • Giacchetti, S, Dugué, PA, Innominato, PF, Bjarnason, GA, Focan, C, Garufi, C, Tumolo, S, Coudert, B, Iacobelli, S, Smaaland, R, Tampellini, M, Adam, R, Moreau, T, Lévi, F & Group, ARTBCIC 2012, « Sex moderates circadian chemotherapy effects on survival of patients with metastatic colorectal cancer: a meta-analysis », Ann Oncol, vol. 23, no. 12, p. 3110-6, viewed sans date, .
    Résumé : BACKGROUND: Molecular circadian clocks can modify cancer chemotherapy effects, with a possible moderation according to sex differences. We investigated whether sex determine the optimal delivery schedule of chemotherapy for metastatic colorectal cancer. PATIENTS AND METHODS: A meta-analysis was performed using individual data from three international Phase III trials comparing 5-fluorouracil, leucovorin and oxaliplatin administered in chronomodulated (chronoFLO) or conventional (CONV) infusions. The data from 345 females and 497 males were updated at 9 years. The main end point was survival. RESULTS: Overall survival was improved in males on chronoFLO when compared with CONV (P = 0.009), with respective median values of 20.8 (95% CL, 18.7 to 22.9) and 17.5 months (16.1 to 18.8). Conversely, median survival was 16.6 months (13.9 to 19.3) on chronoFLO and 18.4 months (16.6 to 20.2) on CONV in females (P = 0.012). The sex versus schedule interaction was a strong predictive factor of optimal treatment schedule, with a hazard ratio of 1.59 (1.30 to 1.75) for overall survival (P = 0.002) in multivariate analysis. CONCLUSIONS: Males lived significantly longer on chronomodulated chemotherapy rather than on conventional chemotherapy. The current chronoFLO schedule deserves prospective assessment as a safe and more effective first-line treatment option than conventional delivery for male patients.
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  • Gines, P, Fernandez, J, Durand, F & Saliba, F 2012, « Management of critically-ill cirrhotic patients », J Hepatol, vol. 56 Suppl 1, p. S13-24.
    Résumé : Cirrhotic patients are prone to develop life-threatening complications that require emergency care and ICU admission. They can present specific decompensations related to cirrhosis such as variceal bleeding and hepatorenal syndrome (HRS) or other critical events also observed in the general population such as severe sepsis or septic shock. Clinical management of all these entities requires a specific approach in cirrhosis. Cirrhotic patients have a hyperdynamic circulation with high cardiac output and low systemic vascular resistance in the absence of infection. Circulatory dysfunction increases the susceptibility of critically-ill cirrhotic patients to develop multiple organ failure and attenuates vascular reactivity to vasopressor drugs. HRS, a severe functional renal failure occurring in patients with advanced cirrhosis and ascites, is also secondary to this circulatory dysfunction that leads to an extreme renal vasoconstriction. Moreover, hypotensive cirrhotic patients require a carefully balanced replacement of volemia, since overtransfusion increases portal hypertension and the risk of variceal bleeding and undertransfusion causes tissue hypoperfusion which increases the risk of multiple organ failure. Cirrhotic patients are also at a high risk for development of other bleeding complications and are more susceptible to nosocomial infections. This extreme complexity of critically-ill cirrhotic patients requires a specific medical approach that should be known by general intensivists since it has a negative impact on patient prognosis. This review will focus on the diagnostic approach and treatment strategies currently recommended in the critical care management of patients with cirrhosis.
    Mots-clés : Acute Kidney Injury/diagnosis/therapy Critical Care Esophageal and Gastric Varices/complications/diagnosis/therapy Gastrointestinal Hemorrhage/etiology/therapy Hepatic Encephalopathy/therapy Humans Liver Cirrhosis/ complications/ therapy Liver Failure, Acute/therapy Sepsis/diagnosis/therapy Severity of Illness Index Shock, Septic/diagnosis/therapy.


  • Giron-Michel, J, Azzi, S, Khawam, K, Mortier, E, Caignard, A, Devocelle, A, Ferrini, S, Croce, M, Francois, H, Lecru, L, Charpentier, B, Chouaib, S, Azzarone, B & Eid, P 2012, « Interleukin-15 plays a central role in human kidney physiology and cancer through the gammac signaling pathway », PLoS One, vol. 7, no. 2, p. e31624, viewed sans date, .
    Résumé : The ability of Interleukin-15 (IL-15) to activate many immune antitumor mechanisms renders the cytokine a good candidate for the therapy of solid tumors, particularly renal cell carcinoma. Although IL-15 is being currently used in clinical trials, the function of the cytokine on kidney's components has not been extensively studied; we thus investigated the role of IL-15 on normal and tumor renal epithelial cells. Herein, we analyzed the expression and the biological functions of IL-15 in normal renal proximal tubuli (RPTEC) and in their neoplastic counterparts, the renal clear cell carcinomas (RCC). This study shows that RPTEC express a functional heterotrimeric IL-15Ralphabetagammac complex whose stimulation with physiologic concentrations of rhIL-15 is sufficient to inhibit epithelial mesenchymal transition (EMT) commitment preserving E-cadherin expression. Indeed, IL-15 is not only a survival factor for epithelial cells, but it can also preserve the renal epithelial phenotype through the gammac-signaling pathway, demonstrating that the cytokine possess a wide range of action in epithelial homeostasis. In contrast, in RCC in vitro and in vivo studies reveal a defect in the expression of gammac-receptor and JAK3 associated kinase, which strongly impacts IL-15 signaling. Indeed, in the absence of the gammac/JAK3 couple we demonstrate the assembly of an unprecedented functional high affinity IL-15Ralphabeta heterodimer, that in response to physiologic concentrations of IL-15, triggers an unbalanced signal causing the down-regulation of the tumor suppressor gene E-cadherin, favoring RCC EMT process. Remarkably, the rescue of IL-15/gammac-dependent signaling (STAT5), by co-transfecting gammac and JAK3 in RCC, inhibits EMT reversion. In conclusion, these data highlight the central role of IL-15 and gammac-receptor signaling in renal homeostasis through the control of E-cadherin expression and preservation of epithelial phenotype both in RPTEC (up-regulation) and RCC (down-regulation).
    Mots-clés : Cadherins/metabolism Carcinoma, Proximal/drug effects/metabolism/*physiopathology *Signal Transduction/drug effects Solubility/drug effects Up-Regulation/drug effects.
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  • Griscelli, F, Féraud, O, Oudrhiri, N, Gobbo, E, Casal, I, Chomel, J-C, Biéche, I, Duvillard, P, Opolon, P, Turhan, AG & Bennaceur-Griscelli, A 2012, « Malignant germ cell-like tumors, expressing Ki-1 antigen (CD30), are revealed during in vivo differentiation of partially reprogrammed human-induced pluripotent stem cells », Am J Pathol, vol. 180, no. 5, p. 2084-96, viewed sans date, .
    Résumé : Because many of the genes used to produce induced pluripotent stem cells (iPSCs) from somatic cells are either outright established oncogenes, such as c-myc and Klf4, or potentially related to tumorigenesis in various cancers, both the safety and the risks of tumorigenesis linked to iPSC generation require evaluation. In this work, we generated, by lentivirus-mediated gene transfer of Oct4, Sox2, Nanog, and Lin28, two types of iPSCs from human mesenchymal stem cells and human amniotic fluid-derived cells: fully reprogrammed iPSCs with silencing of the four transgenes and partially reprogrammed iPSCs that still express one or several transgenes. We assessed the behavior of these cells during both their differentiation and proliferation using in vivo teratoma assays in nonobese diabetic mice with severe combined immunodeficiency. In contrast to fully reprogrammed iPSCs, 43% of partially reprogrammed iPSC cases (6 of 14 teratomas) generated major dysplasia and malignant tumors, with yolk sac tumors and embryonal carcinomas positive for α-fetoprotein, cytokeratin AE1/AE3, and CD30. This correlated with the expression of one or several transgenes used for the reprogramming, down-regulation of CDK 1A mRNA (p21/CDKN1A), and up-regulation of antiapoptotic Bcl-2 mRNA. Therefore, the oncogenicity of therapeutically valuable patient-specific iPSC-derived cells should be scrupulously evaluated before they are used for any clinical applications.
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    <p>22425713</p>
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  • Groheux, D, Hindié, E, Delord, M, Giacchetti, S, Hamy, A-sophie, de Bazelaire, C, de Roquancourt, A, Vercellino, L, Toubert, M-E, Merlet, P & Espié, M 2012, « Prognostic impact of (18)FDG-PET-CT findings in clinical stage III and IIB breast cancer », J Natl Cancer Inst, vol. 104, no. 24, p. 1879-87, viewed sans date, .
    Résumé : BACKGROUND: This study prospectively evaluated the yield of fluorodeoxyglucose positron emission tomography/computed tomography ((18)FDG-PET-CT) in patients with clinical stages II and III breast cancer and the impact of PET-CT results on prognosis. METHODS: In the course of 71 months, 254 consecutive patients with clinical stages II and III breast cancer (based on clinical examination, mammography, breast magnetic resonance imaging, and locoregional ultrasonography) underwent (18)FDG-PET-CT. The yield was assessed in the whole population and for each American Joint Committee on Cancer subgroup. The prognostic impact of PET-CT findings was analyzed. Tests of statistical significance were two-sided. RESULTS: (18)FDG-PET-CT changed the clinical stage in 77 of 254 patients (30.3%; 95% confidence interval [CI] = 25.0% to 36.2%). It showed unsuspected N3 disease (infraclavicular, supraclavicular, or internal mammary nodes) in 40 patients and distant metastases in 53. PET-CT revealed distant metastases in 2.3% (1 of 44) of clinical stage IIA, 10.7% (6 of 56) of stage IIB, 17.5% (11 of 63) of stage IIIA, 36.5% (27 of 74) of stage IIIB, and 47.1% (8 of 17) of stage IIIC patients. Among 189 patients with clinical stage IIB or higher disease and adequate follow-up, disease-specific survival was statistically significantly shorter in the 47 patients scored M1 on (18)FDG-PET-CT in comparison with those scored M0, with a three-year disease-specific survival of 57% vs 88% (P < .001). In multivariable analysis, only distant disease on PET-CT and triple-negative phenotype were statistically significant prognostic factors. The relative risk of death was 26.60 (95% CI = 6.60 to 102.62) for M1 vs M0 patients. CONCLUSIONS: The yield of (18)FDG-PET-CT appeared substantial in patients with clinical stage IIB or higher breast cancer. In these patients, (18)FDG-PET-CT provided powerful prognostic stratification.
    Note Note
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  • Groheux, D, Hindié, E, Giacchetti, S, Delord, M, Hamy, A-S, de Roquancourt, A, Vercellino, L, Berenger, N, Marty, M & Espié, M 2012, « Triple-negative breast cancer: early assessment with 18F-FDG PET/CT during neoadjuvant chemotherapy identifies patients who are unlikely to achieve a pathologic complete response and are at a high risk of early relapse », J Nucl Med, vol. 53, no. 2, p. 249-54, viewed sans date, .
    Résumé : UNLABELLED: Triple-negative breast cancer, an aggressive subtype, represents 15% of invasive breast tumors. This prospective study investigated whether early changes in (18)F-FDG tumor uptake during neoadjuvant chemotherapy (NAC) can predict outcomes. METHODS: Twenty (M0) patients underwent (18)F-FDG PET/CT at baseline and after the second cycle. NAC was continued irrespective of PET results. RESULTS: At surgery, 6 patients had a pathologic complete response, whereas 14 had residual tumor. Four patients showed early relapse (in the 2 y after surgery). There were 11 metabolic responders and 9 nonresponders using a 42% decrease in maximum standardized uptake value as a cutoff. In nonresponding patients, the risk of residual tumor at surgery was 100% (vs. 45% in responders; P = 0.014), and the risk of early relapse was 44% (vs. 0%; P = 0.024). CONCLUSION: A less than 42% decrease in (18)F-FDG uptake at 2 cycles means residual tumor at the end of NAC and a high risk of early relapse.
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  • Guediche, N, Tosca, L, Kara Terki, A, Bas, C, Lecerf, L, Young, J, Briand-Suleau, A, Tou, B, Bouligand, J, Brisset, S, Misrahi, M, Guiochon-Mantel, A, Goossens, M & Tachdjian, G 2012, « Array comparative genomic hybridization analysis of small supernumerary marker chromosomes in human infertility », Reprod Biomed Online, vol. 24, no. 1, p. 72-82, viewed sans date, .
    Résumé : Small supernumerary marker chromosomes (sSMC) are structurally abnormal chromosomes that cannot be unambiguously identified by conventional banding cytogenetics. This study describes four patients with sSMC in relation with infertility. Patient 1 had primary infertility. His brother, fertile, carried the same sSMC (patient 2). Patient 3 presented polycystic ovary syndrome and patient 4 primary ovarian insufficiency. Cytogenetic studies, array comparative genomic hybridization (CGH) and sperm analyses were compared with cases previously reported. sSMC corresponded to the 15q11.2 region (patients 1 and 2), the centromeric chromosome 15 region (patient 3) and the 21p11.2 region (patient 4). Array CGH showed 3.6-Mb gain for patients 1 and 2 and 0.266-Mb gain for patient 4. Sperm fluorescent in-situ hybridization analyses found ratios of 0.37 and 0.30 of sperm nuclei with sSMC(15) for patients 1 and 2, respectively (P < 0.001). An increase of sperm nuclei with disomy X, Y and 18 was noted for patient 1 compared with control and patient 2 (P < 0.001). Among the genes mapped in the unbalanced chromosomal regions, POTE B and BAGE are related to the testis and ovary, respectively. The implication of sSMC in infertility could be due to duplication, but also to mechanical effects perturbing meiosis.
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  • Guediche, N, Tosca, L, Nouchy, M, Lecerf, L, Cornet, D, Brisset, S, Goossens, M & Tachdjian, G 2012, « Small supernumerary marker chromosomes derived from chromosomes 6 and 20 in a woman with recurrent spontaneous abortions », Eur J Med Genet, vol. 55, no. 12, p. 737-42, viewed sans date, .
    Résumé : In this report, we describe a case of multiple small supernumerary marker chromosomes (sSMC) presenting with recurrent abortions. Peripheral blood lymphocytes of a young, healthy and non-consanguineous couple who asked for genetic evaluation after two spontaneous miscarriages were obtained for karyotypes. Lymphocytes of the woman were analyzed by FISH techniques and DNA was extracted and used for array CGH investigation. Karyotyping revealed 48,XX,+2mar[24]/47,XX,+mar[5]/46,XX[3] for the woman and 46,XY for her husband. FISH analysis showed that the two sSMC consisted of chromosomes 6 and 20. Array CGH analysis showed gains of the 6p11.2q12 (9 Mb) and 20 p11.21 (3.3 Mb) chromosomal regions with a total of 42 genes present on both sSMC. Our findings support also the hypothesis that the modification of the expression of some genes involved in embryo implantation, like THBD gene, could be responsible in the recurrent abortions. This report underpins the necessity of array CGH for characterizing precisely sSMC and helping in genotype-phenotype correlations. Furthermore, a literature review on sSMC is included.
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  • Haddad, V, Aboura, A, Tosca, L, Guediche, N, Mas, A-E, L'Herminé, AC, Druart, L, Picone, O, Brisset, S & Tachdjian, G 2012, « Tetrasomy 13q31.1qter due to an inverted duplicated neocentric marker chromosome in a fetus with multiple malformations », Am J Med Genet A, vol. 158A, no. 4, p. 894-900, viewed sans date, .
    Résumé : Small supernumerary marker chromosome (sSMC) lacking alpha satellite DNA or endogenous centromere regions are rare and contain fully functional centromeres, called neocentromeres. We report on a woman with a 14-week gestation pregnancy with a cystic hygroma and cerebellar hypoplasia at ultrasound examination. Cytogenetic studies showed a karyotype 47,XY,+mar dn. This sSMC was observed in chorionic villi, lung, and muscle tissue. Array Comparative Genomic Hybridization showed a gain from 13q31.1 to 13qter region. Fluorescent in situ hybridization with pan alpha satellite probe and probes specific for chromosome 13 showed a marker corresponding to an inversion duplication of the 13q distal chromosomal region without alpha satellite DNA sequence, suggesting the presence of a neocentromere. Examination of the fetus showed dysmorphic features, cystic cervical hygroma, postaxial polydactyly of the right hand and left foot with short fingers, malrotation of the gut, and a micropenis with hypospadias. Genotype-phenotype correlation in tetrasomy 13q is discussed according to the four 13q chromosomal breakpoints reported (13q32, 13q31, 13q21, 13q14) for chromosome 13 supernumerary markers.
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  • Haim-Boukobza, S, Ferey, MP, Vetillard, AL, Jeblaoui, A, Pelissier, E, Pelletier, G, Teillet, L & Roque-Afonso, AM 2012, « Transfusion-transmitted hepatitis E in a misleading context of autoimmunity and drug-induced toxicity », J Hepatol, vol. 57, no. 6, p. 1374-8.
    Résumé : Hepatitis E is currently diagnosed after all other causes of hepatitis have been excluded. Moreover, HEV testing is not performed to prevent blood transmission in developed countries. We report here on the case of a patient with acute hepatitis while receiving potentially hepatotoxic medications for autoimmune disorders, with low-level autoimmune markers and negative "standard" viral markers; it was finally determined that he was suffering from transfusion-transmitted hepatitis E.
    Mots-clés : 80 and over Autoimmune Diseases/ drug therapy Blood Transfusion/ adverse effects Drug-Induced Liver Injury/ etiology Female Hepatitis E/ etiology/transmission Humans Male Middle Aged, Aged Aged.

  • Hamy, A-S, Giacchetti, S, Albiter, M, de Bazelaire, C, Cuvier, C, Perret, F, Bonfils, S, Charvériat, P, Hocini, H, de Roquancourt, A & Espie, M 2012, « BI-RADS categorisation of 2,708 consecutive nonpalpable breast lesions in patients referred to a dedicated breast care unit », Eur Radiol, vol. 22, no. 1, p. 9-17, viewed sans date, .
    Résumé : OBJECTIVES: To determine the malignancy rate of nonpalpable breast lesions, categorised according to the Breast Imaging Reporting and Data System (BI-RADS) classification in the setting of a Breast Care Unit. METHODS: All nonpalpable breast lesions from consecutive patients referred to a dedicated Breast Care Unit were prospectively reviewed and classified into 5 BI-RADS assessment categories (0, 2, 3, 4, and 5). RESULTS: A total of 2708 lesions were diagnosed by mammography (71.6%), ultrasound (8.7%), mammography and ultrasound (19.5%), or MRI (0.2%). The distribution of the lesions by BI-RADS category was: 152 in category 0 (5.6%), 56 in category 2 (2.1%), 742 in category 3 (27.4%), 1523 in category 4 (56.2%) and 235 in category 5 (8.7%). Histology revealed 570 malignant lesions (32.9%), 152 high-risk lesions (8.8%), and 1010 benign lesions (58.3%). Malignancy was detected in 17 (2.3%) category 3 lesions, 364 (23.9%) category 4 lesions and 185 (78.7%) category 5 lesions. Median follow-up was 36.9 months. CONCLUSION: This pragmatic study reflects the assessment and management of breast impalpable abnormalities referred for care to a specialized Breast Unit. Multidisciplinary evaluation with BI-RADS classification accurately predicts malignancy, and reflects the quality of management. This assessment should be encouraged in community practice appraisal.
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  • Hassan, Q, Roche, B, Buffet, C, Bessede, T, Samuel, D, Charpentier, B & Durrbach, A 2012, « Liver-kidney recipients with chronic viral hepatitis C treated with interferon-alpha », Transpl Int, vol. 25, no. 9, p. 941-7, viewed sans date, .
    Résumé : Antiviral therapy with interferon-alpha (IFN-alpha) and pegylated IFN-alpha (PEG-IFN-alpha) for chronic hepatitis C (HCV)-infected kidney recipients remains controversial. IFN-alpha is not recommended in most cases because it induces severe acute graft rejection. However, IFN-alpha, as PEG-IFN-alpha, is associated with a more pronounced immune response, and is well tolerated in HCV-infected liver recipients without causing graft rejection. In combined liver-kidney transplant (LKT) recipients, IFN-alpha has been occasionally used and appears to be well tolerated. All LKT recipients with a functioning kidney and liver having a HCV replication and who needed IFN-alpha therapy have been included in the study. The occurrence of liver and/or renal acute rejection as well as the HCV replication has been collected. A total of 12 LKT patients treated with PEG-IFN-alpha plus ribavirin have been studied. No acute rejection was observed. Renal function remained stable during and after discontinuing treatment, without any graft dysfunction. Two patients had a partial viral response and four had a sustained viral response. All patients, whatever their viral response, had decreased liver-enzyme levels. Response to PEG-IFN-alpha therapy was correlated with steroid dose and transaminase level when PEG-IFN-alpha was started. These data suggest that the combination therapy of PEG-IFN-alpha plus ribavirin did not have a higher risk of acute kidney-graft rejection after liver-kidney transplantation.
    Mots-clés : Acute, Adult, Aged, Agents/therapeutic, Biopsy, C/*immunology/*virology, disease, Failure/*therapy/virology, Female, Graft, Hepatitis, Humans, Immunosuppressive, Insufficiency/*therapy/virology, Interferon-alpha/*therapeutic, Kidney, Liver, Liver/pathology, Male, Middle, Outcome, Recurrence, Rejection, Renal, Retrospective, Ribavirin/*therapeutic, Steroids/therapeutic, Studies, Transaminases/metabolism, Transplantation/*methods, Treatment, use.
  • Honda, A, Valogne, Y, Bou Nader, M, Brechot, C & Faivre, J 2012, « An intron-retaining splice variant of human cyclin A2, expressed in adult differentiated tissues, induces a G1/S cell cycle arrest in vitro », PLoS One, vol. 7, no. 6, p. e39249.
    Résumé : BACKGROUND: Human cyclin A2 is a key regulator of S phase progression and entry into mitosis. Alternative splice variants of the G1 and mitotic cyclins have been shown to interfere with full-length cyclin functions to modulate cell cycle progression and are therefore likely to play a role in differentiation or oncogenesis. The alternative splicing of human cyclin A2 has not yet been studied. METHODOLOGY/PRINCIPAL FINDINGS: Sequence-specific primers were designed to amplify various exon-intron regions of cyclin A2 mRNA in cell lines and human tissues. Intron retaining PCR products were cloned and sequenced and then overexpressed in HeLa cells. The subcellular localization of the splice variants was studied using confocal and time-lapse microscopy, and their impact on the cell cycle by flow cytometry, immunoblotting and histone H1 kinase activity. We found a splice variant of cyclin A2 mRNA called A2V6 that partly retains Intron 6. The gene expression pattern of A2V6 mRNA in human tissues was noticeably different from that of wild-type cyclin A2 (A2WT) mRNA. It was lower in proliferating fetal tissues and stronger in some differentiated adult tissues, especially, heart. In transfected HeLa cells, A2V6 localized exclusively in the cytoplasm whereas A2WT accumulated in the nucleus. We show that A2V6 induced a clear G1/S cell cycle arrest associated with a p21 and p27 upregulation and an inhibition of retinoblastoma protein phosphorylation. Like A2WT, A2V6 bound CDK2, but the A2V6/CDK2 complex did not phosphorylate histone H1. CONCLUSION/SIGNIFICANCE: This study has revealed that some highly differentiated human tissues express an intron-retaining cyclin A2 mRNA that induced a G1/S block in vitro. Contrary to full-length cyclin A2, which regulates cell proliferation, the A2V6 splice variant might play a role in regulating nondividing cell states such as terminal differentiation or senescence.
    Mots-clés : A2/genetics/, Cell, Cells, Cycle/genetics/, Cyclin, Cytometry, Differentiation/genetics/physiology, Flow, G1, genetics, HeLa, Humans, Introns/, Isoforms/genetics/, metabolism, Phase/genetics, physiology, Protein, S.
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  • Hrapczynski, KM, Epstein, NB, Werlinich, CA & LaTaillade, JJ 2012, « Changes in negative attributions during couple therapy for abusive behavior: relations to changes in satisfaction and behavior », J Marital Fam Ther, vol. 38 Suppl 1, p. 117-32, viewed sans date, .
    Résumé : This study examined effects of cognitive-behavioral couple therapy (n = 25 couples) and a variety of systems-oriented couple therapy models (n = 30 couples) in reducing negative attributions and degrees to which decreases in negative attributions were associated with improvements in other aspects of relationship functioning. Couples seeking treatment at a university clinic and experiencing psychological and/or mild-to-moderate physical abuse completed 10 weekly sessions. Attributions, relationship satisfaction, psychological abuse, communication, and negotiation were assessed before and after treatment. Women and men in both treatments exhibited decreased negative attributions, which moderated increases in satisfaction and decreases in negative communication, as well as increases in positive communication for men. The findings reinforce the importance of modifying negative attributions when intervening to reduce abuse.
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  • Innominato, PF, Giacchetti, S, Bjarnason, GA, Focan, C, Garufi, C, Coudert, B, Iacobelli, S, Tampellini, M, Durando, X, Mormont, M-C, Waterhouse, J & Lévi, FA 2012, « Prediction of overall survival through circadian rest-activity monitoring during chemotherapy for metastatic colorectal cancer », Int J Cancer, vol. 131, no. 11, p. 2684-92, viewed sans date, .
    Résumé : The clinical relevance of circadian rhythm modifications in patients on chemotherapy is unknown. Even so, circadian parameter I<O before chemotherapy independently predicted overall survival. This study investigates the relevance of I<O measured during chemotherapy for survival and symptoms. The circadian rest-activity pattern was monitored for 3 days using a wristwatch actigraph while 77 patients were receiving a chemotherapy course within an international randomized Phase III trial. Treatment consisted of first-line chronomodulated or conventional delivery of 5-fluorouracil, leucovorin and oxaliplatin for metastatic colorectal cancer. I<O was computed as the percentage of minutes of activity counts in bed which were below the median of activity out of bed. Circadian disruption was defined by I<O equal to or less than 97.5%. Circadian disruption occurred in 39 patients (51%) on chemotherapy. It was associated with a significantly shorter overall survival, independently of other prognostic factors (multivariate Hazard Ratio: 2.12; p = 0.004). The median survival of patients with a robust circadian rhythm was 22.3 months as compared to 14.7 months in those with circadian disruption during chemotherapy. No toxicity was significantly associated with circadian disruption, but the incidence of grade ≥ 2 fatigue and of body weight loss ≥ 5% was two and threefold higher, respectively, in patients with disrupted circadian rhythm on chemotherapy. Chemotherapy disrupted circadian activity rhythm in nearly 50% of the patients. Circadian disruption on chemotherapy predicted for shorter overall survival. The prevention of chemotherapy-induced circadian disruption might reduce toxicity and improve efficacy in cancer patients.
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  • Jarry, J, Wagner, T, de Pommerol, M, Sa Cunha, A & Collet, D 2012, « Laparoscopic Roux-en-Y gastric bypass: comparison between hand-sewn and mechanical gastrojejunostomy », Updates Surg, vol. 64, no. 1, p. 25-30.
    Résumé : The laparoscopic Roux-en-Y gastric bypass (LRYGB) is one of the ideal operations in the treatment of morbid obesity. There are several variations in the operation, especially during the construction of the gastrojejunostomy (GJA). From June 2006 to September 2008, 104 consecutive obese patients underwent LRYGB. The procedure was standardized, with the exception of the construction of the GJA, which was linear-stapled in 51 patients and hand-sewn in 53 other patients. A retrospective analysis was performed to compare the procedures. The series comprised 81 women and 23 men with a median age of 44 years, and a median BMI of 46.7 kg/m(2). There was no significant difference between the two groups of patients with respect to age, gender, BMI, ASA, and previously failed bariatric surgery. There was no significant difference between the two groups with respect to mortality, conversion, early reoperation, surgical complications, GJA leakage or stricture, and bariatric results. The only significant differences between the two groups were in regards to operating time (190 min for stapled GJA vs. 160 min for hand-sewn GJA, p value 0.029) and operating supply cost (100 Euros less for hand-sewn GJA). In our experience, hand-sewn GJA during LRYGB appears to be as safe as linear-stapled GJA and provides the same bariatric results while remaining slightly less expensive.
    Mots-clés : Adult Aged Body Mass Index Chi-Square Distribution Female Gastric Bypass/ methods Humans Male Middle Aged Obesity, Morbid/ surgery Retrospective Studies Statistics, Nonparametric Surgical Stapling Suture Techniques Time Factors Treatment Outcome Weight Loss.


  • Jimenez-Castro, MB, Elias-Miro, M, Mendes-Braz, M, Lemoine, A, Rimola, A, Rodes, J, Casillas-Ramirez, A & Peralta, C 2012, « Tauroursodeoxycholic acid affects PPARgamma and TLR4 in Steatotic liver transplantation », Am J Transplant, vol. 12, no. 12, p. 3257-71, viewed sans date, .
    Résumé : Numerous steatotic livers are discarded for transplantation because of their poor tolerance to ischemia-reperfusion (I/R). We examined whether tauroursodeoxycholic acid (TUDCA), a known inhibitor of endoplasmic reticulum (ER) stress, protects steatotic and nonsteatotic liver grafts preserved during 6 h in University of Wisconsin (UW) solution and transplanted. The protective mechanisms of TUDCA were also examined. Neither unfolded protein response (UPR) induction nor ER stress was evidenced in steatotic and nonsteatotic liver grafts after 6 h in UW preservation solution. TUDCA only protected steatotic livers grafts and did so through a mechanism independent of ER stress. It reduced proliferator-activated receptor-gamma (PPARgamma) and damage. When PPARgamma was activated, TUDCA did not reduce damage. TUDCA, which inhibited PPARgamma, and the PPARgamma antagonist treatment up-regulated toll-like receptor 4 (TLR4), specifically the TIR domain-containing adaptor inducing IFNbeta (TRIF) pathway. TLR4 agonist treatment reduced damage in steatotic liver grafts. When TLR4 action was inhibited, PPARgamma antagonists did not protect steatotic liver grafts. In conclusion, TUDCA reduced PPARgamma and this in turn up-regulated the TLR4 pathway, thus protecting steatotic liver grafts. TLR4 activating-based strategies could reduce the inherent risk of steatotic liver failure after transplantation.
    Mots-clés : Animals Antiviral Agents/pharmacology Blotting, Isogeneic Unfolded Protein Response/drug effects, Sprague-Dawley Rats, Western Endoplasmic Reticulum/drug effects/metabolism Fatty Liver/metabolism/*prevention & control *Liver Transplantation Male Obesity *Organ Preservation PPAR gamma/*metabolism Rats Rats, Wistar Rats, Zucker Reperfusion Injury/*prevention & control Taurochenodeoxycholic Acid/*pharmacology Toll-Like Receptor 4/*metabolism Transplantation.
  • Johanet, C & Ballot, E 2012, « Auto-antibodies in autoimmune hepatitis: anti-smooth muscle antibodies (ASMA) », Clin Res Hepatol Gastroenterol, vol. 36, no. 2, p. 189-91.
    Résumé : Johanet, Catherine; Ballot, Eric; France; Clin Res Hepatol Gastroenterol. 2012 Apr;36(2):189-91. doi: 10.1016/j.clinre.2011.10.012. Epub 2011 Dec 27.
    Mots-clés : Animals Autoantibodies/analysis/ immunology Hepatitis, Autoimmune/diagnosis/ immunology Humans Muscle, Smooth/ immunology.
  • Johanet, C & Ballot, E 2012, « Auto-antibodies in autoimmune hepatitis: anti-soluble liver antigen (SLA) », Clin Res Hepatol Gastroenterol, vol. 36, no. 3, p. 244-6.
    Résumé : Johanet, Catherine; Ballot, Eric; Review; France; Clin Res Hepatol Gastroenterol. 2012 Jun;36(3):244-6. doi: 10.1016/j.clinre.2011.10.013. Epub 2012 Feb 3.
    Mots-clés : Autoantibodies/ analysis Autoantigens/ analysis Biological Markers/analysis HLA-DR3 Antigen/analysis Hepatitis, Autoimmune/drug therapy/ immunology Humans Prognosis Recurrence Remission Induction Risk Assessment.
  • Johanet, C, Beleoken, E & Ballot, E 2012, « Autoantibodies in autoimmune hepatitis: antinuclear antibodies (ANA) », Clin Res Hepatol Gastroenterol, vol. 36, no. 4, p. 394-6.
    Résumé : Johanet, Catherine; Beleoken, Elvire; Ballot, Eric; Review; France; Clin Res Hepatol Gastroenterol. 2012 Aug;36(4):394-6. doi: 10.1016/j.clinre.2012.02.005. Epub 2012 Apr 4.
    Mots-clés : Antibodies, Antinuclear/ blood Hepatitis, Autoimmune/ blood/immunology Humans.
  • Kascakova, S, Maigre, L, Chevalier, J, Refregiers, M & Pages, JM 2012, « Antibiotic transport in resistant bacteria: synchrotron UV fluorescence microscopy to determine antibiotic accumulation with single cell resolution », PLoS One, vol. 7, no. 6, p. e38624.
    Résumé : A molecular definition of the mechanism conferring bacterial multidrug resistance is clinically crucial and today methods for quantitative determination of the uptake of antimicrobial agents with single cell resolution are missing. Using the naturally occurring fluorescence of antibacterial agents after deep ultraviolet (DUV) excitation, we developed a method to non-invasively monitor the quinolones uptake in single bacteria. Our approach is based on a DUV fluorescence microscope coupled to a synchrotron beamline providing tuneable excitation from 200 to 600 nm. A full spectrum was acquired at each pixel of the image, to study the DUV excited fluorescence emitted from quinolones within single bacteria. Measuring spectra allowed us to separate the antibiotic fluorescence from the autofluorescence contribution. By performing spectroscopic analysis, the quantification of the antibiotic signal was possible. To our knowledge, this is the first time that the intracellular accumulation of a clinical antibiotic could be determined and discussed in relation with the level of drug susceptibility for a multiresistant strain. This method is especially important to follow the behavior of quinolone molecules at individual cell level, to quantify the intracellular concentration of the antibiotic and develop new strategies to combat the dissemination of MDR-bacteria. In addition, this original approach also indicates the heterogeneity of bacterial population when the same strain is under environmental stress like antibiotic attack.
    Mots-clés : Anti-Bacterial Agents/ metabolism Bacteria/ metabolism Drug Resistance, Fluorescence/ methods Synchrotrons Ultraviolet Rays, Microbial Microscopy.
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  • Klionsky, DJ, Abdalla, FC, Abeliovich, H, Abraham, RT, Acevedo-Arozena, A, Adeli, K, Agholme, L, Agnello, M, Agostinis, P, Aguirre-Ghiso, JA, Ahn, HJ, Ait-Mohamed, O, Ait-Si-Ali, S, Akematsu, T, Akira, S, Al-Younes, HM, Al-Zeer, MA, Albert, ML, Albin, RL, Alegre-Abarrategui, J, Aleo, MF, Alirezaei, M, Almasan, A, Almonte-Becerril, M, Amano, A, Amaravadi, R, Amarnath, S, Amer, AO, Andrieu-Abadie, N, Anantharam, V, Ann, DK, Anoopkumar-Dukie, S, Aoki, H, Apostolova, N, Arancia, G, Aris, JP, Asanuma, K, Asare, NY, Ashida, H, Askanas, V, Askew, DS, Auberger, P, Baba, M, Backues, SK, Baehrecke, EH, Bahr, BA, Bai, XY, Bailly, Y, Baiocchi, R, Baldini, G, Balduini, W, Ballabio, A, Bamber, BA, Bampton, ET, Banhegyi, G, Bartholomew, CR, Bassham, DC, Bast, R. C., J, Batoko, H, Bay, BH, Beau, I, Bechet, DM, Begley, TJ, Behl, C, Behrends, C, Bekri, S, Bellaire, B, Bendall, LJ, Benetti, L, Berliocchi, L, Bernardi, H, Bernassola, F, Besteiro, S, Bhatia-Kissova, I, Bi, X, Biard-Piechaczyk, M, Blum, JS, Boise, LH, Bonaldo, P, Boone, DL, Bornhauser, BC, Bortoluci, KR, Bossis, I, Bost, F, Bourquin, JP, Boya, P, Boyer-Guittaut, M, Bozhkov, PV, Brady, NR, Brancolini, C, Brech, A, Brenman, JE, Brennand, A, Bresnick, EH, Brest, P, Bridges, D, Bristol, ML, Brookes, PS, Brown, EJ, Brumell, JH & others, 2012, « Guidelines for the use and interpretation of assays for monitoring autophagy », Autophagy, vol. 8, no. 4, p. 445-544, viewed sans date, .
    Résumé : In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
    Mots-clés : Animals *Autophagy/genetics Biological Assay/*methods Humans Models, Biological.
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  • Kobari, L, Yates, F, Oudrhiri, N, Francina, A, Kiger, L, Mazurier, C, Rouzbeh, S, El-Nemer, W, Hebert, N, Giarratana, M-C, François, S, Chapel, A, Lapillonne, H, Luton, D, Bennaceur-Griscelli, A & Douay, L 2012, « Human induced pluripotent stem cells can reach complete terminal maturation: in vivo and in vitro evidence in the erythropoietic differentiation model », Haematologica, vol. 97, no. 12, p. 1795-803, viewed sans date, .
    Résumé : BACKGROUND: Human induced pluripotent stem cells offer perspectives for cell therapy and research models for diseases. We applied this approach to the normal and pathological erythroid differentiation model by establishing induced pluripotent stem cells from normal and homozygous sickle cell disease donors. DESIGN AND METHODS: We addressed the question as to whether these cells can reach complete erythroid terminal maturation notably with a complete switch from fetal to adult hemoglobin. Sickle cell disease induced pluripotent stem cells were differentiated in vitro into red blood cells and characterized for their terminal maturation in terms of hemoglobin content, oxygen transport capacity, deformability, sickling and adherence. Nucleated erythroblast populations generated from normal and pathological induced pluripotent stem cells were then injected into non-obese diabetic severe combined immunodeficiency mice to follow the in vivo hemoglobin maturation. RESULTS: We observed that in vitro erythroid differentiation results in predominance of fetal hemoglobin which rescues the functionality of red blood cells in the pathological model of sickle cell disease. We observed, in vivo, the switch from fetal to adult hemoglobin after infusion of nucleated erythroid precursors derived from either normal or pathological induced pluripotent stem cells into mice. CONCLUSIONS: These results demonstrate that human induced pluripotent stem cells: i) can achieve complete terminal erythroid maturation, in vitro in terms of nucleus expulsion and in vivo in terms of hemoglobin maturation; and ii) open the way to generation of functionally corrected red blood cells from sickle cell disease induced pluripotent stem cells, without any genetic modification or drug treatment.
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  • Lacoste, C, Herve, J, Bou Nader, M, Dos Santos, A, Moniaux, N, Valogne, Y, Montjean, R, Dorseuil, O, Samuel, D, Cassio, D, Portulano, C, Carrasco, N, Brechot, C & Faivre, J 2012, « Iodide transporter NIS regulates cancer cell motility and invasiveness by interacting with the Rho guanine nucleotide exchange factor LARG », Cancer Res, vol. 72, no. 21, p. 5505-15.
    Résumé : A number of solute carrier (SLC) proteins are subject to changes in expression and activity during carcinogenesis. Whether these changes play a role in carcinogenesis is unclear, except for some nutrients and ion carriers whose deregulation ensures the necessary reprogramming of energy metabolism in cancer cells. In this study, we investigated the functional role in tumor progression of the sodium/iodide symporter (NIS; aka SLC5A5), which is upregulated and mislocalized in many human carcinomas. Notably, we found that NIS enhanced cell migration and invasion without ion transport being involved. These functions were mediated by NIS binding to leukemia-associated RhoA guanine exchange factor, a Rho guanine exchange factor that activates the small GTPase RhoA. Sequestering NIS in intracellular organelles or impairing its targeting to the cell surface (as observed in many cancers) led to a further increase in cell motility and invasiveness. In sum, our results established NIS as a carrier protein that interacts with a major cell signaling hub to facilitate tumor cell locomotion and invasion.
    Mots-clés : Cell Line, Genetic Two-Hybrid System Techniques, Small Interfering Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Signal Transduction/ physiology Symporters/ metabolism Transduction, Tumor Cell Movement/physiology Fluorescent Antibody Technique Guanine Nucleotide Exchange Factors/ metabolism Humans Immunoblotting Immunoprecipitation Neoplasm Invasiveness/ pathology RNA.

  • Larbi, A, Gombert, J-M, Auvray, C, l'Homme, B, Magniez, A, Féraud, O, Coulombel, L, Chapel, A, Mitjavila-Garcia, MT, Turhan, AG, Haddad, R & Bennaceur-Griscelli, A 2012, « The HOXB4 homeoprotein promotes the ex vivo enrichment of functional human embryonic stem cell-derived NK cells », PLoS One, vol. 7, no. 6, p. e39514, viewed sans date, .
    Résumé : Human embryonic stem cells (hESCs) can be induced to differentiate into blood cells using either co-culture with stromal cells or following human embryoid bodies (hEBs) formation. It is now well established that the HOXB4 homeoprotein promotes the expansion of human adult hematopoietic stem cells (HSCs) but also myeloid and lymphoid progenitors. However, the role of HOXB4 in the development of hematopoietic cells from hESCs and particularly in the generation of hESC-derived NK-progenitor cells remains elusive. Based on the ability of HOXB4 to passively enter hematopoietic cells in a system that comprises a co-culture with the MS-5/SP-HOXB4 stromal cells, we provide evidence that HOXB4 delivery promotes the enrichment of hEB-derived precursors that could differentiate into fully mature and functional NK. These hEB-derived NK cells enriched by HOXB4 were characterized according to their CMH class I receptor expression, their cytotoxic arsenal, their expression of IFNγ and CD107a after stimulation and their lytic activity. Furthermore our study provides new insights into the gene expression profile of hEB-derived cells exposed to HOXB4 and shows the emergence of CD34(+)CD45RA(+) precursors from hEBs indicating the lymphoid specification of hESC-derived hematopoietic precursors. Altogether, our results outline the effects of HOXB4 in combination with stromal cells in the development of NK cells from hESCs and suggest the potential use of HOXB4 protein for NK-cell enrichment from pluripotent stem cells.
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  • Lavergne, M, Derkaoui, M, Delmau, C, Letourneur, D, Uzan, G & Le Visage, C 2012, « Porous polysaccharide-based scaffolds for human endothelial progenitor cells », Macromol Biosci, vol. 12, no. 7, p. 901-10, viewed sans date, .
    Résumé : Human ECFCs contribute to vascular repair. For this reason, they are considered as valuable cell therapy products in ischemic diseases. Porous scaffolds are prepared that are composed of natural polysaccharides, pullulan and dextran, by chemical crosslinking without use of organic solvents. These porous scaffolds, which have pores with an average size of 42 µm and a porosity of 21%, preserve the viability and the proliferation of cord-blood ECFCs. After 7 d of culture in porous scaffolds, ECFCs express endothelial markers (CD31 and vWf) and maintain endothelial functions. The cultured cells can be easily retrieved by enzymatic degradation of the porous scaffolds. In vitro results suggest that the porous scaffold could allow cell delivery of ECFCs for treatment of vascular diseases.
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  • Le Bousse-Kerdilès, M-C 2012, « Primary myelofibrosis and the "bad seeds in bad soil" concept », Fibrogenesis Tissue Repair, vol. 5 Suppl 1, p. S20, viewed sans date, .
    Résumé : Primary Myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by a clonal myeloproliferation and a myelofibrosis. The concomitant presence of neoangiogenesis and osteosclerosis suggests a deregulation of medullar stem cell niches in which hematopoietic stem cells are engaged in a constant crosstalk with their stromal environment. Despite the recently discovered mutations including the JAK2Val617F mutation, the primitive molecular event responsible for the clonal hematopoietic proliferation is still unknown. We propose that the "specificity" of the pathological process that caracterizes PMF results from alterations in the cross talk between hematopoietic and stromal cells. These alterations contribute in creating a abnormal microenvironment that participates in the maintenance of the neoplasic clone leading to a misbalance disfavouring normal hematopoiesis; in return or simultaneously, stromal cells constituting the niches are modulated by hematopoietic cells resulting in stroma dysfunctions. Therefore, PMF is a remarkable "model" in which deregulation of the stem cell niche is of utmost importance for the disease development. A better understanding of the crosstalk between stem cells and their niches should imply new therapeutic strategies targeting not only intrinsic defects in stem cells but also regulatory niche-derived signals and, consequently, hematopoietic cell proliferation.
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  • Le Guelte, A, Galan-Moya, EM, Dwyer, J, Treps, L, Kettler, G, Hebda, JK, Dubois, S, Auffray, C, Chneiweiss, H, Bidere, N & Gavard, J 2012, « Semaphorin 3A elevates endothelial cell permeability through PP2A inactivation », J Cell Sci, vol. 125, no. Pt 17, p. 4137-46, viewed sans date, .
    Résumé : VE-cadherin-mediated cell-cell junction weakening increases paracellular permeability in response to both angiogenic and inflammatory stimuli. Although Semaphorin 3A has emerged as one of the few known anti-angiogenic factors to exhibit pro-permeability activity, little is known about how it triggers vascular leakage. Here we report that Semaphorin 3A induced VE-cadherin serine phosphorylation and internalisation, cell-cell junction destabilisation, and loss of barrier integrity in brain endothelial cells. In addition, high-grade glioma-isolated tumour-initiating cells were found to secrete Semaphorin 3A, which promoted brain endothelial monolayer permeability. From a mechanistic standpoint, Semaphorin 3A impinged upon the basal activity of the serine phosphatase PP2A and disrupted PP2A interaction with VE-cadherin, leading to cell-cell junction disorganization and increased permeability. Accordingly, both pharmacological inhibition and siRNA-based knockdown of PP2A mimicked Semaphorin 3A effects on VE-cadherin. Hence, local Semaphorin 3A production impacts on the PP2A/VE-cadherin equilibrium and contributes to elevated vascular permeability.
    Mots-clés : Animals Brain/metabolism/pathology Brain Neoplasms/enzymology/pathology/secretion Cell Line, Inbred C57BL Neoplastic Stem Cells/secretion Protein Phosphatase 2/antagonists & inhibitors/*metabolism Semaphorin-3A/*metabolism src-Family Kinases/metabolism, Tumor *Cell Membrane Permeability Endothelial Cells/*enzymology/*pathology Enzyme Activation Glioma/enzymology/pathology/secretion Humans Mice Mice.
  • Le Naour, F, Sandt, C, Peng, C, Trcera, N, Chiappini, F, Flank, AM, Guettier, C & Dumas, P 2012, « In situ chemical composition analysis of cirrhosis by combining synchrotron fourier transform infrared and synchrotron X-ray fluorescence microspectroscopies on the same tissue section », Anal Chem, vol. 84, no. 23, p. 10260-6.
    Résumé : Liver is subject to various chronic pathologies, progressively leading to cirrhosis, which is associated with an increased risk of hepatocellular carcinoma. There is an urgent need for diagnostic and prognostic markers of chronic liver diseases and liver cancer. Spectroscopy-based approaches can provide an overview of the chemical composition of a tissue sample offering the possibility of investigating in depth the subtle chemical changes associated with pathological states. In this study, we have addressed the composition of cirrhotic liver tissue by combining synchrotron Fourier transform infrared (FTIR) microspectroscopy and synchrotron micro-X-ray fluorescence (XRF) on the same tissue section using a single sample holder in copper. This allowed investigation of the in situ biochemical as well as elemental composition of cells and tissues at high spatial resolution. Cirrhosis is characterized by regeneration nodules surrounded by annular fibrosis. Hepatocytes within cirrhotic nodules were characterized by high content in esters and sugars as well as in phosphorus and iron compared with fibrotic septa. A high heterogeneity was observed between cirrhotic nodules in their content in sugars and iron. On fibrosis, synchrotron XRF revealed enrichment in calcium compared to cirrhotic hepatocytes. Careful scrutiny of tissue sections led to detection of the presence of microcrystals that were demonstrated as precipitates of calcite using synchrotron FTIR. These results demonstrated that synchrotron FTIR and synchrotron XRF microspectroscopies provide complementary information on the chemical composition of cirrhotic hepatocytes and fibrotic septa in cirrhosis.

  • Lebacle, C, Pignot, G, Mateus, C, Bigot, P, Rocher, L, Ferlicot, S & Patard, JJ 2012, « Metastatic melanoma in upper urinary tract: three cases and literature review », Prog Urol, vol. 22, no. 12, p. 736-9, viewed sans date, .
    Résumé : Melanoma is a slowly growing malignancy, with potential distant metastasis at various sites. In this article, we reported three original cases of melanoma metastases in the upper urinary tract, and we achieved a literature review. Symptoms are inconstant and non-specific (pain or haematuria). Nephroureterectomy is performed in the majority of cases. Even if this metastatic location remains uncommon, it should be timely detected in order to allow an appropriate management and to improve the prognostic of melanoma.
    Mots-clés : Aged, Female, Hematuria/etiology, Humans, Male, Melanoma/*pathology/surgery, Middle, Neoplasms/*pathology, Neoplasms/*pathology/surgery, Nephrectomy, Skin, Ureter/surgery, Urologic.
  • Levesque, E, Hoti, E, Azoulay, D, Honore, I, Guignard, B, Vibert, E, Ichai, P, Antoun, F, Saliba, F & Samuel, D 2012, « Pulmonary complications after elective liver transplantation-incidence, risk factors, and outcome », Transplantation, vol. 94, no. 5, p. 532-8.
    Résumé : After liver transplantation (LT), postoperative pulmonary complications (PPC) occur in approximately 35% to 50% of the recipients. Among these PPC, pneumonia is the most frequently encountered. Pulmonary dysfunction has also been widely reported among patients awaiting LT. The links between this dysfunction and PPC have not been clearly established. In this present cohort study, we evaluated the incidence and profile of post-LT pneumonia and identified potential preoperative risk factors. METHODS: The postoperative clinical course of 212 liver transplant recipients between January 2008 and April 2010 was analyzed. These patients were treated in a single intensive care unit and received standardized postoperative care. RESULTS: During the postoperative period, 47 (22%) patients developed pneumonia, of whom 20 (43%) developed respiratory failure requiring mechanical ventilation. Univariate analysis showed that several preoperative factors (age of recipient, model for end-stage liver disease score, indication for LT, platelet count, and restrictive lung pattern revealed by preoperative pulmonary function tests) and the transfusion (blood units and fresh frozen plasma units) during the operative period were associated with pneumonia. Using multivariate analysis by logistic regression, only a restrictive lung pattern (odds ratio=3.14; 95% confidence interval, 1.51-6.51; P=0.002) and the international normalized ratio measured prior LT (OR=4.95; 95% confidence interval, 1.86-8.59; P=0.0004) were independent predictors of pneumonia after LT. CONCLUSION: Pneumonia is common among patients undergoing LT and is a major cause of morbidity. A restrictive pattern on preoperative pulmonary testing and a higher international normalized ratio measured prior LT were associated with more risk of postoperative pneumonia.
    Mots-clés : Adolescent Adult Aged Female France/epidemiology Hospital Mortality Humans Incidence Length of Stay Liver Transplantation/ adverse effects/mortality Logistic Models Male Middle Aged Multivariate Analysis Odds Ratio Pneumonia, Artificial Respiratory Insufficiency/etiology/therapy Risk Assessment Risk Factors Spirometry Surgical Procedures, Bacterial/diagnosis/ epidemiology/microbiology/mortality/therapy Predictive Value of Tests Respiration, Elective Time Factors Treatment Outcome Young Adult.


  • Levesque, E, Hoti, E, Azoulay, D, Ichaï, P, Habouchi, H, Castaing, D, Samuel, D & Saliba, F 2012, « Prospective evaluation of the prognostic scores for cirrhotic patients admitted to an intensive care unit », J Hepatol, vol. 56, no. 1, p. 95-102, viewed sans date, .
    Résumé : BACKGROUND & AIMS: Cirrhotic patients admitted to an Intensive Care Unit (ICU) have a poor prognosis. Identifying patients in whom ICU care will be useful can be challenging. The aim of this study was to assess the predictive value of prognostic scores with respect to mortality and to identify mortality risk factors. METHODS: Three hundred and seventy-seven cirrhotic patients admitted to a Liver ICU between May 2005 and March 2009 were enrolled in this study. Their average age was 55.5±11.4 years. The etiology of cirrhosis was alcohol (68%), virus hepatitis (18%), or mixed (5.5%). The main causes of hospitalization were gastrointestinal hemorrhage (43%), sepsis (19%), and hepatic encephalopathy (12%). RESULTS: ICU and in-hospital mortality rates were 34.7% and 43.0%, respectively. Infection was the major cause of death (81.6%). ROC curve analysis demonstrated that SOFA (0.92) and SAPS II (0.89) scores calculated within 24h of admission predicted ICU mortality better than the Child-Pugh score (0.79) or MELD scores with (0.79-0.82) or without the incorporation of serum sodium levels (0.82). Statistical analysis showed that the prognostic severity scores, organ replacement therapy, and infection were accurate predictors of mortality. On multivariate analysis, mechanical ventilation, vasopressor therapy, bilirubin level at admission, and infection were independently associated with ICU mortality. CONCLUSIONS: For cirrhotic patients admitted to the ICU, SAPS II, and SOFA scores predicted ICU mortality better than liver-specific scores. Mechanical ventilation or vasopressor therapy, bilirubin levels at admission and infection in patients with advanced cirrhosis were associated with a poor outcome.
    Mots-clés : Artificial Risk Factors Severity of Illness Index Vasoconstrictor Agents/therapeutic use.
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  • Martel, C, Esposti, DD, Bouchet, A, Brenner, C & Lemoine, A 2012, « Non-alcoholic steatohepatitis: new insights from OMICS studies », Curr Pharm Biotechnol, vol. 13, no. 5, p. 726-35, viewed sans date, .
    Résumé : Non-alcoholic fatty liver disease (NAFLD) is the most common liver pathology characterized by fat accumulation in a context of metabolic syndrome or insulin resistance. It can be associated with obesity, diabetes, hyperinsulinemia, dyslipidemia as well as hypertension. NAFLD consists of a large spectrum of hepatic lesions including benign steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis or hepatocellular carcinoma. Upon chronic stress, NASH would occur via at least "two-hits" process involving modulation of a high number of genes and proteins. Firstly, the accumulation of fat, either due to the increased inflow of free fatty acids or de novo lipogenesis, leads to steatosis. Secondly, when adaptive mechanisms for stress tolerance are overwhelmed, lipotoxicity and chronic inflammation trigger major hepatic damages, mainly via oxidative and inflammatory stress, lipid peroxidation and cell death. As a consequence, all these processes concur to favor steatohepatitis, fibrosis and cancer. Recently, the elucidation of physiopathological signaling cascades controlling NAFLD and NASH benefited from large-scale studies, namely the omics, such as transcriptomics, genomics, proteomics, and lipidomics. The advent of lipidomics would allow shedding light upon the respective roles of triglyceride and fatty acid metabolites in the lipotoxic liver injury hypothesis for the pathogenesis of NASH. In this review, the contribution of the omics to the understanding of the molecular basis of NASH is discussed that could offer perspectives for novel biomarkers discovery.
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  • Mathoulin-Pelissier, S, Becouarn, Y, Belleannee, G, Pinon, E, Jaffre, A, Coureau, G, Auby, D, Renaud-Salis, JL & Rullier, E 2012, « Quality indicators for colorectal cancer surgery and care according to patient-, tumor-, and hospital-related factors », BMC Cancer, vol. 12, p. 297.
    Résumé : BACKGROUND: Colorectal cancer (CRC) care has improved considerably, particularly since the implementation of a quality of care program centered on national evidence-based guidelines. Formal quality assessment is however still needed. The aim of this research was to identify factors associated with practice variation in CRC patient care. METHODS: CRC patients identified from all cancer centers in South-West France were included. We investigated variations in practices (from diagnosis to surgery), and compliance with recommended guidelines for colon and rectal cancer. We identified factors associated with three colon cancer practice variations potentially linked to better survival: examination of >/= 12 lymph nodes (LN), non-use and use of adjuvant chemotherapy for stage II and stage III patients, respectively. RESULTS: We included 1,206 patients, 825 (68%) with colon and 381 (32%) with rectal cancer, from 53 hospitals. Compliance was high for resection, pathology report, LN examination, and chemotherapy use for stage III patients. In colon cancer, 26% of stage II patients received adjuvant chemotherapy and 71% of stage III patients. 84% of stage US T3T4 rectal cancer patients received pre-operative radiotherapy. In colon cancer, factors associated with examination of >/= 12 LNs were: lower ECOG score, advanced stage and larger hospital volume; factors negatively associated were: left sided tumor location and one hospital district. Use of chemotherapy in stage II patients was associated with younger age, advanced stage, emergency setting and care structure (private and location); whereas under-use in stage III patients was associated with advanced age, presence of comorbidities and private hospitals. CONCLUSIONS: Although some changes in practices may have occurred since this observational study, these findings represent the most recent report on practices in CRC in this region, and offer a useful methodological approach for assessing quality of care. Guideline compliance was high, although some organizational factors such as hospital size or location influence practice variation. These factors should be the focus of any future guideline implementation.
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  • Mattos, RO, Linhares, MM, Matos, D, Adam, R, Bismuth, H, Castaing, D & Azoulay, D 2012, « Liver re-transplantation: internal validation of a predictive mathematical model of survival », Hepatogastroenterology, vol. 59, no. 116, p. 1230-3.
    Résumé : BACKGROUND/AIMS: Because of the worse results from re-transplantation, a model for determining the long-term survival has been previously developed. Its effectiveness had to be tested and validated, as proposed in this study, using a different sample population than the one used to build it. METHODOLOGY: Age, recipient creatinine, urgency of re-transplantation, interval between primary liver transplant and re-transplantation (RETx) of 92 patients that received first liver RETx, from a different sample of patients, in a different time period than those used to develop the initial model. The proposed mathematical model was used to predict survival at six months after undergoing liver RETx. We compared the areas under the ROC curves (AROC) corresponding to the two independent samples (derivation and validation samples). By the log-rank technique, the survival curves were also compared and classified into tertiles according to the risk scores of the original model: high risk (>32), medium risk (24-32) and low risk (<24). RESULTS: Age, creatinine, time between primary liver transplant and re-transplantation and the urgency with which patients were enrolled, had comparable survival curves among the derivation and validation samples. When comparing the AROC of the derivation (0.733) and validation (0.741) samples, there was no statistically significant difference (p=0.915), therefore sensitivity and specificity ratios between the two are similar. CONCLUSIONS: This study made it possible to internally validate the original model for predicting survival at six months after undergoing liver RETx, although an external validation still needs to be done.
    Mots-clés : Adolescent Adult Child Child, Preschool Female Humans Infant Liver Transplantation/ mortality Male Middle Aged Models, Theoretical ROC Curve Reoperation.

  • Mayeur-Rousse, C, Sorel, N, Voldoire, M, Canioni, D, Brizard, F, Randriamalala, E, Turhan, AG & Chomel, J-C 2012, « Unique association of systemic mastocytosis and myeloid/lymphoid neoplasm in blast crisis with abnormality of FGFR1 gene », Leuk Res, vol. 36, no. 3, p. 377-81, viewed sans date, .
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  • Merle, N, Féraud, O, Gilquin, B, Hubstenberger, A, Kieffer-Jacquinot, S, Assard, N, Bennaceur-Griscelli, A, Honnorat, J & Baudier, J 2012, « ATAD3B is a human embryonic stem cell specific mitochondrial protein, re-expressed in cancer cells, that functions as dominant negative for the ubiquitous ATAD3A », Mitochondrion, vol. 12, no. 4, p. 441-8, viewed sans date, .
    Résumé : Here we report on the identification of a human pluripotent embryonic stem cell (hESC) specific mitochondrial protein that is re-expressed in cancer cells, ATAD3B. ATAD3B belongs to the AAA+ ATPase ATAD3 protein family of mitochondrial proteins specific to multicellular eukaryotes. Using loss- and gain-of-function approaches, we show that ATAD3B associates with the ubiquitous ATAD3A species, negatively regulates the interaction of ATAD3A with matrix nucleoid complexes and contributes to a mitochondria fragmentation phenotype. We conclude that ATAD3B is a negative regulator of ATAD3A and may function as an adaptor of mitochondrial homeostasis and metabolism in hESCs and cancer cells.
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  • Mihaila, L, Defrance, G, Levesque, E, Ichai, P, Garnier, F, Derouin, V, Decousser, JW, Doucet-Populaire, F & Bourgeois-Nicolaos, N 2012, « A dual outbreak of bloodstream infections with linezolid-resistant Staphylococcus epidermidis and Staphylococcus pettenkoferi in a liver Intensive Care Unit », Int J Antimicrob Agents, vol. 40, no. 5, p. 472-4.
    Résumé : Mihaila, L; Defrance, G; Levesque, E; Ichai, P; Garnier, F; Derouin, V; Decousser, J W; Doucet-Populaire, F; Bourgeois-Nicolaos, N; Letter; Research Support, Non-U.S. Gov't; Netherlands; Int J Antimicrob Agents. 2012 Nov;40(5):472-4. doi: 10.1016/j.ijantimicag.2012.06.014. Epub 2012 Aug 9.
    Mots-clés : Acetamides/ pharmacology Adult Aged Anti-Bacterial Agents/ pharmacology Cross Infection/ epidemiology/microbiology DNA, Bacterial Female Humans Intensive Care Units Male Microbial Sensitivity Tests Middle Aged Molecular Sequence Data Oxazolidinones/ pharmacology Sequence Analysis, Bacterial/chemistry/genetics Disease Outbreaks Drug Resistance, DNA Staphylococcal Infections/ epidemiology/microbiology Staphylococcus/classification/ drug effects/genetics/isolation & purification.

  • Miro, JM, Montejo, M, Castells, L, Rafecas, A, Moreno, S, Aguero, F, Abradelo, M, Miralles, P, Torre-Cisneros, J, Pedreira, JD, Cordero, E, de la Rosa, G, Moyano, B, Moreno, A, Perez, I & Rimola, A 2012, « Outcome of HCV/HIV-coinfected liver transplant recipients: a prospective and multicenter cohort study », Am J Transplant, vol. 12, no. 7, p. 1866-76, viewed sans date, .
    Résumé : Eighty-four HCV/HIV-coinfected and 252-matched HCV-monoinfected liver transplant recipients were included in a prospective multicenter study. Thirty-six (43%) HCV/HIV-coinfected and 75 (30%) HCV-monoinfected patients died, with a survival rate at 5 years of 54% (95% CI, 42-64) and 71% (95% CI, 66 to 77; p = 0.008), respectively. When both groups were considered together, HIV infection was an independent predictor of mortality (HR, 2.202; 95% CI, 1.420-3.413 [p < 0.001]). Multivariate analysis of only the HCV/HIV-coinfected recipients, revealed HCV genotype 1 (HR, 2.98; 95% CI, 1.32-6.76), donor risk index (HR, 9.48; 95% CI, 2.75-32.73) and negative plasma HCV RNA (HR, 0.14; 95% CI, 0.03-0.62) to be associated with mortality. When this analysis was restricted to pretransplant variables, we identified three independent factors (HCV genotype 1, pretransplant MELD score and centers with <1 liver transplantation/year in HIV-infected patients) that allowed us to identify a subset of 60 (71%) patients with a similar 5-year prognosis (69%[95% CI, 54-80]) to that of HCV-monoinfected recipients. In conclusion, 5-year survival in HCV/HIV-coinfected liver recipients was lower than in HCV-monoinfected recipients, although an important subset with a favorable prognosis was identified in the former.
  • Moniaux, N, Darnaud, M, Dos Santos, A, Jamot, L, Samuel, D, Amouyal, P, Amouyal, G, Brechot, C & Faivre, J 2012, « [HIP/PAP, a new drug for acute liver failure] », Med Sci (Paris), vol. 28, no. 3, p. 239-41.
    Résumé : Moniaux, Nicolas; Darnaud, Marion; Dos Santos, Alexandre; Jamot, Laure; Samuel, Didier; Amouyal, Paul; Amouyal, Gilles; Brechot, Christian; Faivre, Jamila; News; France; Med Sci (Paris). 2012 Mar;28(3):239-41. doi: 10.1051/medsci/2012283004. Epub 2012 Apr 6.
    Mots-clés : Acetaminophen/toxicity Acute Disease Animals Antigens, Animal Drug Evaluation, Biological/adverse effects/ physiology/therapeutic use, C-Type/ physiology/therapeutic use Liver Failure/ drug therapy Liver Regeneration Mice Mice, CD95/agonists Antigens, Inbred C57BL Mice, Neoplasm/adverse effects/ physiology/therapeutic use Clinical Trials, Phase I as Topic Clinical Trials, Phase II as Topic Disease Models, Preclinical Drug-Induced Liver Injury/drug therapy/etiology Hepatitis/ drug therapy/etiology Humans Lectins, Transgenic Multicenter Studies as Topic Reactive Oxygen Species/metabolism Recombinant Proteins/adverse effects/therapeutic use Tumor Markers.

  • Moulin, B, Merville, P, Renaudin, K, Buob, D, Ferlicot, S, Delahousse, M, Dantal, J, Albano, L, Barbet, C, Mourad, G & Noel, LH 2012, « Evaluation of protocol biopsy utility 12 months after renal transplantation: a multicenter observational analysis », J Transplant, vol. 2012, p. 781263, viewed sans date, .
    Résumé : The clinical merit of surveillance kidney graft biopsies remains controversial. A retrospective, multicenter analysis evaluated 12-month surveillance biopsies (SB, 154 patients) versus no SB (NSB, 138 patients (11 with diagnostic biopsy)) in patients >18 months posttransplant with estimated GFR (eGFR) >/=30 mL/min. The primary objective was to describe renal function at 18 months post-transplant in patients with or without SB at month 12. Globally, most recipients in both cohorts were at low immunological risk (<10% of patients with PRA >/=30%). The immunosuppressive regimen remained unchanged following more than half of SB that exhibited chronic lesions (18/33, 54.5%). Mean (SD) eGFR at month 18 (primary endpoint) was 56 (19) mL/min/1.73 m(2) with SB and 54 (15) mL/min/1.73 m(2) with NSB (P = 0.48). In the SB group, slight nonspecific changes were observed in 51 cases, rejection (acute or chronic) in 6 cases, CNI-related toxicity in 15 cases, recurrence of initial disease in two cases, and interstitial fibrosis/tubular atrophy (IF/TA) in 83 cases (71.6%), of which 35 cases (30.2%) were grade II/III lesions. eGFR <50 mL/min/1.73 m(2) at month 6 predicted IF/TA grade II or III (OR 3.85, 95% CI 1.64, 9.05, P < 0.002). SB at 12 months posttransplant did not prompt significant modification of immunosuppression, and no renal benefit was observed.
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  • Nalpas, B, Francoz, C, Ichai, P, Jamot, L, Faivre, J, Lemoinne, S, Samuel, D, Durand, F, Bernuau, J, Brechot, C, Amouyal, P & Amouyal, G 2012, « Prothrombin index slope is an early prognostic marker in patients with severe acute liver diseases », Gut, vol. 61, no. 7, p. 1098-100.
    Résumé : Nalpas, Bertrand; Francoz, Claire; Ichai, Philippe; Jamot, Laure; Faivre, Jamila; Lemoinne, Sara; Samuel, Didier; Durand, Francois; Bernuau, Jacques; Brechot, Christian; Amouyal, Paul; Amouyal, Gilles; Comment; Letter; England; Gut. 2012 Jul;61(7):1098-100. doi: 10.1136/gutjnl-2011-301316. Epub 2011 Oct 24.
    Mots-clés : Female Hemodynamics/ physiology Humans Hypertension, Portal/ blood Liver Cirrhosis/ blood Male von Willebrand Factor/ metabolism.
  • Neumann, U, Samuel, D, Trunecka, P, Gugenheim, J, Gerunda, GE & Friman, S 2012, « A Randomized Multicenter Study Comparing a Tacrolimus-Based Protocol with and without Steroids in HCV-Positive Liver Allograft Recipients », J Transplant, vol. 2012, p. 894215.
    Résumé : Allograft reinfection with hepatitis C virus (HCV) occurs universally in liver transplant recipients. Corticosteroids can contribute to HCV recurrence. This randomized study evaluated HCV recurrence in HCV-positive liver allograft recipients using steroid-free immunosuppression. All patients received tacrolimus (TAC) at an initial dose of 0.10-0.15 mg/kg. The steroid-free arm (TAC/daclizumab (TAC/DAC, n = 67)) received daclizumab induction, and the steroid arm (TAC/steroid (TAC/STR, n = 68)) received a steroid bolus (</= 500mg) followed by 15-20 mg/day with discontinuation after month 3. Median HCV viral load at month 12, the primary endpoint, was similar at 5.46 (0.95-6.54) IU/mL with TAC/DAC and 5.91 (0.95-6.89) IU/mL with TAC/STR. Small numerical differences in the estimated rate of freedom from HCV recurrence (19.1 versus 13.8%) and freedom from biopsy proven rejection (78.4 versus 66.1%) were observed between TAC/DAC and TAC/STR. Patient survival estimates were significantly lower with TAC/DAC than with TAC/STR (83.1 versus 95.5%; 95% CI, -0.227 to -0.019%), and graft survival was numerically lower (80.1 versus 91.1%, P = NS). Completion rates (45 versus 82%) indicated poorer tolerability with TAC/DAC than with TAC/STR. Steroid-free immunosuppression had no real impact on HCV viral load. HCV recurrence was higher with TAC/STR. Results are inconclusive due to the unexpected lower completion rates in the TAC/DAC arm.
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  • Nordlinger, B, Adam, R, Arnold, D, Zalcberg, JR & Gruenberger, T 2012, « The role of biological agents in the resection of colorectal liver metastases », Clin Oncol (R Coll Radiol), vol. 24, no. 6, p. 432-42, viewed sans date, .
    Résumé : Surgically resecting liver metastases from colorectal cancer (CLMs) offers the only potentially curative option. Chemotherapy-induced downsizing of CLMs increases the proportion of patients with resectable metastases. Several recent studies have reported that adding a biological agent such as cetuximab, panitumumab or bevacizumab to chemotherapy could further increase response and resectability rates. This overview discusses the reported resection rates for biological agents combined with chemotherapy and the difficulties of cross-trial comparisons, the pre-, peri- and postoperative roles of biological agents, particularly with regards to comparisons of surgical complications, and ongoing clinical trials in which the resectability of CLMs is a predefined end point. Currently, targeted therapies combined with chemotherapy probably increase the resection rate of CLMs, although this has been shown in only one phase III randomised study and it is difficult to draw definitive conclusions about the relative efficacy and safety of the different available biological agents in terms of converting unresectable CLMs to resectable lesions. Available data for each of them are discussed. More data from phase III trials are expected to confirm the utility of the different biological agents in converting patients with unresectable CLMs to a resectable status.
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  • Nouet, Y, Dahan, J, Labalette, C, Levillayer, F, Julien, B, Jouvion, G, Cairo, S, Vives, FL, Ribeiro, A, Huerre, M, Colnot, S, Perret, C, Nhieu, JT, Tordjmann, T, Buendia, MA & Wei, Y 2012, « The four and a half LIM-only protein 2 regulates liver homeostasis and contributes to carcinogenesis », J Hepatol, vol. 57, no. 5, p. 1029-36.
    Résumé : BACKGROUND & AIMS: The four and a half LIM-only protein 2 (FHL2) is upregulated in diverse pathological conditions. Here, we analyzed the effects of FHL2 overexpression in the liver of FHL2 transgenic mice (Apo-FHL2). METHODS: We first examined cell proliferation and apoptosis in Apo-FHL2 livers and performed partial hepatectomy to investigate high FHL2 expression in liver regeneration. Expression of FHL2 was then analyzed by real time PCR in human hepatocellular carcinoma and adjacent non-tumorous livers. Finally, the role of FHL2 in hepatocarcinogenesis was assessed using Apo-FHL2;Apc(lox/lox) mice. RESULTS: Six-fold increase in cell proliferation in transgenic livers was associated with concomitant apoptosis, resulting in normal liver mass. In Apo-FHL2 livers, both cyclin D1 and p53 were markedly increased. Evidence supporting a p53-dependent cell death mechanism was provided by the findings that FHL2 bound to and activated the p53 promoter, and that a dominant negative p53 mutant compromised FHL2-induced apoptosis in hepatic cells. Following partial hepatectomy in Apo-FHL2 mice, hepatocytes displayed advanced G1 phase entry and DNA synthesis leading to accelerated liver weight restoration. Interestingly, FHL2 upregulation in human liver specimens showed significant association with increasing inflammation score and cirrhosis. Finally, while Apo-FHL2 mice developed no tumors, the FHL2 transgene enhanced hepatocarcinogenesis induced by liver-specific deletion of the adenomatous polyposis coli gene and aberrant Wnt/beta-catenin signaling in Apc(lox/lox) animals. CONCLUSIONS: Our results implicate FHL2 in the regulation of signaling pathways that couple proliferation and cell death machineries, and underscore the important role of FHL2 in liver homeostasis and carcinogenesis.
    Mots-clés : Animal Female Hepatectomy Homeostasis/ physiology Humans LIM-Homeodomain Proteins/genetics/ metabolism Liver/ metabolism/ pathology/surgery Liver Neoplasms/metabolism/pathology/surgery Liver Regeneration/physiology Male Mice Mice, Animals Apoptosis/physiology Carcinoma, Hepatocellular/metabolism/pathology/surgery Cell Proliferation Cell Transformation, Neoplastic/ metabolism/ pathology Cyclin D1/metabolism Disease Models, Transgenic Muscle Proteins/genetics/ metabolism Transcription Factors/genetics/ metabolism Tumor Suppressor Protein p53/metabolism.

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