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c-Fos overexpression increases the proliferation of human hepatocytes by stabilizing nuclear Cyclin D1

World Journal of Gastroenterology 2008年第41期14卷 6339-6346页

作者： meryem Güller Kahina Toualbi-Abed Agnès Legrand laurence michel Alain mauviel Dominique Bernuau Fanny Daniel institut national de lasanté et de la recherche médicale u697 Hpital Saint-Louis institut national de la santé et de la recherchemédicale u591 Faculté de Médecine Necker institut national de la santé et de la recherchemédicale u773 Centre de Recherche Bichat Beaujon CRB3and Université Paris 7 Denis Diderot site Bichat

AIm： To investigate the effect of stable c-Fos over- expression on immortalized human hepatocyte （IHH） proliferation. metHODS： IHHs stably transfected with c-Fos （IHH- Fos） or an empty vector （IHH-C） were grown in me- dium supplemented with 1% serum or stimulated with 10% serum. Cell proliferation was assessed by cell counts, 3H-thymidine uptake and flow cytometry analyses. The levels of cell cycle regulatory proteins （Cyclin DI, E, A） cyclin dependent kinases （cdk） cdk2, cdk4, cdk6, and their inhibitors p15, p16, p21, p27, total and phosphorylated GSK-3β and epidermal growth factor receptor （EGF-R） were assayed by Western blotting. Analysis of O/c/in D1 mRNA levels was performed by reverse transcription-polymerase chain reaction and real-time polymerase chain reaction （PCR） analysis. Stability of Cyclin DI was studied by cycloheximide blockade experiments. RESuLTS： Stable c-Fos overexpression increased cell proliferation under low serum conditions and resulted in a two-fold increase in [3H]-thymidine incorpora- tion following serum addition. Cell cycle analysis by flow cytometry showed that c-Fos accelerated the cell cycle kinetics. Following serum stimulation, Cyclin D1 was more abundantly expressed in c-Fos overexpress- ing cells. Cyclin D1 accumulation did not result from increased transcriptional activation, but from nuclear stabilization. Overexpression of c-Fos correlated with higher nuclear levels of inactive phosphorylated GSK- 3β, a kinase involved in Cyclin D1 degradation and higher levels of EGF-R mRNA, and EGF-R protein com- pared to IHH-C both in serum starved, and in serum stimulated cells. Abrogation of EGF-R signalling in IHH- Fos by treatment with AG1478, a specific EGF-R tyro- sine kinase inhibitor, prevented the phosphorylation of GSK-3β induced by serum stimulation and decreased Cyclin D1 stability in the nucleus. CONCLuSION： Our results clearly indicate a positive role for c-Fos in cell cycle regulation in hepatocytes. Importantly, we delineate

关键词： c-Fos Cyclin DI GSK-3 Cell growth, Cell cycle Hepatoma Epidermal growth factor

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Ecto-F_1-ATPase: A moonlighting protein complex and an unexpected apoA-I receptor

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World Journal of Gastroenterology 2010年第47期16卷 5925-5935页

作者： Pierre Vantourout Claudia Radojkovic laeticia Lichtenstein Véronique Pons Eric Champagne laurent O martinez institut national de la santé et de la recherche médicale u1048 institute of metabolic and Cardiovascular Diseases Université Toulouse III Paul-Sabatier

mitochondrial ATP synthase has been recently detected at the surface of different cell types, where it is a high affinity receptor for apoA-I, the major protein component in high density lipoproteins (HDL). Cell surface ATP synthase (namely ecto-F1-ATPase) expression is related to different biological effects, such as regulation of HDL uptake by hepatocytes, endothelial cell proliferation or antitumor activity of Vγ9/Vδ2 T lymphocytes. This paper reviews the recently discovered functions and regulations of ecto-F1-ATPase. Particularly, the role of the F1-ATPase pathway(s) in HDL-cholesterol uptake and apoA-Imediated endothelial protection suggests its potential importance in reverse cholesterol transport and its regulation might represent a potential therapeutic target for HDL-related therapy for cardiovascular diseases. Therefore, it is timely for us to better understand how this ecto-enzyme and downstream pathways are regulated and to develop pharmacologic interventions.

关键词： F1Fo ATP synthase High density lipoproteins receptor Apolipoprotein A-I Purinergic receptor P2Y13 Adenylate kinase Nucleotide Endothelium Antitumor immunity

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Virtual brain twins: from basic neuroscience to clinical use

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national Science Review 2024年第5期11卷 72-86页

作者： Huifang E.Wang Paul Triebkorn martin Breyton Borana Dollomaja Jean-Didier Lemarechal Spase Petkoski Pierpaolo Sorrentino Damien depannemaecker meysam Hashemi Viktor K.Jirsa Aix marseille université Institut National de la Santéet de la Recherche Médicale Institut de Neurosciences des Systèmes(INS) UMR1106 Service de Pharmacologie Clinique et Pharmacosurveillance AP–HM

Virtual brain twins are personalized, generative and adaptive brain models based on data from an individual's brain for scientific and clinical use. After a description of the key elements of virtual brain twins,we present the standard model for personalized whole-brain network models. The personalization is accomplished using a subject's brain imaging data by three means:(1) assemble cortical and subcortical areas in the subject-specific brain space;(2) directly map connectivity into the brain models, which can be generalized to other parameters; and(3) estimate relevant parameters through model inversion, typically using probabilistic machine learning. We present the use of personalized whole-brain network models in healthy ageing and five clinical diseases: epilepsy, Alzheimer's disease, multiple sclerosis, Parkinson's disease and psychiatric disorders. Specifically, we introduce spatial masks for relevant parameters and demonstrate their use based on the physiological and pathophysiological hypotheses. Finally, we pinpoint the key challenges and future directions.

关键词： virtual brain twin personalized modeling inference neuroscience brain disorder

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Folfirinox in elderly patients with pancreatic or colorectal cancer-tolerance and efficacy

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World Journal of Gastroenterology 2016年第42期22卷 9378-9386页

作者： Jean-Florian Guion-Dusserre Aurélie Bertaut Fran?ois Ghiringhelli Julie Vincent Valérie Quipourt Sophie marilier Zoé Tharin Leila Bengrine-Lefevre department of medical Oncology Centre Georges-Fran?ois Leclerc institut national de la santé et de la recherche médicale University of Burgundy

AIm To study the tolerance and the efficiency of FOLFIRINOX in elderly patients diagnosed with colorectal or pancreatic *** This retrospective study included elderly patients aged over 70 years of age treated at Georges-Francois Leclerc Center by FOLFIRINOX for histological proved colorectal or pancreatic cancer between January 2009 and January 2015. Chemotheapy regimen consisted of oxaliplatin(85 mg/m2 in over 120 min) followed by leucovorin(400 mg/m2 in over 120 min), with the addition, after 30 min of irinotecan(180 mg/m2 in over 90 min) then 5 fluorouracil(5Fu)(400 mg/m2 administred intravenous bolus), followed by 5Fu(2400 mg/m2 intraveinous infusion over 46 h) repeated every 2 wk. Geriatric parameters were recorded at the beginning. Toxicities were evaluated with the Common Terminology Criteria for Adverse Events 4.03. Tumor response was evaluated by CT scan. Treatment continued until disease progression, unacceptable toxicities or patient *** Fifty-two patients aged from 70 to 87 years were treated by FOLFIRINOX, 34 had colorectal cancer and 18 had pancreatic cancer. most of them were in good general condition, 82.7% had a 0-1 performance status and 61.5% had a Charlson Comorbidity Index most frequent severe toxicities were neutropenia(17 patients, n = 32.7%) and diarrhea(35 patients n = 67.3%); 10 of the case of neutropenia and 5 of diarrhea registered a grade 4 toxicity. Thirty-nine patients(75%) initially received an adapted dose of chemotherapy. The dosage was adjusted for 26% of patients during the course of treatment. Tumor response evaluated by RECIST criteria showed a controlled disease for 25 patients(48.1%), a stable disease for 13 and a partial response for 12 patients. Time under treatment was higher for colorectal cancer with a median time of 2.44 mo(95%CI: 1.61-3.25). Overall survival was 43.88 mo for colorectal cancer and 12.51 mo for pancreatic cancer. In univariate or multivariate analysis, none of geriatric pa

关键词： Elderly patients Feasibility treatment Pancreatic cancer Colorectal cancer FOLFIRINOX

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FOLFIRI plus bevacizumab as a second-line therapy for metastatic intrahepatic cholangiocarcinoma

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World Journal of Gastroenterology 2015年第7期21卷 2096-2101页

作者： Jean-Florian Guion-Dusserre Veronique Lorgis Julie Vincent Leila Bengrine Francois Ghiringhelli department of medical Oncology Centre Georges-Fran?ois Leclerc institut national de la santé et de la recherche médicale University of Burgundy

AIm:To evaluate the efficacy and tolerance of FOLFIRI plus bevacizumab treatment outcome as second-line treatment for metastatic intrahepatic ***:Thirteen consecutive patients with metastatic intrahepatic cholangiocarcinoma who were refractory tofirst-line therapy consisting of gemcitabine plus oxaliplatinbased first-line chemotherapy given intravenously via intra-arterial infusion were treated with FOLFIRI[irinotecan(180 mg/m2 *** 90 min)concurrently with folinic acid(400 mg/m2 *** 120 min)followed by fluorouracil(400 mg/m2 ***)then fluorouracil 2400 mg/m2 intravenous infusion over 46 h]and bevacizumab(5mg/kg)every 2 *** response was evaluated by computed tomography scan every 4 ***:The best tumor responses using response evaluation criteria in solid tumor criteria were:complete response for 1 patient,partial response for 4 patients,and stable disease for 6 patients after 6 mo of *** response rate was 38.4%(95%CI:12.5-89)and the disease control rate was 84.5%(95%CI:42-100).Seven deaths occurred at the time of analysis,progression free survival was 8 mo(95%CI:7-16),and median overall survival was 20 mo(95%CI:8-48).No grade 4toxic events were *** grade 3 hematological toxicities and one grade 3 digestive toxicity *** adaptive reduction in chemotherapy dosage was required in 2 patients due to hematological toxicity,and a delay in chemotherapy cycles was required for 3 ***:FOLFIRI plus bevacizumab combination treatment showed promising efficacy and safety as second-line treatment for metastatic intrahepatic cholangiocarcinoma after failure of the first-line treatment of gemcitabine plus oxaliplatin chemotherapy.

关键词： Biliary tract cancer Intrahepatic cholangiocarcino

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Dimensions of hepatocellular carcinoma phenotypic diversity

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World Journal of Gastroenterology 2018年第40期24卷 4536-4547页

作者： Romain Désert Natalia Nieto Orlando musso institut NumeCan Université de Rennes 1 Institut national de la recherche agronomique (INRA) Institut national de la santé et de la recherche médicale (INSERM) department of Pathology Department of Medicine (Gastroenterology and Hepatology) University of Illinois at Chicago

Hepatocellular carcinoma(HCC) is the 3^(rd) leading cause of cancer-related death worldwide. more than 80% of HCCs arise within chronic liver disease resulting from viral hepatitis, alcohol, hemochromatosis, obesity and metabolic syndrome or genotoxins. Projections based on Western lifestyle and its metabolic consequences anticipate a further increase in incidence, despite recent breakthroughs in the management of viral hepatitis. HCCs display high heterogeneity of molecular phenotypes, which challenges clinical management. However, emerging molecular classifications of HCCs have not yet formed a unified corpus translatable to the clinical practice. Thus, patient management is currently based upon tumor number, size, vascular invasion, performance status and functional liver reserve. Nonetheless, an impressive body of molecular evidence emerged within the last 20 years and is becoming increasingly available to medical practitioners and researchers in the form of repositories. Therefore, the aim this work is to review molecular data underlying HCC classifications and to organize this corpus into the major dimensions explaining HCC phenotypic diversity. major efforts have been recently made worldwide toward a unifying "clinically-friendly" molecular landscape. As a result, a consensus emerges on three major dimensions explaining the HCC heterogeneity. In the first dimension, tumor cell proliferation and differentiation enabled allocation of HCCs to two major classes presenting profoundly different clinical aggressiveness. In the second dimension, HCC microenvironment and tumor immunity underlie recent therapeutic breakthroughs prolonging patients' survival. In the third dimension,metabolic reprogramming, with the recent emergence of subclass-specific metabolic profiles, may lead to adaptive and combined therapeutic approaches. Therefore, here we review recent molecular evidence, their impact on tumor histopathological features and clinical behavior and highlight the r

关键词： Liver metabolism Liver zonation Hepatocellular carcinoma classification Wnt/β-catenin TP53 Tumor microenvironment Inflammation Tumor immunity Hepatocyte proliferation Hepatocyte differentiation

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Associations between physical activity levels and ATPase inhibitory factor 1 concentrations in older adults

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Journal of Sport and Health Science 2024年第3期13卷 409-418页

作者： Jérémy Raffin Yves Rolland Annelise Genoux Guillaume Combes mikael Croyal Bertrand Perret Sophie Guyonnet Bruno Vellas laurent O.martinez Philipe de Souto Barreto For the mAPT/DSA Group institut du Vieillissement Gérontopôle de ToulouseCentre Hospitalo-Universitaire de ToulouseToulouse 31000France Centre d'Epidémiologie et de recherche en santédes Populations UnitéMixte de Recherche 1295Institut National de la Santéet de la Recherche MédicaleUniversitéToulouse-III-Paul-SabatierToulouse 31000France LimitAging Team Institut des Maladies Métaboliques et CardiovasculairesUnitéMixte de Recherche 1297Institut National de la Santéet de la Recherche MédicaleUniversitéToulouse III-Paul SabatierToulouse 31432France Service de Biochimie Pôle de biologieHôpital de PurpanCentre Hospitalo-Universitaire de ToulouseToulouse 31300France L'institut du Thorax Institut National de la Santéet de la Recherche MédicaleCentre National de la Recherche ScientifiqueCentre Hospitalo-Universitaire de NantesNantes UniversitéNantes 44000France BioCore US16Structure Fédérative de Recherche BonamyInstitut National de la Santéet de la Recherche MédicaleCentre National de la Recherche ScientifiqueCentre Hospitalo-Universitaire de NantesNantes UniversitéNantes 44000France Plate-forme de spectrométrie de masse Centre de Recherche en Nutrition HumaineOuestNantes 44000France 不详

Background:Adenosine triphosphatase inhibitory factor 1(IF1)is a key protein involved in energy ***1 has been linked to various agerelated diseases,although its relationship with physical activity(PA)remains ***,the apolipoprotein A-I(apoA-I),a PA-modulated lipoprotein,could play a role in this relationship because it shares a binding site with IF1 on the cell-surface ATP *** examined here the associations between chronic PA and plasma IF1 concentrations among older adults,and we investigated whether apoA-I mediated these ***:In the present work,1096 healthy adults(63.8%females)aged 70 years and over who were involved in the multidomain Alzheimer Prevention Trial study were ***1 plasma concentrations(square root of ng/mL)were measured at the 1-year visit of the multidomain Alzheimer Prevention Trial,while PA levels(square root of metabolic equivalent task min/week)were assessed using questionnaires administered each year from baseline to the 3-year *** linear regressions were performed to investigate the associations between the first-year mean PA levels and IF1 *** analyses were conducted to examine whether apoA-I mediated these *** linear regressions were carried out to investigate whether the 1-year visit IF1 concentrations predicted subsequent changes in ***:multiple linear regressions indicated that first-year mean PA levels were positively associated with IF1 concentrations(B=0.021;SE=0.010;p=0.043).mediation analyses revealed that about 37.7%of this relationship was mediated by apoA-I(B_(ab)=0.008;SE=0.004;p=0.023).Longitudinal investigations demonstrated that higher concentrations of IF1 at the 1-year visit predicted a faster decline in PA levels over the subsequent 2 years(time×IF1:B=0.148;SE=0.066;p=0.025).Conclusion:This study demonstrates that regular PA is associated with plasma IF1 concentrations,and it suggests that apoA-I partly med

关键词： Aging Apolipoprotein Bioenergetics Exerkine mitochondria

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deletion of the immunoglobulin heavy chain 3′ regulatory region super-enhancer affects somatic hypermutation in B1 B cells

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Cellular & molecular Immunology 2019年第2期16卷 195-197页

作者： Issaoui Hussein Ghazzaui Nour Boyer François denizot Yves Saintamand Alexis Centre national de la recherche Scientifique unitémixte de recherche 7276 Institut National de la Santéet de la Recherche Médicale U1262CBRSrue du Pr.Descottes87025 LimogesFrance INSERm u1236 UniversitéRennes 1RennesFrance

mouse B1 B cells originate in the embryonic liver and are the major B-cell population in the peritoneal and pleural cavities.1–5 By contrast,mouse B2 B cells originate in the bone marrow and are the major B-cell population in the bone marrow,spleen,and blood.B1 and B2 B cells differ not only in their origin and locations,but also in their antigen specificity,cell surface markers,capacities for class-switch recombination(CSR)and somatic hypermutation(SHm).IgH cis-regulatory regions and,particularly,transcriptional super-enhancers are major locus regulators under both normal and pathological conditions.6,7 Important differences have been found regarding the ability of the IgH 3′regulatory region(3′RR)super-enhancer to control the B1 and B2 B-cell fate.

关键词： spleen specificity peritoneal

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A novel regulatory region controls IgH locus transcription and switch recombination to a subset of isotypes

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Cellular & molecular Immunology 2019年第11期16卷 887-889页

作者： Rocío Amoretti-Villa mélanie Rogier Isabelle Robert Vincent Heyer Bernardo Reina-San-martin institut de Génétique et de Biologie moléculaire et Cellulaire(IGBmC) IllkirchFrance institut national de la santéet de la recherche médicale(INSERm) U1258IllkirchFrance Centre national de la recherche Scientifique(CNRS) UMR7104IllkirchFrance universitéde Strasbourg IllkirchFrance

Class switch recombination(CSR)occurs at the IgH locus and replaces the immunoglobulin(Ig)isotype expressed from Igm to IgG,IgE or IgA,endowing the B cell receptor with novel effector *** is triggered by activation-induced cytidine deaminase(AID),1 an enzyme that deaminates cytosines to uracils in single-stranded DNA exposed by *** distinct antibody isotypes are encoded in the IgH locus in individual transcription units composed of a cytokine-inducible promoter,an intronic exon,and a switch region(Sx),followed by the exons encoding the constant region(Cx)(Fig.S1a).During CSR,the choice of recombination to a particular isotype is determined by the stimulation-dependent activation of specific promoters,triggering the generation of noncoding germline transcripts(GLTs).2 Thus far,the transcriptional regulation of the IgH locus is known to be controlled by the Eμenhancer,located downstream of the variable region and upstream of the donor switch region(Sμ),and the 3′regulatory region(3′RR)super-enhancer located downstream of Cα.

关键词： IgH stimulation replace

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Impact of high-fat diet and vitamin D_3 supplementation on aortic stenosis establishment in waved-2 epidermal growth factor receptor mutant mice

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Journal of Integrative medicine 2019年第2期17卷 107-114页

作者： Bérénice Colleville Nicolas Perzo Guillaume Avinée Ana?s Dumesnil Frederic Ziegler Paul Billoir Hélène Eltchaninoff Vincent Richard Eric Durand department of Biology Institut National de la Santé et de la Recherche Médicale U1096 (Endothélium Valvulopathies et Insuffisance Cardiaque) Normandie University Fédération Hospitalo-universitaire REmOdeling in Valvulopathy and Heart Failure department of Cardiology Rouen University Hospital department of Biology Institut National de la Santé et de la Recherche Médicale U1073 (Nutrition Inflammation et Dysfonction de l’axe Intestin-Cerveau) Normandie University institute for Clinical Biology-General Biochemistry unit Rouen University Hospital department of Vascular Hemostasis Rouen University Hospital

Objective: The use of animal models of aortic stenosis(AS) remains essential to further elucidate its pathophysiology and to evaluate new therapeutic strategies. The waved-2 mouse AS model has been proposed;data have indicated that while aortic regurgitation(AR) is effectively induced, development of AS is *** aimed to evaluate the effect of high-fat diet(HFD) and vitamin D_3 supplementation in this ***: HFD and subcutaneous vitamin D_3 injections were initiated at the age of 6 weeks until the age of 6(n = 16, 6-month treatment group) and 9(n = 11, 9-month treatment group) months. Twelve waved-2 mice without supplementation were used as control. Echocardiography was performed at 3, 6 and 9 months. Blood serum analysis(calcium, 1,25(OH)_2D_3 and cholesterol), histology and immunohistochemistry(CD-31, CD-68 and osteopontin) were evaluated at the end of the experiment(6 or 9 months).Results: Total cholesterol and 1,25(OH)_2D_3 were significantly increased relative to the control group. HFD and vitamin D_3 supplementation did result in improvements to the model, since AS was only detected in 6(15.3%) mice(2 in the 3 groups) and AR was developed in the remaining animals. Echocardiographic parameters, fibrosis, thickness, inflammation and valvular calcification, were not significantly different between the 6-month treatment and control groups. Similar results were also observed in the 9-month treatment ***: These results suggest that HFD and vitamin D_3 supplementation have no effect in the waved-2 mouse model. This model essentially mimics AR and rarely AS. Further studies are needed to find a reliable animal model of AS.

关键词： Experimental model Epidermal growth factor receptor Vitamin D3 High-fat diet Aortic stenosis Aortic regurgitation

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