Biblio

Gelu-Simeon, M, Burlaud, A, Young, J, Pelletier, G & Buffet, C 2009, « Evolution and predictive factors of thyroid disorder due to interferon alpha in the treatment of hepatitis C », World J Gastroenterol, vol. 15, no. 3, p. 328-33.

Résumé : AIM: To study predictive factors of thyroid dysfunction associated with interferon-alpha (IFNalpha) therapy in chronic hepatitis C (CHC) and to describe its long-term evolution in a large population without previous thyroid dysfunction. METHODS: We performed a follow-up of thyroid function and detection of thyroid antibodies in 301 patients treated for CHC with IFNalpha from 1999 to 2004. RESULTS: Thyroid disorder developed in 30/301 (10%) patients with a mean delay of 6 +/- 3.75 mo: 13 patients had hyperthyroidism, 11 had hypothyroidism, and 6 had biphasic evolution. During a mean follow-up of 41.59 +/- 15.39 mo, 9 patients with hyperthyroidism, 3 with hypothyroidism, and 4 with biphasic evolution normalized thyroid function in 7.88 +/- 5.46 mo. Recovery rate of dysthyroidism was not modified by treatment discontinuation, but was better for patients with negative thyroid antibodies before antiviral treatment (P = 0.02). Women had significantly more dysthyroidism (P = 0.05). Positive thyroid peroxidase and thyroglobulin antibodies were more frequent before antiviral treatment in patients who developed dysthyroidism (P < 0.0003 and P = 0.0003, respectively). In a multivariate model, low fibrosis was found to be a predictive factor of dysthyroidism (P = 0.039). CONCLUSION: In this monocentric population of CHC, dysthyroidism, especially hyperthyroidism, developed in 10% of patients. Low fibrosis was found to be a predictive factor of dysthyroidism. Thyroid disorder recovered in 16/30 patients (53%) and recovery was better in the non-autoimmune form.

Mots-clés : Adult, Aged, Agents/adverse, Antiviral, Autoantibodies/immunology, C/diagnosis/, chemically, Diseases/, drug, effects/therapeutic, Female, Fibrosis/pathology, Follow-Up, Hepatitis, Humans, induced/classification/pathology, Interferon-alpha/adverse, Male, Middle, Studies, Therapy, Thyroid, use.

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Giron-Michel, J, Menard, F, Negrini, S, Devocelle, A, Azzarone, B & Besson, C 2009, « EBV-associated mononucleosis does not induce long-term global deficit in T-cell responsiveness to IL-15 », Blood, vol. 113, no. 19, p. 4541-7, viewed sans date, .

Résumé : It has been reported that infectious mononucleosis (IM)-symptomatic primary Epstein-Barr virus infection produces a global down-regulation of interleukin-15 receptor-alpha (IL-15Ralpha) on T cells and natural killer cells associated with a defective IL-15 responsiveness that lasts for many years after the disease episode. In contrast with these results, our data indicate that, in the T-cell compartment derived from remote IM subjects, there is no quantitative or qualitative defect in the expression of the IL-15Ralpha chain and no deficit in T-cell responsiveness to IL-15. We observed efficient signal transduction, survival, and proliferation even in response to low IL-15 concentrations. These data are relevant and shed new light on the immune long-term response in IM subjects because they contradict the hypothesis that defects in Epstein-Barr virus-host immune balance may be correlated with a long-lasting global deficit in T-cell responsiveness to IL-15.

Mots-clés : Apoptosis/physiology Blotting, Human/*pathogenicity Humans Infectious Mononucleosis/*immunology/virology Interleukin-15/*pharmacology Interleukin-15 Receptor alpha Subunit/metabolism Phosphorylation STAT5 Transcription Factor, Western CD8-Positive T-Lymphocytes/cytology/*immunology/virology Case-Control Studies Epstein-Barr Virus Infections/*immunology/virology Flow Cytometry Herpesvirus 4.

Goldman, O, Feraud, O, Boyer-Di Ponio, J, Driancourt, C, Clay, D, Le Bousse-Kerdiles, M-C, Bennaceur-Griscelli, A & Uzan, G 2009, « A boost of BMP4 accelerates the commitment of human embryonic stem cells to the endothelial lineage », Stem Cells, vol. 27, no. 8, p. 1750-9, viewed sans date, .

Résumé : Embryoid bodies (EBs) generated during differentiation of human embryonic stem cells (hESCs) contain vascular-like structures, suggesting that commitment of mesoderm progenitors into endothelial cells occurs spontaneously. We showed that bone morphogenetic protein 4 (BMP4), an inducer of mesoderm, accelerates the peak expression of CD133/kinase insert domain-containing receptor (KDR) and CD144/KDR. Because the CD133(+)KDR(+) population could represent endothelial progenitors, we sorted them at day 7 and cultured them in endothelial medium. These cells were, however, unable to differentiate into endothelial cells. Under standard conditions, the CD144(+)KDR(+) population represents up to 10% of the total cells at day 12. In culture, these cells, if sorted, give rise to a homogeneous population with a morphology typical of endothelial cells and express endothelial markers. These endothelial cells derived from the day 12 sorted population were functional, as assessed by different in vitro assays. When EBs were stimulated by BMP4, the CD144(+)KDR(+) peak was shifted to day 7. Most of these cells, however, were CD31(-), becoming CD31(+) in culture. They then expressed von Willebrand factor and were functional. This suggests that, initially, the BMP4-boosted day 7, CD144(+)KDR(+)CD31(-) population represents immature endothelial cells that differentiate into mature endothelial cells in culture. The expression of OCT3/4, a marker of immaturity for hESCs decreases during EB differentiation, decreasing faster following BMP4 induction. We also show that BMP4 inhibits the global expression of GATA2 and RUNX1, two transcription factors involved in hemangioblast formation, at day 7 and day 12.

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Groheux, D, Moretti, J-L, Giacchetti, S, Hindié, E, Teyton, P, Cuvier, C, Bousquet, G, Misset, J-L, Boin, C & Espié, M 2009, « [PET/CT in breast cancer: an update] », Bull Cancer, vol. 96, no. 11, p. 1053-70, viewed sans date, .

Résumé : The authors discuss the various roles of 18F-FDG PET/CT in the management of breast cancer. Roles of new tracers such as F-18 fluoro-L-thymidine (a marker of cell proliferation), 18-fluoro-17-B-estradiol (marker of estrogen receptor) and sodium fluoride (marker of bone matrix) are also mentioned. There is little justification for the use of FDG-PET/CT in patient with clinically T1 (< or = 2 cm) N0 tumours. Notably, it cannot be used as a substitute to SLNB "sentinel lymph node biopsy" for axillary staging due to limited sensitivity for the detection of small metastases. The case is different in higher risk patients, and especially so in patients with locally advanced disease. FDG-PET/CT in these patients might depict lymph node involvement in the level III of Berg or in supraclavicular or internal mammary basins. It might also uncover occult distant metastases, notably, early osteomedullary infiltration. Thus, for these tumors, initial PET/CT can enable better intramodality treatment planning or a change in treatment. PET/CT as a whole-body examination is also very efficient in case of suspicion of recurrence. On the other hand, many studies show that this functional imaging could be used to assess early response to neoadjuvant chemotherapy or to chemotherapy of metastatic disease. 18FDG-PET/CT could thus become an unavoidable modality to answer various clinical situations.

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Groheux, D, Hindié, E, Rubello, D, Espié, M, Baillet, G, Giacchetti, S, Misset, J-L & Moretti, J-L 2009, « Should FDG PET/CT be used for the initial staging of breast cancer? », Eur J Nucl Med Mol Imaging, vol. 36, no. 10, p. 1539-42, viewed sans date, .

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Guerin, F, Porras, J, Fabre, M, Guettier, C, Pariente, D, Bernard, O & Gauthier, F 2009, « Liver nodules after portal systemic shunt surgery for extrahepatic portal vein obstruction in children », J Pediatr Surg, vol. 44, no. 7, p. 1337-43.

Résumé : BACKGROUND: Liver nodules have been reported after portal systemic shunt surgery (PSSS) in animal experiments or in humans with liver cirrhosis. The aim of our study was to assess the incidence of liver nodules after surgery for extrahepatic portal vein obstruction (EHPVO) in children without associated liver disease. METHODS: We retrospectively reviewed the charts of 45 children who had surgery from 1979 to 2005 for EHPVO in our institution, consisting of 38 PSSS and 7 portal reperfusion procedures (PRPs). We assessed the presence of liver nodules on ultrasonography. RESULTS: Of 45 patients, 7 (15%) had liver nodules during a median of 80 months of follow-up. All the nodules occurred after PSSS. Five nodules were subjected to biopsy; we found 2 liver cell adenomas and 3 focal nodular hyperplasias. CONCLUSIONS: In this study, liver nodules occurred in 18% of cases after PSSS for EHPVO in children and not after PRP. As many children have undergone PSSS throughout the world, the presence of liver nodules should be considered during the follow-up of those patients.

Mots-clés : Biopsy Child Child, Differential Female Focal Nodular Hyperplasia/ etiology/pathology/ultrasonography Follow-Up Studies Humans Infant Infant, Newborn Magnetic Resonance Imaging Male Portal Vein Portasystemic Shunt, Preschool Diagnosis, Surgical/ adverse effects/methods Postoperative Complications Retrospective Studies Time Factors Venous Thrombosis/diagnosis/ surgery.

Guillois-Becel, Y, Couturier, E, Le Saux, JC, Roque-Afonso, AM, Le Guyader, FS, Le Goas, A, Pernes, J, Le Bechec, S, Briand, A, Robert, C, Dussaix, E, Pommepuy, M & Vaillant, V 2009, « An oyster-associated hepatitis A outbreak in France in 2007 », Euro Surveill, vol. 14, no. 10.

Résumé : Following the notification of nine hepatitis A cases clustered in the Cotes d Armor district in northwestern France, epidemiological, environmental and microbiological investigations were set up in order to identify the source and vehicle of contamination and implement control measures. In total, 111 cases were identified in the outbreak, all of whom lived or had stayed as tourists in the Cotes d Armor district. Of the cases, 87% had eaten raw shellfish, and 81% specifically oysters. Traceback investigations carried out on raw shellfish consumed by the cases showed that the raw shellfish originated from a single shellfish farm. The shellfish were probably contaminated either in the submersible tanks or in a depuration land-based tank where they were stored. The source of contamination was not identified but shellfish could have been tainted by sewage overflows or by wastewater releases from a polluted storm sewer close to the shellfish farm or from on-site sanitation facilities. To prevent future hepatitis A outbreaks due to shellfish consumption from this area, hazards specific to each farm should be analysed. Timely information on sewage overflows should also be part of communities efforts regarding sewage collection and treatment.

Mots-clés : &, A, A/, Assessment/methods, Contamination/, data, disease, Diseases/, epidemiology, epidemiology/virology, Factors, Food, Foodborne, France/epidemiology, Hepatitis, Humans, Incidence, numerical, Outbreaks/, Population, purification, Risk, Shellfish/, statistics, Surveillance, virology, virus/isolation.

Hajj, P, Ferlicot, S, Massoud, W, Awad, A, Hammoudi, Y, Charpentier, B, Durrbach, A, Droupy, S & Benoit, G 2009, « Prevalence of renal cell carcinoma in patients with autosomal dominant polycystic kidney disease and chronic renal failure », Urology, vol. 74, no. 3, p. 631-4, viewed sans date, .

Résumé : OBJECTIVES: To study the prevalence and the characteristics of renal cell carcinoma (RCC) in patients with autosomal dominant polycystic kidney disease (ADPKD) in our series. METHODS: We reviewed retrospectively all the nephrectomies performed in our department between 1982 and 2003 in patients with ADPKD and chronic renal failure. RESULTS: Seventy-nine patients (42 males and 37 females) with ADPKD and chronic renal failure underwent 89 nephrectomies; in 10 of 79, both kidneys were removed but not simultaneously. Mean age was 50.4 years (range, 32-69 years). Of 79 patients, 50 had end-stage renal disease (ESRD) and were on hemodialysis or had received a transplant for >1 year. On histologic examination, 11 of 89 kidneys were diagnosed with carcinomas. There was 1 patient with bilateral tumor (tubulopapillary Ca) and 3 kidneys (27.3%) with multifocal tumors. Regarding the histologic type, there were 7 of 12 (58.3%) clear cell carcinomas and the remaining 5 (41.7%) were tubulopapillary carcinomas. CONCLUSIONS: The prevalence of RCC was higher in patients with ADPKD and ESRD, with >1 year on dialysis or renal transplantation undergoing nephrectomy according the protocol. It would be 2 to 3 times more frequent than RCC in patients with ESRD alone. The clinician should maintain a high alert of suspicion for RCC in such patients.

Mots-clés : Autosomal Dominant/*complications/surgery Prevalence Retrospective Studies, Carcinoma, Chronic/*complications Kidney Neoplasms/*complications/*epidemiology/surgery Male Middle Aged Polycystic Kidney, Renal Cell/*complications/*epidemiology/surgery Female Humans Kidney Failure.

Hashibe, M, Brennan, P, Chuang, S-C, Boccia, S, Castellsague, X, Chen, C, Curado, MP, Dal Maso, L, Daudt, AW, Fabianova, E, Fernandez, L, Wünsch-Filho, V, Franceschi, S, Hayes, RB, Herrero, R, Kelsey, K, Koifman, S, La Vecchia, C, Lazarus, P, Levi, F, Lence, JJ, Mates, D, Matos, E, Menezes, A, McClean, MD, Muscat, J, Eluf-Neto, J, Olshan, AF, Purdue, M, Rudnai, P, Schwartz, SM, Smith, E, Sturgis, EM, Szeszenia-Dabrowska, N, Talamini, R, Wei, Q, Winn, DM, Shangina, O, Pilarska, A, Zhang, Z-F, Ferro, G, Berthiller, J & Boffetta, P 2009, « Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium », Cancer Epidemiol Biomarkers Prev, vol. 18, no. 2, p. 541-50, viewed sans date, .

Résumé : BACKGROUND: The magnitude of risk conferred by the interaction between tobacco and alcohol use on the risk of head and neck cancers is not clear because studies have used various methods to quantify the excess head and neck cancer burden. METHODS: We analyzed individual-level pooled data from 17 European and American case-control studies (11,221 cases and 16,168 controls) participating in the International Head and Neck Cancer Epidemiology consortium. We estimated the multiplicative interaction parameter (psi) and population attributable risks (PAR). RESULTS: A greater than multiplicative joint effect between ever tobacco and alcohol use was observed for head and neck cancer risk (psi = 2.15; 95% confidence interval, 1.53-3.04). The PAR for tobacco or alcohol was 72% (95% confidence interval, 61-79%) for head and neck cancer, of which 4% was due to alcohol alone, 33% was due to tobacco alone, and 35% was due to tobacco and alcohol combined. The total PAR differed by subsite (64% for oral cavity cancer, 72% for pharyngeal cancer, 89% for laryngeal cancer), by sex (74% for men, 57% for women), by age (33% for cases <45 years, 73% for cases >60 years), and by region (84% in Europe, 51% in North America, 83% in Latin America). CONCLUSIONS: Our results confirm that the joint effect between tobacco and alcohol use is greater than multiplicative on head and neck cancer risk. However, a substantial proportion of head and neck cancers cannot be attributed to tobacco or alcohol use, particularly for oral cavity cancer and for head and neck cancer among women and among young-onset cases.

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Hindié, E, Groheux, D, Espie, M, Bourstyn, E, Toubert, M-E, Sarandi, F, de Roquancourt, A, Giacchetti, S, Cuvier, C, Cahen-Doidy, L, Teyton, P, Misset, J-L, Maylin, C & Moretti, J-L 2009, « [Sentinel node biopsy in breast cancer] », Bull Cancer, vol. 96, no. 6, p. 713-25, viewed sans date, .

Résumé : As compared to conventional axillary dissection, the sentinel node technique is accompanied by reduced morbidity and shorter hospital stay. Based on available data, the use of this technique does not seem to yield higher rates of axillary recurrence. A combination of both radioisotope detection and blue dye increases the identification rate, while also reducing false-negative rate. Surgical results are optimized when preoperative lymphoscintigraphy mapping is obtained in addition to peroperative probe detection. Considering the site of injection, the subareolar injection can be easy to apply even in case of non-palpable tumours, and gives higher count rates. However, the intraparenchymal, peritumoral, injection is necessary to evidence cases of extra-axillary drainage (internal mammary, infra- or supraclavicular) that is present in about 20% of patients. With the advent of hybrid cameras (SPECT-CT), the topography of these extra-axillary nodes can be given with high precision. Use of the sentinel node technique has been accompanied by an increase in the percent of patients with node involvement, due to an increased detection of micrometastases inferior or equal to 2 mm. Following an overview of basic principles, and of the main results with the sentinel node technique we focus the discussion on several points that are still open to debate, such as: 1) which group of patients can benefit from the sentinel node technique? 2) What is the optimal methodology? 3) What is the prognostic significance of micrometastases and of isolated tumour cells? 4) What attention should be given to extra-axillary drainage?

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Honoré, C, Vibert, E, Hoti, E, Azoulay, D, Adam, R & Castaing, D 2009, « Management of excluded segmental bile duct leakage following liver resection », HPB (Oxford), vol. 11, no. 4, p. 364-9, viewed sans date, .

Résumé : BACKGROUND: Postoperative bile leak secondary to a fistula is a known complication of hepatic surgery. Four different biliary fistula sub-types have been described: type A refers to minor leakage from the bile duct stump; type B to major leakage caused by insufficient closure of the bile duct stump; type C to major leakage caused by injury to the bile duct, and type D (the rarest) to the division and exclusion of a bile duct. This complication results from functional liver parenchyma in which bile drainage is excluded from the main duct. METHODS: A retrospective review of the database for 163 patients diagnosed with post-hepatic surgery bile leak from April 1992 to June 2007 was performed. RESULTS: Three patients were found to have type D biliary fistula, with durations of 3-21 months. The bile leak developed after a right hepatectomy in two patients and a right hepatectomy extending to segment IV in one patient. All three patients were rescheduled for surgical exploration, following failure of medical treatment. The procedure consisted of repeat resection of the independent liver parenchyma containing the fistula. One patient developed a postoperative leak from a hepaticojejunal anastomosis (treated conservatively) and the other two patients had an uneventful recovery. No recurrence of bile leak was encountered during their follow-up. CONCLUSIONS: Our experience indicates that conservative treatment is deceptive and not efficacious. For this condition, surgical intervention is the treatment of choice because it is very effective and is associated with a low morbidity.

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Hulin, A, Blanchet, B, Audard, V, Barau, C, Furlan, V, Durrbach, A, Taieb, F, Lang, P, Grimbert, P & Tod, M 2009, « Comparison of 3 estimation methods of mycophenolic acid AUC based on a limited sampling strategy in renal transplant patients », Ther Drug Monit, vol. 31, no. 2, p. 224-32, viewed sans date, .

Résumé : A significant relationship between mycophenolic acid (MPA) area under the plasma concentration-time curve (AUC) and the risk for rejection has been reported. Based on 3 concentration measurements, 3 approaches have been proposed for the estimation of MPA AUC, involving either a multilinear regression approach model (MLRA) or a Bayesian estimation using either gamma absorption or zero-order absorption population models. The aim of the study was to compare the 3 approaches for the estimation of MPA AUC in 150 renal transplant patients treated with mycophenolate mofetil and tacrolimus. The population parameters were determined in 77 patients (learning study). The AUC estimation methods were compared in the learning population and in 73 patients from another center (validation study). In the latter study, the reference AUCs were estimated by the trapezoidal rule on 8 measurements. MPA concentrations were measured by liquid chromatography. The gamma absorption model gave the best fit. In the learning study, the AUCs estimated by both Bayesian methods were very similar, whereas the multilinear approach was highly correlated but yielded estimates about 20% lower than Bayesian methods. This resulted in dosing recommendations differing by 250 mg/12 h or more in 27% of cases. In the validation study, AUC estimates based on the Bayesian method with gamma absorption model and multilinear regression approach model were, respectively, 12% higher and 7% lower than the reference values. To conclude, the bicompartmental model with gamma absorption rate gave the best fit. The 3 AUC estimation methods are highly correlated but not concordant. For a given patient, the same estimation method should always be used.

Mots-clés : *Kidney, Acid/blood/*pharmacokinetics, Adult, Aged, Agents/blood/*pharmacokinetics, Analysis, Area, Bayes, Curve, drug, Female, Humans, Immunosuppressive, Longitudinal, Male, Middle, Monitoring/methods, Mycophenolic, of, Regression, Reproducibility, Results, Studies, Theorem, Transplantation, Under.

Ichai, P & Saliba, F 2009, « [Fulminant and subfulminant hepatitis: causes and treatment] », Presse Med, vol. 38, no. 9, p. 1290-8.

Résumé : Fulminant hepatitis is an emergency because within a few hours, the physician must find the cause of the hepatitis (not identified in 15 to 20% of cases), rule out any contraindication to liver transplantation, verify that it is indicated, and prevent and/or treat the complications associated with liver failure. Viruses (especially hepatitis viruses A and B), drugs, and toxic agents are the most common causes of fulminant hepatitis, with the proportions varying between countries. Hepatitis viruses, the leading cause through 1995-1996, have fallen behind drugs and in particular paracetamol, which is now the leading cause of this disease in Europe and in the United States. There are also other rarer causes: other viruses (e.g., herpes virus HSV1 or 2, hepatitis virus E, parvovirus B19, and chickenpox-herpes zoster), Wilson Disease, acute Budd-Chiari and Reyes syndromes, autoimmune hepatitis, neoplastic infiltration of the liver, hypoxic hepatitis, heatstroke, acute pregnancy-related steatosis, and the HELLP syndrome. Prognosis is essentially determined by neurological status, but is also affected very rapidly by damage to other organs. Liver transplantation has revolutionized the prognosis of fulminant hepatitis, causing survival to increase from 10-20% (all causes combined) to 75-80% at 1 year and 70% at 5 years. These patients can be treated only in specialized centers with access to liver transplantation and to different modern means of liver resuscitation (hypothermia, artificial liver support, albumin dialysis, monitoring intracranial pressure and cerebral perfusion, etc.) -all from the onset of the disease.

Mots-clés : Acute/ etiology/ therapy Liver Transplantation/ standards Liver, Algorithms Hepatic Encephalopathy/etiology Humans Liver Failure, Artificial Prognosis.

Ichai, P & Samuel, D 2009, « [Liver transplantation for fulminant hepatitis] », Gastroenterol Clin Biol, vol. 33, no. 1 Pt 1, p. 51-60.

Résumé : Ichai, P; Samuel, D; France; Gastroenterol Clin Biol. 2009 Jan;33(1 Pt 1):51-60. doi: 10.1016/j.gcb.2008.11.006. Epub 2008 Dec 25.

Mots-clés : Acute/complications/etiology/ surgery Liver Transplantation Prognosis Sorption Detoxification, Humans Liver Failure.

Innominato, PF, Focan, C, Gorlia, T, Moreau, T, Garufi, C, Waterhouse, J, Giacchetti, S, Coudert, B, Iacobelli, S, Genet, D, Tampellini, M, Chollet, P, Lentz, M-A, Mormont, M-C, Lévi, F, Bjarnason, GA, Research, CG of the EO for & Cancer, T of 2009, « Circadian rhythm in rest and activity: a biological correlate of quality of life and a predictor of survival in patients with metastatic colorectal cancer », Cancer Res, vol. 69, no. 11, p. 4700-7, viewed sans date, .

Résumé : The rest-activity circadian rhythm (CircAct) reflects the function of the circadian timing system. In a prior single-institution study, the extent of CircAct perturbation independently predicted for survival and tumor response in 192 patients receiving chemotherapy for metastatic colorectal cancer. Moreover, the main CircAct parameters correlated with several health-related quality of life (HRQoL) scales. In this prospective study, we attempted to extend these results to an independent cohort of chemotherapy-naive metastatic colorectal cancer patients participating in an international randomized phase III trial (European Organisation for Research and Treatment of Cancer 05963). Patients were randomized to receive chronomodulated or conventional infusion of 5-fluorouracil, leucovorin, and oxaliplatin as first-line treatment for metastatic colorectal cancer. Patients from nine institutions completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and wore a wrist accelerometer (actigraph) for 3 days before chemotherapy delivery. Two validated parameters (I<O and r24) were used to estimate CircAct. Of 130 patients with baseline CircAct assessments, 96 had baseline HRQoL data. I<O was confirmed to correlate with global quality of life, physical functioning, social functioning, fatigue, and appetite loss (r > |0.25|; P < 0.01). I<O further independently predicted for overall survival with a hazard ratio of 0.94 (P < 0.0001). The associations between CircAct parameters, HRQoL, and survival, which were shown in this international study involving previously untreated metastatic colorectal cancer patients, confirm prior single-institution findings in mostly pretreated metastatic colorectal cancer patients. The circadian timing system constitutes a novel therapeutic target. Interventions that normalize circadian timing system dysfunction may affect quality of life and survival in cancer patients.

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Innominato, PF, Mormont, M-C, Rich, TA, Waterhouse, J, Lévi, FA & Bjarnason, GA 2009, « Circadian disruption, fatigue, and anorexia clustering in advanced cancer patients: implications for innovative therapeutic approaches », Integr Cancer Ther, vol. 8, no. 4, p. 361-70, viewed sans date, .

Résumé : A disruption of the circadian timing system, as identified by monitoring of marker biorhythms, is common in cancer patients. The recording of the rest-activity rhythm with a wrist actigraph has been commonly used. This noninvasive monitoring allows a robust estimation of circadian disruption. The authors have previously found that altered patterns of circadian rest-activity rhythms are significantly and independently associated with the severity of fatigue and anorexia in patients with metastatic colorectal cancer. Elevated proinflammatory cytokines could partly account for this circadian disruption and its associated constitutional symptoms. Here, the authors present and discuss the data supporting the hypothesis that circadian disruption is often associated with fatigue and anorexia, which in turn further alter and dampen circadian synchronization, thus, creating a vicious cycle. This body of evidence paves the path for innovative therapeutic approaches targeting the circadian timing system in an effort to diminish constitutional symptoms induced by cancer and some anticancer treatments.

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Iurisci, I, Filipski, E, Sallam, H, Harper, F, Guettier, C, Maire, I, Hassan, M, Iacobelli, S & Lévi, F 2009, « Liver circadian clock, a pharmacologic target of cyclin-dependent kinase inhibitor seliciclib », Chronobiol Int, vol. 26, no. 6, p. 1169-88, viewed sans date, .

Résumé : Circadian disruption accelerates malignant growth and shortens survival, both in experimental tumor models and cancer patients. In previous experiments, tumor circadian disruption was rescued with seliciclib, an inhibitor of cyclin-dependent kinases (CDKs). This effect occurred at a selective dosing time and was associated with improved antitumor activity. In the current study, seliciclib altered robust circadian mRNA expression of the clock genes Rev-erb alpha, Per2, and Bmal1 in mouse liver following dosing at zeitgeber time (ZT) 3 (i.e., 3 h after the onset of the 12 h light span), when mice start to rest, but not at ZT19, near the middle of the 12 h dark span, when mice are most active. However, liver exposure to seliciclib, as estimated by the liver area under the concentration x time curve (AUC), was approximately 80% higher at ZT19 than at ZT3 (p = 0.049). Circadian clock disruption was associated with increased serum liver enzymes and modified glycogen distribution in hepatocytes, as revealed by biochemical determinations and optic and electronic microscopy. The extent of increase in liver enzymes was most pronounced following dosing at ZT3, as compared to ZT19 (p < 0.04). Seliciclib further up-regulated the transcriptional activity of c-Myc, a cell cycle gene that promotes cell cycle entry and G1-S transition (p < 0.001), and down-regulated that of Wee1, which gates cell cycle transition from G2 to M (p < 0.001). These effects did not depend upon drug dosing time. Overall, the results suggest the circadian time of seliciclib delivery is more critical than the amount of drug exposure in determining its effects on the circadian clock. Seliciclib-induced disruption of the liver molecular clock could account for liver toxicity through the resulting disruption of clock-controlled detoxification pathways. Modifications of cell cycle gene expression in the liver likely involve other mechanisms. Circadian clocks represent relevant targets to consider for optimization of therapeutic schedules of CDK inhibitors.

Mots-clés : Animals Antineoplastic Agents/pharmacokinetics/pharmacology/toxicity Area Under Curve Biological Clocks/ drug effects/physiology Cell Cycle Cyclin-Dependent Kinases/ antagonists & inhibitors Dose-Response Relationship, Drug Drug-Induced Liver Injury Gastrointestinal Diseases/chemically induced Gene Expression Regulation Liver/drug effects/ metabolism Male Mice Purines/pharmacokinetics/ pharmacology/toxicity.

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Jacquet, A, Francois, H, Beaudreuil, S, Hebibi, H, Seidowsky, A, Ahmad, L, Charpentier, B & Durrbach, A 2009, « The challenge of preserving renal function after liver transplantation », Panminerva Med, vol. 51, no. 4, p. 249-55, viewed sans date, .

Résumé : Thanks to new surgical techniques and the use of calcineurin inhibitors for the prevention of allograft rejection, the long-term outcome of liver transplantation has recently improved. In case of liver transplantation, the occurrence of renal failure can impair the outcome. Renal function preservation is, therefore, necessary to improve transplantation outcome.

Mots-clés : &, *Liver, Agents/adverse, Assessment, control, disease, effects, Factors, Failure/complications/physiopathology/*surgery, Graft, Humans, Immunosuppressive, Insufficiency/complications/physiopathology/*therapy, Kidney/*physiopathology, Liver, Outcome, Progression, Rejection/immunology/prevention, Renal, Risk, Survival/drug, Transplantation/adverse, Treatment.

Jacquet, A, Francois, H, Frangie, C, Yahiaoui, Y, Ferlicot, S, Micelli, C, Mariette, X & Durrbach, A 2009, « IgA nephropathy associated with ankylosing spondylitis is not controlled by infliximab therapy », Nephrol Dial Transplant, vol. 24, no. 11, p. 3540-2, viewed sans date, .

Résumé : The association between seronegative spondyloarthro- pathies and IgA nephropathy is well documented, mainly in cases of ankylosing spondylitis (AS). However, although these diseases have been associated, the physiopathological links between each other appear unclear. Anti-TNFalpha agents have transformed the outcome of axial forms of AS resistant to conventional anti-inflammatory therapies. Infliximab, a monoclonal anti-TNFalpha antibody, has greatly improved the evolution of AS although several adverse events have been described. On the other hand, infliximab has been demonstrated to reduce renal symptoms associated with chronic inflammatory rheumatological diseases, such as amyloid A (AA) amyloidosis, but few data are available on its efficacy in controlling IgA nephropathy associated with AS [1,2]. We report here a case of IgA nephropathy associated with AS that became symptomatic, whereas infliximab therapy efficiently controlled the rheumatological disease. This suggests that even though infliximab therapy effectively controls rheumatological manifestations, it may not be able to prevent IgA nephropathy associated with AS. Thus, this case report illustrates the complexity of the physiopathology of both diseases.

Mots-clés : Adult Antibodies, Ankylosing/complications/*drug therapy Tumor Necrosis Factor-alpha/*antagonists & inhibitors, IGA/*drug therapy Humans Male Spondylitis, Monoclonal/*therapeutic use Antirheumatic Agents/*therapeutic use Glomerulonephritis.

Jarboui, S, Moussi, A, Jarraya, H, Ben Mna, K, Abdesselem, MM, Kourda, A, Ben Jilani, S, Guettier, C & Zaouche, A 2009, « Primary dedifferentiated liposarcoma of the colon: a case report », Gastroenterol Clin Biol, vol. 33, no. 10-11, p. 1016-8.

Résumé : Jarboui, S; Moussi, A; Jarraya, H; Ben Mna, K; Abdesselem, M M; Kourda, A; Ben Jilani, S; Guettier, C; Zaouche, A; Case Reports; Letter; France; Gastroenterol Clin Biol. 2009 Oct-Nov;33(10-11):1016-8. doi: 10.1016/j.gcb.2008.11.014. Epub 2009 Mar 9.

Mots-clés : Aged, Colonic, Colonoscopy, Humans, Intestinal, Liposarcoma/, Male, Neoplasms/, Obstruction/etiology/surgery, pathology/, surgery.

Karie-Guigues, S, Janus, N, Saliba, F, Dumortier, J, Duvoux, C, Calmus, Y, Lorho, R, Deray, G, Launay-Vacher, V & Pageaux, GP 2009, « Long-term renal function in liver transplant recipients and impact of immunosuppressive regimens (calcineurin inhibitors alone or in combination with mycophenolate mofetil): the TRY study », Liver Transpl, vol. 15, no. 9, p. 1083-91.

Résumé : The prevalence of renal insufficiency before and at 1, 12, and 60 months after liver transplantation (LTx; primary endpoint) and the changes in the glomerular filtration rate (GFR) at same time points according to the immunosuppressive regimen (coprimary endpoint) were investigated. The primary outcome was determined for the entire cohort, whereas the coprimary endpoint was determined only for 2 groups of patients: those who started and remained on a calcineurin inhibitor (CNI) alone, that is, the CNI-alone group (n = 624), and those who started and remained on a CNI in combination with mycophenolate mofetil (MMF), that is, the MMF group (n = 117). GFR was <60 mL/minute/1.73 kg/m(2) in 11%, 48%, 51% and 58% of the patients at baseline and at 1, 12, and 60 months, respectively. The decrease in GFR was significantly lower in the MMF group compared to the CNI-alone group at 12 and 60 months (-16% versus -30% and -15% versus -33%, respectively), whereas the GFR decrease at 1 month was not different between the 2 groups. There were no significant differences between the 2 groups in CNI doses or blood levels at 12 and 60 months. In conclusion, there was a worsening of renal failure in 83% of patients post-LTx; 58% and 5% had GFRs of <60 and <30 mL/minute/1.73 kg/m(2), respectively, at 5 years after LTx. The reduction of the GFR was significantly less marked in the MMF group compared to the CNI-alone group, and this could be related to less important CNI exposure early after LTx. It seems likely that early intervention for CNI reduction is best for reducing the use of CNIs in the long term.

Mots-clés : Adolescent Adult Aged Calcineurin/ antagonists & inhibitors Cyclosporine/ adverse effects Diabetes Mellitus/etiology Drug Therapy.

Kellermann, G, Boudechiche, L, Weber, A & Hadchouel, M 2009, « Increased engraftment of hepatic progenitors after activation of the hepatocyte growth factor signaling pathway by protein transduction », Exp Biol Med (Maywood), vol. 234, no. 9, p. 1102-8, viewed sans date, .

Résumé : Cell transplantation has become a major focus in biomedical research. However, efficient engraftment in solid tissues remains a challenge. Hepatocyte growth factor (HGF) signaling increases survival, proliferation, migration, and invasion of many cell types through Met, its cell surface receptor. Therefore, activation of this signaling pathway may improve the ability of many cells to be transplanted. We constructed a constitutively activated form of Met (Tpr-Met) fused to the protein transduction domain of HIV-TAT to activate the HGF/Met pathway for a few hours following cell injection. Matrix-assisted refolding was used to renature TAT-Tpr-Met protein, which was efficiently delivered into cells and recapitulated several biological functions of Met in vitro. Furthermore, treatment of hepatic progenitors with this molecule for one hour before transplantation significantly improved engraftment efficiency (31% untreated cells, 58% treated cells). These findings suggest that the transient transfer of Tpr-Met may provide a new approach to increase the proportion of successfully engrafted cells.

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Khawam, K, Giron-Michel, J, Gu, Y, Perier, A, Giuliani, M, Caignard, A, Devocelle, A, Ferrini, S, Fabbi, M, Charpentier, B, Ludwig, A, Chouaib, S, Azzarone, B & Eid, P 2009, « Human renal cancer cells express a novel membrane-bound interleukin-15 that induces, in response to the soluble interleukin-15 receptor alpha chain, epithelial-to-mesenchymal transition », Cancer Res, vol. 69, no. 4, p. 1561-9, viewed sans date, .

Résumé : Although interleukin-15 (IL-15) is a powerful immunomodulatory factor that has been proposed for cancer immunotherapy, its intratumoral expression may be correlated with tumor progression and/or poor clinical outcome. Therefore, neoplasias potentially sensitive to immunotherapy should be checked for their IL-15 expression and function before choosing immunotherapy protocols. Primary human renal cancer cells (RCC) express a novel form of membrane-bound IL-15 (mb-IL-15), which displays three major original properties: (a) It is expressed as a functional membrane homodimer of 27 kDa, (b) it is shed in the extracellular environment by the metalloproteases ADAM17 and ADAM10, and (c) its stimulation by soluble IL-15 receptor alpha (s-IL-15Ralpha) chain triggers a complex reverse signal (mitogen-activated protein kinases, FAK, pMLC) necessary and sufficient to induce epithelial-mesenchymal transdifferentiation (EMT), a crucial process in tumor progression whose induction is unprecedented for IL-15. In these cells, complete EMT is characterized by a dynamic reorganization of the cytoskeleton with the subsequent generation of a mesenchymal/contractile phenotype (alpha-SMA and vimentin networks) and the loss of the epithelial markers E-cadherin and ZO-1. The retrosignaling functions are, however, hindered through an unprecedented cytokine/receptor interaction of mb-IL-15 with membrane-associated IL-15Ralpha subunit that tunes its signaling potential competing with low concentrations of the s-IL-15Ralpha chain. Thus, human RCC express an IL-15/IL-15R system, which displays unique biochemical and functional properties that seem to be directly involved in renal tumoral progression.

Mots-clés : Antibodies, Cultured, Interleukin-15/*immunology Sodium Acetate/pharmacology Tetradecanoylphorbol Acetate/pharmacology Tumor Cells, Monoclonal/therapeutic use Carcinoma, Renal Cell/*immunology/pathology Carcinoma, Small Cell/immunology/pathology Cell Differentiation Cell Line.

Klibi, J, Niki, T, Riedel, A, Pioche-Durieu, C, Souquere, S, Rubinstein, E, Le Moulec, S, Moulec, SLE, Guigay, J, Hirashima, M, Guemira, F, Adhikary, D, Mautner, J & Busson, P 2009, « Blood diffusion and Th1-suppressive effects of galectin-9-containing exosomes released by Epstein-Barr virus-infected nasopharyngeal carcinoma cells », Blood, vol. 113, no. 9, p. 1957-66, viewed sans date, .

Résumé : Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) is the third most frequent virus-associated human malignancy. How this tumor escapes immune recognition despite the expression of several viral antigens has remained poorly understood. Our previous in vitro studies have shown that NPC cells release exosomes containing high amounts of galectin-9, a ligand of the membrane receptor Tim-3, which is able to induce apoptosis in mature Th1 lymphocytes. Here, we sought to determine whether galectin-9-carrying exosomes were produced in NPC patients and whether such exosomes might play a role in the immune evasion of NPC cells. We report that galectin-9-containing exosomes are selectively detected in plasma samples from NPC patients and mice xenografted with NPC tumors. The incorporation into exosomes protects galectin-9 against proteolytic cleavage but retains its Tim-3-binding capacity. Importantly, NPC exosomes induce massive apoptosis in EBV-specific CD4(+) cells used as a model of target T cells. This effect is inhibited by both anti-Tim-3 and antigalectin-9 blocking antibodies. These results indicate that blocking galectin-9/Tim-3 interaction in vivo might alleviate the Th1-suppressive effect of NPC exosomes and sustain antitumoral T-cell responses and thereby improve clinical efficacy of immunotherapeutic approaches against NPC.

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Le Naour, F, Bralet, MP, Debois, D, Sandt, C, Guettier, C, Dumas, P, Brunelle, A & Laprevote, O 2009, « Chemical imaging on liver steatosis using synchrotron infrared and ToF-SIMS microspectroscopies », PLoS One, vol. 4, no. 10, p. e7408.

Résumé : Fatty liver or steatosis is a frequent histopathological change. It is a precursor for steatohepatitis that may progress to cirrhosis and in some cases to hepatocellular carcinoma. In this study we addressed the in situ composition and distribution of biochemical compounds on tissue sections of steatotic liver using both synchrotron FTIR (Fourier transform infrared) and ToF-SIMS (time of flight secondary ion mass spectrometry) microspectroscopies. FTIR is a vibrational spectroscopy that allows investigating the global biochemical composition and ToF-SIMS lead to identify molecular species in particular lipids. Synchrotron FTIR microspectroscopy demonstrated that bands linked to lipid contribution such as -CH(3) and -CH(2) as well as esters were highly intense in steatotic vesicles. Moreover, a careful analysis of the -CH(2) symmetric and anti-symmetric stretching modes revealed a slight downward shift in spectra recorded inside steatotic vesicles when compared to spectra recorded outside, suggesting a different lipid environment inside the steatotic vesicles. ToF-SIMS analysis of such steatotic vesicles disclosed a selective enrichment in cholesterol as well as in diacylglycerol (DAG) species carrying long alkyl chains. Indeed, DAG C36 species were selectively localized inside the steatotic vesicles whereas DAG C30 species were detected mostly outside. Furthermore, FTIR detected a signal corresponding to olefin (C = C, 3000-3060 cm(-1)) and revealed a selective localization of unsaturated lipids inside the steatotic vesicles. ToF-SIMS analysis definitely demonstrated that DAG species C30, C32, C34 and C36 carrying at least one unsaturated alkyl chain were selectively concentrated into the steatotic vesicles. On the other hand, investigations performed on the non-steatotic part of the fatty livers have revealed important changes when compared to the normal liver. Although the non-steatotic regions of fatty livers exhibited normal histological aspect, IR spectra demonstrated an increase in the lipid content and ToF-SIMS detected small lipid droplets corresponding most likely to the first steps of lipid accretion.

Mots-clés : Adult Aged Alkenes/chemistry Diglycerides/metabolism Fatty Liver/ diagnosis/ pathology Female Humans Infrared Rays Lipids/chemistry Male Middle Aged Spectrometry, Fourier Transform Infrared/methods Synchrotrons, Mass, Secondary Ion/ methods Spectroscopy.

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Le Naour, F, Guettier, C, Brunelle, A, Laprevote, O & Dumas, P 2009, « [Synchrotron SOLEIL radiation reveals discrete biochemical changes in human steatosis] », Med Sci (Paris), vol. 25, no. 11, p. 987-90.

Résumé : Le Naour, Francois; Guettier, Catherine; Brunelle, Alain; Laprevote, Olivier; Dumas, Paul; France; Med Sci (Paris). 2009 Nov;25(11):987-90. doi: 10.1051/medsci/20092511987.

Mots-clés : Cholesterol/analysis, Fatty, Humans, Lipids/analysis, Liver/, Proteins/analysis, radiography, Synchrotrons, Vacuoles/radiography.

Lefort, N, Feyeux, M, Bas, C, Féraud, O, Bennaceur-Griscelli, A, Tachdjian, G, Peschanski, M & L Perrier, A 2009, « [A recurrent hotspot of genomic instability identified in human ES cells] », Med Sci (Paris), vol. 25, no. 1, p. 99-101, viewed sans date, .

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Legrand-Abravanel, F, Colson, P, Leguillou-Guillemette, H, Alric, L, Ravaux, I, Lunel-Fabiani, F, Bouviers-Alias, M, Trimoulet, P, Chaix, ML, Hezode, C, Foucher, J, Fontaine, H, Roque-Afonso, AM, Gassin, M, Schvoerer, E, Gaudy, C, Roche, B, Doffoel, M, D'Alteroche, L, Vallet, S, Baazia, Y, Pozzetto, B, Thibault, V, Nousbaum, JB, Roulot, D, Coppere, H, Poynard, T, Payan, C & Izopet, J 2009, « Influence of the HCV subtype on the virological response to pegylated interferon and ribavirin therapy », J Med Virol, vol. 81, no. 12, p. 2029-35.

Résumé : The hepatitis C virus genotype is considered to be the most important baseline predictor of a sustained virological response in patients with chronic hepatitis C treated with pegylated interferon and ribavirin. The influence of the subtype on the sustained virological response was investigated in patients infected with genotypes 1, 4, 5, or 6. This study was done on 597 patients with chronic hepatitis C who were given pegylated interferon and ribavirin for 48 weeks. The overall rate of sustained virological response in the 597 patients was 37.8%. Univariate analysis indicated that the sustained virological response of patients infected with subtype 1b (39%) tended to be higher than that of patients infected with subtype 1a (30.6%; P = 0.06) and it was similar to those patients infected with subtypes 4a (51.3%; P = 0.12) or 4d (51.7%; P = 0.16). Multivariate analysis indicated that five factors were independently associated with sustained virological response: the age (OR 0.97; 95% CI = 0.95-0.99), absence of cirrhosis (OR: 2.92; 95% CI = 1.7-5.0; P < 0.01), absence of HIV co-infection (OR: 2.08; 95% CI = 1.2-3.5; P < 0.01), low baseline plasma HCV RNA concentration (OR: 1.74; 95% CI = 1.2-2.6; P < 0.01), and the subtype 1b (OR: 1.61; 95% CI = 1.0-2.5; P = 0.04) or subtypes 4a and 4d (OR: 2.03; 95% CI = 1.1-3.8; P = 0.03). In conclusion, among difficult-to-treat genotypes, the subtype 1a is associated with a lower response to anti-HCV therapy than subtypes 1b, 4a, and 4d.

Mots-clés : Adult Antiviral Agents/ administration & dosage Drug Therapy, Chronic/drug therapy/virology Humans Interferon-alpha/ administration & dosage Male Middle Aged Recombinant Proteins Ribavirin/ administration & dosage Treatment Outcome, Combination Female Genetic Variation Genome, Viral Hepacivirus/drug effects/genetics Hepatitis C.

Levesque, E, Saliba, F, Benhamida, S, Ichaï, P, Azoulay, D, Adam, R, Castaing, D & Samuel, D 2009, « Plasma disappearance rate of indocyanine green: a tool to evaluate early graft outcome after liver transplantation », Liver Transpl, vol. 15, no. 10, p. 1358-64, viewed sans date, .

Résumé : Indocyanine green clearance (Cl-ICG) has been used to assess liver function and hepatic blood flow mainly before and after hepatic surgery. Cl-ICG (invasive method) has been reported to be a good marker of early graft function after liver transplantation (LT). The goal of this study was to determine if the indocyanine green plasma disappearance rate (PDR-ICG), measured by a noninvasive technique (LiMON, Impulse Medical System, Munich, Germany), is predictive of complications and graft outcome after LT. From September 2005 to June 2006, 72 LT recipients were included in the study. PDR-ICG was measured daily (from day 0 to day 5 after LT) with a digital sensor after patients were injected with 0.25 mg/kg indocyanine green. A PDR-ICG cutoff level of 12.85%/minute was predictive of the development of a serious postoperative complication. The sequential changes of PDR-ICG enabled us to differentiate 2 groups: (1) patients with early severe complications (hepatic artery thrombosis, primary graft nonfunction, or sepsis) who had a low value of PDR-ICG during the first 5 posttransplantation days (average, 8.8 +/- 4.5%/minute) and (2) patients who developed acute rejection and who had a progressive reduction of PDR-ICG between days 0 and 5 (from 25.5 +/- 4.8 to 10.3 +/- 2.5%/minute; P < 0.002). In conclusion, after LT, PDR-ICG (a noninvasive technique), measured regularly during the first 5 postoperative days, is a safe technique that can predict early postoperative complications.

Mots-clés : Doppler/methods.

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Mangin, PH, Kleitz, L, Boucheix, C, Gachet, C & Lanza, F 2009, « CD9 negatively regulates integrin alphaIIbbeta3 activation and could thus prevent excessive platelet recruitment at sites of vascular injury », J Thromb Haemost, vol. 7, no. 5, p. 900-2, viewed sans date, .

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Massoud, W, Ferlicot, S, Hajj, P, Awad, A, Iaaza, LA, Hammoudi, Y, Droupy, S & Benoit, G 2009, « Metastatic breast carcinoma to the bladder », Urology, vol. 74, no. 4, p. 785-6, viewed sans date, .

Résumé : Bladder involvement in metastatic breast carcinoma is a rare situation and accounts for about 3% of secondary bladder neoplasms. Most patients are symptomatic, with evidence of disseminated disease at diagnosis.

Mots-clés : Breast Neoplasms/*pathology Carcinoma, Lobular/*secondary Female Humans Middle Aged Urinary Bladder Neoplasms/*secondary.

Maurin, M-L, Labrune, P, Brisset, S, Le Lorc'h, M, Pineau, D, Castel, C, Romana, S & Tachdjian, G 2009, « Molecular cytogenetic characterization of a 4p15.1-pter duplication and a 4q35.1-qter deletion in a recombinant of chromosome 4 pericentric inversion », Am J Med Genet A, vol. 149A, no. 2, p. 226-31, viewed sans date, .

Résumé : To date, 10 cases of recombinant of chromosome 4 pericentric inversion involving sub-bands p14p15 and q35 have been described. We report on the first case analyzed using array-CGH in a female infant presenting psychomotor and growth retardation, facial anomalies, axial hypotonia, short neck, wide spaced nipples and cardiac defects. Conventional karyotype associated to FISH revealed a recombinant chromosome 4 with partial 4p duplication and 4q deletion derived from a paternal pericentric inversion. Array-CGH allowed us to precise rec4 breakpoints: the proposita carried a small 4.82-4.97 Mb 4q35.1 terminal deletion and a large 35.3-36.7 Mb 4p15.1 terminal duplication. Duplications of the distal 2/3 of short arm of chromosome 4 give rise to recognizable craniofacial features but no specific visceral malformation. A contrario small terminal 4q deletions are associated with cardiac defects. This case and review of literature suggest that two genes ArgBP2 and PDLIM3, located at 4q35.1 and both involved in cardiac and muscle development, could be responsible for cardiac defects observed in terminal 4q35.1 deletions.

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Mollicone, R, Moore, SEH, Bovin, N, Garcia-Rosasco, M, Candelier, J-J, Martinez-Duncker, I & Oriol, R 2009, « Activity, splice variants, conserved peptide motifs, and phylogeny of two new alpha1,3-fucosyltransferase families (FUT10 and FUT11) », J Biol Chem, vol. 284, no. 7, p. 4723-38, viewed sans date, .

Résumé : We report the cloning of three splice variants of the FUT10 gene, encoding for active alpha-l-fucosyltransferase-isoforms of 391, 419, and 479 amino acids, and two splice variants of the FUT11 gene, encoding for two related alpha-l-fucosyltransferases of 476 and 492 amino acids. The FUT10 and FUT11 appeared 830 million years ago, whereas the other alpha1,3-fucosyltransferases emerged 450 million years ago. FUT10-391 and FUT10-419 were expressed in human embryos, whereas FUT10-479 was cloned from adult brain and was not found in embryos. Recombinant FUT10-419 and FUT10-479 have a type II trans-membrane topology and are retained in the endoplasmic reticulum (ER) by a membrane retention signal at their NH(2) termini. The FUT10-479 has, in addition, a COOH-ER membrane retention signal. The FUT10-391 is a soluble protein without a trans-membrane domain or ER retention signal that transiently localizes to the Golgi and then is routed to the lysosome. After transfection in COS7 cells, the three FUT10s and at least one FUT11, link alpha-l-fucose onto conalbumin glycopeptides and biantennary N-glycan acceptors but not onto short lactosaminyl acceptor substrates as do classical monoexonic alpha1,3-fucosyltransferases. Modifications of the innermost core GlcNAc of the N-glycan, by substitution with ManNAc or with an opened GlcNAc ring or by the addition of an alpha1,6-fucose, suggest that the FUT10 transfer is performed on the innermost GlcNAc of the core chitobiose. We can exclude alpha1,3-fucosylation of the two peripheral GlcNAcs linked to the trimannosyl core of the acceptor, because the FUT10 fucosylated biantennary N-glycan product loses both terminal GlcNAc residues after digestion with human placenta alpha-N-acetylglucosaminidase.

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Moniaux, N, Nemos, C, Deb, S, Zhu, B, Dornreiter, I, Hollingsworth, MA & Batra, SK 2009, « The human RNA polymerase II-associated factor 1 (hPaf1): a new regulator of cell-cycle progression », PLoS One, vol. 4, no. 9, p. e7077.

Résumé : BACKGROUND: The human PAF (hPAF) complex is part of the RNA polymerase II transcription apparatus and regulates multiple steps in gene expression. Further, the yeast homolog of hPaf1 has a role in regulating the expression of a subset of genes involved in the cell-cycle. We therefore investigated the role of hPaf1 during progression of the cell-cycle. METHODOLOGY/FINDINGS: Herein, we report that the expression of hPaf1, a subunit of the hPAF complex, increases with cell-cycle progression and is regulated in a cell-cycle dependant manner. hPaf1 specifically regulates a subclass of genes directly implicated in cell-cycle progression during G1/S, S/G2, and G2/M. In prophase, hPaf1 aligns in filament-like structures, whereas in metaphase it is present within the pole forming a crown-like structure, surrounding the centrosomes. Moreover, hPaf1 is degraded during the metaphase to anaphase transition. In the nucleus, hPaf1 regulates the expression of cyclins A1, A2, D1, E1, B1, and Cdk1. In addition, expression of hPaf1 delays DNA replication but favors the G2/M transition, in part through microtubule assembly and mitotic spindle formation. CONCLUSION/SIGNIFICANCE: Our results identify hPaf1 and the hPAF complex as key regulators of cell-cycle progression. Mutation or loss of stoichiometry of at least one of the members may potentially lead to cancer development.

Mots-clés : Anaphase Cell Cycle Cell Line, Biological Nuclear Proteins/ metabolism Transcription, Genetic, Neoplastic Humans Metaphase Microtubules/metabolism Mitotic Spindle Apparatus Models, Tumor Cell Nucleus/metabolism Centrosome/metabolism Disease Progression Gene Expression Regulation.

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Monsuez, JJ, Carcelain, G, Charniot, JC, Barriere, J, Duclos-Vallee, JC, Parent, F & Autran, B 2009, « T cells subtypes in a patient with interferon-alpha induced sarcoidosis », Am J Med Sci, vol. 337, no. 1, p. 60-2.

Résumé : A 47-year-old woman with a history of blood transfusion-acquired hepatitis C was treated with interferon-alpha when she developed fever, arthralgia, erythema nodosum, dyspnea, and diffuse alveolitis. The diagnosis of IFN-alpha-induced sarcoidosis was retained. The patient's clinical status rapidly improved after IFN-alpha discontinuation, with complete resolution of signs and symptoms. Admission and follow-up assessment of peripheral blood CD4 T cells showed a transient activation process that peaked at 1 to 3 months after onset of symptoms and discontinuation of IFN-alpha. It was marked by a mild increase in activated cells (expressing R-IL2 and HLADR), and a markedly reduced percentage of CD4 T cells expressing the costimulation molecule CD28, ie, an expansion of the CD4CD28 negative subset that is associated with proinflammatory and tissue damaging properties. This activation process also improved over time, but more slowly than clinical symptoms.

Mots-clés : Activation, adverse, Aged, Agents/, Antiviral, C/drug, chemically, effects, Female, Hepatitis, Humans, immunology, induced/immunology, Interferon-alpha/, Lymphocyte, Middle, Sarcoidosis/, Subsets/, T-Lymphocyte, Therapy.

Nakamoto, T, Murayama, Y, Oritani, K, Boucheix, C, Rubinstein, E, Nishida, M, Katsube, F, Watabe, K, Kiso, S, Tsutsui, S, Tamura, S, Shinomura, Y & Hayashi, N 2009, « A novel therapeutic strategy with anti-CD9 antibody in gastric cancers », J Gastroenterol, vol. 44, no. 9, p. 889-96, viewed sans date, .

Résumé : BACKGROUND: CD9 is a member of the tetraspanins, and has been shown to be involved in a variety of cellular activities such as motility, cell signaling, proliferation, adhesion, and metastasis. However, very little is known about the involvement of CD9 in the process of development of primary tumors. In the present study, we investigated whether anti-CD9 monoclonal antibody (ALB6) has antitumor effects in human gastric cancer cell xenografts. METHODS: Human gastric cancer cell lines (MKN-28) (5 x 10(6) cells/animal) were inoculated subcutaneously into the dorsal region of SCID mice (five mice in each group). After a tumor was visualized, animals were assigned to either the ALB6 treatment group or the control IgG treatment group (100 microg/body/time, intravenous, three times per week. Day 1, 4, and 7 of first week). Then tumor volumes were monitored every day. Proliferation of tumor was analyzed by 5-bromo-2'-deoxyuridine (BrdU) immunostaining, apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) methods, and angiogenesis was assessed by counting the number of CD34-positive endothelial cells. RESULTS: Tumor volume was significantly suppressed (1,682 +/- 683 mm(3) versus 4,507 +/- 1,012 mm(3); P = 0.049), the BrdU labeling indexes were significantly decreased (10.9 +/- 1.1% versus 17.2 +/- 1.4%; P = 0.009), the apoptotic indexes were significantly increased (1.98 +/- 0.48% versus 0.72 +/- 0.09%; P = 0.034), and tumor microvessel densities were significantly suppressed (671,922 +/- 34,505 pixels/mm(2) versus 1,135,043 +/- 36,086 pixels/mm(2); P = 0.037) in the ALB6 treatment group compared with the control IgG treatment group. CONCLUSIONS: These results suggest that administration of anti-CD9 antibody to mice bearing human gastric cancer cells successfully inhibits tumor progression via antiproliferative, proapoptotic, and antiangiogenetic effects.

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Nashan, B, Saliba, F, Durand, F, Barcena, R, Herrero, JI, Mentha, G, Neuhaus, P, Bowles, M, Patch, D, Bernardos, A, Klempnauer, J, Bouw, R, Ives, J, Mamelok, R, McKay, D, Truman, M & Marotta, P 2009, « Pharmacokinetics, efficacy, and safety of mycophenolate mofetil in combination with standard-dose or reduced-dose tacrolimus in liver transplant recipients », Liver Transpl, vol. 15, no. 2, p. 136-47.

Résumé : The pharmacokinetics of mycophenolate mofetil (MMF) in liver transplant recipients may change because of pharmacokinetic interactions with coadministered immunosuppressants or because changes in the enterohepatic anatomy may affect biotransformation of MMF to mycophenolic acid (MPA) and enterohepatic recirculation of MPA through the hydrolysis of mycophenolate acid glucuronide to MPA in the gut. In the latter case, the choice of formulation (oral versus intravenous) could have important clinical implications. We randomized liver transplant patients (n = 60) to standard (10-15 ng/mL) or reduced (5-8 ng/mL) trough levels of tacrolimus plus intravenous MMF followed by oral MMF (1 g twice daily) with corticosteroids. Pharmacokinetic sampling was performed after the last intravenous MMF dose, after the first oral MMF dose, and at selected times over 52 weeks. The efficacy and safety of the 2 regimens were also assessed. Twenty-eight and 27 patients in the tacrolimus standard-dose and reduced-dose groups, respectively, were evaluated. No significant differences between the tacrolimus standard-dose and reduced-dose groups were seen in dose-normalized MPA values of the time to the maximum plasma concentration (1.25 versus 1.28 hours), the maximum plasma concentration (15.5 +/- 7.93 versus 13.6 +/- 7.03 microg/mL), or the area under the concentration-time curve from 0 to 12 hours (AUC(0-12); 53.0 +/- 20.6 versus 43.8 +/- 15.5 microg h/mL) at week 26 or at any other time point. No relationship was observed between the tacrolimus trough or AUC(0-12) and MPA AUC(0-12). Exposure to MPA after oral and intravenous administration was similar. Safety and efficacy were similar in the two treatment groups. In conclusion, exposure to MPA is not a function of exposure to tacrolimus. The similar safety and efficacy seen with MMF plus standard or reduced doses of tacrolimus suggest that MMF could be combined with reduced doses of tacrolimus.

Mots-clés : Administration, Combination Female Humans Immunosuppressive Agents/administration & dosage/blood/ pharmacokinetics Infusions, Intravenous Liver Transplantation Male Middle Aged Mycophenolic Acid/administration & dosage/ analogs & derivatives/blood/pharmacokinetics Tacrolimus/administration & dosage/blood/ pharmacokinetics Treatment Outcome, Oral Adult Drug Interactions Drug Therapy.

Neuberger, JM, Mamelok, RD, Neuhaus, P, Pirenne, J, Samuel, D, Isoniemi, H, Rostaing, L, Rimola, A, Marshall, S & Mayer, AD 2009, « Delayed introduction of reduced-dose tacrolimus, and renal function in liver transplantation: the 'ReSpECT' study », Am J Transplant, vol. 9, no. 2, p. 327-36.

Résumé : We report a multicenter, prospective, randomized, open-label trial investigating the effect of lower levels and delayed introduction of tacrolimus on renal function in liver transplant recipients. Adult patients with good renal function undergoing primary liver transplant were randomized to either: group A (standard-dose tacrolimus [target trough levels >10 ng/mL] and corticosteroids; n = 183); group B (mycophenolate mofetil [MMF] 2g/day, reduced-dose tacrolimus [target trough levels </=8 ng/mL], and corticosteroids; n = 170); group C (daclizumab induction, MMF, reduced-dose tacrolimus delayed until the fifth day posttransplant and corticosteroids, n = 172). The primary endpoint was change from baseline in estimated glomerular filtration rate (eGFR) at 52 weeks. The eGFR decreased by 23.61, 21.22 and 13.63 mL/min in groups A, B and C, respectively (A vs C, p = 0.012; A vs B, p = 0.199). Renal dialysis was required less frequently in group C versus group A (4.2% vs. 9.9%; p = 0.037). Biopsy-proven acute rejection rates were 27.6%, 29.2% and 19.0%, respectively. Patient and graft survival was similar. In conclusion, daclizumab induction, MMF, corticosteroids and delayed reduced-dose tacrolimus was associated with less nephrotoxicity than therapy with standard-dose tacrolimus and corticosteroids without compromising efficacy or tolerability.

Mots-clés : Adolescent Adrenal Cortex Hormones/administration & dosage Adult Aged Antibodies, Drug Drug Therapy, Epidermal Growth Factor/metabolism Tacrolimus/ administration & dosage Treatment Outcome Young Adult, Humanized Dose-Response Relationship, Monoclonal, Monoclonal/administration & dosage Antibodies.

Nguyen, TH, Mainot, S, Lainas, P, Groyer-Picard, M-T, Franco, D, Dagher, I & Weber, A 2009, « Ex vivo liver-directed gene therapy for the treatment of metabolic diseases: advances in hepatocyte transplantation and retroviral vectors », Curr Gene Ther, vol. 9, no. 2, p. 136-49, viewed sans date, .

Résumé : Transplantation of hepatocytes, whether genetically modified or not, has become an alternative to orthotopic liver transplantation for the treatment of patients with metabolic disease. However, more than ten years after the first clinical trial of ex vivo gene therapy to treat patients with Familial Hypercholesterolemia, there are still a number of impediments to these approaches. Numerous animal models are still being developed on the one hand to improve hepatocyte integration within hepatic parenchyma and function, and on the other hand to develop vectors that drive long-term transgene expression in situ. These include large animal models such as non-human primates, which have recently led to significant progress in hepatocyte transplantation. Simultaneous development of lentiviral vectors from different lentivirus species has permitted the transfer of genes into mitotically-quiescent primary cells including differentiated hepatocytes. Particularly third generation vectors derived from HIV-1 lentivirus are the most widely used and have significantly improved the safety and efficiency of these vectors. Given the shortage of organs and problems related to immunosuppression on one hand, and recent progresses in hepatocyte transduction and transplantation on the other hand, ex vivo approach is becoming a real alternative to allogeneic hepatocyte transplantation. We review the present progresses and limits of the ex vivo liver gene therapy approach in different animal models, emphasizing clinically relevant procedures.

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Noman, MZ, Buart, S, Van Pelt, J, Richon, C, Hasmim, M, Leleu, N, Suchorska, WM, Jalil, A, Lecluse, Y, El Hage, F, Giuliani, M, Pichon, C, Azzarone, B, Mazure, N, Romero, P, Mami-Chouaib, F & Chouaib, S 2009, « The cooperative induction of hypoxia-inducible factor-1 alpha and STAT3 during hypoxia induced an impairment of tumor susceptibility to CTL-mediated cell lysis », J Immunol, vol. 182, no. 6, p. 3510-21, viewed sans date, .

Résumé : Hypoxia is an essential component of tumor microenvironment. In this study, we investigated the influence of hypoxia (1% PO(2)) on CTL-mediated tumor cell lysis. We demonstrate that exposure of target tumor cells to hypoxia has an inhibitory effect on the CTL clone (Heu171)-induced autologous target cell lysis. Such inhibition correlates with hypoxia-inducible factor-1alpha (HIF-1alpha) induction but is not associated with an alteration of CTL reactivity as revealed by granzyme B polarization or morphological change. Western blot analysis indicates that although hypoxia had no effect on p53 accumulation, it induced the phosphorylation of STAT3 in tumor cells by a mechanism at least in part involving vascular endothelial growth factor secretion. We additionally show that a simultaneous nuclear translocation of HIF-1alpha and phospho-STAT3 was observed. Interestingly, gene silencing of STAT3 by small interfering RNA resulted in HIF-1alpha inhibition and a significant restoration of target cell susceptibility to CTL-induced killing under hypoxic conditions by a mechanism involving at least in part down-regulation of AKT phosphorylation. Moreover, knockdown of HIF-1alpha resulted in the restoration of target cell lysis under hypoxic conditions. This was further supported by DNA microarray analysis where STAT3 inhibition resulted in a partly reversal of the hypoxia-induced gene expression profile. The present study demonstrates that the concomitant hypoxic induction of phospho-STAT3 and HIF-1alpha are functionally linked to the alteration of non-small cell lung carcinoma target susceptibility to CTL-mediated killing. Considering the eminent functions of STAT3 and HIF-1alpha in the tumor microenvironment, their targeting may represent novel strategies for immunotherapeutic intervention.

Mots-clés : alpha Subunit/*biosynthesis/physiology Immunity, Anoxia/*immunology/metabolism/pathology Cell Line, Cytotoxic/*immunology/metabolism/pathology, Immunologic Gene Expression Regulation, Innate Lung Neoplasms/*immunology/metabolism/pathology STAT3 Transcription Factor/antagonists & inhibitors/*biosynthesis/genetics/physiology T-Lymphocytes, Neoplastic/immunology Humans Hypoxia-Inducible Factor 1, Tumor Clone Cells *Cytotoxicity.

Oprisan, G, Szmal, C, Dinu, S, Oprisoreanu, AM, Thiers, V, Panait, M, Otelea, D, Mavromara, P, Ruta, S, Sultana, C, Alexiu, I, Manolescu, L, Anton, G, Grancea, C, Neagu, A, Sencovici, C, Calistru, PJ, Tardei, G, Motoc, A, Lazar, S, Ionescu, C, Ceausu, E, Cristea, C, Voiculescu, G, Brehar-Cioflec, D, Popovici, D, Chicin, G & Claici, C 2009, « Comparative methods for genotyping hepatitis C virus isolates from Romania », Roum Arch Microbiol Immunol, vol. 68, no. 3, p. 151-7.

Résumé : Accurate genotyping of hepatitis C virus (HCV) has clinical implications for treatment orientation and epidemiological impact in tracing the contamination sources. The aim of the study was to compare a genotyping assay by restriction fragment length polymorphism (RFLP) in the HCV 5'untranslated region (5'UTR) with sequencing in the 5'untranslated and NS5B regions. One hundred and three samples, collected between 2004 and 2006 from chronically infected patients with HCV, were tested with the 5'UTR and NS5B protocols. Of the total number of the samples tested by the 5'UTR-RFLP assay (n=103) the HCV subtype could be inferred by this method for 92 samples, by 5'UTR sequencing for 16 samples out of 23 tested (n=23) and by using the NS5B sequencing for all the samples tested (n=34). Our results showed that the HCV genotype distribution in Romania is: 1b–86.4%, 1a–10.7% and 4a–2.9%. In conclusion, RFLP screening in the 5'UTR is a convenient method for HCV genotyping and discrimination between 1b and non-1b genotypes but has a poor resolving power for subtyping and evaluation of the transmission routes. Sequencing in NS5B region is more adapted than RFLP and sequencing in 5'UTR for subtyping and epidemiological investigation.

Mots-clés : 5' Untranslated Regions Genotype Hepacivirus/ genetics/isolation & purification Hepatitis, Chronic/blood/ virology Humans Phylogeny Polymorphism, Restriction Fragment Length RNA, Viral/chemistry/genetics Reverse Transcriptase Polymerase Chain Reaction Romania Viral Nonstructural Proteins/chemistry/genetics.

Petit, FM, Hébert, M, Picone, O, Brisset, S, Maurin, M-L, Parisot, F, Capel, L, Benattar, C, Sénat, M-V, Tachdjian, G & Labrune, P 2009, « A new mutation in the AFP gene responsible for a total absence of alpha feto-protein on second trimester maternal serum screening for Down syndrome », Eur J Hum Genet, vol. 17, no. 3, p. 387-90, viewed sans date, .

Résumé : Alpha feto-protein (AFP) is a major plasma protein produced by the yolk sac and the liver during the fetal period. During the second trimester of pregnancy, APF and betahCG serum concentrations are commonly used for screening Down syndrome. AFP deficiency is rare (estimated to be 1/105,000 newborns) and only one sequence alteration has previously been reported in the AFP gene. We report a new mutation in exon 5 of the AFP gene, leading to a total absence of AFP on 2nd-trimester maternal serum screening for Down syndrome, confirmed on the amniotic fluid. Despite this, fetal development and birth were normal. After PCR-amplification, the whole AFP gene was sequenced. The new mutation was a guanine to adenine transition in position 543 creating a premature stop codon in position 181. In order to search for eventual modifications of the amniotic fluid profile, proteins were separated by electrophoresis and compared with 10 normal amniotic fluids sampled at the same developmental age (18 weeks). In the amniotic fluid of our patient albumin rate was reduced whereas alpha1 and beta protein fractions were increased, suggesting that AFP deficiency may modify the distribution of protein fractions. This observation emphasizes the complex molecular mechanisms of compensation of serum protein deficiency. Studies on other families with AFP deficiency are necessary to confirm this observation.

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Pierre-Louis, O, Clay, D, Brunet de la Grange, P, Blazsek, I, Desterke, C, Guerton, B, Blondeau, C, Malfuson, J-V, Prat, M, Bennaceur-Griscelli, A, Lataillade, J-J & Le Bousse-Kerdilès, M-C 2009, « Dual SP/ALDH functionalities refine the human hematopoietic Lin-CD34+CD38- stem/progenitor cell compartment », Stem Cells, vol. 27, no. 10, p. 2552-62, viewed sans date, .

Résumé : Identification of prevalent specific markers is crucial to stem/progenitor cell purification. Determinants such as the surface antigens CD34 and CD38 are traditionally used to analyze and purify hematopoietic stem/progenitor cells (HSCs/HPCs). However, the variable expression of these membrane antigens poses some limitations to their use in HSC/HPC purification. Techniques based on drug/stain efflux through the ATP-binding cassette (ABC)G2 pump (side population [SP] phenotype) or on detection of aldehyde dehydrogenase (ALDH) activity have been independently developed and distinguish the SP and ALDH(Bright) (ALDH(Br)) cell subsets for their phenotype and proliferative capability. In this study, we developed a multiparametric flow cytometric method associating both SP and ALDH activities on human lineage negative (Lin(-)) bone marrow cells and sorted different cell fractions according to their SP/ALDH activity level. We find that Lin(-)CD34(+)CD38(Low/-) cells are found throughout the spectrum of ALDH expression and are enriched especially in ALDH(Br) cells when associated with SP functionality (SP/ALDH(Br) fraction). Furthermore, the SP marker identified G(0) cells in all ALDH fractions, allowing us to sort quiescent cells regardless of ALDH activity. Moreover, we show that, within the Lin(-)CD34(+)CD38(-)ALDH(Br) population, the SP marker identifies cells with higher primitive characteristics, in terms of stemness-related gene expression and in vitro and in vivo proliferative potential, than the Lin(-)CD34(+) CD38(-)ALDH(Br) main population cells. In conclusion, our study shows that the coexpression of SP and ALDH markers refines the Lin(-)CD34(+)CD38(-) hematopoietic compartment and identifies an SP/ALDH(Br) cell subset enriched in quiescent primitive HSCs/HPCs.

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Ploussard, G, Droupy, S, Ferlicot, S, Ples, R, Rocher, L, Richard, S & Benoit, G 2009, « [Renal oncocytosis: case report] », Prog Urol, vol. 19, no. 2, p. 142-4, viewed sans date, .

Résumé : Renal oncocytoma represent 5% of kidney tumors. Oncocytoma is a benign tumor, usually asymptomatic and fortuitous discovery. Standard treatment is tumorectomy when technically feasible. Surgery is indicated when oncocytoma becomes symptomatic, large or grows quickly. In a small proportion of cases, oncocytomas are bilateral and/or multifocal. These forms are most often sporadic or are integrated in the Birt-Hogg-Dube syndrome. We report here the case of a patient suffering from renal oncocytosis responsible for a diffuse renal involvement by numerous oncocytic nodules.

Mots-clés : *Oxyphil, Aged, Cells, Diseases/diagnosis/*pathology, Humans, Kidney, Male, Middle.

Rachagani, S, Torres, MP, Moniaux, N & Batra, SK 2009, « Current status of mucins in the diagnosis and therapy of cancer », Biofactors, vol. 35, no. 6, p. 509-27.

Résumé : Mucins are the most abundant high molecular weight glycoproteins in mucus. Their nature and glycosylation content dictates the biochemical and biophysical properties of viscoelastic secretions, pointing out an important role in diverse biological functions, such as differentiation, cell adhesions, immune responses, and cell signaling. Mucins are expressed in tubular organs by specialized epithelial cells in the body. Their aberrant expression is well documented in a variety of inflammatory or malignant diseases. From a prognosis point of view, their expression and alterations in glycosylation are associated with the development and progression of malignant diseases. Therefore, mucins can be used as valuable markers to distinguish between normal and disease conditions. Indeed, this alteration in glycosylation patterns generates several epitopes in the oligosaccharide side chains that can be used as diagnostic and/or prognostic markers. Furthermore, these characteristic tumor-associated epitopes are extensively used as appropriate immunotargets of malignant epithelial cells. Therefore, in an effort to detect and treat cancer at the earliest stage possible, mucins are analyzed as potential markers of disease for diagnosis, progression, and for therapeutic purposes. In this review, we focused on the current status of the distribution of mucins in normal and pathologic conditions and their clinical use both in cancer diagnosis and therapeutics treatments.

Mots-clés : Animals Antibodies/therapeutic use Biological Markers/ metabolism Humans Models, Biological Mucins/immunology/ metabolism Neoplasms/ diagnosis/drug therapy/ therapy.

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Rocha-Perugini, V, Lavie, M, Delgrange, D, Canton, J, Pillez, A, Potel, J, Lecoeur, C, Rubinstein, E, Dubuisson, J, Wychowski, C & Cocquerel, L 2009, « The association of CD81 with tetraspanin-enriched microdomains is not essential for Hepatitis C virus entry », BMC Microbiol, vol. 9, p. 111, viewed sans date, .

Résumé : BACKGROUND: Three percent of the world's population is chronically infected with hepatitis C virus (HCV) and thus at risk of developing liver cancer. Although precise mechanisms regulating HCV entry into hepatic cells are still unknown, several cell surface proteins have been identified as entry factors for this virus. Among these molecules, the tetraspanin CD81 is essential for HCV entry. Interestingly, CD81 is also required for Plasmodium infection. A major characteristic of tetraspanins is their ability to interact with each other and other transmembrane proteins to build tetraspanin-enriched microdomains (TEM). RESULTS: In our study, we describe a human hepatoma Huh-7 cell clone (Huh-7w7) which has lost CD81 expression and can be infected by HCV when human CD81 (hCD81) or mouse CD81 (mCD81) is ectopically expressed. We took advantage of these permissive cells expressing mCD81 and the previously described MT81/MT81w mAbs to analyze the role of TEM-associated CD81 in HCV infection. Importantly, MT81w antibody, which only recognizes TEM-associated mCD81, did not strongly affect HCV infection. Furthermore, cholesterol depletion, which inhibits HCV infection and reduces total cell surface expression of CD81, did not affect TEM-associated CD81 levels. In addition, sphingomyelinase treatment, which also reduces HCV infection and cell surface expression of total CD81, raised TEM-associated CD81 levels. CONCLUSION: In contrast to Plasmodium infection, our data show that association of CD81 with TEM is not essential for the early steps of HCV life cycle, indicating that these two pathogens, while using the same molecules, invade their host by different mechanisms.

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Roche, B & Samuel, D 2009, « Antiviral therapy in HCV-infected cirrhotics awaiting liver transplantation: A costly strategy for mixed virological results », J Hepatol, vol. 50, no. 4, p. 652-4.

Résumé : Roche, Bruno; Samuel, Didier; Comment; Editorial; England; J Hepatol. 2009 Apr;50(4):652-4. doi: 10.1016/j.jhep.2009.01.008. Epub 2009 Feb 11.

Mots-clés : &, adverse, Agents/, Antiviral, Bacterial, C/, control/, drug, effects, effects/therapeutic, epidemiology, Glycols/adverse, Hepatitis, Humans, Infections/, Interferon-alpha/adverse, Lists, Liver, Polyethylene, Proteins, Recombinant, Ribavirin/adverse, Safety, surgery, therapy/prevention, Transplantation, use, Waiting.

Roche, B & Samuel, D 2009, « Transplantation: Steroid use in HCV-infected liver transplant recipients », Nat Rev Gastroenterol Hepatol, vol. 6, no. 4, p. 198-200.

Résumé : Roche, Bruno; Samuel, Didier; News; England; Nat Rev Gastroenterol Hepatol. 2009 Apr;6(4):198-200. doi: 10.1038/nrgastro.2009.38.

Mots-clés : Adrenal Cortex Hormones/pharmacology/ therapeutic use Graft Survival/drug effects Hepatitis C, Chronic/ prevention & control/ surgery Humans Immunosuppressive Agents/pharmacology/therapeutic use Liver Transplantation Recurrence/prevention & control Viral Load.

Rodder, S, Scherer, A, Raulf, F, Berthier, CC, Hertig, A, Couzi, L, Durrbach, A, Rondeau, E & Marti, HP 2009, « Renal allografts with IF/TA display distinct expression profiles of metzincins and related genes », Am J Transplant, vol. 9, no. 3, p. 517-26, viewed sans date, .

Résumé : Chronic renal allograft injury is often reflected by interstitial fibrosis (IF) and tubular atrophy (TA) without evidence of specific etiology. In most instances, IF/TA remains an irreversible disorder, representing a major cause of long-term allograft loss. As members of the protease family metzincins and functionally related genes are involved in fibrotic and sclerotic processes of the extracellular matrix (ECM), we hypothesized their deregulation in IF/TA. Gene expression and protein level analyses using allograft biopsies with and without Banff'05 classified IF/TA illustrated their deregulation. Expression profiles of these genes differentiated IF/TA from Banff'05 classified Normal biopsies in three independent microarray studies and demonstrated histological progression of IF/TA I to III. Significant upregulation of matrix metalloprotease-7 (MMP-7) and thrombospondin-2 (THBS-2) in IF/TA biopsies and sera was revealed in two independent patient sets. Furthermore, elevated THBS-2, osteopontin (SPP1) and beta-catenin may play regulatory roles on MMP. Our findings further suggest that deregulated ECM remodeling and possibly epithelial to mesenchymal transition (EMT) are implicated in IF/TA of kidney transplants, and that metzincins and related genes play an important role in these processes. Profiling of these genes may be used to complement IF/TA diagnosis and to disclose IF/TA progression in kidney transplant recipients.

Mots-clés : Homologous, Messenger/genetics Thrombospondins/genetics Transplantation.

Roque-Afonso, AM 2009, « Hepatitis B virus cellular immunity after liver transplantation: a role in preventing hepatitis B virus recurrence? », Liver Transpl, vol. 15, no. 3, p. 269-72.

Résumé : Roque-Afonso, Anne Marie; Comment; Editorial; United States; Liver Transpl. 2009 Mar;15(3):269-72. doi: 10.1002/lt.21729.

Mots-clés : CD4-Positive T-Lymphocytes/ immunology Hepatitis B virus/ immunology/physiology Hepatitis B, Cellular Immunization, Chronic/ immunology Humans Immunity, Passive/ methods Immunoglobulins/ therapeutic use Liver Transplantation/ immunology Recurrence Virus Replication/immunology.

Recherche bibliographique scientifique

2009