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Classification tool for the systematic histological assessment of hepatocellular carcinoma, macroregenerative nodules, and dysplastic nodules in cirrhotic liver

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World Journal of Gastroenterology 2005年第40期11卷 6262-6268页

作者： A Quaglia MA Jutand A Dhillon A Godfrey R Togni P Bioulac-Sage C Balabaud M Winnock AP Dhillon Department of Histopathology inserm u593 Lab pathology

AIM： To design a classification tool for the histological assessment of hepatocellular carcinoma （HCC）, dysplastic nodules （DN）, and macroregenerative nodules （MRN） in cirrhotic liver. METHODS： Two hundred and twelve hepatocellular nodules （106 HCC; 74 IRN, 32 DN） were assessed systematically, quantitatively, and semiquantitatively as appropriate for 10 histological features that have been described as helpful in distinguishing small HCC, DN, and MRN in cirrhotic livers. The data were analyzed by multiple correspondence analysis （MCA）. RESuLTS： HCA distributed HCC, DN, and HRN as defined by traditional histological evaluation as well as the individual histological variables, in a ＂malignancy scale＂. Based on the MCA data representation, we created a classification tool, which categorizes an individual nodular lesion as MRN, DN, or HCC based on the balance of all histological features （i.e., vascular invasion, capsular invasion, tumor necrosis, tumor heterogeneity, reticulin loss, capillarization of sinusoids, trabecular thickness, nuclear atypia, and mitotic activity）. The classification tool classified most （83%） of a validation set of 47 nodules in the same way as the routine histological assessment. No discrepandes were present for DN and MRN between the routine histological assignment and the dassification tool. Of 25 HCC assigned by routine assessment in the validation set, 8 were assigned to the DN category by the classification tool. CONCLuSION： We have designed a classification tool for the histological assessment of HCC and its putative precursors in cirrhotic liver. Application of this toolsystematically records histological features of diagnostic importance in the evaluation of small HCC.

关键词： Hepatocellular carcinoma Cirrhosis Multiplecorrespondence analysis Large regenerative nodule Dysplastic nodule

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Cyclin-dependent kinase inhibitors p21 and p27 function as critical regulators of liver regeneration following 90%hepatectomy in the rat

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World Journal of Hepatology 2020年第12期12卷 1198-1210页

作者： Nicolas Moniaux Laurence Lacaze Adelie Gothland Alice Deshayes Didier Samuel Jamila Faivre inserm U1193Paul-Brousse University HospitalHepatobiliary CentreVillejuif 94800France universitéParis-Saclay Facultéde Médecine Le KremlinBicêtre 94270France Department of Pôle de Biologie Médicale Laboratoire d’Onco-HématologieAssistance Publique-Hôpitaux de Paris(AP-HP)Paul-Brousse University HospitalVillejuif 94800France

BACKGROuND Liver reduction is the main curative treatment for primary liver cancer,but its use remains limited as liver regeneration requires a minimum of 30%functional *** To study the dynamics of the liver regeneration process and consequent behavior of cell cycle regulators in rats after extended hepatectomy(90%)and postoperative glucose *** Post-hepatectomy liver failure was triggered in 84 Wistar rats by reducing their liver mass by 90%.The animals received a post-operative glucose infusion and were randomly assigned to two groups:One to investigate the survival rate and the other for biochemical *** that underwent laparotomy or 70%hepatectomy were used as *** and liver samples were collected on postoperative days 1 to *** morphology,function,and regeneration were studied with histology,immunohistochemistry,and western *** Postoperative mortality after major resection reached 20%and 55%in the first 24 h and 48 h,respectively,with an overall total of 70%7 d after *** apparent signs of apoptotic cell death were detected in the extended hepatectomy rat livers,but hepatocytes displaying a clear cytoplasm and an accumulation of hyaline material testified to changes affecting their functional *** regeneration started properly,as early events initiating cell proliferation occurred within the first 3 h,and the G1 to S transition was detected in less than 12 ***,a rise in p27(Kip1)followed by p21(Waf1/Cip1)cell cycle inhibitor levels led to a delayed S phase progression and ***,liver regeneration in rats with a 90%hepatectomy was delayed by 24 h and associated with a delayed onset and lower peak magnitude of hepatocellular deoxyribonucleic acid *** This work highlights the critical importance of the cyclin/cyclin-dependent kinase inhibitors of the Cip/Kip family in regulating the liver regeneration timeline following extended hepatectomy.

关键词： Major hepatectomy Liver failure Liver regeneration Post-hepatectomy liver failure p21 p27

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Lipid-derived radical-trapping antioxidants suppress ferroptosis

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Life Metabolism 2024年第2期3卷 6-8页

作者： Ruoxi Zhang Guido Kroemer Daolin Tang Department of Surgery UT Southwestern Medical CenterDallasTX 75390United States Centre de Recherche des Cordeliers INSERM U1138Equipe labellisée-Ligue contre le cancerUniversitéParis CitéSorbonne UniversitéInstitut Universitaire de FranceParis 75006France Metabolomics and Cell Biology Platforms Gustave Roussy Cancer CampusVillejuif 94800France Institut du Cancer Paris CARPEM Department of BiologyHôpital Européen Georges PompidouAssistance Publique-Hôpitaux de ParisParis 75015France

Ferroptosis,characterized by lipid peroxidation-mediated cell demise,is governed by a nuanced interplay of lipid species influencing its *** recent publications in Nature discovered 7-dehydrocholesterol,a cholesterol precursor,as a radical-trapping antioxidant that can suppress ferroptosis,thereby presenting a novel metabolic target to improve ferroptosis-related cancer therapy.

关键词： Lipid peroxidation cholesterol

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Prokineticin 2/Bv8 is expressed in Kupffer cells in liver and is down regulated in human hepatocellular carcinoma

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World Journal of Gastroenterology 2008年第8期14卷 1182-1191页

作者： Justin Monnier Claire Piquet-Pellorce Jean-Jacques Feige Orlando Musso Bruno Clément Bruno Turlin Nathalie Théret Michel Samson inserm u620 université de Rennes 1 IFR140 2 avenue du Pr. Léon Bernard Rennes cedex 35043 France inserm u522 Rennes France inserm u878 Grenoble France Service d'Anatomo-pathologie CHU Pontchaillou Rennes France

AIM： TO study the implication of prokineticin 1 （PKI/EGVEGF） and prokineticin 2 （PK2/13v8） in hepatocellular carcinoma angiogenesis.METHODS： The gene induction of PK1/EG-VEGF and PK2/Bv8 was investigated in 10 normal, 28 fibrotic and 28 tumoral livers by using real time PCR. Their expression was compared to the expression of VEGF （an angiogenesis marker）, vWF （an endothelial cell marker） and to CD68 （a monocyte/macrophage marker）. Furthermore, the rnRNA levels of PK1/EG-VEGF, PK2/Bv8, prokineticin receptor 1 and 2 were evaluated by real time PCR in isolated liver cell populations. Finally, PK2/Bv8 protein was detected in normal liver paraffin sections and in isolated liver cells by immunohistochernistry and immunocytochemistry.RESuLTS： PK2/Bv8 mRNA but not PK1/EG-VEGF was expressed in all types of normal liver samples examined. In the context of liver tumor development, we reported that PK2/13v8 correlates only with CD68 and showed a significant decrease in expression as the pathology evolves towards cancer. Whereas, VEGF and vWF mRNA were significantly upregulated in both fibrosis and HCC,as expected. In addition, out of all isolated liver cells examined, only Kupffer cells （liver resident macrophages） express significant levels of PK2/Bv8 and its receptors, prokineticin receptor 1 and 2.CONCLuSION： In normal liver PK2/Bv8 and its receptors were specifically expressed by Kupffer cells. PK2/Bv8 expression decreased as the liver evolves towards cancer and did not correlate with HCC angiogenesis.

关键词： Prokineticin Hepatocellular carcinoma PK2/Bv8 Angiogenesis Kupffer cells Vascular endothelial growth factor Liver

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Trans-silencing effect of the 3′RR immunoglobulin heavy chain enhancer on Igκtranscription at the pro-B cell stage

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Cellular & Molecular Immunology 2019年第7期16卷 668-670页

作者： Nour Ghazzaui Hussein Issaoui Ophélie Alyssa Martin Alexis Saintamand Jeanne Cook-Moreau Yves Denizot François Boyer CNRS uMR 7276 Inserm U1262Universitéde LimogesLimogesFrance Present address:inserm u1236 UniversitéRennes 1RennesFrance

Due to their impact on nuclear organization,enhancers are master regulators of cell fate.1,2 The immunoglobulin heavy chain(IgH)locus undergoes numerous changes(such as transcription,accessibility,DNA breaks,and mutations)throughout B-cell *** of these events are controlled by the IgH 3′regulatory region(3′RR).The 3′RR is the master control element of mature B-cell IgH transcription,3 somatic hypermutation(SHM),4,5 conventional class switch recombination(CSR),4,6–10 and locus suicide recombination(LSR).11 In contrast,the 3′RR is expected to be dispensable for V(D)J recombination.12,13 During Bcell development,the heavy and light chain loci are poised for their VDJ and VJ rearrangements,*** IgH locus rearranges first,with D-J joining at the pro-B-cell stages,followed by V-DJ joining at the pre-B-cell *** Igk locus is poised for VJ rearrangements at the pre-B cell stage.

关键词： effect joining recombination

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Axonal protein synthesis in central nervous system regeneration:is building an axon a local matter?

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Neural Regeneration Research 2022年第5期17卷 987-988页

作者： Julia Schaeffer Stephane Belin universitéGrenoble Alpes InsermU1216Grenoble Institut NeurosciencesGrenobleFrance

Neurons of the mature central nervous system(CNS,mainly the brain and spinal cord)are unable to regenerate spontaneously after a lesion,in contrast to neurons of the peripheral nervous system(PNS).While the extraneuronal environment was long thought to be limiting,evidence was given less than 15 years ago that neurons themselves are critical players of their own regeneration(Park et al.,2008).Indeed,CNS neurons show a decline of axon growth capacity as they mature and after an ***,the role of axonal translation is actively explored in the paradigm of embryonic neuronal growth and in peripheral nerve injury and regeneration,but less is known about the role of local protein synthesis in regrowth of adult CNS *** we discuss how the current understanding of axonal translation in the CNS may contribute to the development of novel strategies to enhance axon regeneration in the injured CNS.

关键词： synthesis system local

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Pathology of hepatic iron overload

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World Journal of Gastroenterology 2007年第35期13卷 4755-4760页

作者： Yves Deugnier Bruno Turlin Liver unit and CIC inserm 0203 Pontchaillou University HospitalRennes 35033France Department of Pathology and inserm u 522 Pontchaillou University HospitalRennes 35033France

Although progress in imaging and genetics allow for a noninvasive diagnosis of most cases of genetic iron overload, liver pathology remains often useful （1） to assess prognosis by grading fibrosis and seeking for associated lesions and （2） to guide the etiological diagnosis, especially when no molecular marker is available. Then, the type of liver siderosis （parenchymal, mesenchymal or mixed） and its distribution throughout the Iobule and the liver are useful means for suggesting its etiology： HLA-linked hemochromatosis gene （HFE） hemochromatosis or other rare genetic hemochromatosis, nonhemochromatotic genetic iron overload （ferroportin disease, aceruloplasminemia）, or iron overload secondary to excessive iron supply, inflammatory syndrome, noncirrhotic chronic liver diseases including dysmetabolic iron overload syndrome, cirrhosis, and blood disorders.

关键词： Iron Liver Biopsy Hemochromatosis Ferroportin HLA-linked hemochromatosis gene Hepcidin Metabolic syndrome

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Genomic integrity of human induced pluripotent stem cells:Reprogramming, differentiation and applications

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World Journal of Stem Cells 2019年第10期11卷 729-747页

作者： Clara Steichen Zara Hannoun Eléanor Luce Thierry Hauet Anne Dubart-Kupperschmitt inserm u1082 IRTOMIT CHU de PoitiersPoitiers F-86021France universitéde Poitiers Facultéde Médecine et PharmacieBatiment D16 rue de la milétrieTSA 5111586073 Poitiers Cedex 9France inserm u1193 Hopital Paul BrousseVillejuif F-94800France uMR_S1193 UniversitéParis_SaclayH?pital Paul BrousseVillejuif F-94800France The Jenner Institute University of OxfordOxford OX3 7DQUnited Kingdom Departement Hospitalo-universitaire Hepatinov Hopital Paul BrousseVillejuif F-94807France Service de Biochimie Pole BiospharmCHU de PoitiersPoitiers F-86021France Fédération Hospitalo-universitaire SuPORT CHU de PoitiersPoitiers F-86021France

Ten years after the initial generation of induced pluripotent stem cells(hiPSCs)from human tissues,their potential is no longer questioned,with over 15000 publications listed on PubMed,covering various fields of research;including disease modeling,cell therapy strategies,pharmacology/toxicology screening and 3D organoid ***,despite evidences that the presence of mutations in hiPSCs should be a concern,publications addressing genomic integrity of these cells represent less than 1%of the *** a first overview of the mutation types currently reported in hiPSCs,including karyotype abnormalities,copy number variations,single point mutation as well as uniparental disomy,this review will discuss the impact of reprogramming parameters such as starting cell type and reprogramming method on the maintenance of the cellular genomic ***,a specific focus will be placed on culture conditions and subsequent differentiation protocols and how their may also trigger genomic aberrations within the cell population of ***,in a last section,the impact of genomic alterations on the possible usages of hiPSCs and their derivatives will also be exemplified and *** will also discuss which techniques or combination of techniques should be used to screen for genomic abnormalities with a particular focus on the necessary quality controls and the potential alternatives.

关键词： Induced pluripotent stem cells Genomic integrity Mutations Karyotype Differentiation Cell therapy Quality control Reprogramming

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uracil-DNA glycosylase is not implicated in the choice of the DNA repair pathway during B-cell class switch recombination

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Cellular & Molecular Immunology 2019年第1期16卷 93-95页

作者： Nour Ghazzaui Hussein Issaoui Alexis Saintamand Yves Denizot François Boyer uMR CNRS 7276 INSERM U1262University of LimogesCBRSrue Pr.Descottes87025 LimogesFrance inserm u1236 Rennes 1 UniversityRennesFrance

Mature B-cells express membrane IgM and IgD(of same specificity)through alternative splicing of a pre-mRNA encompassing constant(C)μand Cδ*** encountering antigen,Bcells undergo class switch recombination(CSR)that substitutes the Cμgene with Cγ,Cε,or Cα,thereby generating IgG,IgE,and IgA antibodies with the same antigenic specificity but new effector ***-editing enzyme activation-induced deaminase(AID)is essential for CSR by targeting switch(S)regions preceding Cμ(namely,the Sμdonor region)and the Cγ,Cε,and Cαgenes(namely,the Sγ,ε,αacceptor regions).1,2 CSR is controlled in cis by IgH locus super-enhancers3 and in trans by a wide spectrum of enzymes and proteins.1,2 Among them,the role of the uracil DNA glycosylase(uNG)remains *** is a key enzyme of base excision repair,which carries out faithful *** authors estimate that during CSR,the uNG enzymatic activity removes the AID-induced dC to du converted base of singlestrand DNA,generating abasic sites and leading to DNA strand breaks.1 For other authors,the role of uNG is to stabilize the S–S synapse and to recruit DNA repair factors that facilitate the endjoining process.4,5 Thus,the classical non-homogenous end joining pathway would be increased over the alternative end joining(A-EJ)pathway in uNG-deficient mice,4 suggesting an intriguing role of uNG in promoting the A-EJ pathway.

关键词： generating joining specificity

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High-throughput sequencing reveals similar molecular signatures for class switch recombination junctions for theγandαisotypes

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Cellular & Molecular Immunology 2019年第1期16卷 90-92页

作者： ussein Issaoui Nour Ghazzaui Alexis Saintamand Yves Denizot François Boyer uMR CNRS 7276 INSERM U1262CBRSLimoges Universityrue Pr.DescottesLimoges 87025France inserm u1236 Rennes 1 UniversityRennesFrance

INTRODuCTION After encountering an antigen,B cells undergo class switch recombination(CSR),which substitutes the Cμgene with Cγ,Cε,or Cαto generate IgG,IgE,and IgA antibodies with the same antigenic specificity but new effector functions.1 The DNAediting enzyme activation-induced deaminase(AID)is essential for CSR by targeting switch(S)regions preceding Cμ(namely,the Sμdonor region)and the Cγ,Cε,and Cαgenes(namely,the Sγ,ε,αacceptor regions).1 Cis-and trans-controlled DNA double strand beaks are generated during this process.2–6 Recruitment of DNA repair factors that facilitate the end-joining process is a crucial step of class switch *** pathways are implicated in this end *** classical non-homogenous end joining(c-NHEJ)pathway ligates DNA ends with no or little *** contrast,the alternative end joining(A-EJ)pathways is used to ligate DNA ends that have microhomology.

关键词： functions. process. joining

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