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1. Hepatocellular carcinoma hosts cholinergic neural cells and tumoral hepatocytes harboring targetable muscarinic receptors

Author: Charlotte A. Hernandez, Claire Verzeroli, Armando Andres Roca Suarez, Abud-José Farca-Luna, Laurie Tonon, Roger Esteban-Fabró, Roser Pinyol, Marie-Laure Plissonnier, Ievgeniia Chicherova, Anaëlle Dubois, Pascale Bellaud, Marine Seffals, Bruno Turlin, Alain Fautrel, Gabriel Ichim, Michel Rivoire, Guillaume Passot, Zuzana Macek-Jilkova, Thomas Decaens, Alain Viari, Barbara Testoni, Sandra Rebouissou, Josep M. Llovet, Fabien Zoulim, and Romain Parent
Subjects: HCC, autonomic nervous system, neuronal score, transcriptomics, scRNA-seq, cholinergic, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Background & Aims: Owing to unexplained interpatient variation and treatment failure in hepatocellular carcinoma (HCC), novel therapeutic approaches remain an urgent clinical need. Hepatic neurons, belonging to the autonomic nervous system (ANS), mediate liver/whole body crosstalk. Pathological innervation of the ANS has been identified in cancer, nurturing tumor stroma and conferring stronger carcinogenic properties. Methods: We characterized the innervation of liver tumors from the French Liver Biobank, then applied bioinformatics to TCGA (The Cancer Genome Atlas), several other datasets and a European validation cohort, to re-evaluate patient stratification. Cell biology and pharmacology studies were also performed. Results: Densely packed nucleated DCX+, synaptophysin+, NeuN+, VAChT+, TH-, CD31-, CD45- clusters, to date undetected, were identified in human HCCs, and independently confirmed by single-cell RNA sequencing data. Using the new concept of a neuronal score, human and rat HCCs displayed tightly netrin-1-associated neural reconfiguration towards cholinergic polarity, which was associated with chronic liver disease progression, cancer onset and many features of aggressive (proliferative class) HCC, including shortened survival. This score was conditioned by tumoral hepatocytes, and predicted sorafenib efficacy in the STORM HCC phase III trial. Conversely, intratumoral adrenergic lymphocytes were enriched in TEMRA and cytotoxic phenotypes. Amongst all cholinergic transcripts, the medically targeted CHRM3 receptor was enriched and associated with pathogenic traits in HCC, as well as poor prognosis in HCC stages 1-2, while its level dropped upon experimental re-differentiation. Its pharmacological inhibition with low concentrations of anticholinergic drugs, but not cholinomimetics, decreased anchorage-independent growth and anoikis, synergized with sorafenib and lenvatinib in HCC class 1 to 3 lines, yet not in primary human hepatocytes, and preserved mature hepatocyte functions. Conclusion: These data identify cholinergic processes as instrumental in liver carcinogenesis and support the use of EMA/FDA-approved cholinergic drugs in HCC research. Impact and implications:: Hepatocellular carcinoma (HCC) care has long been hampered by the enigmatic nature of disease evolution, as well as of response or resistance to treatment. Hepatic neurons are likely the least studied liver cell type and mediate patients singularities from the ANS to the organ in real-time. Cholinergic inputs identified in this study as pathogenic may be targeted with the well charted pharmacopoeia of neurotropic drugs already available, for basic or clinical research purposes, with an expected high level of safety.
Published: 2025
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2. SARS-CoV-2 receptor ACE2 is upregulated by fatty acids in human MASH

Author: Luis Cano, Lise Desquilles, Gevorg Ghukasyan, Gaëlle Angenard, Clémence Landreau, Anne Corlu, Bruno Clément, Bruno Turlin, Eric Le Ferrec, Caroline Aninat, Julie Massart, and Orlando Musso
Subjects: Metabolism, DC-SIGNR, CLEC4M, TMPRSS2, DPP4, SARS-CoV-2, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) results in steatosis, inflammation (steatohepatitis), and fibrosis. Patients with MASLD more likely develop liver injury in coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As viral RNA has been identified in liver tissues, we studied expression levels and cellular sources of the viral receptor angiotensin-converting enzyme 2 (ACE2) and coreceptors in MASLD and fibroinflammatory liver diseases. Methods: We built a transcriptomic MASLD meta-dataset (N = 243) to study SARS-CoV-2 receptor expression and verified results in 161 additional cases of fibroinflammatory liver diseases. We assessed the fibroinflammatory microenvironment by deconvoluting immune cell populations. We studied the cellular sources of ACE2 by multiplex immunohistochemistry followed by high-resolution confocal microscopy (N = 9 fatty livers; N = 7 controls), meta-analysis of two single-cell RNA sequencing datasets (N = 5 cirrhotic livers; N = 14 normal livers), and bulk transcriptomics from 745 primary cell samples. In vitro, we tested ACE2 mRNA expression in primary human hepatocytes treated with inflammatory cytokines, bacterial lipopolysaccharides, or long-chain fatty acids. Results: We detected ACE2 at the apical and basal poles of hepatocyte chords, in CLEC4M+ liver sinusoidal endothelial cells, the lumen of ABCC2+ bile canaliculi, HepPar-1+-TMPRSS2+ hepatocytes, cholangiocytes, and CD34+ capillary vessels. ACE2 steeply increased between 30 and 50 years of age; was related to liver fat area, inflammation, high immune reactivity, and fibrogenesis; and was upregulated in steatohepatitis. Although ACE2 mRNA was unmodified in alcoholic or viral hepatitis, it was upregulated in fibroinflammatory livers from overweight patients. In vitro, treatment of primary human hepatocytes with inflammatory cytokines alone downregulated but long chain fatty acids upregulated ACE2 mRNA expression. Conclusions: Lipid overload in fatty liver disease leads to an increased availability of ACE2 receptors. Impact and implications: COVID-19 can be a deadly disease in vulnerable individuals. Patients with fatty liver disease are at a higher risk of experiencing severe COVID-19 and liver injury. Recent studies have indicated that one of the reasons for this vulnerability is the presence of a key cell surface protein called ACE2, which serves as the main SARS-CoV-2 virus receptor. We describe the cellular sources of ACE2 in the liver. In patients with fatty liver disease, ACE2 levels increase with age, liver fat content, fibroinflammatory changes, enhanced positive immune checkpoint levels, and innate immune reactivity. Moreover, we show that long chain fatty acids can induce ACE2 expression in primary human hepatocytes. Understanding the cellular sources of ACE2 in the liver and the factors that influence its availability is crucial. This knowledge will guide further research and help protect potentially vulnerable patients through timely vaccination boosters, dietary adjustments, and improved hygiene practices.
Published: 2024
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3. Role of non-invasive methods in detecting liver impairment in familial Mediterranean fever adult patients with persistent hepatic cytolysis

Author: Samuel Deshayes, Thibault Fraisse, Soraya Fellahi, Olivier Steichen, Léa Savey, Bruno Turlin, Mona Munteanu, Achille Aouba, Rim Bourguiba, Véronique Hentgen, Jean-Manuel Faintuch, Irina Giurgea, Gilles Grateau, Jean-Philippe Bastard, and Sophie Georgin-Lavialle
Subjects: Medicine, Science
Abstract: Abstract Familial Mediterranean fever (FMF) patients may have hepatic cytolysis, although its origin is not formally elucidated. We aimed to evaluate liver involvement in familial Mediterranean fever (FMF) using non-invasive methods. All adult FMF patients harboring two non-ambiguous mutations of the MEFV gene with hepatic cytolysis were identified in a French tertiary adult center for FMF. Liver impairment was explored with FibroMax (a non-invasive method to estimate hepatic steatosis, necrosis, inflammation and fibrosis) and liver ultrasound. Among 520 FMF adult patients, 43 had persistent hepatic cytolysis and 20 patients were included (11 women, median age at inclusion: 49.5 years). According to the FibroMax results, patients were classified as having steatosis, fibrosis, and possible or definite nonalcoholic steato-hepatitis in 10 (50%), 9 (45%) and 7 (35%) of cases, respectively. The score of steatosis did not seem associated with the usual metabolic risk factors. No significant association was found between the cumulated dose of colchicine and any of the scores included in FibroMax. In adult FMF patients with persistent hepatic cytolysis, steatosis is the first cause to consider even in the absence of usual metabolic risk factors, suggesting other mechanisms. Colchicine did not seem to be involved in this toxicity.
Published: 2022
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4. Artificial Intelligence in Predicting Microsatellite Instability and KRAS, BRAF Mutations from Whole-Slide Images in Colorectal Cancer: A Systematic Review

Author: Theo Guitton, Pierre Allaume, Noémie Rabilloud, Nathalie Rioux-Leclercq, Sébastien Henno, Bruno Turlin, Marie-Dominique Galibert-Anne, Astrid Lièvre, Alexandra Lespagnol, Thierry Pécot, and Solène-Florence Kammerer-Jacquet
Subjects: digital pathology, artificial intelligence, colorectal cancer, deep learning, microsatellite instability, mismatch repair deficiency, Medicine (General), R5-920
Abstract: Mismatch repair deficiency (d-MMR)/microsatellite instability (MSI), KRAS, and BRAF mutational status are crucial for treating advanced colorectal cancer patients. Traditional methods like immunohistochemistry or polymerase chain reaction (PCR) can be challenged by artificial intelligence (AI) based on whole slide images (WSI) to predict tumor status. In this systematic review, we evaluated the role of AI in predicting MSI status, KRAS, and BRAF mutations in colorectal cancer. Studies published in PubMed up to June 2023 were included (n = 17), and we reported the risk of bias and the performance for each study. Some studies were impacted by the reduced number of slides included in the data set and the lack of external validation cohorts. Deep learning models for the d-MMR/MSI status showed a good performance in training cohorts (mean AUC = 0.89, [0.74–0.97]) but slightly less than expected in the validation cohort when available (mean AUC = 0.82, [0.63–0.98]). Contrary to the MSI status, the prediction of KRAS and BRAF mutations was less explored with a less robust methodology. The performance was lower, with a maximum of 0.77 in the training cohort, 0.58 in the validation cohort for KRAS, and 0.82 AUC in the training cohort for BRAF.
Published: 2023
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5. Well-differentiated liver cancers reveal the potential link between ACE2 dysfunction and metabolic breakdown

Author: Lise Desquilles, Luis Cano, Gevorg Ghukasyan, Nicolas Mouchet, Clémence Landreau, Anne Corlu, Bruno Clément, Bruno Turlin, Romain Désert, and Orlando Musso
Subjects: Medicine, Science
Abstract: Abstract Angiotensin-converting enzyme 2 (ACE2) is the receptor of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causing Coronavirus disease 2019 (COVID-19). Transmembrane serine protease 2 (TMPRSS2) is a coreceptor. Abnormal hepatic function in COVID-19 suggests specific or bystander liver disease. Because liver cancer cells express the ACE2 viral receptor, they are widely used as models of SARS-CoV-2 infection in vitro. Therefore, the purpose of this study was to analyze ACE2 and TMPRSS2 expression and localization in human liver cancers and in non-tumor livers. We studied ACE2 and TMPRSS2 in transcriptomic datasets totaling 1503 liver cancers, followed by high-resolution confocal multiplex immunohistochemistry and quantitative image analysis of a 41-HCC tissue microarray. In cancers, we detected ACE2 and TMPRSS2 at the biliary pole of tumor hepatocytes. In whole mount sections of five normal liver samples, we identified ACE2 in hepatocyte’s bile canaliculi, biliary epithelium, sinusoidal and capillary endothelial cells. Tumors carrying mutated β-catenin showed ACE2 DNA hypomethylation and higher mRNA and protein expression, consistently with predicted β-catenin response sites in the ACE2 promoter. Finally, ACE2 and TMPRSS2 co-expression networks highlighted hepatocyte-specific functions, oxidative stress and inflammation, suggesting a link between inflammation, ACE2 dysfunction and metabolic breakdown.
Published: 2022
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6. Metallomic profile in non-cirrhotic hepatocellular carcinoma supports a phenomenon of metal metabolism adaptation in tumor cells

Author: Luis Cano, Stéphane Bertani, Marie-Laure Island, Juan Pablo Cerapio, Eloy Ruiz, Pascal Pineau, Valérie Monbet, Karim Boudjema, Luis Taxa, Sandro Casavilca-Zambrano, Martine Ropert, Bruno Turlin, and Olivier Loréal
Subjects: Medicine, Science
Abstract: Abstract We have previously described a form of hepatocellular carcinoma (HCC) in non-cirrhotic liver (HCC-NC) developed by Peruvian patients. We analyzed the metallomic profile in hepatic tissues from two independent cohorts exhibiting HCC-NC. Clinical, histopathological data, and HCC and non-tumoral liver (NTL) samples of 38 Peruvian and 38 French HCC-NC patients, were studied. Twelve metals were quantified using ICP/MS: Mn, Fe, Cu, Co, Zn, As, Se, Rb, Mo, Cd, Pb, and Sn. Associations between metals and survival were assessed. Our data showed significant differences between cohorts. Mean ages were 40.6 ± 20, 67.5 ± 9 years old for Peruvians and French, respectively. Fifty percent of the Peruvian patients were positive for the HBsAg, versus 3% in French patients. Mn, Cu, Zn, As, Se, Rb, Mo, Cd, Sn metal concentrations were higher in NTL of Peruvians. Importantly, metal concentrations were lower in HCC areas compared to NTL tissues in both cohorts, except for Cu for which mean concentration was higher in HCC (p
Published: 2021
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7. Artificial Intelligence-Based Opportunities in Liver Pathology—A Systematic Review

Author: Pierre Allaume, Noémie Rabilloud, Bruno Turlin, Edouard Bardou-Jacquet, Olivier Loréal, Julien Calderaro, Zine-Eddine Khene, Oscar Acosta, Renaud De Crevoisier, Nathalie Rioux-Leclercq, Thierry Pecot, and Solène-Florence Kammerer-Jacquet
Subjects: digital pathology, liver, hepatology, deep learning, artificial intelligence, performance metrics, Medicine (General), R5-920
Abstract: Background: Artificial Intelligence (AI)-based Deep Neural Networks (DNNs) can handle a wide range of applications in image analysis, ranging from automated segmentation to diagnostic and prediction. As such, they have revolutionized healthcare, including in the liver pathology field. Objective: The present study aims to provide a systematic review of applications and performances provided by DNN algorithms in liver pathology throughout the Pubmed and Embase databases up to December 2022, for tumoral, metabolic and inflammatory fields. Results: 42 articles were selected and fully reviewed. Each article was evaluated through the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool, highlighting their risks of bias. Conclusions: DNN-based models are well represented in the field of liver pathology, and their applications are diverse. Most studies, however, presented at least one domain with a high risk of bias according to the QUADAS-2 tool. Hence, DNN models in liver pathology present future opportunities and persistent limitations. To our knowledge, this review is the first one solely focused on DNN-based applications in liver pathology, and to evaluate their bias through the lens of the QUADAS2 tool.
Published: 2023
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8. Adding the oxygen carrier M101 to a cold-storage solution could be an alternative to HOPE for liver graft preservation

Author: Pierre Alix, David Val-Laillet, Bruno Turlin, Ismail Ben Mosbah, Agnes Burel, Eric Bobillier, Claude Bendavid, Eric Delpy, Franck Zal, Anne Corlu, and Karim Boudjema
Subjects: Liver transplantation, Haemoglobin, Hepatocyte, Inflammation, Oxidative stress, Cell necrosis, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Background & Aims: Hypothermic oxygenated machine perfusion (HOPE) is a promising technique for providing oxygen to the liver during graft preservation; however, because of associated logistical constraints, addition of an oxygen transporter to static cold-storage solutions (SCS) might be easier. M101 is marine worm haemoglobin that has been shown to improve kidney preservation in the clinic when added to SCS. This study evaluated the effects of the addition of M101 to SCS on the quality of pig liver graft preservation. Methods: Pig liver grafts were preserved using SCS, HOPE, or SCS+M101, and the liver functions were compared during cold preservation and after orthotopic allotransplantation (OLT) in pigs. Results: During preservation of the liver grafts, mitochondrial function, ATP synthesis, antioxidant capacities, and hepatocyte architecture were better preserved, and free radical production, antioxidant activities, and inflammatory mediators were lower, with HOPE or SCS+M101 than with SCS alone. However, after 1 h of preservation, liver functions with HOPE were superior to those with SCS+M101. After 6 h of preservation and OLT, blood levels of aspartate and alanine aminotransferases and lactate dehydrogenase increased with a peak effect at Day 1 post-transplant; values were similar with HOPE and SCS+M101, and were significantly lower than those in the SCS group. At Days 1 and 3, tumor necrosis factor α levels remained lower with HOPE and SCS+M101 vs. SCS. At Day 7, liver cell necrosis and inflammation were less marked in both oxygenated groups. Conclusions: When added to SCS, M101 effectively oxygenates liver grafts during preservation, preventing post-transplant injury; although graft performances are below those achieved with HOPE. Lay summary: When transported between donors and recipients, even cold-stored liver grafts need oxygen to maintain their viability. To provide them with oxygen, we added a marine worm super haemoglobin (M101) to the cold-storage solution UWCS. Using a pig liver transplant model, we revealed that livers cold stored with UWCS+M101 showed improved oxygenation compared with simple cold-storage solutions, but did not reach the oxygenation level achieved with machine perfusion.
Published: 2020
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9. Gene expression profiling of the tumor microenvironment in human intrahepatic cholangiocarcinoma

Author: Laurent Sulpice, Mireille Desille, Bruno Turlin, Alain Fautrel, Karim Boudjema, Bruno Clément, and Cédric Coulouarn
Subjects: Genetics, QH426-470
Abstract: Intrahepatic cholangiocarcinoma (ICC) is the second most common type of malignant primary tumors in the liver. ICC is an aggressive cancer with a poor survival and limited therapeutic options. At the histological level, ICC is characterized by an abundant stroma (i.e. the tumor microenvironment that notably includes components of the extracellular matrix, stromal cells and soluble factors). Tumor microenvironment is known to play a key role in tumor onset and progression but it is poorly characterized at the molecular level. Thus, this study was specifically designed to identify genes that are significantly deregulated in the tumor microenvironment of human ICC. Here we provide a detailed description of the experimental design and methods used to acquire the genomic data deposited into Gene Expression Omnibus (GEO) under the accession number GSE45001. Our genomic dataset provides insights on the molecular pathways altered in the microenvironment of ICC and allows the identification of novel ICC biomarkers, as exemplified previously in Hepatology (PMID: 23775819). Keywords: Liver, Cancer, Cholangiocarcinoma, Microenvironment, Profiling
Published: 2016
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10. WED-227 Transient elastography performance for the diagnosis of liver fibrosis in MASLD is independent of steatosis level as determined by MRI proton density fat fraction in a prospective multicentrer study

Author: Masrour, Oumnia, primary, Ehrhard, Florent, additional, Guillaume, Maeva, additional, Boursier, Jerome, additional, Gournay, Jérôme, additional, Aziz, Karim, additional, Schnee, Matthieu, additional, Garlantezec, Ronan, additional, de Lédinghen, Victor, additional, Fabrice, Laine, additional, Bruno, Turlin, additional, Gandon, Yves, additional, and Bardou-Jacquet, Edouard, additional
Published: 2024
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11. WED-162 Performance of transient elastography, Fib4 and APRI in the diagnosis of severe liver fibrosis in patient with HFE hemochromatosis

Author: Trubert, Lise, primary, Masrour, Oumnia, additional, Jeff, Morcet, additional, Fabrice, Laine, additional, Bruno, Turlin, additional, and Bardou-Jacquet, Edouard, additional
Published: 2024
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12. SAT-043 Liver transplantation for locally advanced, unresectable intrahepatic cholangiocarcinoma following neoadjuvant treatment with chemotherapy and radioembolization

Author: Giguet, Baptiste, primary, Uguen, Thomas, additional, Jeddou, Heithem, additional, Houssel-Debry, Pauline, additional, Jezequel, Caroline, additional, Robin, Fabien, additional, Chebaro, Alexandre, additional, Boudjema, Karim, additional, Garin, Etienne, additional, Beuzit, Luc, additional, Bruno, Turlin, additional, Edeline, Julien, additional, Bardou-Jacquet, Edouard, additional, and Artru, Florent, additional
Published: 2024
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13. Integrating Biobank Data into a Clinical Data Research Network: The IBCB Project.

Author: Guillaume Bouzillé, Vianney Jouhet, Bruno Turlin, Bruno Clement, Mireille Desille, Christine Riou, Moufid Hajjar, Denis Delamarre, Danielle Le Quilleuc, Frantz Thiessard, and Marc Cuggia
Published: 2018
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14. Early diagnosis of NAFLD-NASH transition using mid infrared spectroscopy.

Author: Siouar Bensaid, Amar Kachenoura, Nathalie Costet, Victor De Ledinghen, Julien Vergniol, Fabrice Laine, Bruno Turlin, Hugues Tariel, and Lotfi Senhadji
Published: 2016
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15. Non‐invasive diagnosis of alcohol‐related steatohepatitis in patients ongoing alcohol withdrawal based on cytokeratin 18 and transient elastography

Author: Arnaud Chalin, Bruno Turlin, Ahmad Ousmen, Sophie Michalak, Johannes Mueller, Sebastian Mueller, Ludivine Legros, Edouard Bardou‐Jacquet, Jean François Viel, Michel Samson, Romain Moirand, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Universität Heidelberg [Heidelberg] = Heidelberg University, and Programme Hospitalier de Recherche Clinique, French Ministry of Health, 2012
Subjects: Hepatology, [SDV]Life Sciences [q-bio], Gastroenterology, Pharmacology (medical)
Abstract: International audience; BACKGROUND AND AIMS: The diagnosis of alcoholic steatohepatitis (ASH) is based on liver biopsy, which is costly and invasive with non-negligible morbidity. The aim of this study was to evaluate the accuracy of circulating cytokeratin 18 M65 fragment (K18-M65) alone or in association with other markers for the non-invasive diagnosis of ASH in patients ongoing alcohol withdrawal. METHODS: This study examined the serum level of K18-M65 in a test cohort of 196 patients. All patients underwent liver biopsy, transient elastography (TE) and serum collection. The diagnostic accuracy of K18-M65 alone or combined with clinico-biological data was assessed and the best defined cut-offs were validated in an independent validation cohort of 58 patients. RESULTS: K18-M65 had an area under the curve (AUC) of 0.82 (test cohort) and 0.90 (validation cohort). Using two cut-off decision points, K18-M65 was able to classify 46.9% (test cohort) and 34.5% (validation cohort) of patients with 95% sensitivity or specificity. Combining K18-M65, alpha-2-macroglobulin, TE, body mass index, and age, we created a score allowing accurate diagnosis of ASH with an AUC of 0.93 (test cohort) and 0.94 (validation cohort). This new score was able to rule out or rule in the diagnosis of steatohepatitis for probability ≤0.135 or ≥0.667 respectively in more than two-thirds of patients. CONCLUSIONS: We propose a new validated non-invasive score for the diagnosis of ASH in patients ongoing alcohol withdrawal. This score can help to identify patients that may benefit from potential therapeutics or motivate them to reduce alcohol consumption.
Published: 2023
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16. Automatic Definition of the Oncologic EHR Data Elements from NCIT in OWL.

Author: Marc Cuggia, Annabel Bourde, Bruno Turlin, Sebastien Vincendeau, Valérie Bertaud, Catherine Bohec, and Régis Duvauferrier
Published: 2011
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17. Design of an automatic coding algorithm for a multi-axial classification in pathology.

Author: André Happe, Marc Cuggia, Bruno Turlin, and Pierre Le Beux
Published: 2008
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18. Blood, cellular, and tissular calcineurin inhibitors pharmacokinetic-pharmacodynamic relationship in heart transplant recipients: the INTRACAR study

Author: Gwendal, Coste, Céline, Chabanne, Camille, Tron, Bernard, Lelong, Marie-Clémence, Verdier, Mikael, Roussel, François, Le Gall, Bruno, Turlin, Mireille, Desille-Dugast, Erwan, Flécher, Bruno, Laviolle, Florian, Lemaitre, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération Hospitalo-universitaire SUrvival oPtimization in ORgan Transplantation (FHU SUPORT), Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)-Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Cellules Dendritiques, Immunomodulation et Greffes, Université de Tours (UT)-Université de Tours (UT)-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut National de la Santé et de la Recherche Médicale (INSERM), The authors acknowledge the Centre de Ressources Biologiques (CRB) Santé of Rennes BB-0033- 00056 for managing patient samples., and Jonchère, Laurent
Subjects: [SDV.IB] Life Sciences [q-bio]/Bioengineering, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Pharmacology, Pharmacology (medical), [SDV.IB]Life Sciences [q-bio]/Bioengineering, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences
Abstract: International audience; BACKGROUND: After heart transplantation, calcineurin inhibitors (CNI) (cyclosporin A and tacrolimus) are key immunosuppressive drugs to prevent graft rejection. Whole-blood concentration (Cblood)-guided therapeutic drug monitoring (TDM) is systematically performed to improve graft outcomes. However, some patients will still experience graft rejection and/or adverse events despite CNI Cblood within the therapeutic range. Other pharmacokinetic parameters, such as the intra-graft, or intracellular concentration at the CNI site of action could refine their TDM. Nonetheless, these remain to be explored. The objective of the INTRACAR study was to describe the relationship between whole blood, intra-graft, and intracellular CNI concentrations as well as their efficacy in heart transplant recipients (HTR). METHODS: In a cohort of HTR, protocol endomyocardial biopsies (EMB) were collected to assess rejection by anatomopathological analysis. Part of the EMB was used to measure the intra-graft concentrations of CNI (CEMB). Cblood, and the concentration inside peripheral blood mononuclear cells (CPBMC), a cellular fraction enriched with lymphocytes, were also monitored. Concentrations in the three matrices were compared between patients with and without biopsy-proven acute rejection (BPAR). RESULTS: Thirty-four HTR were included, representing nearly 100 pharmacokinetic (PK) samples for each CNI. Cblood, CEMB and CPBMC correlated for both CNI. BPAR was observed in 74 biopsies (39.6 %) from 26 patients (76.5 %), all except one of low-grade. None of the PK parameters (Cblood, CEMB, CPBMC, CEMB/blood and CPBMC/blood) was associated with BPAR. CONCLUSION: In this cohort of well-immunosuppressed patients, no association was observed for any of the PK parameters including Cblood, with the occurrence of BPAR. However, a trend was noticed for the CEMB and CEMB/blood of cyclosporin A. Further studies in higher-risk patients may help optimize the use of CEMB and CPBMC for CNI TDM in HTR.
Published: 2022
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19. Hepatocellular carcinoma hosts immature neurons and cholinergic tumors that correlate with adverse molecular features and outcomes

Author: Charlotte A. Hernandez, Claire Verzeroli, Ievgeniia Chicherova, Abud-José Farca-Luna, Laurie Tonon, Pascale Bellaud, Bruno Turlin, Alain Fautrel, Zuzana Macek-Jilkova, Thomas Decaens, Sandra Rebouissou, Alain Viari, Fabien Zoulim, and Romain Parent
Abstract: Background & aimsThe unexplained interpatient variation in hepatocellular carcinoma (HCC) remains a major challenge. We aimed at addressing the under-explored association between the disease and the hepatic autonomic nervous system (ANS).Methods & ResultsWe in-depth characterized the innervation of French biobanks HCC samples by conventional biochemistry methods. We also applied bioinformatics approaches to the TCGA dataset in order to stratify samples according to neural features and molecular correlates. We highlighted the predominant parasympathetic polarity of HCC nerves, and demonstrated that a cirrhotic rat model of aggressive HCC hosts liver neurogenesis with cholinergic features. Using the TCGA dataset, we then defined an HCC neural signature, derived from adrenergic and cholinergic receptor levels, that allowed patient stratification into two classes. Cholinergic tumors correlated with TP53 mutations (p ≤ 0.05), shorter progression-free interval (PFI) and overall survival (OS), displayed more pathogenic molecular traits (e.g., AFP-rich, proliferative tumors, mitotic functions including DNA repair, EMT, Ras, and Akt/mTOR pathways), aggressive HCC signatures and B cell accumulation. Instead, adrenergic tumors, predominant in patients aged >60 and with mutated CTNNB1, were correlated with better OS and PFI (p < 0.05), and numerous immune pathways.ConclusionsOur results depict neural features of HCC and how the existing tumor classification may also be shaped by neural inputs. Altogether, we show that the parasympathetic branch of the ANS is implicated in the pathobiology of HCC, and advocate for the use of ANS-targeting drugs in HCC research, many of which are clinically safe and well characterized.
Published: 2022
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20. Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study

Author: Eric Trépo, Stefano Caruso, Jie Yang, Sandrine Imbeaud, Gabrielle Couchy, Quentin Bayard, Eric Letouzé, Nathalie Ganne-Carrié, Christophe Moreno, Abderrahim Oussalah, Cyrille Féray, Jean Frédéric Blanc, Bruno Clément, Patrick Hillon, Jérôme Boursier, Valérie Paradis, Julien Calderaro, Viviane Gnemmi, Jean-Charles Nault, Jean-Louis Guéant, Jacques Devière, Isabelle Archambeaud, Carole Vitellius, Bruno Turlin, Jean-Pierre Bronowicki, Thierry Gustot, Angela Sutton, Marianne Ziol, Pierre Nahon, Jessica Zucman-Rossi, Clément Meiller, Qian Cao, Théo Z. Hirsch, Sandra Rebouissou, Delphine Degré, Lukas Otero Sanchez, Nicolas Rosewick, Eric Quertinmont, Mireille Desille-Dugast, Muriel François-Vié, Cécile Moins, Emmanuelle Leteurtre, Guillaume Lassailly, Massih Ningarhari, Emmanuel Boleslawski, Vanessa Cottet, Université libre de Bruxelles (ULB), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), People's Hospital of Peking University (PKUPH), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital Paul Brousse, CHU Bordeaux [Bordeaux], Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Pontchaillou [Rennes], Centre de Ressources Biologiques Santé (CRB Santé), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-CRLCC Eugène Marquis (CRLCC), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital Beaujon [AP-HP], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Institut des Maladies de l'Appareil Digestif, Université de Nantes (UN), Hôtel-Dieu de Nantes, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hôpitaux Universitaires Paris Seine-Saint-Denis [Sevran] (HUP2SD), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), BB-0033-00027, H2020 Marie Skłodowska-Curie Actions, MSCA, University Hospitals, UH: NCT03311152, Bpifrance, Agence Nationale de la Recherche, ANR: ANR-11-LABX-0021, Institut National de la Santé et de la Recherche Médicale, Inserm, Assistance Publique - Hôpitaux de Paris, AP-HP, Ligue Contre le Cancer, Fondation de France, Institut National Du Cancer, INCa, Université Libre de Bruxelles, Conseil régional de Bourgogne-Franche-Comté, Korean Association for the Study of the Liver, KASL, GENTHEP Consortium: Clément Meiller, Qian Cao, Théo Z Hirsch, Sandra Rebouissou, Delphine Degré, Lukas Otero Sanchez, Nicolas Rosewick, Eric Quertinmont, Mireille Desille-Dugast, Muriel François-Vié, Cécile Moins, Emmanuelle Leteurtre, Guillaume Lassailly, Massih Ningarhari, Emmanuel Boleslawski, Vanessa Cottet, ANR-11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer(2011), École pratique des hautes études (EPHE), Jonchère, Laurent, Laboratoires d'excellence - Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer - - Lipstic2011 - ANR-11-LABX-0021 - LABX - VALID, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-CRLCC Eugène Marquis (CRLCC), Faculté de Médecine [Bruxelles] [ULB], Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)], Biochimie – Biologie moléculaire et Nutrition [CHRU Nancy], Institut National de la Santé et de la Recherche Médicale [INSERM], Centre Hépato-Biliaire [Hôpital Paul Brousse] [CHB], Bordeaux Research In Translational Oncology [Bordeaux] [BaRITOn], Lipides - Nutrition - Cancer [Dijon - U1231] [LNC], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand [CHU Dijon], Centre Hospitalier Universitaire d'Angers [CHU Angers], Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques [HIFIH], Université Paris-Est Créteil Val-de-Marne - Paris 12 [UPEC UP12], Institut Mondor de Recherche Biomédicale [IMRB], Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER], Université Sorbonne Paris Nord, Centre Hospitalier Régional Universitaire de Nancy [CHRU Nancy], Nutrition-Génétique et Exposition aux Risques Environnementaux [NGERE], Nutrition, Métabolismes et Cancer [NuMeCan], Laboratoire de Recherche Vasculaire Translationnelle [LVTS (UMR_S_1148 / U1148)], Hôpital Européen Georges Pompidou [APHP] [HEGP], Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 [ONCO-THAI], and Equipe EPICAD (LNC - U1231)
Subjects: Adult, Male, Carcinoma, Hepatocellular, Genotype, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Polymorphism, Single Nucleotide, Young Adult, [SDV.CAN] Life Sciences [q-bio]/Cancer, Wnt3A Protein, Humans, Genetic Predisposition to Disease, Aged, Aged, 80 and over, Liver Neoplasms, Genetic Variation, Middle Aged, Wnt Proteins, [SDV] Life Sciences [q-bio], Oncology, Case-Control Studies, Phospholipases A2, Calcium-Independent, Female, Alcohol-Related Disorders, Acyltransferases, Genome-Wide Association Study
Abstract: International audience; Background: Hepatocellular carcinoma is a frequent consequence of alcohol-related liver disease, with variable incidence among heavy drinkers. We did a genome-wide association study (GWAS) to identify common genetic variants for alcohol-related hepatocellular carcinoma. Methods: We conducted a two-stage case-control GWAS in a discovery cohort of 2107 unrelated European patients with alcohol-related liver disease aged 20–92 years recruited between Oct 22, 1993, and March 12, 2017. Cases were patients with alcohol-related hepatocellular carcinoma diagnosed by imaging or histology. Controls were patients with alcohol-related liver disease without hepatocellular carcinoma. We used an additive logistic regression model adjusted for the first ten principal components to assess genetic variants associated with alcohol-related hepatocellular carcinoma. We did another analysis with adjustment for age, sex, and liver fibrosis. New candidate associations (pandlt;1 × 10−6) and variants previously associated with alcohol-related hepatocellular carcinoma were evaluated in a validation cohort of 1933 patients with alcohol-related liver disease aged 29–92 years recruited between July 21, 1995, and May 2, 2019. We did a meta-analysis of the two case–control cohorts. Findings: The discovery cohort included 775 cases and 1332 controls. Of 7 962 325 variants assessed, we identified WNT3A-WNT9A (rs708113; p=1·11 × 10−8) and found support for previously reported regions associated with alcohol-related hepatocellular carcinoma risk at TM6SF2 (rs58542926; p=6·02 × 10−10), PNPLA3 (rs738409; p=9·29 × 10−7), and HSD17B13 (rs72613567; p=2·49 × 10−4). The validation cohort included 874 cases and 1059 controls and three variants were replicated: WNT3A-WNT9A (rs708113; p=1·17 × 10−3), TM6SF2 (rs58542926; p=4·06 × 10−5), and PNPLA3 (rs738409; p=1·17 × 10−4). All three variants reached GWAS significance in the meta-analysis: WNT3A-WNT9A (odds ratio 0·73, 95% CI 0·66–0·81; p=3·93 × 10−10), TM6SF2 (1·77, 1·52–2·07; p=3·84×10−13), PNPLA3 (1·34, 1·22–1·47; p=7·30 × 10−10). Adjustment for clinical covariates yielded similar results. We observed an additive effect of at-risk alleles on alcohol-related hepatocellular carcinoma. WNT3A-WNT9A rs708113 was not associated with liver fibrosis. Interpretation: WNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt–β-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis.
Published: 2022
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21. Well-Differentiated Liver Cancers Reveal the Potential Link Between ACE2 Dysfunction and Metabolic Breakdown

Author: Bruno Turlin, Clémence Landreau, Bruno Clément, Anne Corlu, Orlando Musso, Lise Desquilles, Luis Cano, Gevorg Ghukasyan, and Romain Desert
Subjects: Metabolic breakdown, Cancer research, Biology, Well differentiated
Abstract: Angiotensin-converting enzyme 2 (ACE2) is the receptor of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causing Coronavirus disease 2019 (COVID-19).Transmembrane serine protease 2 (TMPRSS2)is a coreceptor.Abnormal hepatic function in COVID-19 suggests specific or bystander liver disease.Because liver cancer cells express the ACE2viral receptor, they arewidely usedas models of SARS-CoV-2 infection in vitro. Therefore, the purpose of this study was to analyze ACE2 and TMPRSS2 expression and localization in human liver cancers and in non-tumor livers.We studiedACE2 and TMPRSS2 in two transcriptomic datasets totaling 1503 liver cancersand 47 non-tumor samplesand in tissue microarrays including 41 HCCs and five non-tumor samples by multiplex high-resolution confocal immunohistochemistryand quantitative image analysis.In liver cancers, wedetectedACE2 and TMPRSS2 at the biliary pole of tumor hepatocytes. In non-tumor livers, we identifiedACE2 in hepatocyte’s bile canaliculi, biliary epithelium,sinusoidal and capillary endothelial cells.Tumors carrying mutated β-catenin showedACE2 DNA hypomethylation and higher mRNA and protein expression, consistently with predicted β-catenin response sites in the ACE2 promoter.Finally, ACE2 and TMPRSS2 co-expression networkshighlightedhepatocyte-specific functions, oxidative stress and inflammation, suggesting a link between inflammation, ACE2 dysfunction and metabolic breakdown.
Published: 2021
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22. Fatal acetaminophen poisoning with hepatic microvesicular steatosis in a child after repeated administration of therapeutic doses

Author: Bruno Turlin, Renaud Bouvet, Alain Baert, Aurélie Cauchois, Bernard Fromenty, Isabelle Morel, Thomas Gicquel, Institut du droit public et de la science politique (IDPSP), Université de Rennes (UR), CHU Pontchaillou [Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1)
Subjects: Pediatric acute-liver, medicine.medical_specialty, Necrosis, failureMicrovesicular steatosis, [SDV]Life Sciences [q-bio], Encephalopathy, Microvesicular Steatosis, Respiratory chain, 01 natural sciences, Gastroenterology, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Painkiller toxicity, medicine, 030216 legal & forensic medicine, Fulminant hepatitis, Hepatitis, medicine.diagnostic_test, business.industry, Pediatric acute-liver failure, 010401 analytical chemistry, Microvesicular steatosis, medicine.disease, 3. Good health, 0104 chemical sciences, Acetaminophen, Death, Liver biopsy, Acetaminophen-induced hepatotoxicity, medicine.symptom, business, Law, medicine.drug
Abstract: International audience; Acetaminophen is the leading cause of acute liver failure worldwide following massive ingestion. We present here a fatal acute liver failure after repeated administration of four therapeutic doses of acetaminophen at 4-h intervals in a previously healthy 9-year-old female who presented dental pain after a facial trauma during sport practice. A diagnosis of paracetamol-induced hepatitis was deduced from the clinical picture of fulminant hepatitis and tubular necrosis, the encephalopathy with oedema and without signs of trauma. Liver biopsy showed typical acetaminophen-induced necrosis and a microvesicular steatosis in periportal hepatocytes. These injuries might have been favored by pre-existing mitochondrial dysfunction related, for instance, to a deficiency in an enzyme of the mitochondrial β-oxidation pathway, or the respiratory chain. The observation of microvesicular steatosis in the periportal areas suggests an increased vulnerability via pre-existing mitochondrial dysfunction. As the liver status of patients is mostly unknown, the frequency of administration (every six hours) must be respected and the use of pharmaceutical forms allowing to adjust the dose as closely as possible to the child's weight should be promoted.
Published: 2020
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23. Oral Abstracts (Abstracts 1–263)

Author: Florian Rohart, Stéphanie Renaud, Anne Corlu, Bruno Clément, Mireille Desille, Bruno Turlin, Frédéric Canal, Pascale Bellaud, Kim-Anh Le Cao, Laurent Sulpice, Christelle Reynes, Damien Bergeat, Orlando Musso, Robert Sabatier, Christine Perret, Marie Sicard, Romain Desert, and Damien Gregoire
Subjects: Hepatocyte differentiation, Beta-catenin, Hepatology, biology, business.industry, 030208 emergency & critical care medicine, Phenotype, 03 medical and health sciences, 0302 clinical medicine, Cancer research, biology.protein, Medicine, 030211 gastroenterology & hepatology, business
Published: 2017
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24. Human hepatocellular carcinomas with a periportal phenotype have the lowest potential for early recurrence after curative resection

Author: Kim-Anh Lê Cao, Mireille Desille, Bruno Turlin, Pascale Bellaud, Frédéric Canal, Marie Sicard, Stéphanie Renaud, Romain Desert, Orlando Musso, Bruno Clément, Florian Rohart, Christine Perret, CHU Pontchaillou [Rennes], Nutrition, Métabolismes et Cancer ( NuMeCan ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Queensland University of Technology [Brisbane] ( QUT ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Diamantina Institute, University of Queensland [Brisbane], INSERM, Universite de Rennes 1, Region Bretagne (VALCIPRE), Agence Nationale de la Recherche [ANR-11-ISV1-0001], Institut National du Cancer (WntHCC), Fondation Recherche Medicale [ING20121226393], Ligue Nationale Contre le Cancer (Comite des Cotes d'Armor), Feder, Contrat de Plan Etat Region, projet Canceropole, Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Queensland University of Technology [Brisbane] (QUT), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Jonchère, Laurent, Blanc International II - Ciblage de la voie de signalisation Wnt/beta-caténine dans les cancers primitifs du foie - - BetaCatHCC2011 - ANR-11-ISV1-0001 - Blanc International II - VALID, Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and ANR-11-ISV1-0001,BetaCatHCC,Ciblage de la voie de signalisation Wnt/beta-caténine dans les cancers primitifs du foie(2011)
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Carcinoma, Hepatocellular, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, chronic hepatitis-c, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, virus-infection, simple noninvasive index, 03 medical and health sciences, Liver disease, [SDV.CAN] Life Sciences [q-bio]/Cancer, children, medicine, Carcinoma, Humans, beta Catenin, Hepatology, Liver Neoplasms, Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, HCCS, medicine.disease, transient elastography, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, digestive system diseases, 3. Good health, Transplantation, Hepatocyte nuclear factors, Phenotype, 030104 developmental biology, Hepatocyte Nuclear Factor 4, Liver, Hepatocyte nuclear factor 4, fatty liver-disease, Mutation, Cancer research, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, France, Neoplasm Recurrence, Local, diagnostic-accuracy, Transcriptome, Liver cancer, significant fibrosis, nafld fibrosis, magnetic-resonance elastography
Abstract: International audience; Hepatocellular carcinomas (HCCs) exhibit a diversity of molecular phenotypes, raising major challenges in clinical management. HCCs detected by surveillance programs at an early stage are candidates for potentially curative therapies (local ablation, resection, or transplantation). In the long term, transplantation provides the lowest recurrence rates. Treatment allocation is based on tumor number, size, vascular invasion, performance status, functional liver reserve, and the prediction of early (< 2 years) recurrence, which reflects the intrinsic aggressiveness of the tumor. Well-differentiated, potentially low-aggressiveness tumors form the heterogeneous molecular class of nonproliferative HCCs, characterized by an approximate 50% b-catenin mutation rate. To define the clinical, pathological, and molecular features and the outcome of nonproliferative HCCs, we constructed a 1,133HCC transcriptomic metadata set and validated findings in a publically available 210-HCC RNA sequencing set. We show that nonproliferative HCCs preserve the zonation program that distributes metabolic functions along the portocentral axis in normal liver. More precisely, we identified two well-differentiated, nonproliferation subclasses, namely periportal-type (wild-type b-catenin) and perivenous-type (mutant b-catenin), which expressed negatively correlated gene networks. The new periportal-type subclass represented 29% of all HCCs; expressed a hepatocyte nuclear factor 4A-driven gene network, which was downregulated in mouse hepatocyte nuclear factor 4A knockout mice; were early-stage tumors by Barcelona Clinic Liver Cancer, Cancer of the Liver Italian Program, and tumor-node-metastasis staging systems; had no macrovascular invasion; and showed the lowest metastasis-specific gene expression levels and TP53 mutation rates. Also, we identified an eight-gene periportal-type HCC signature, which was independently associated with the highest 2-year recurrence-free survival by multivariate analyses in two independent cohorts of 247 and 210 patients. Conclusion: Well-differentiated HCCs display mutually exclusive periportal or perivenous zonation programs. Among all HCCs, periportal-type tumors have the lowest intrinsic potential for early recurrence after curative resection.
Published: 2017
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25. Non-alcoholic steatohepatitis is a risk factor for intrahepatic cholangiocarcinoma and affects its long-time outcome: results from a multicenter international case-control study

Author: Stefania De Lorenzo, Francesco Tovoli, Alessandro Mazzotta, Francesco Vasuri, Deborah Malvi, Maria Antonietta D’Errico, Karim Boudjema, Bruno Turlin, Astrid Lievre, and Giovanni Brandi
Subjects: Hepatology
Published: 2020
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26. Performance of B-mode ratio and 2D shear wave elastography for the detection and quantification of hepatic steatosis and fibrosis after liver transplantation

Author: Luc Beuzit, Bruno Turlin, Christophe Aubé, Marine Dubois, Pauline Houssel-Debry, Maxime Ronot, Magali Auger, Anita Paisant, Michel Rayar, Vanessa Brun, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: Liver Cirrhosis, medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Liver transplantation, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, Internal medicine, medicine, Humans, ComputingMilieux_MISCELLANEOUS, Hepatology, medicine.diagnostic_test, Receiver operating characteristic, business.industry, Ultrasound, Gold standard (test), medicine.disease, Liver Transplantation, 3. Good health, Fatty Liver, Transplantation, Liver, 030220 oncology & carcinogenesis, Liver biopsy, Elasticity Imaging Techniques, 030211 gastroenterology & hepatology, Steatosis, business
Abstract: OBJECTIVES To evaluate the diagnostic performance of B-mode ratio and shear wave elastography (SWE) for the assessment of steatosis and liver fibrosis after liver transplantation. MATERIALS AND METHODS Patients hospitalized for a systematic check-up after liver transplantation underwent the same day hepatic ultrasound with B-mode ratio and SWE, followed by liver biopsy and biological examinations. Steatosis was measured using hepatorenal sonographic index of B-mode ratio and liver stiffness using SWE. Liver biopsy, used as gold standard, graded steatosis S0(
Published: 2020
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27. De novo HAPLN1 expression hallmarks Wnt-induced stem cell and fibrogenic networks leading to aggressive human hepatocellular carcinomas

Author: Laurent Sulpice, Cédric Coulouarn, Pascale Bellaud, Sihem Mebarki, Bruno Clément, Rémy Le Guével, Orlando Musso, Frédéric Canal, Bruno Turlin, Mireille Desille, Elise Lavergne, Marie Sicard, Hélène Dubois-Pot Schneider, Romain Desert, Anne Corlu, Christine Perret, Damien Bergeat, Foie, métabolismes et cancer, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Chirurgie Hépatobiliaire et Digestive, Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Centre de ressources biologiques de Rennes, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Plate-forme ImPACcell ( ImPACcell ), Inserm,Université de Rennes 1, Région Bretagne, AgenceNationale de la Recherche, Institut National du Cancer,Fondation Recherche Médicale, Ligue Nationale Contrele Cancer (Comité des Côtes d’Armor), Feder, Contrat dePlan Etat Région 2007-2013, projet Cancéropôle., Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Chirurgie Hépatobiliaire et Digestive [Rennes] = Hepatobiliary and Digestive Surgery [Rennes], CHU Pontchaillou [Rennes], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plate-forme ImPACcell (ImPACcell), Bos, Mireille, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Pathology, Ligands, Stem cell marker, Mesoderm, Research Paper: Gerotarget (Focus on Aging), Cluster Analysis, CD44, Extracellular Matrix Proteins, biology, Gerotarget, Stem Cells, Liver Neoplasms, Wnt signaling pathway, LGR5, Cell Differentiation, Middle Aged, Immunohistochemistry, 3. Good health, Gene Expression Regulation, Neoplastic, Liver, Oncology, Female, Proteoglycans, Hepatocyte dedifferentiation, Stem cell, Signal Transduction, medicine.medical_specialty, Carcinoma, Hepatocellular, epithelial-mesenchymal transition, Cell Line, Wnt, 03 medical and health sciences, Cell Line, Tumor, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, Neoplasm Invasiveness, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Progenitor cell, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Aged, Gene Expression Profiling, Fibroblasts, β-catenin, HCCS, Wnt Proteins, 030104 developmental biology, Tissue Array Analysis, biology.protein, Cancer research, Follow-Up Studies
Abstract: International audience; About 20% hepatocellular carcinomas (HCCs) display wild-type β-catenin, enhanced Wnt signaling, hepatocyte dedifferentiation and bad outcome, suggesting a specific impact of Wnt signals on HCC stem/progenitor cells. To study Wnt-specific molecular pathways, cell fates and clinical outcome, we fine-tuned Wnt/β-catenin signaling in liver progenitor cells, using the prototypical Wnt ligand Wnt3a. Cell biology assays and transcriptomic profiling were performed in HepaRG hepatic progenitors exposed to Wnt3a after β-catenin knockdown or Wnt inhibition with FZD8_CRD. Gene expression network, molecular pathology and survival analyses were performed on HCCs and matching non-tumor livers from 70 patients by real-time PCR and tissue micro-array-based immunohistochemistry. Wnt3a reprogrammed liver progenitors to replicating fibrogenic myofibroblast-like cells displaying stem and invasive features. Invasion was inhibited by 30 nM FZD7 and FZD8 CRDs. Translation of these data to human HCCs revealed two tight gene networks associating cell surface Wnt signaling, stem/progenitor markers and mesenchymal commitment. Both networks were linked by Hyaluronan And Proteoglycan Link Protein 1 (HAPLN1), that appeared de novo in aggressive HCCs expressing cytoplasmic β-catenin and stem cell markers. HAPLN1 was independently associated with bad overall and disease-free outcome. In vitro, HAPLN1 was expressed de novo in EPCAM¯/NCAM+ mesoderm-committed progenitors, upon spontaneous epithelial-mesenchymal transition and de-differentiation of hepatocyte-like cells to liver progenitors. In these cells, HAPLN1 knockdown downregulated key markers of mesenchymal cells, such as Snail, LGR5, collagen IV and α-SMA. In conclusion, HAPLN1 reflects a signaling network leading to stemness, mesenchymal commitment and HCC progression.
Published: 2016
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28. Fast and Non-Invasive Medical Diagnostic Using Mid Infrared Sensor

Author: M. Le Corvec, Fabrice Lainé, A. Kachenoura, Valérie Monbet, H. Tariel, S. Bensaid, J.F. Betagne, Bruno Turlin, Lotfi Senhadji, Olivier Loréal, Edouard Bardou-Jacquet, S. Henno, Frédéric Charpentier, and Olivier Sire
Subjects: Medical diagnostic, Optical fiber, Computer science, Healthy population, 010401 analytical chemistry, Non invasive, Biomedical Engineering, Biophysics, Mid infrared, Mechanical resistance, Linear discriminant analysis, 01 natural sciences, 0104 chemical sciences, law.invention, 010309 optics, law, 0103 physical sciences, Point of care, Biomedical engineering
Abstract: Aim Amnifir project, part of the ANR TECSAN program, intended to assess the capabilities of a new Mid InfraRed spectroscopy (MIR) device. It used a simple fiber optic sampling method: Fiber Evanescent Wave Spectroscopy (FEWS), which makes Point of Care applications possible and delivers a result within a few minutes. Material and method To investigate the technology application range, different biological media (tissues, fluids) as well as pathologies (chronic, cancerous) were considered during the project. We present work on one cancer diagnostic, measuring tissues (colorectal polyp examination), and one chronic disease diagnostic, using a fluid sample (Non-Alcoholic SteatoHepatitis (NASH) markers in serum). We used specific FEWS sensors for both cases, made of chalcogenide infrared glass fiber, as well as proper signal analysis algorithm that first selected spectra area of interest by genetic algorithm, then discriminated the healthy population from the sick one by linear discriminant analysis. Results Measurements using liquid samples provide very encouraging results for NASH identification. On other hand, fiber sensor proved more difficult to use on tissues, as the fiber mechanical resistance appeared too low to sustain a contact with the hardest polyps. Conclusions AMNIFIR project demonstrated capabilities of MIR FEWS for medical diagnostic using biological fluids, leading to recruitments of further cohorts of NASH and other hepatic disorders patients. Mechanical resistance of fiber needs to be improved for tissues diagnostics.
Published: 2016
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29. Non-Alcoholic Steatohepatitis as a Risk Factor for Intrahepatic Cholangiocarcinoma and Its Prognostic Role

Author: Francesco Tovoli, Alessandro Mazzotta, Deborah Malvi, Francesco Vasuri, Matteo Cescon, Julien Edeline, Stefania De Lorenzo, Giovanni Brandi, Antonietta D'Errico, Alessandro Granito, Bruno Turlin, Matteo Renzulli, Heithem Jeddou, Thomas Uguen, Astrid Lièvre, Karim Boudjema, De Lorenzo S., Tovoli F., Mazzotta A., Vasuri F., Edeline J., Malvi D., Boudjema K., Renzulli M., Jeddou H., D'errico A., Turlin B., Cescon M., Uguen T., Granito A., Lievre A., Brandi G., Jonchère, Laurent, University of Bologna/Università di Bologna, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Policlinico S. Orsola-malpighi, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO)-Servizio sanitario regionale Emilia-Romagna, Centre Eugène Marquis (CRLCC), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Ressources Biologiques Santé (CRB Santé), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-CRLCC Eugène Marquis (CRLCC), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Bologna, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-CRLCC Eugène Marquis (CRLCC), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Cancer Research, medicine.medical_specialty, liver cirrhosis, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, digestive system, Gastroenterology, Article, Liver cirrhosi, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Medicine, Risk factor, education, Intrahepatic cholangiocarcinoma, Outcome, education.field_of_study, business.industry, Proportional hazards model, Hazard ratio, Fatty liver, nutritional and metabolic diseases, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, digestive system diseases, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Relative risk, Hepatocellular carcinoma, 030211 gastroenterology & hepatology, non-alcoholic steatohepatitis, Steatohepatitis, business, Non-alcoholic steatohepatiti, Non-alcoholic fatty liver disease
Abstract: Non-alcoholic fatty liver disease (NAFLD) and its most aggressive form, non-alcoholic steatohepatitis (NASH), are causing a rise in the prevalence of hepatocellular carcinoma. Data about NAFLD/NASH and intrahepatic cholangiocarcinoma (iCCA) are few and contradictory, coming from population registries that do not correctly distinguish between NAFLD and NASH. We evaluated the prevalence of NAFLD and NASH in peritumoral tissue of resected iCCA (n = 180) and in needle biopsies of matched liver donors. Data of iCCA patients were subsequently analysed to compare NASH-related iCCA (Group A), iCCA arisen in a healthy liver (Group B) or in patients with classical iCCA risk factors (Group C). NASH was found in 22.5% of 129 iCCA patients without known risk factors and in 6.2% of matched controls (risk ratio 3.625, 95% confidence interval 1.723&ndash, 7.626, p &lt, 0.001), while NAFLD was equally represented in both groups. The overall survival of NASH-related iCCA was inferior to that of patients with healthy liver (38.5 vs. 48.1 months, p = 0.003) and similar to that of patients with known risk factors (31.9 months, p = 0.948), regardless of liver fibrosis. The multivariable Cox regression confirmed NASH as a prognostic factor (hazard ratio 1.773, 95% confidence interval 1.156&ndash, 2.718, p = 0.009). We concluded that NASH (but not NAFLD) is a risk factor for iCCA and might affect its prognosis. Dissecting NASH from NAFLD by histology is necessary to correctly assess the actual role of these conditions. Prevention protocols for NASH patients should also consider the risk for iCCA and not only HCC. Mechanistic studies aimed to find a direct pathogenic link between NASH and iCCA could add further relevant information.
Published: 2020
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30. EGFR Expression Is Unreliable to Decide for Cetuximab Treatment in Patients with Metastatic Colorectal Cancer: Results from 'ERBITUX-OUEST'

Author: Corinne Alleaume, F. Grude, Arnaud Uguen, Nacr Eddine Achour, Daniel Ten Martin, Gilles Lemasson, A. Volant, Joseph Politis, Olivier Capitain, Claire Stampfli, Laurent Miglianico, Jérome Chettrit, Jean-François Ramée, Philippe Deguiral, Véronique Verriele, Claire Magois, Norbert Padilla, Annie Wdowik, Sophie Michalak, Murielle Broyer-Petit, Erick Gamelin, Pierre-Luc Etienne, Pierre Marie Girardot, Jean-Philippe Metges, Jean-Jacques Auger, Christian Laboisse, Roger Faroux, Serge Eloit, V. Klein, Fanny Marhuenda, A. Gourlaouen, Marie-Aude Coulon, Delphine Deniel Lagadec, Isabelle Cumin, Louis-Rémi De Ybarlucea, Christian Riche, Bruno Turlin, Olivier Dupuis, Alain Bargain, Eric Lavoine, Ludovic Rosenfeld, Alain Penchet, Jean-Luc Raoul, Jean-Yves Douillard, Viorel Vasiliu, Nathalie Heresbach, Yann Touchefeu, Karine Bideau, and Frédéric Staroz
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, biology, Cetuximab, business.industry, Colorectal cancer, medicine.disease, digestive system diseases, Egfr expression, Oxaliplatin, Irinotecan, 03 medical and health sciences, Regimen, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, biology.protein, Immunohistochemistry, Epidermal growth factor receptor, business, medicine.drug
Abstract: Purpose: Although controversial, assessment of epidermal growth factor receptor (EGFR) expression is required for the approved indications of Cetuximab in metastatic colorectal cancer (mCRC). With the objective of improving patient selection, “ERBITUX-OUEST” study aimed at analyzing EGFR status in a large cohort of mCRC patients who received cetuximab without preliminary EGFR screening, and assessing the correlation between EGFR status and response to treatment retrospectively. Patients and methods: 332 patients treated with Irinotecan Cetuximab based regimen after progression on irinotecan or oxaliplatin therapy were included. EGFR status was assessed using three available immunohistochemistry (IHC) tests and in situ hybridization in case of negativity. Clinical outcomes of EGFR-positive and EGFR-non-detected (or considered as negative with at least one test) patients were compared. Results: Of the 332 samples centrally screened, 194 were classified as full-positive (i.e., EGFR-positive for all three tests), 86 as full-negative, and 52 as discordant. One third of the 131 negative samples with FDA approved test should be reclassified as positive with at least one of the two others tests. Regarding results from FDA approved test only, neither objective response rate (ORR), progression-free survival (PFS) nor overall survival (OS) differed significantly between EGFR-negative and EGFR-positive patients (P = 0.788, 0.326 and 0.888, respectively). Similarly, comparison of full-negative to other groups did not show any significant difference in terms of ORR (P = 0.507), PFS (P = 0.222) or OS (P = 0.686). Conclusion: These data strongly argue against mCRC patients selection for Cetuximab treatment based on EGFR expression as measured by currently available IHC technics.
Published: 2016
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31. Molecular profiling of stroma identifies osteopontin as an independent predictor of poor prognosis in intrahepatic cholangiocarcinoma

Author: Laurent Sulpice, Michel Rayar, Mireille Desille, Cédric Coulouarn, Francisco Llamas-Gutierrez, Alain Fautrel, Karim Boudjema, Bruno Turlin, Bernard Meunier, Bruno Clément, Eveline Boucher, Service de Chirurgie Hépatobiliaire et Digestive [Rennes] = Hepatobiliary and Digestive Surgery [Rennes], CHU Pontchaillou [Rennes], Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Biologie, CRLCC Eugène Marquis (CRLCC), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], Hépatotoxicité et xénobiotiques, Détoxication et réparation Tissulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Foie, métabolismes et cancer, and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Male, Pathology, medicine.medical_specialty, Stromal cell, [SDV]Life Sciences [q-bio], Laser Capture Microdissection, Cholangiocarcinoma, 03 medical and health sciences, 0302 clinical medicine, Stroma, Transforming Growth Factor beta, Laminin, medicine, Humans, Osteopontin, Aged, Laser capture microdissection, Hepatology, biology, Gene Expression Profiling, Liver Neoplasms, Transforming growth factor beta, Middle Aged, Cell cycle, Prognosis, Up-Regulation, 3. Good health, Gene expression profiling, Bile Ducts, Intrahepatic, Bile Duct Neoplasms, Liver, 030220 oncology & carcinogenesis, biology.protein, Female, 030211 gastroenterology & hepatology, Stromal Cells
Abstract: International audience; Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary cancer in the liver. ICC is an aggressive cancer with poor prognosis and limited therapeutic strategies. The identification of new drug targets and prognostic biomarkers is an important clinical challenge for ICC. The presence of an abundant stroma is a histological hallmark of ICC. Given the well-established role of the stromal compartment in the progression of cancer diseases, we hypothesized that relevant biomarkers could be identified by analyzing the stroma of ICC. By combining laser capture microdissection and gene expression profiling, we demonstrate that ICC stromal cells exhibit dramatic genomic changes. We identified a signature of 1,073 nonredundant genes that significantly discriminate the tumor stroma from nontumor fibrous tissue. Functional analysis of differentially expressed genes demonstrated that up-regulated genes in the stroma of ICC were related to cell cycle, extracellular matrix, and transforming growth factor beta (TGFβ) pathways. Tissue microarray analysis using an independent cohort of 40 ICC patients validated at a protein level the increased expression of collagen 4A1/COL4A1, laminin gamma 2/LAMC2, osteopontin/SPP1, KIAA0101, and TGFβ2 genes in the stroma of ICC. Statistical analysis of clinical and pathological features demonstrated that the expression of osteopontin, TGFβ2, and laminin in the stroma of ICC was significantly correlated with overall patient survival. More important, multivariate analysis demonstrated that the stromal expression of osteopontin was an independent prognostic marker for overall and disease-free survival. CONCLUSION: The study identifies clinically relevant genomic alterations in the stroma of ICC, including candidate biomarkers for prognosis, supporting the idea that tumor stroma is an important factor for ICC onset and progression.
Published: 2013
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32. The effects of a maintenance therapy with peg-interferon alpha-2a on liver fibrosis in HIV/HCV co-infected patients: A randomized controlled trial

Author: Dominique Guyader, Catherine Mouchel, Eric Bellissant, Alain Renault, J.M. Chapplain, Jean-Michel Molina, Christian Michelet, Bruno Turlin, Gilles Pialoux, Isabelle Poizot-Martin, P. Perré, Service des maladies infectieuses et réanimation médicale [Rennes] = Infectious Disease and Intensive Care [Rennes], CHU Pontchaillou [Rennes], Unité d’Investigation Neurologique [CHU Rennes] (CIC-P 0203 INSERM), CHU Pontchaillou [Rennes]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut des Neurosciences Cliniques de Rennes (INCR), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépato-gastro-entérologie [Rennes] = Gastroenterology [Rennes], Service des Maladies Infectieuses et Tropicales, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service d'immuno-hématologie clinique (CISIH), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Internal Medicine Department, CHG, CHG, Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), French National Agency for AIDS, Viral Hepatitis, ANRS HC-12 Study Group, CHU Pontchaillou [Rennes]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut des Neurosciences Cliniques de Rennes = Institute of Clinical Neurosciences of Rennes (INCR), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Adult, Liver Cirrhosis, Male, Microbiology (medical), METAVIR Fibrosis Score, medicine.medical_specialty, Cirrhosis, Biopsy, Hepatitis C virus, Liver fibrosis, HIV Infections, medicine.disease_cause, Antiviral Agents, Severity of Illness Index, Gastroenterology, HIV/HCV co-infection, Polyethylene Glycols, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Maintenance therapy, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Fibrosis, Interquartile range, Internal medicine, medicine, Clinical endpoint, Humans, 030304 developmental biology, 0303 health sciences, Peg-interferon, business.industry, Ribavirin, Interferon-alpha, Metavir fibrosis score, Hepatitis C, Chronic, Middle Aged, medicine.disease, Survival Analysis, Recombinant Proteins, 3. Good health, Treatment Outcome, Infectious Diseases, chemistry, Randomized controlled trial, Immunology, Female, 030211 gastroenterology & hepatology, business
Abstract: International audience; OBJECTIVE: We hypothesized that, in Human Immunodeficiency Virus and Hepatitis C Virus (HIV/HCV) co-infected patients who did not respond to peg-interferon and ribavirin, a maintenance therapy with peg-interferon could induce fibrosis regression. METHODS: This was a randomized study with two parallel groups. HIV/HCV co-infected patients received peg-interferon α-2a at 180 μg/week or remained on observation for 96 weeks. The primary endpoint was the percentage of patients who experienced a decrease of at least one point in their Metavir fibrosis score between initial and final liver biopsies. Secondary endpoints included plasma fibrosis markers at week 96, occurrence of HCV-related complications, and survival. RESULTS: A total of 52 patients were randomized (peg-interferon: 25; control: 27) including 18 with cirrhosis. The median (interquartile range) age was 44 (40-46) years, and 69% were male. A total of 64% had ALT levels >1.5 normal values, and the CD4 cell count was 391 (296-537) cells/mm(3); 67% of patients had HIV RNA
Published: 2013
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33. Severe Prenatal Renal Anomalies Associated with Mutations in HNF1B or PAX2 Genes

Author: Tania Attié-Bitach, Rémi Salomon, Pierre Dechelotte, Jelena Martinovic, Bruno Turlin, Vincent Morinière, Michèle Mathieu, Corinne Antignac, Uffe Birk Jensen, Nathalie Leporrier, Cécile Jeanpierre, Philippe Loget, Marie-Claire Gubler, Christel Thauvin-Robinet, Dominique Gaillard, Laurence Heidet, Raymonde Bouvier, and Leire Madariaga
Subjects: Male, Pathology, medicine.medical_specialty, Pediatrics, Heredity, Epidemiology, Genetic counseling, Urinary system, medicine.medical_treatment, DNA Mutational Analysis, Autopsy, Critical Care and Intensive Care Medicine, Severity of Illness Index, Ultrasonography, Prenatal, Predictive Value of Tests, Pregnancy, Prenatal Diagnosis, Humans, Medicine, Genetic Predisposition to Disease, Renal replacement therapy, Family history, Abortion, Therapeutic, Hepatocyte Nuclear Factor 1-beta, Retrospective Studies, Vesico-Ureteral Reflux, Transplantation, Kidney, business.industry, PAX2 Transcription Factor, Original Articles, medicine.disease, HNF1B, Pedigree, Phenotype, medicine.anatomical_structure, Nephrology, Urogenital Abnormalities, Mutation, Female, business
Abstract: Summary Background and objectives Congenital anomalies of the kidney and urinary tract (CAKUT) are a frequent cause of renal failure in children, and their detection in utero is now common with fetal screening ultrasonography. The clinical course of CAKUT detected before birth is very heterogeneous and depends on the level of nephron reduction. The most severe forms cause life-threatening renal failure, leading to perinatal death or the need for very early renal replacement therapy. Design, setting, participants, & measurements This study reports the screening of two genes (HNF1B and PAX2) involved in monogenic syndromic CAKUT in a cohort of 103 fetuses from 91 families with very severe CAKUT that appeared isolated by fetal ultrasound examination and led to termination of pregnancy. Results This study identified a disease-causing mutation in HNF1B in 12 cases from 11 families and a mutation in PAX2 in 4 unrelated cases. Various renal phenotypes were observed, but no case of bilateral agenesis was associated with HNF1B or PAX2 mutations. Autopsy identified extrarenal abnormalities not detected by ultrasonography in eight cases but confirmed the absence of extrarenal defects in eight other cases. A positive family history of renal disease was not significantly more frequent in cases with an identified mutation. Moreover, in cases with an inherited mutation, there was a great phenotypic variability regarding the severity of the renal disease within a single family. Conclusions Our results suggest that mutations in genes involved in syndromic CAKUT with Mendelian inheritance are not rare in fetal cases with severe CAKUT appearing isolated at prenatal ultrasound, a finding of clinical importance because of genetic counseling.
Published: 2013
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34. Assessment of liver iron overload by 3 T MRI

Author: Anita Paisant, Anne Boulic, Fabrice Lainé, Yves Gandon, Gaspard d’Assignies, Edouard Bardou-Jacquet, Bruno Turlin, Elise Bannier, Tramonti, Pierre, Département de Radiologie [CHU de Rennes], Université de Rennes (UR), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Vision, Action et Gestion d'informations en Santé (VisAGeS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pathologie [Rennes] = Pathology [Rennes], Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Service des maladies du foie, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes], SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Université de Rennes (UNIV-RENNES)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UNIV-RENNES)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes 1 (UR1) - Hôpital Pontchaillou - Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 (UR1) - CHU Pontchaillou [Rennes], Institut National de la Santé et de la Recherche Médicale (INSERM) - Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria) - Institut National de Recherche en Informatique et en Automatique (Inria) - SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA_D5), Université de Rennes 1 (UR1) - Institut National des Sciences Appliquées - Rennes (INSA Rennes) - Université de Bretagne Sud (UBS) - École normale supérieure - Rennes (ENS Rennes) - Institut National de Recherche en Informatique et en Automatique (Inria) - CentraleSupélec - Centre National de la Recherche Scientifique (CNRS) - IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique) - Université de Rennes 1 (UR1) - Institut National des Sciences Appliquées - Rennes (INSA Rennes) - Université de Bretagne Sud (UBS) - École normale supérieure - Rennes (ENS Rennes) - Institut National de Recherche en Informatique et en Automatique (Inria) - CentraleSupélec - Centre National de la Recherche Scientifique (CNRS) - IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique) - Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes 1 (UR1) - Institut National des Sciences Appliquées - Rennes (INSA Rennes) - Université de Bretagne Sud (UBS) - École normale supérieure - Rennes (ENS Rennes) - Institut National de Recherche en Informatique et en Automatique (Inria) - CentraleSupélec - Centre National de la Recherche Scientifique (CNRS) - IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique) - Université de Rennes 1 (UR1) - Institut National des Sciences Appliquées - Rennes (INSA Rennes) - Université de Bretagne Sud (UBS) - École normale supérieure - Rennes (ENS Rennes) - CentraleSupélec - Centre National de la Recherche Scientifique (CNRS) - IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Université de Rennes 1 (UR1) - Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 (UR1) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'hépatologie [CHU Pontchaillou], CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Télécom Bretagne-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), and Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Télécom Bretagne-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Liver Iron Concentration, medicine.medical_specialty, Correlation coefficient, Biopsy, Urology, Sensitivity and Specificity, Article, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Quantification, medicine, Humans, Liver iron, Iron overload, Radiology, Nuclear Medicine and imaging, Mri scan, [SDV.IB] Life Sciences [q-bio]/Bioengineering, Radiological and Ultrasound Technology, medicine.diagnostic_test, business.industry, Liver Diseases, Gastroenterology, Magnetic resonance imaging, Middle Aged, Hepatology, Magnetic Resonance Imaging, Hepatic Iron Concentration, Liver, 030220 oncology & carcinogenesis, Liver biopsy, Female, [SDV.IB]Life Sciences [q-bio]/Bioengineering, 3 Tesla, business, Nuclear medicine, Algorithms, MRI
Abstract: International audience; Purpose - To evaluate the performance and limitations of the signal intensity ratio method for quantifying liver iron overload at 3 T. Methods - Institutional review board approval and written informed consent from all participants were obtained. One hundred and five patients were included prospectively. All patients underwent a liver biopsy with biochemical assessment of hepatic iron concentration and a 3 T MRI scan with 5 breath-hold single-echo gradient-echo sequences. Linear correlation between liver-to-muscle signal intensity ratio and liver iron concentration was calculated. The algorithm for calculating magnetic resonance hepatic iron concentration was adapted from the method described by Gandon et al. with echo times divided by 2. Sensitivity and specificity were calculated. Results - Five patients were excluded (coil selection failure or missing sequence) and 100 patients were analyzed, 64 men and 36 women, 52 ± 13.3 years old, with a biochemical hepatic iron concentration range of 0-630 µmol/g. Linear correlation between biochemical hepatic iron concentration and MR-hepatic iron concentration was excellent with a correlation coefficient = 0.96, p
Published: 2017
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35. 'Fibrous nests' in human hepatocellular carcinoma express a Wnt-induced gene signature associated with poor clinical outcome

Author: Romain Desert, Sihem Mebarki, Bruno Clément, Laurent Sulpice, Damien Bergeat, Orlando Musso, Mireille Desille, Bruno Turlin, Marie Sicard, Stéphanie Renaud, Elise Lavergne, Christine Perret, Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Inserm, Université de Rennes 1, Région Bretagne, Agence Nationale de la Recherche, Institut National du Cancer, Fondation Recherche Médicale, Ligue Nationale Contre le Cancer (Comité des Côtes d’Armor), Feder, Contrat de Plan Etat Région 2007-2013 projet Cancéropôle., ANR-11-ISV1-0001,BetaCatHCC,Ciblage de la voie de signalisation Wnt/beta-caténine dans les cancers primitifs du foie(2011), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and ANR-11-ISV1-0001,BetaCatHCC,Ciblage de la voie de signalisation Wnt/beta-caténine dans les cancers primitifs du foie ( 2011 )
Subjects: Liver Cirrhosis, 0301 basic medicine, Frizzled, [SDV]Life Sciences [q-bio], [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biochemistry, Basement Membrane, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mesoderm, Recurrence, WNT2, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], extracellular matrix remodeling, CD44, Myofibroblasts, [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], transit-amplifying liver progenitor cells, Wnt Signaling Pathway, ComputingMilieux_MISCELLANEOUS, SFRP, Liver Neoplasms, Wnt signaling pathway, LGR5, Cell Differentiation, hepatocellular carcinoma, Prognosis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Gene Expression Regulation, Neoplastic, [STAT]Statistics [stat], Neoplastic Stem Cells, Stem cell, Carcinoma, Hepatocellular, [ STAT ] Statistics [stat], [SDV.CAN]Life Sciences [q-bio]/Cancer, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BID]Life Sciences [q-bio]/Biodiversity, Biology, [ SDV.BC.IC ] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], 03 medical and health sciences, Wnt, Cancer stem cell, stem cells, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Biomarkers, Tumor, Humans, tumor microenvironment, Neoplasm Invasiveness, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Progenitor cell, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BID ] Life Sciences [q-bio]/Biodiversity, [ SDV ] Life Sciences [q-bio], [ SDV.BC.BC ] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, β-catenin, fibrogenesis, Actins, Wnt Proteins, 030104 developmental biology, Cancer research, biology.protein, Laminin, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; AbstractHepatocellular carcinoma (HCC) is the 3rd cause of cancer-related death worldwide. Most cases arise in a background of chronic inflammation, extracellular matrix (ECM) remodeling, severe fibrosis and stem/progenitor cell amplification. Although HCCs are soft cellular tumors, they may contain fibrous nests within the tumor mass. Thus, the aim of this study was to explore cancer cell phenotypes in fibrous nests. Combined anatomic pathology, tissue microarray and real-time PCR analyses revealed that HCCs (n=82) containing fibrous nests were poorly differentiated, expressed Wnt pathway components and target genes, as well as markers of stem/progenitor cells, such as CD44, LGR5 and SOX9. Consistently, in severe liver fibroses (n=66) and in HCCs containing fibrous nests, weighted correlation analysis revealed a gene network including the myofibroblast marker ACTA2, the basement membrane components COL4A1 and LAMC1, the Wnt pathway members FZD1; FZD7; WNT2; LEF1; DKK1 and the Secreted Frizzled Related Proteins (SFRPs) 1; 2 and 5. Moreover, unbiased random survival forest analysis of a transcriptomic dataset of 247 HCC patients revealed high DKK1, COL4A1, SFRP1 and LAMC1 to be associated with advanced tumor staging as well as with bad overall and disease-free survival. In vitro, these genes were upregulated in liver cancer stem/progenitor cells upon Wnt-induced mesenchymal commitment and myofibroblast differentiation. In conclusion, fibrous nests express Wnt target genes, as well as markers of cancer stem cells and mesenchymal commitment. Fibrous nests embody the specific microenvironment of the cancer stem cell niche and can be detected by routine anatomic pathology analyses.
Published: 2016
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36. Early diagnosis of NAFLD-NASH transition using mid infrared spectroscopy

Author: Julien Vergniol, Bruno Turlin, Nathalie Costet, H. Tariel, Fabrice Lainé, Siouar Bensaid, Lotfi Senhadji, Victor de Lédinghen, Amar Kachenoura, Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre d ' investigation de la fibrose hépatique, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service des maladies du foie, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes], Foie, métabolismes et cancer, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), DIAFIR, ANR-12-TECS-0012,AMNIFIR,Analyse Médicale Non invasive et Immédiate par Fibre optique Infra Rouge pour la detection de maladies chroniques et de tumeurs(2012), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service des maladies du foie [CHU Rennes], Centre Hospitalier Universitaire [Rennes], Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Senhadji, Lotfi, and Technologie pour la santé et l'autonomie - Analyse Médicale Non invasive et Immédiate par Fibre optique Infra Rouge pour la detection de maladies chroniques et de tumeurs - - AMNIFIR2012 - ANR-12-TECS-0012 - TecSan - VALID
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Cirrhosis, Spectrophotometry, Infrared, Diagnosis tool, 01 natural sciences, Mid infrared spectroscopy, Sensitivity and Specificity, digestive system, 010309 optics, 03 medical and health sciences, 0302 clinical medicine, Blood serum, Non-alcoholic Fatty Liver Disease, 0103 physical sciences, medicine, Humans, Spectroscopy, [SPI.SIGNAL] Engineering Sciences [physics]/Signal and Image processing, [SDV.IB] Life Sciences [q-bio]/Bioengineering, business.industry, Fatty liver, nutritional and metabolic diseases, medicine.disease, digestive system diseases, 3. Good health, Correlation, Fatty Liver, Early Diagnosis, Liver, Hepatocellular carcinoma, Optical sensors, Linear Models, 030211 gastroenterology & hepatology, Female, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Steatohepatitis, business, Hepatic fibrosis, Biomedical optical imaging, Optical attenuators, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing
Abstract: International audience; Non-alcoholic fatty liver disease (NAFLD) is defined as an excessive accumulation of fat in the liver in the absence of excessive drinking of alcohol. Initially considered as benign and self-limited, NAFLD may progress to the malignant stage of non-alcoholic steatohepatitis (NASH) characterized by degenerate hepatocellular ballooning and lobular inflammation. NASH can lead to hepatic fibrosis and ultimately to cirrhosis and hepatocellular carcinoma. Unfortunately, the transition from NAFLD to NASH is difficult to detect so far. In this paper, we propose to evaluate the characterization of NASH using mid infrared fiber evanescent wave spectroscopy on blood serum. We used an heuristic variable selection method and a generalized linear model to classify NAFLD and NASH spectra. The obtained results proved that this technique is a promising non-invasive and simple diagnosis tool for NASH.
Published: 2016
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37. Acoustic radiation force impulse imaging for assessing liver fibrosis in alcoholic liver disease

Author: Antonia Le Gruyer, Edouard Bardou-Jacquet, Anita Kiani, Fabrice Lainé, Bruno Turlin, Vanessa Brun, Ludivine Legros, Jeff Morcet, Yves Gandon, Sophie Michalak, Romain Moirand, Département de Radiologie [CHU de Rennes], Université de Rennes (UR), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Laboratoire de Pathologie Cellulaire et Tissulaire, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Adult, Male, Alcoholic liver disease, medicine.medical_specialty, Acoustic radiation force impulse, Biopsy, [SDV]Life Sciences [q-bio], Severity of Illness Index, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, Liver Cirrhosis, Alcoholic, Predictive Value of Tests, medicine, Humans, Prospective Studies, Non-invasive, Prospective cohort study, Acoustic radiation force impulse imaging, medicine.diagnostic_test, business.industry, Gastroenterology, Reproducibility of Results, General Medicine, Middle Aged, medicine.disease, 3. Good health, Liver, ROC Curve, Liver biopsy, Predictive value of tests, Area Under Curve, Elasticity Imaging Techniques, Prospective Study, 030211 gastroenterology & hepatology, Female, Elastography, Radiology, business, Nuclear medicine
Abstract: International audience; AIM: To evaluate the performance of elastography by ultrasound with acoustic radiation force impulse (ARFI) in determining fibrosis stage in patients with alcoholic liver disease (ALD) undergoing alcoholic detoxification in relation to biopsy. METHODS: Eighty-three patients with ALD undergoing detoxification were prospectively enrolled. Each patient underwent ARFI imaging and a liver biopsy on the same day. Fibrosis was staged according to the METAVIR scoring system. The median of 10 valid ARFI measurements was calculated for each patient. RESULTS: Sixty-nine males and thirteen females (one patient excluded due to insufficient biopsy size) were assessed with a mean alcohol consumption of 132.4 ± 128.8 standard drinks per week and mean cumulative year duration of 17.6 ± 9.5 years. Sensitivity and specificity were respectively 82.4% (0.70-0.95) and 83.3% (0.73-0.94) (AUROC = 0.87) for F ≥ 2 with a cut-off value of 1.63m/s; 82.4% (0.64-1.00) and 78.5% (0.69-0.89) (AUROC = 0.86) for F ≥ 3 with a cut-off value of 1.84m/s; and 92.3% (0.78-1.00] and 81.6% (0.72-0.90) (AUROC = 0.89) for F = 4 with a cut-off value of 1.94 m/s. CONCLUSION: ARFI is an accurate, non-invasive and easy method for assessing liver fibrosis in patients with ALD undergoing alcoholic detoxification
Published: 2016
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38. LOXL2 is a prognosis biomarker and a potential therapeutic target in intrahepatic cholangiocarcinoma

Author: Damien Bergeat, Bruno Turlin, L Sulpice, Karim Boudjema, Bernard Meunier, Alain Fautrel, Cédric Coulouarn, Michel Rayar, Aude Merdrignac, Bruno Clément, CHU Pontchaillou [Rennes], Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Chirurgie Hépatobiliaire et Digestive [Rennes] = Hepatobiliary and Digestive Surgery [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Oncology, medicine.medical_specialty, LOXL2, Hepatology, business.industry, [SDV]Life Sciences [q-bio], Gastroenterology, 030230 surgery, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Prognosis biomarker, Internal medicine, medicine, 030211 gastroenterology & hepatology, business, ComputingMilieux_MISCELLANEOUS, Intrahepatic Cholangiocarcinoma
Abstract: International audience; no abstract
Published: 2016
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39. AFP-specific immunotherapy impairs growth of autochthonous hepatocellular carcinoma in mice

Author: Lucile Tran, Bruno Pitard, Jean-Pierre Couty, Isabelle Archambeaud, Bruno Turlin, Vanessa Gauttier, Benoit Barteau, Nicolas Ferry, Sophie Conchon, Jeannette Cany, and Georges Vassaux
Subjects: Male, Pathology, medicine.medical_specialty, medicine.medical_treatment, Genetic Vectors, Context (language use), CD8-Positive T-Lymphocytes, Cancer Vaccines, DNA vaccination, Mice, Liver Neoplasms, Experimental, MHC class I, Vaccines, DNA, medicine, Animals, Diethylnitrosamine, Mice, Inbred C3H, Hepatology, biology, business.industry, H-2 Antigens, Immunotherapy, Active, Cancer, Immunotherapy, medicine.disease, digestive system diseases, Mice, Inbred C57BL, Hepatocellular carcinoma, biology.protein, Cancer research, Female, alpha-Fetoproteins, Alpha-fetoprotein, business, Adjuvant
Abstract: Background and Aims In this study, we have assessed the potential of antigen-specific immunotherapy against hepatocellular carcinoma (HCC) in conditions of low tumour burden, in an autochthonous HCC model. Methods Diethylnitrosamine (DEN) injected into infant mice results in the development of multi-nodular HCC in which alpha-fetoprotein (AFP) is re-expressed. DEN-injected animals received an antigen-specific immunization with a synthetic vector consisting of a low dose of AFP-encoding plasmid formulated with the amphiphilic block copolymer 704 (DNAmAFP/704). Animals were treated at 4 and 5 months, before macroscopic nodules were detected, and were sacrificed at 8 months. The tumour burden, as well as liver histology, was assessed. AFP and MHC class I molecule expression in the nodules were monitored by qRT-PCR. Results The AFP-specific immunotherapy led to a significant (65%) reduction in tumour size. The reduced expression of AFP and MHC class I molecules was measured in the remaining nodules taken from the DNAmAFP/704-treated group. Conclusions This is the first study demonstrating the relevance of antigen-specific immunotherapy in an autochthonous HCC model. In this context, we validated the use of an anti-tumour immunotherapy based on vaccination with nanoparticles consisting of low dose antigen-encoding DNA formulated with a block copolymer. Our results demonstrate the potential of this strategy as adjuvant immunotherapy to reduce the recurrence risk after local treatment of HCC patients.
Published: 2011
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40. Pathology Analysis Reveals That Dysplastic Pancreatic Ductal Lesions Are Frequent in Patients With Hereditary Pancreatitis

Author: Pascal Hammel, Pierre Bedossa, Philippe Lévy, Jean-Yves Scoazec, Marie–Sophie Soubeyrand, Jean–François Mosnier, Philippe Ruszniewski, Bruno Turlin, Anne Couvelard, Vinciane Rebours, and Jean François Fléjou
Subjects: Adult, Male, medicine.medical_specialty, Pathology, Adolescent, endocrine system diseases, medicine.medical_treatment, Pancreatic Intraepithelial Neoplasia, Gastroenterology, Young Adult, Pancreatectomy, Pancreatic cancer, Internal medicine, Carcinoma, Humans, Medicine, Trypsin, Child, Retrospective Studies, Hereditary pancreatitis, Hepatology, business.industry, Genetic Diseases, Inborn, Pancreatic Ducts, Retrospective cohort study, Middle Aged, medicine.disease, Pancreatic Neoplasms, Pancreatitis, Dysplasia, Child, Preschool, Adenocarcinoma, Female, business, Carcinoma in Situ, Carcinoma, Pancreatic Ductal
Abstract: Background & Aims Hereditary pancreatitis (HP) is a risk factor for pancreatic adenocarcinoma. We performed a retrospective, multicenter study to characterize and evaluate the frequency of pancreatic intraepithelial neoplasia (PanIN) and to describe the characteristics of fibrosis in pancreatic surgical specimens from patients with HP. Methods Samples from partial pancreatectomies (n = 13) of patients with HP complications (n = 12; 7 males; mean age, 24 y; 1 patient underwent 2 surgeries over 16 years) were analyzed by histologic and immunohistologic analyses; patients with suspected or proven pancreatic adenocarcinoma were excluded. HP diagnosis was confirmed by analysis of PRSS1 mutations. Dysplastic lesions were described according to the PanIN classification. Results Eleven patients were found to have the R122H mutation in PRSS1 and 1 patient was found to have the N29I mutation in PRSS1. Fifty-one PanIN lesions were observed in 10 specimens (77%): PanIN lesions 1a, 1b, 2, and 3 were observed in 8, 5, 8, and 5 specimens, respectively. The median number of PanIN lesions was 3.5 for each specimen. The density of the lesions was 2.6 per 10 cm2. The size of lesions was greater than 0.5 mm in 55% of the samples. Two patients with PanIN-3 developed pancreatic cancer, 18 months and 44 years after surgery. Conclusions PanIN lesions are frequent, severe, and occur early in the course of HP. Among patients with PanINs, 50% had PanIN-3 lesions. Pancreatectomy could be considered as a prophylactic against pancreatic cancer in patients with high-grade dysplasia.
Published: 2010
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41. Chronic Ethanol Consumption Lessens the Gain of Body Weight, Liver Triglycerides, and Diabetes in Obese ob/ob Mice

Author: Marie-Anne Robin, Bernard Fromenty, Philippe Lettéron, Nadège Barri-Ova, Julie Massart, Alain Fautrel, Nathalie Vadrot, and Bruno Turlin
Subjects: Male, medicine.medical_specialty, Alcohol Drinking, Mice, Obese, Blood sugar, Blood lipids, Type 2 diabetes, Carbohydrate metabolism, Weight Gain, Diabetes Mellitus, Experimental, Mice, Insulin resistance, Internal medicine, Diabetes mellitus, medicine, Animals, Humans, Lipolysis, Triglycerides, Pharmacology, Ethanol, Chemistry, Body Weight, medicine.disease, Mice, Inbred C57BL, Endocrinology, Diabetes Mellitus, Type 2, Liver, Molecular Medicine, Liver function
Abstract: Clinical studies suggest that moderate alcohol consumption can have beneficial effects, in particular regarding cardiovascular events, insulin resistance, and type 2 diabetes. In this study, lean and obese diabetic ob/ob mice were submitted or not to chronic ethanol intake via the drinking water for 6 months, which was associated with moderate levels of plasma ethanol. Plasma levels of alanine aminotransferase and aspartate aminotransferase were not increased by alcohol intake. Ethanol consumption progressively reduced the gain of body weight in ob/ob mice, but not in lean mice, and this was observed despite higher calorie intake. Increased plasma free fatty acids and glycerol in ethanol-treated ob/ob mice suggested peripheral lipolysis. Glycemia and insulinemia were significantly reduced, whereas adiponectinemia was increased in ethanol-treated ob/ob mice. Liver weight and triglycerides were significantly decreased in ethanol-treated ob/ob mice, and this was associated with less microvesicular steatosis. Hepatic levels of AMP-activated protein kinase and the phosphorylated form of acetyl-CoA carboxylase were higher in ethanol-treated ob/ob mice, suggesting better fatty acid oxidation. However, hepatic mRNA expression of several lipogenic genes was not reduced by ethanol consumption. Finally, mild oxidative stress was noticed in the liver of ethanol-treated mice, regardless of their genotype. Hence, our data are in keeping with clinical studies suggesting that moderate ethanol intake can have beneficial effects on type 2 diabetes and insulin sensitivity, at least in part through increased levels of plasma adiponectin. However, further studies are needed to determine whether long-term drinking of light-to-moderate amounts of ethanol is safe for the liver.
Published: 2009
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42. Interleukin-33 overexpression is associated with liver fibrosis in mice and humans

Author: Annie L'Helgoualc'h, Mariette Lisbonne, Hugues Gascan, Michel Rauch, Katia Bourd-Boittin, Nathalie Théret, Bruno Turlin, Claire Piquet-Pellorce, Michel Samson, Pierrick Marvie, Laurence Preisser, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Groupe d'Etude de la Reproduction Chez l'Homme et les Mammiferes (GERHM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Centre de ressources biologiques de Rennes, Hôpital Pontchaillou, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Cytokines : structure, signalisation et prolifération tumorale, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: MESH: Inflammation, Liver Cirrhosis, Male, Pathology, Mice, 0302 clinical medicine, MESH: Liver Neoplasms, Fibrosis, Gene expression, MESH: Animals, MESH: Endothelial Cells, MESH: Carcinoma, Hepatocellular, Cells, Cultured, Regulation of gene expression, 0303 health sciences, MESH: Middle Aged, Liver Neoplasms, Interleukin, Middle Aged, MESH: Gene Expression Regulation, Protein Transport, Liver, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Molecular Medicine, Female, MESH: Liver Cirrhosis, medicine.symptom, MESH: Cells, Cultured, MESH: Cell Nucleus, MESH: Protein Transport, medicine.medical_specialty, MESH: Interleukins, Carcinoma, Hepatocellular, Inflammation, Biology, MESH: Hepatic Stellate Cells, 03 medical and health sciences, Hepatic Stellate Cells, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, MESH: Mice, MESH: RNA, Messenger, 030304 developmental biology, Cell Nucleus, MESH: Humans, Interleukins, fibrosis, Endothelial Cells, Original Articles, Cell Biology, ST2, Interleukin-33, medicine.disease, MESH: Male, Interleukin 33, Gene Expression Regulation, IL-33, Hepatic stellate cell, Cancer research, MESH: Interleukin-1 Receptor Accessory Protein, Th2 cytokines, Interleukin-1 Receptor Accessory Protein, MESH: Female, MESH: Liver
Abstract: International audience; Interleukin-33 (IL-33), the most recently identified member of the IL-1 family, induces synthesis of T Helper 2 (Th2)-type cytokines via its heterodimeric ST2/IL-1RAcP receptor. Th2-type cytokines play an important role in fibrosis; thus, we investigated the role of IL-33 in liver fibrosis. IL-33, ST2 and IL-1RAcP gene expression was analysed in mouse and human normal (n= 6) and fibrotic livers (n= 28), and in human hepatocellular carcinoma (HCC; n= 22), using real-time PCR. IL-33 protein was detected in normal and fibrotic liver sections and in isolated liver cells using Western blotting and immunolocalization approaches. Our results showed that IL-33 and ST2 mRNA was overproduced in mouse and human fibrotic livers, but not in human HCC. IL-33 expression correlated with ST2 expression and also with collagen expression in fibrotic livers. The major sources of IL-33 in normal liver from both mice and human beings are the liver sinusoidal endothelial cells and, in fibrotic liver, the activated hepatic stellate cells (HSC). Moreover, IL-33 expression was increased in cultured HSC when stimulated by pro-inflammatory cytokines. In conclusion, IL-33 is strongly associated with fibrosis in chronic liver injury and activated HSC are a source of IL-33.
Published: 2009
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43. Assessment of hepatic steatosis: comparison of quantitative and semiquantitative methods in 108 liver biopsies

Author: Bruno Turlin, Fabrice Lainé, David M. Purdie, Graeme A. Macdonald, Michelle Perrin, Grant A. Ramm, and Yves Deugnier
Subjects: medicine.medical_specialty, Hepatology, medicine.diagnostic_test, business.industry, Fatty liver, medicine.disease, Gastroenterology, Insulin resistance, Liver biopsy, Predictive value of tests, Internal medicine, Biopsy, medicine, Histopathology, Steatosis, business, Grading (tumors)
Abstract: Background: There is growing interest in the role of hepatic steatosis in liver injury. The current standard for steatosis assessment is histological grading, although there is variability in the scoring systems used. Aims: The aim of this study was to compare steatosis assessment by image analysis and histological grading. Methods: Three methods were used to measure steatosis: histological grading (from 0 to 4); estimation of the percentage of hepatocytes (to nearest 5%) with steatosis; and computer-assisted image analysis. Image analysis was performed on multiple fields for each biopsy with image pro plus 4.5, with steatotic droplets identified on the basis of shape, colour and size. Computer-selected objects were reviewed to ensure that these were steatotic droplets. The predictive accuracy of the three techniques was assessed using measures of obesity and insulin resistance (homeostasis model assessment) as the outcome variables. Results: There was a strong correlation between the results of image analysis and histological grade (r = 0.89, P < 0.01), and estimated per cent steatosis (r = 0.93, P < 0.01). The variability in the area of steatosis calculated by image analysis in different fields of a biopsy correlated with the total steatosis area (r = 0.93, P < 0.01). Conclusions: Image analysis did not offer any additional predictive value when the association between degree of obesity or insulin resistance was correlated with the different methods of assessing steatosis. Image analysis allows measurement of area of steatosis in liver biopsy material and generates a continuous variable that facilitates statistical analysis. These aspects may prove beneficial in research settings. © 2009 The Authors. Journal compilation
Published: 2009
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44. L’analyse du sérum par spectroscopie moyen infrarouge permet d’obtenir une signature du statut métabolique du foie chez la souris

Author: Martine Ropert, M. Le Corvec, Alain Fautrel, Karima Begriche, Coralie Allain, Olivier Loréal, Patricia Leroyer, Bruno Turlin, Olivier Sire, Pascal Guggenbuhl, Salim Lardjane, Bernard Fromenty, Valérie Monbet, Thibault Cavey, Laboratoire dÍngénierie des Matériaux de Bretagne, Equipe E2PIC, Université de Bretagne Sud, France, Laboratoire d'Ingénierie des Matériaux de Bretagne (LIMATB), Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université de Brest (UBO), Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de Mathématiques de Bretagne Atlantique (LMBA), Université de Brest (UBO)-Université de Bretagne Sud (UBS)-Centre National de la Recherche Scientifique (CNRS), CHU Pontchaillou [Rennes], H2P2 - Histo Pathologie Hight Precision (H2P2), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Recherche Mathématique de Rennes (IRMAR), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Applications of interacting particle systems to statistics (ASPI), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-AGROCAMPUS OUEST, Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de rhumatologie [Rennes] = Rheumatology [Rennes], IRMAR-STAT, Laboratoire d'Ingénierie des Matériaux de Bretagne ( LIMATB ), Université de Bretagne Sud ( UBS ) -Université de Brest ( UBO ) -Institut Brestois du Numérique et des Mathématiques ( IBNM ), Université de Brest ( UBO ) -Université de Brest ( UBO ) -Université de Bretagne Sud ( UBS ) -Université de Brest ( UBO ) -Institut Brestois du Numérique et des Mathématiques ( IBNM ), Université de Brest ( UBO ) -Université de Brest ( UBO ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de Mathématiques de Bretagne Atlantique ( LMBA ), Université de Bretagne Sud ( UBS ) -Université de Brest ( UBO ) -Centre National de la Recherche Scientifique ( CNRS ), H2P2 - Histo Pathologie Hight Precision ( H2P2 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Recherche Mathématique de Rennes ( IRMAR ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -AGROCAMPUS OUEST-École normale supérieure - Rennes ( ENS Rennes ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National des Sciences Appliquées ( INSA ) -Université de Rennes 2 ( UR2 ), Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ), Applications of interacting particle systems to statistics ( ASPI ), Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique ( Inria ), Nutrition, Métabolismes et Cancer ( NuMeCan ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de rhumatologie, Hôpital Sud, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École normale supérieure - Rennes (ENS Rennes)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-INSTITUT AGRO Agrocampus Ouest, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Inria Rennes – Bretagne Atlantique, Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR-11-LABX-0020,LEBESGUE,Centre de Mathématiques Henri Lebesgue : fondements, interactions, applications et Formation(2011)
Subjects: 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Nutrition and Dietetics, 030309 nutrition & dietetics, [MATH.MATH-ST]Mathematics [math]/Statistics [math.ST], Endocrinology, Diabetes and Metabolism, Internal Medicine, 030209 endocrinology & metabolism, [ MATH.MATH-ST ] Mathematics [math]/Statistics [math.ST], ComputingMilieux_MISCELLANEOUS, 3. Good health
Abstract: Introduction et but de l’etude Les hepatopathies steatosiques non alcooliques (NAFLD) sont potentiellement observees lorsque existent une obesite, un syndrome metabolique et/ou un diabete. La NASH favorise la survenue de complications hepatiques, et est une etape majeure dans l’histoire naturelle de la maladie. La possibilite de detecter, de facon non invasive, une alteration de l’etat hepatique pourrait ameliorer le suivi des patients. Il est possible d’evaluer, chez la souris, par l’analyse du serum, le potentiel de la spectroscopie moyen infrarouge (MIR) pour preciser l’etat hepatique au cours des NAFLD. Materiel et methodes Des souris ont recu une alimentation controle ou riche en lipides (HF) ou riche en lipides et glucides (HFHC) (n = 25 par groupe). Nous avons analyse : (i) les parametres biochimiques seriques du metabolisme glucido-lipidiques, les transaminases, (ii) les niveaux d’ARNm de genes hepatiques impliques dans le controle de ces deux metabolismes et ceux de la C-reactive proteine, l’interleukine 6 et la chaine α1 du collagene 1 (Col1α1). Les steatoses hepatiques micro- et macrovesiculaires ont ete quantifiees (histologie et analyse d’image). Les spectres MIR ont ete analyses afin de mettre au point un modele predictif de la steatose hepatique. Resultats et analyse statistique Les animaux soumis aux regimes enrichis etaient obeses. Une steatose hepatique, sans lesions de NASH, etait retrouvee chez tous les animaux et etait plus severe dans les groupes HF et HFHC. La relation entre les niveaux de steatose predits (analyse spectroscopique) et ceux observes histologiquement faisait apparaitre une zone de transition a 10 % de steatose macrovesiculaire. De part et d’autre de cette zone, les variables spectrales contribuant aux modeles predictifs etaient differentes, suggerant l’existence de differences metaboliques. Chez les animaux ayant une steatose superieure a 10 % (HF : n = 3 ; HFHC : n = 7), il existait une augmentation statistiquement significative des ALAT et du niveau des ARNm du col1α1 hepatique. Conclusion Ces donnees indiquent que la spectroscopie MIR combinee a l’analyse statistique peut identifier, dans le serum, des signatures spectrales qui refletent l’etat hepatique au cours des NAFLD. Financements MLC a beneficie d’une bourse de these cofinancee par Diafir et l’ ANRT .
Published: 2016
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45. Mid-infrared fibre evanescent wave spectroscopy of serum allows fingerprinting of the hepatic metabolic status in mice

Author: Bernard Fromenty, Maëna Le Corvec, Bruno Turlin, Martine Ropert, Olivier Loréal, Pascal Guggenbuhl, Alain Fautrel, Karima Begriche, Coralie Allain, Thibault Cavey, Salim Lardjane, Valérie Monbet, Olivier Sire, Patricia Leroyer, DIAFIR, Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de Mathématiques de Bretagne Atlantique (LMBA), Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Centre National de la Recherche Scientifique (CNRS), CHU Pontchaillou [Rennes], H2P2 - Histo Pathologie Hight Precision (H2P2), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Applications of interacting particle systems to statistics (ASPI), Institut de Recherche Mathématique de Rennes (IRMAR), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-AGROCAMPUS OUEST, Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Service de rhumatologie [Rennes] = Rheumatology [Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire d'Ingénierie des Matériaux de Bretagne (LIMATB), Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université de Brest (UBO), ANRT, Association Nationale de la Recherche et de la Technologie, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École normale supérieure - Rennes (ENS Rennes)-Université de Rennes 2 (UR2)-Centre National de la Recherche Scientifique (CNRS)-INSTITUT AGRO Agrocampus Ouest, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Inria Rennes – Bretagne Atlantique, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de Mathématiques de Bretagne Atlantique ( LMBA ), Université de Bretagne Sud ( UBS ) -Université de Brest ( UBO ) -Centre National de la Recherche Scientifique ( CNRS ), H2P2 - Histo Pathologie Hight Precision ( H2P2 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Applications of interacting particle systems to statistics ( ASPI ), Institut de Recherche Mathématique de Rennes ( IRMAR ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -AGROCAMPUS OUEST-École normale supérieure - Rennes ( ENS Rennes ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Institut National des Sciences Appliquées ( INSA ) -Université de Rennes 2 ( UR2 ), Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique ( Inria ), Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ), Service de rhumatologie, Hôpital Sud, Nutrition, Métabolismes et Cancer ( NuMeCan ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire d'Ingénierie des Matériaux de Bretagne ( LIMATB ), Université de Bretagne Sud ( UBS ) -Université de Brest ( UBO ) -Institut Brestois du Numérique et des Mathématiques ( IBNM ), Université de Brest ( UBO ) -Université de Brest ( UBO ), and ANR-11-LABX-0020,LEBESGUE,Centre de Mathématiques Henri Lebesgue : fondements, interactions, applications et Formation(2011)
Subjects: Male, medicine.medical_specialty, spectroscopy, Spectrophotometry, Infrared, [ STAT ] Statistics [stat], [SDV]Life Sciences [q-bio], Disease, Biology, Biochemistry, [ CHIM ] Chemical Sciences, Analytical Chemistry, Mice, 03 medical and health sciences, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Internal medicine, Diabetes mellitus, Electrochemistry, medicine, genetic algorithm, Animals, Environmental Chemistry, [CHIM]Chemical Sciences, Obesity, medicine.diagnostic_test, [ SDV ] Life Sciences [q-bio], Fatty liver, Cross-validation, Carbohydrate, medicine.disease, Mice, Inbred C57BL, [STAT]Statistics [stat], Endocrinology, Liver, 030220 oncology & carcinogenesis, Liver biopsy, 030211 gastroenterology & hepatology, Metabolic syndrome, Steatosis, variable selection
Abstract: International audience; Non-alcoholic fatty liver disease is associated with obesity, diabetes, and metabolic syndrome. The detection of systemic metabolic changes associated with alterations in the liver status during non-alcoholic fatty liver disease could improve patient follow-up. The aim of the present study was to evaluate the potential of mid-infrared fibre evanescent wave spectroscopy as a minimum-invasive method for evaluating the liver status during non-alcoholic fatty liver disease. Seventy-five mice were subjected to a control, high-fat or high-fat–high carbohydrate diets. We analysed the serum biochemical parameters and mRNA levels of hepatic genes by quantitative RT-PCR. Steatosis was quantified by image analysis. The mid-infrared spectra were acquired from serum, and then analysed to develop a predictive model of the steatosis level. Animals subjected to enriched diets were obese. Hepatic steatosis was found in all animals. The relationship between the spectroscopy-predicted and observed levels of steatosis, expressed as percentages of the liver biopsy area, was not linear. A transition around 10% steatosis was observed, leading us to consider two distinct predictive models (10%) based on two different sets of discriminative spectral variables. The model performance was evaluated using random cross-validation (10%). The hypothesis that additional metabolic changes occur beyond this transition was supported by the fact that it was associated with increased serum ALT levels, and Col1α1 chain mRNA levels. Our data suggest that mid-infrared spectroscopy combined with statistical analysis allows identifying serum mid-infrared signatures that reflect the liver status during non-alcoholic fatty liver disease.
Published: 2016
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46. Gene expression profiling of the tumor microenvironment in human intrahepatic cholangiocarcinoma

Author: Karim Boudjema, Alain Fautrel, Cédric Coulouarn, Laurent Sulpice, Bruno Turlin, Mireille Desille, Bruno Clément, Service de Chirurgie Hépatobiliaire et Digestive [Rennes] = Hepatobiliary and Digestive Surgery [Rennes], CHU Pontchaillou [Rennes], Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], The authors thank Biosit and Biogenouest for access to Plateforme Génomique Santé, Centre de Ressources Biologiques Santé, and H2P2 histopathological platform. This work was supported by Grants from Inserm, Université de Rennes 1, Institut National du Cancer (Cancéropoles IDF & GO), Ligue contre le cancer and Novartis Oncology., Jonchère, Laurent, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, medicine.medical_specialty, Stromal cell, Microenvironment, lcsh:QH426-470, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Bioinformatics, Biochemistry, Extracellular matrix, Cholangiocarcinoma, 03 medical and health sciences, 0302 clinical medicine, Stroma, Internal medicine, Data in Brief, Genetics, medicine, Gene, Intrahepatic Cholangiocarcinoma, Cancer, Tumor microenvironment, [SDV.GEN]Life Sciences [q-bio]/Genetics, Profiling, Hepatology, 3. Good health, Gene expression profiling, lcsh:Genetics, 030104 developmental biology, Liver, 030220 oncology & carcinogenesis, Cancer research, Molecular Medicine, Biotechnology
Abstract: Intrahepatic cholangiocarcinoma (ICC) is the second most common type of malignant primary tumors in the liver. ICC is an aggressive cancer with a poor survival and limited therapeutic options. At the histological level, ICC is characterized by an abundant stroma (i.e. the tumor microenvironment that notably includes components of the extracellular matrix, stromal cells and soluble factors). Tumor microenvironment is known to play a key role in tumor onset and progression but it is poorly characterized at the molecular level. Thus, this study was specifically designed to identify genes that are significantly deregulated in the tumor microenvironment of human ICC. Here we provide a detailed description of the experimental design and methods used to acquire the genomic data deposited into Gene Expression Omnibus (GEO) under the accession number GSE45001. Our genomic dataset provides insights on the molecular pathways altered in the microenvironment of ICC and allows the identification of novel ICC biomarkers, as exemplified previously in Hepatology (PMID: 23775819). Keywords: Liver, Cancer, Cholangiocarcinoma, Microenvironment, Profiling
Published: 2016
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47. Myriocin prevents muscle ceramide accumulation, but not muscle fiber atrophy during short-term mechanical unloading

Author: Bruno Turlin, Frédéric Derbré, Brice Martin, Luz Lefeuvre-Orfila, Erwann Salaun, Thibault Cavey, Olivier Loréal, Martine Ropert, Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES), Laboratoire Mouvement Sport Santé (M2S), École normale supérieure - Cachan (ENS Cachan)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université de Brest (UBO)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], Centre de référence des surcharges en fer rares d'origine génétique, Conseil Régional de Bretagne (Brittany Council), École normale supérieure - Cachan (ENS Cachan)-Université de Rennes (UR)-Université de Brest (UBO)-Université de Rennes 2 (UR2)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Ceramide, medicine.medical_specialty, hepatotoxicity, Physiology, [SDV]Life Sciences [q-bio], Muscle Fibers, Skeletal, Apoptosis, Hindlimb, Protein degradation, Biology, Ceramides, Fatty Acids, Monounsaturated, 03 medical and health sciences, chemistry.chemical_compound, Physiology (medical), Internal medicine, Myriocin, medicine, Animals, NF-kappaB, Rats, Wistar, Beta oxidation, Transaminases, Soleus muscle, Fatty Acids, Ubiquitination, Skeletal muscle, Rats, 3. Good health, Muscular Atrophy, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Hindlimb Suspension, chemistry, Biochemistry, Hepatocytes, disuse
Abstract: International audience; Bedridden patients in intensive care unit or after surgery intervention commonly develop skeletal muscle weakness. The latter is promoted by a variety of prolonged hospitalization-associated conditions. Muscle disuse is the most ubiquitous, and contributes to rapid skeletal muscle atrophy and progressive functional strength reduction. Disuse causes a reduction in fatty acid oxidation leading to their accumulation in skeletal muscle. We hypothesized that muscle fatty acids accumulation could stimulate ceramide synthesis and promote skeletal muscle weakness. Therefore, the present study was designed to determine the effects of sphingolipid metabolism on skeletal muscle atrophy induced by 7 days of disuse. For this purpose, male Wistar rats were treated with myriocin, an inhibitor of de novo synthesis of ceramides and subjected to hindlimb unloading (HU) for 7 days. Soleus muscles were assayed for fiber diameter, ceramide levels, protein degradation and apoptosis signaling. Serum and liver were removed to evaluate the potential hepatoxicity of myriocin treatment. We found that HU increases content of saturated C16:0 and C18:0 ceramides and decreases soleus muscle weight and fiber diameter. HU increased the level of polyubiquitinated proteins and induced apoptosis in skeletal muscle. Despite a prevention of C16:0 and C18:0 muscle accumulation, myriocin treatment did not prevent skeletal muscle atrophy and concomitant induction of apoptosis and proteolysis. Moreover, myriocin treatment increased serum transaminases and induced hepatocyte necrosis. These data highlight that inhibit de novo synthesis of ceramides during immobilization is not an efficient strategy to prevent skeletal muscle atrophy, and exerts adverse effects like hepatotoxicity
Published: 2016
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48. Non-invasive assessment of liver fibrosis in C282Y homozygous HFE hemochromatosis

Author: Fabrice Lainé, Marianne Latournerie, Yoann Désille, Yves Deugnier, Romain Moirand, Ludivine Legros, Anne Guillygomarc'h, Dominique Guyader, Caroline Le Lan, Edouard Bardou-Jacquet, Bruno Turlin, Pierre Brissot, Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépato-gastro-entérologie [Rennes] = Gastroenterology [Rennes], Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], Centre Hospitalier Universitaire [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Liver Cirrhosis, Male, medicine.medical_specialty, Cirrhosis, Biopsy, [SDV]Life Sciences [q-bio], Gastroenterology, Fibrosis, Internal medicine, hyaluronic acid, medicine, Humans, Prospective Studies, Hemochromatosis, Transaminases, liver fibrosis, Hepatology, medicine.diagnostic_test, business.industry, cirrhosis, Homozygote, serum ferritin, Middle Aged, medicine.disease, transient elastography, 3. Good health, Surgery, Liver, ROC Curve, Liver biopsy, Concomitant, Ferritins, Mutation, Elevated transaminases, Elasticity Imaging Techniques, Female, Transient elastography, business, Cohort study
Abstract: International audience; Background & aims - C282Y homozygotes with serum ferritin (SF) levels >1000 μg/L and/or increased serum transaminase levels are at risk of severe F3/F4 fibrosis. Current practical guidelines recommend liver biopsy in such individuals. This prospective observational cohort study aimed to evaluate non-invasive alternative means such as hyaluronic acid (HA) and transient elastography (TE) for the assessment of severe fibrosis in patients with SF >1000 μg/L or elevated transaminases. Methods - Between September 2005 and April 2013, 77 patients diagnosed C282Y homozygotes underwent a liver biopsy because of SF >1000 μg/L and/or increased transaminases according to current guidelines, with concomitant TE. All of them had clinical and biological evaluation, including HA measurement in 52 cases. Results - A total of 19.5% of patients had F3-F4 severe fibrosis. HA was higher in patients with severe fibrosis, but did not accurately predict severe fibrosis. TE was significantly higher in patients with severe fibrosis (17.2 vs. 4.9 kPa; P
Published: 2015
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49. Direct Effects of 3 Combinations of Enalapril, Metoprolol, and Spironolactone on Cardiac Remodeling in Dilated Cardiomyopathic Hamsters

Author: Bruno Turlin, Eric Bellissant, Danielle Pape, and Bruno Laviolle
Subjects: Cardiomyopathy, Dilated, Male, medicine.medical_specialty, Adrenergic beta-Antagonists, Cardiomyopathy, Angiotensin-Converting Enzyme Inhibitors, Spironolactone, Cardiovascular System, chemistry.chemical_compound, Enalapril, Cricetinae, Internal medicine, Animals, Medicine, Lung, Mineralocorticoid Receptor Antagonists, Metoprolol, Ventricular Remodeling, business.industry, Myocardium, Direct effects, medicine.disease, Blood pressure, Liver, chemistry, Systemic hemodynamics, Heart failure, Cardiology, Drug Therapy, Combination, Cardiology and Cardiovascular Medicine, business, medicine.drug
Abstract: Background In congestive heart failure, enalapril (E), metoprolol (M), and spironolactone (S) improve survival. Their direct effects on cardiac remodeling, when administered in combination, remain to be assessed. Methods and Results One hundred and five cardiomyopathic hamsters were divided into 5 groups (control, E, E-M, E-S, E-M-S) and treated from 150 to 240 days of age (E: 3 mg/kg, M: 1 mg/kg, S: 20 mg/kg). Cardiac and systemic hemodynamics, and cardiac remodeling were investigated. There was no difference between groups on blood pressure. Compared with C, both S-treated groups significantly increased cardiac index (E-S: +49%; E-M-S: +46%). Compared with C, E significantly decreased left ventricular (LV) cavity area (−10%). Compared with E, all combinations significantly decreased LV cavity area (E-M: −13%, E-S: −22%, E-M-S: −19%) and right ventricular (RV) collagen density (E-M: −18%, E-S: −30%, E-M-S: −34%), and the tri-therapy significantly decreased LV collagen density (−18%). Compared with bi-therapies, the tri-therapy significantly decreased LV (−19% vs. E-M, −16% vs. E-S) and RV (−20% vs. E-M) collagen densities. Conclusion At subdepressor doses, both bi-therapies induced similar effects on myocardial remodeling, enhancing the effects of E on LV cavity area and reducing RV collagen density. Compared with bi-therapies, the tri-therapy induced additional effects on LV and RV collagen densities.
Published: 2006
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50. Upregulation of the tumor suppressor gene menin in hepatocellular carcinomas and its significance in fibrogenesis

Author: Chang Xian Zhang, Bruno Turlin, Bruno Clément, Marie Bérangère Troadec, Antony Le Béchec, Olivier Loréal, Nathalie Théret, Katia Bourd-Boitin, Orlando Musso, Jean J. Leger, Dominique Bonnier, Pierre Zindy, Annie L'Helgoualc'h, Denise Glaise, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UR), Détoxication et réparation tissulaire, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique moléculaire, signalisation et cancer (GMSC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Régulations des équilibres fonctionnels du foie normal et pathologique, Physiopathologie et pharmacologie cellulaires et moléculaires, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Liver Cirrhosis, Microarray, polymerase chain reaction, MESH: Collagen Type I, HSC, multiple endocrine neoplasia type 1, NF-κB, MESH: Hepatocytes, 0302 clinical medicine, suppression subtractive hybridization, MESH: Up-Regulation, Genes, Tumor Suppressor, HCC, MESH: Carcinoma, Hepatocellular, Oligonucleotide Array Sequence Analysis, hepatic stellate cell, nontumor, transforming growth factor beta, 0303 health sciences, biology, hepatocellular carcinoma, Up-Regulation, PCR, MEN1, nuclear factor-kappaB, 030220 oncology & carcinogenesis, reverse transcription quantitative polymerase chain reaction, MESH: Liver Cirrhosis, TGF-β, Carcinoma, Hepatocellular, Tumor suppressor gene, antisense, NT, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Transfection, Collagen Type I, 03 medical and health sciences, Proto-Oncogene Proteins, MESH: Gene Library, Humans, RNA, Messenger, SSH, Gene, MESH: Transforming Growth Factor beta, Gene Library, MESH: RNA, Messenger, 030304 developmental biology, MESH: Humans, Hepatology, MESH: Transfection, RT-qPCR, Transforming growth factor beta, MESH: Genes, Tumor Suppressor, Hepatic stellate cell activation, MESH: Proto-Oncogene Proteins, Suppression subtractive hybridization, MESH: Oligonucleotide Array Sequence Analysis, Hepatocytes, biology.protein, Cancer research, Hepatic stellate cell, AS
Abstract: International audience; The molecular mechanisms underlying the progression of cirrhosis toward hepatocellular carcinoma were investigated by a combination of DNA microarray analysis and literature data mining. By using a microarray screening of suppression subtractive hybridization cDNA libraries, we first analyzed genes differentially expressed in tumor and nontumor livers with cirrhosis from 15 patients with hepatocellular carcinomas. Seventy-four genes were similarly recovered in tumor (57.8% of differentially expressed genes) and adjacent nontumor tissues (64% of differentially expressed genes) compared with histologically normal livers. Gene ontology analyses revealed that downregulated genes (n = 35) were mostly associated with hepatic functions. Upregulated genes (n = 39) included both known genes associated with extracellular matrix remodeling, cell communication, metabolism, and post-transcriptional regulation gene (e.g., ZFP36L1), as well as the tumor suppressor gene menin (multiple endocrine neoplasia type 1; MEN1). MEN1 was further identified as an important node of a regulatory network graph that integrated array data with array-independent literature mining. Upregulation of MEN1 in tumor was confirmed in an independent set of samples and associated with tumor size (P = .016). In the underlying liver with cirrhosis, increased steady-state MEN1 mRNA levels were correlated with those of collagen alpha2(I) mRNA (P < .01). In addition, MEN1 expression was associated with hepatic stellate cell activation during fibrogenesis and involved in transforming growth factor beta (TGF-beta)-dependent collagen alpha2(I) regulation. In conclusion, menin is a key regulator of gene networks that are activated in fibrogenesis associated with hepatocellular carcinoma through the modulation of TGF-beta response.
Published: 2006
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