` &TT @@@ @@@@5>r >\TT EN DB T     & . 67 GbrU  ? ` R Ain1997 Argentini1995 Argentini1997 Argentini1999 Bilbao2000 Bougueleret1990 Bralet20000 Brechot2000 Bruni1995 Bruni1997 Bruni1999 Buendia1990 Buendia1990 Ciccaglione1995" Cote19899 Cote19969 D'Ugo1995 D'Ugo1997 D'Ugo1999 Damen2001 Dandri1996L Dirsch20010  Duque-Campos1997Etiemble1990 Fiedler2001 Fourel1990 Fourel1990& Gerin1987" Gerin1989Gerolami2000 Giuseppetti1995 Giuseppetti1997 Giuseppetti1999 Gouillat1997 Graham20011 Guillaud1997Henglein19909 Hsu1990 Jamard1997s" Korba1989 Manganas1997 Marion19966Ponzetto19909$ Ponzetto A1991& Popper1987 Praves1997s Prieto20000& Purcell1987 Putzer2001 Qian20000 Rapicetta1995 Rapicetta1997 Rapicetta1999 Rivkina1996Robinson1996Rodicker2001 Roggendorf2001 Rogler1996& Roth19878 Ruhm2001 Saguier1997 Scherer2001 Schildgen2001 Schirmacher1996 Sims19799# Snyder1985%Snyder R1961 Stiewe2001& Tennant1987" Tennant1989 Tennant1996 Tennant2000 Tennant2001 Tennant2001Tiollais19909Tiollais1990 Tran20000 Trepo1990 Trepo1997 Vitrey19979 Young1979 Zoulim19979im19979 Zoulim1997979 Zoulim19979 Zoulim19979 Zoulim19979 Zoulim19979 Zoulim19979 Zoulim19979 Zoulim19979 Zoulim1997979 Zoulim19979 Zoulim19979 Zoulim199791979 Zoulim19979 Zoulim1997979 Zoulim1997979 Zoulim19979 Zoulim1997979 Zoulim1997979 Zoulim19979 Zoulim19979 Zoulim19979 Zoulim19979 Zoulim19979 Zoulim19979 Zoulim1997979 Zoulim19979 Zoulim199791979 Zoulim19979 Zoulim19979 Zoulim19979 Zoulim19979 Zoulim1997998 Zoulim199791998 Zoulim19979 Zoulim19979 Zoulim1997998 Zoulim1997998 Zoulim1997998 Zoulim19979 Zoulim19979 Zoulim1997998 Zoulim19979 Zoulim19979 Zoulim1997998 Zoulim19979 Zoulim1997998 Zoulim199791998 Zoulim19979 Zoulim1997998 Zoulim19979 Zoulim19979 Zoulim19979 Zoulim19979 Zoulim19979 Zoulim19979 Zoulim199799 Zoulim19979999 Zoulim19979 Zoulim199799 Zoulim19979 Zoulim19979 Zoulim199799 Zoulim19979 Zoulim199799 Zoulim19979 Zoulim19979 Zoulim199791999 Zoulim19979 Zoulim19979 Zoulim19979 Zoulim19979 AuthorsJournals Keywords a                                 8 Ain, J. F.Aldrich, C. E. Antonetti, M. Aoyama, H. Aoyama, S. Argentini, C.Baldwin, D. C., Jr.Barth, R. J., Jr. Beadle, J. R.Bellezza, C. A. Bilbao, R. Bosch, R. J.Bothe, A., Jr.Bougueleret, L. Bralet, M. P. Brechot, C. Bruni, R.Buendia, M. A.Burchard, K. W. Charrow, J.Churchill, N. D.Ciccaglione, A. R.Civetta, J. M. Coffin, C. S.Condreay, L. D. Cote, P. J.D'Angelica, M. D'Ugo, E. Damen, U. Dandri, M.Daugherty, S. R.Deslauriers, M. Dirsch, O. Dobkin, E. D. Doyle, J.Duque-Campos, R. Etiemble, J. Fiedler, M.Foster, H. W., Jr. Fourel, G. Freake, D. S. Fukuoka, K. Gerin, J. L. Gerolami, R.Giuseppetti, R. Gouillat, C. Graham, F. L.Griffith, C. H., 3rd Guillaud, M. Guo, J. T. Hattori, N. Henglein, B.Hornbuckle, W. E.Hostetler, K. Y. Hsu, T. Y. Ishikawa, T. Itai, Y. Jamard, C. Kaneko, S. Kelly, A. Kirton, O. C. Kobayashi, K. Korba, B. E. Koshimizu, K. La Sorsa, V. Leach, D. C. Litwin, S. Manganas, D. Marion, P. L. Marks, F. Mason, W. S.Matsushita, F.Michalak, T. I. Migita, S. Minasi, J. S.Molnar-Kimber, K. L.Morejon, O. V. Morimoto, H. Morioka, T. Moriyama, T. Mott, L. A. Murakami, S.Newberg, D. S. Nunes, F. A. Ogston, C. W. Ohnishi, S. Ohno, S. Oshima, T. Pardoe, I. U.Ponzetto A, Forzani B Ponzetto, A. Popper, H. Praves, M. Prieto, J. Pruett, T. L.Purcell, R. H. Putzer, B. M. Qian, C. Rapicetta, M. Reilly, P. J. Rich, E. C. Rivkina, M.Robinson, W. S. Rodicker, F.Roggendorf, M. Rogler, C. E. Rosen, M. Roth, L.Rowland-Morin, P. A. Rowley, B. D. Ruhm, S. Saguier, G. Saputelli, J. Sasaki, N. Sawyer, R. G.Schechter, E. M. Scherer, C. Schildgen, O.Schirmacher, P. Seeger, C.Seltzer, V. L.Serebriakov, II Shiga, J. Sims, E. A. Smith, P. Snyder$Snyder R, David D, Christian J Snyder, R.L.Steele, G., Jr. Stiewe, T. Stone, M. D. Summers, J. Tanaka, N. Tanz, R. R. Tennant, B.Tennant, B. C. Tiollais, P.Tochkov, I. A. Tolle, T. K. Tran, P. L.Trelegan, C. L. Trepo, C.Tribble, C. G. Unoura, M. Vitrey, D. Wang, H. P. Westhoff, C. Wilson, J. F. Wilson, J. M. Yamamoto, K. Yoshikawa, H. Young, R. A. Zhang, L. Zhou, T. Zoulim, F.  (Academic Medicine,(American Journal of Diseases of Children(#Antimicrobial Agents & ChemotherapyArchives of SurgeryArchives of Virology Cancer Detection & PreventionCancer Gene TherapyCarcinogenesisClinics in Liver Disease Gastroenterologia Japonica Hepatology$International Journal of Cancer Intervirology Italian J Gastroenterology J MammalJama($Journal of General Internal Medicine Journal of General VirologyJournal of Hepatology0+Journal of the American College of Surgeons,(Journal of the National Cancer InstituteJournal of VirologyG Lab AnimLaboratory Animal Science NatureObstetrics & GynecologyTOProceedings of the National Academy of Sciences of the United States of America Surgery Virology  g(%*Acyclovir/aa [Analogs & Derivatives]$*Acyclovir/tu [Therapeutic Use]ti *Adenoviridae *Adenoviridae/ge [Genetics] *Adenoviridae/im [Immunology] *Aflatoxin B1/to [Toxicity]$*Animal Husbandry/mt [Methods]*Animals, Laboratory83*Antineoplastic Agents/ad [Administration & Dosage],(*Antineoplastic Agents/pd [Pharmacology](#*Antiviral Agents/pd [Pharmacology]p,&*Antiviral Agents/tu [Therapeutic Use] *Attitude of Health Personnel *Carcinogens/to [Toxicity]]0,*Carcinoma, Hepatocellular/dt [Drug Therapy],(*Carcinoma, Hepatocellular/et [Etiology]0**Carcinoma, Hepatocellular/me [Metabolism],'*Carcinoma, Hepatocellular/su [Surgery],'*Carcinoma, Hepatocellular/th [Therapy]0**Carcinoma, Hepatocellular/ve [Veterinary],(*Carcinoma, Hepatocellular/vi [Virology] *Cell Line*Chromosome Aberrations*Communicationria*Convalescenceeto*Disease Models, Animal*DNA, Neoplasmpin *DNA, Viralas*DNA, Viral/ge [Genetics]*Educational Measurement*Evolution, Molecular$!*Ganciclovir/tu [Therapeutic Use]*Gene Expression,'*Gene Expression Regulation, Neoplasticry("*Gene Expression Regulation, Viral`(%*Gene Products, tax/bi [Biosynthesis] *Gene Therapy/mt [Methods] *Genes, mycss *Genes, p53an *Gynecology/ed [Education]nel *Hepadnaviridae Infectionsogy *Hepadnaviridae/ge [Genetics] *Hepatitis B *Hepatitis B Virus, Woodchuck4/*Hepatitis B Virus, Woodchuck/de [Drug Effects]0+*Hepatitis B Virus, Woodchuck/ge [Genetics]ts0-*Hepatitis B Virus, Woodchuck/im [Immunology]0-*Hepatitis B Virus, Woodchuck/ph [Physiology]$ *Hepatitis B Virus/ge [Genetics],'*Hepatitis B, Chronic/dt [Drug Therapy]ol(%*Hepatitis B, Chronic/im [Immunology]$*Hepatitis B/co [Complications]en$*Hepatitis B/dt [Drug Therapy]ugc *Hepatitis B/me [Metabolism]y *Hepatitis B/ve [Veterinary] *Hepatitis B/vi [Virology]]py(%*Hepatitis Viruses/py [Pathogenicity],'*Hepatitis, Viral, Animal/vi [Virology]ti,)*Herpesviridae Infections/ve [Veterinary]0,*Herpesviridae/ip [Isolation & Purification],&*Hospitals, Pediatric/ut [Utilization]Num<7*Hospitals, Teaching/og [Organization & Administration]*Immunotherapyhro *Immunotherapy/mt [Methods]0,*Interleukin-12/ad [Administration & Dosage]$!*Interleukin-12/pd [Pharmacology] *Internet*Internship and Residency@:*Internship and Residency/lj [Legislation & Jurisprudence],&*Internship and Residency/mt [Methods]@<*Internship and Residency/og [Organization & Administration]@:*Internship and Residency/sn [Statistics & Numerical Data],Z*Job Satisfaction *Lamivudine/pd [Pharmacology]$ *Lamivudine/tu [Therapeutic Use]y$*Liver Neoplasms, Experimental4.*Liver Neoplasms, Experimental/me [Metabolism]ڕ40*Liver Neoplasms, Experimental/mi [Microbiology]0-*Liver Neoplasms, Experimental/pa [Pathology]0+*Liver Neoplasms, Experimental/th [Therapy]4.*Liver Neoplasms, Experimental/ve [Veterinary]("*Liver Neoplasms/dt [Drug Therapy]$*Liver Neoplasms/et [Etiology]]en("*Liver Neoplasms/mi [Microbiology] *Liver Neoplasms/su [Surgery]$ *Liver Neoplasms/ve [Veterinary] $*Liver Neoplasms/vi [Virology]ge *Liver/mi [Microbiology]*Liver/pa [Pathology] *Longevitylas *Marmota*Marmota/ge [Genetics] *Marmota/mi [Microbiology]*Marmota/ph [Physiology]*Marmota/vi [Virology]col *Mutation *Obstetrics/ed [Education]lj $!*Patient Admission/st [Standards]*Patient Satisfaction *Pediatrics aHC*Personnel Staffing and Scheduling/lj [Legislation & Jurisprudence]HE*Personnel Staffing and Scheduling/og [Organization & Administration]0,*Proto-Oncogene Proteins c-myc/ge [Genetics]  h{,&*Proto-Oncogene Proteins/ge [Genetics]@:*Quality of Health Care/og [Organization & Administration]n]83*Reverse Transcriptase Inhibitors/pd [Pharmacology]nt<6*Reverse Transcriptase Inhibitors/tu [Therapeutic Use]*RNA, Antisensenf *RNA, Viralen("*Rodent Diseases/mi [Microbiology]*Rodentia/ph [Physiology] *Sciuridae*Sciuridae/ge [Genetics] *Sciuridae/mi [Microbiology] *Simplexvirus/en [Enzymology]*Sleep Deprivationsid*Stress/et [Etiology]0+*Surgery Department, Hospital/ma [Manpower]*Surgery/ed [Education]cy*Teaching/mt [Methods]]sn$*Thymidine Kinase/ge [Genetics]*Transduction, Genetic*Virus IntegrationGov*Virus Replicationt, *Work Schedule Toleranceo *Workload Accreditation/st [Standards] Acute Disease Acyclovir/pd [Pharmacology]riAdaptation, PhysiologicalAdministration, OralpAgedhAlbumins/an [Analysis]Amino Acid SequenceAnalysis of Variance Animalvir$Antibodies, Viral/an [Analysis] Antigens, Viral/an [Analysis]("Antiviral Agents/pd [Pharmacology]es]$Antiviral Agents/to [Toxicity](%Antiviral Agents/tu [Therapeutic Use]Aotus trivirgatus Apache Apoptosis Base Sequence($beta-Galactosidase/bi [Biosynthesis] Binding Sites Body Weight BreedingCarcinoma, Hepatocellular0,Carcinoma, Hepatocellular/co [Complications],'Carcinoma, Hepatocellular/et [Etiology],'Carcinoma, Hepatocellular/ge [Genetics],)Carcinoma, Hepatocellular/im [Immunology],)Carcinoma, Hepatocellular/me [Metabolism]0+Carcinoma, Hepatocellular/mi [Microbiology],(Carcinoma, Hepatocellular/pa [Pathology]m4.Carcinoma, Hepatocellular/us [Ultrasonography],)Carcinoma, Hepatocellular/ve [Veterinary],'Carcinoma, Hepatocellular/vi [Virology]]mCats Cell Division Cell LineCells, CulturedtsCercopithecus aethiops Chicagos Chromosome DeletionChromosome MappingcelChronic DiseasetoCloning, MolecularCodon/ge [Genetics]og CognitionCombined Modality TherapyComparative Study Connecticut Continuity of Patient CarenelCross-Sectional Studiesso$Cytomegalovirus/en [Enzymology] Cytopathogenic Effect, ViralData Collection SDisease Models, AnimalThe DNA, Neoplasm/ge [Genetics] DNA, Viral HeDNA, Viral/an [Analysis]rDNA, Viral/bl [Blood]DNA, Viral/ge [Genetics]l,)DNA-Directed DNA Polymerase/ge [Genetics]$ Dose-Response Relationship, Drugc,(Drug Resistance, Microbial/ge [Genetics]Drug Therapy, CombinationEducational Measurement0*Enhancer Elements (Genetics)/ge [Genetics]Exons FemaleollFollow-Up StudiesGanciclovir/to [Toxicity]Gene Expressionto Genes, mycGenetic Vectorsn  Genome, Viral Genotypei Gynecology Hamsters,&Heart Failure, Congestive/th [Therapy]Hepadnaviridae$Hepadnaviridae/im [Immunology]Eti0,Hepadnaviridae/ip [Isolation & Purification]$Hepadnaviridae/ph [Physiology] Pu0*Hepatitis B Surface Antigens/an [Analysis]Hepatitis B Vaccines4.Hepatitis B Virus, Woodchuck/de [Drug Effects]ڕ<6Hepatitis B Virus, Woodchuck/gd [Growth & Development]0*Hepatitis B Virus, Woodchuck/ge [Genetics]@:Hepatitis B Virus, Woodchuck/ip [Isolation & Purification]40Hepatitis B Virus, Woodchuck/ul [Ultrastructure]$!Hepatitis B Virus/im [Immunology]($Hepatitis B Virus/py [Pathogenicity]("Hepatitis B, Chronic/vi [Virology]gy]Hepatitis B/bl [Blood]era Hepatitis B/en [Enzymology]py Hepatitis B/im [Immunology] Hepatitis B/pa [Pathology]m]y(%Hepatitis B/pc [Prevention & Control] Hepatitis B/ve [Veterinary]Hepatitis B/vi [Virology]$!Hepatitis Viruses/im [Immunology]  L$Hepatitis, Animal/et [Etiology]Pu$ Hepatitis, Animal/pa [Pathology]u0+Hepatitis, Viral, Animal/co [Complications]0*Hepatitis, Viral, Animal/mi [Microbiology],'Hepatitis, Viral, Animal/pa [Pathology]0+Herpesviridae Infections/co [Complications]0*Herpesviridae Infections/mi [Microbiology] Herpesviridae/ge [Genetics] Herpesviridae/ph [Physiology] Hibernation$!Hospital Bed Capacity, 100 to 299("Hospitals, Pediatric/ma [Manpower]85Hospitals, Pediatric/sn [Statistics & Numerical Data]Hospitals, TeachingdiHospitals, VeteransesHousing, AnimalHuman$ Interferon Type II/an [Analysis] Interleukin-12/ge [Genetics],'Internship and Residency/ec [Economics]<9Internship and Residency/lj [Legislation & Jurisprudence]<9Internship and Residency/sn [Statistics & Numerical Data],'Internship and Residency/st [Standards] Introns Karyotyping Kentuckyh Lac Operon LearningiLength of Stayd R Linear Models0-Liver Neoplasms, Experimental/en [Enzymology]0+Liver Neoplasms, Experimental/ge [Genetics]0-Liver Neoplasms, Experimental/im [Immunology]0-Liver Neoplasms, Experimental/me [Metabolism]0,Liver Neoplasms, Experimental/pa [Pathology]m41Liver Neoplasms, Experimental/ul [Ultrastructure]0+Liver Neoplasms, Experimental/vi [Virology]]m("Liver Neoplasms/co [Complications] Liver Neoplasms/et [Etiology] Liver Neoplasms/ge [Genetics]$Liver Neoplasms/im [Immunology]$!Liver Neoplasms/mi [Microbiology]$Liver Neoplasms/pa [Pathology]($Liver Neoplasms/us [Ultrasonography]$Liver Neoplasms/ve [Veterinary] Liver Neoplasms/vi [Virology]Liver/me [Metabolism]Liver/pa [Pathology]nLiver/vi [Virology]]n,'Lung Diseases, Obstructive/th [Therapy]ioLymphocytes/vi [Virology]Lysogeny/ge [Genetics]Malen MarmotaNeMarmota/ge [Genetics]Marmota/im [Immunology]Marmota/mi [Microbiology]Marmota/vi [Virology]Miceo Mice, Nude B Mice, Transgenic Microscopy, Phase-Contrast Middle AgesesModels, ImmunologicalMolecular Sequence DataolMultivariate Analysis Mutagenesis, Site-Directedgy] MutationsMutation/ge [Genetics]adc Necrosis New Englande New Yorkh Night CaresesNucleic Acid Conformation Nucleic Acid Hybridization(%Nucleocapsid Proteins/im [Immunology]Nucleotides/ge [Genetics] Obstetricsp a$!Open Reading Frames/ge [Genetics]Operating Roomson40Personnel Staffing and Scheduling/st [Standards]i Phenotype PhylogenyPolymerase Chain ReactionProblem Solvingfi(#Problem-Based Learning/mt [Methods]ti<7Problem-Based Learning/sn [Statistics & Numerical Data]a]Program Evaluationsid Promoter Regions (Genetics)Prospective Studiesid Proto-Oncogene Proteins c-mycProto-Oncogenes PQuality of Health Cared SQuality of LifethQuestionnairesethRats($Recombinant Proteins/im [Immunology]Regression AnalysisidRestriction Mapping RNA SplicingRNA, Viral/ge [Genetics]Sciuridae/ge [Genetics]Sciuridae/im [Immunology] Sciuridae/mi [Microbiology] Seasons Sequence Homology, Amino Acid$Sequence Homology, Nucleic AcidSocial BehaviorysSpecies SpecificitySupport, Non-U.S. Gov'tcy Support, U.S. Gov't, P.H.S.bi,)Teaching/sn [Statistics & Numerical Data] Time FactorsiTranscription, Genetic TransfectionTreatment OutcomeTumor Cells, Cultured United StatesVariation (Genetics)v Viral Proteins/ge [Genetics]tVirus CultivationVirus IntegrationVirus Replication(#Virus Replication/de [Drug Effects]u $!Virus Replication/ph [Physiology]Work Schedule Tolerancecy Workloade RXRBruni, R. Argentini, C. D'Ugo, E. Giuseppetti, R. Ciccaglione, A. R. Rapicetta, M.ZTRecurrence of WHV integration in the b3n locus in woodchuck hepatocellular carcinomaVirology 1995 214t1  229-34D>Animal Base Sequence *Carcinoma, Hepatocellular/vi [Virology] Chromosome Mapping DNA, Neoplasm/ge [Genetics] DNA, Viral/ge [Genetics] Female *Hepatitis B Virus, Woodchuck/ge [Genetics] Hepatitis B Virus, Woodchuck/ip [Isolation & Purification] Marmota Molecular Sequence Data Support, Non-U.S. Gov't *Virus IntegrationFrequent occurrence of woodchuck hepatitis virus DNA (WHV DNA) integration into or in proximity to myc oncogenes and in the win locus of cellular genome in woodchuck hepatocellular carcinomas (HCC) has been described by several authors. We report a further cellular locus as a recurrent target for WHV integration in woodchuck HCCs. A WHV DNA integration and its cellular flanking regions were cloned from a HCC developed in a chronically WHV-infected woodchuck. Sequence analysis showed integration of rearranged C, PreS1, and 5' truncated X regions of the WHV genome, located in a cellular locus previously described for WHV integration in another woodchuck HCC. The two integration sites are only about 0.5 kb apart. In addition to Alu-like repeats and a gag-like coding region, previously described, we found several features of MAR (matrix attachment region) chromosomal sequences in the normal cellular locus, leading us to predict that part of it might be a previously unrecognized MAR.F?Bruni, R. Argentini, C. D'Ugo, E. Giuseppetti, R. Rapicetta, M.Woodchuck hepatitis virus DNA integration in a common chromosomal region of the woodchuck genome in two independent hepatocellular carcinomassArchives of Virology 1997 142M3M499-509rAnimal Binding Sites Carcinoma, Hepatocellular/ge [Genetics] *Carcinoma, Hepatocellular/vi [Virology] Chromosome Mapping *DNA, Neoplasm *DNA, Viral Female *Hepatitis B Virus, Woodchuck/ge [Genetics] Liver Neoplasms/ge [Genetics] *Liver Neoplasms/vi [Virology] Marmota Molecular Sequence Data Nucleic Acid Conformation Polymerase Chain Reaction Support, Non-U.S. Gov't *Virus Integration In woodchuck hepatocellular carcinoma (HCC) the myc-oncogene family (particularly N-myc2) and the win locus of cellular genome have been reported as frequent targets for integration of woodchuck hepatitis virus (WHV) DNA. In this paper a further cellular locus, b3n, is reported as recurrent target for WHV integration in woodchuck HCC. Cloning and sequencing of a WHV-DNA integration and its cellular flanking regions showed that viral DNA was inserted in a chromosomal region already described for WHV integration in another single HCC. The two integration sites are only 0.5 kb apart. A link between WHV integration in b3n and HCC development may be postulated. Careful analysis of the sequence of the unoccupied locus revealed that, in addition to Alu-like repeats and a gag-like coding region, already described, several features of Matrix Attachment Region (MAR) sequences are present. Thus (part of) b3n might be a previously unrecognized MAR. Organization of the chromatin in functional domains and regulation of gene expression are some functions attributed to MAR sequences. The occurrence of WHV-DNA integration close to the same putative MAR in two different HCCs suggests that a mechanism of deregulation of MAR functions by WHV insertion might act in some liver tumors.F?Bruni, R. D'Ugo, E. Giuseppetti, R. Argentini, C. Rapicetta, M.CActivation of the N-myc2 oncogene by woodchuck hepatitis virus integration in the linked downstream b3n locus in woodchuck hepatocellular carcinoma Virology 1999 257n2i 483-90b\Animal Carcinoma, Hepatocellular/ge [Genetics] *Carcinoma, Hepatocellular/ve [Veterinary] *Gene Expression Regulation, Neoplastic *Hepatitis B Virus, Woodchuck/ge [Genetics] Liver Neoplasms/ge [Genetics] *Liver Neoplasms/ve [Veterinary] Marmota *Proto-Oncogene Proteins c-myc/ge [Genetics] Proto-Oncogenes Support, Non-U.S. Gov't *Virus IntegrationIn the woodchuck hepatitis virus (WHV)/woodchuck model for hepatitis B virus-induced hepatocellular carcinoma, frequent activation of N-myc oncogenes by WHV integration has been firmly established. N-myc2, the most frequently affected gene, was reported to be activated by WHV insertion either in the proximity of the gene or in a distant uncoding locus, win. We previously reported that a WHV integration cloned from a liver tumor was located in a chromosomal locus already described by others as the site of WHV integration in another hepatocellular carcinoma. On this basis, the locus, named b3n, was defined as a recurrent site of WHV integration. A scaffold or matrix attachment region (S/MAR) element was subsequently shown to be located in this locus approximately 1 kb from the WHV insertion sites. S/MARs are genetic elements involved both in structural and functional organization of chromosomal DNA and in stimulation of gene expression. In the present work, we investigated the possibility that an N-myc gene might be affected by integration in b3n. Analysis of a liver tumor harboring WHV integration in this locus showed N-myc2 overexpression. By restriction analysis, the b3n locus was shown to be located downstream of N-myc2, so the known sites of viral insertion in b3n were approximately 11 kb downstream of the N-myc2 promoter. Although these data support that WHV insertion in b3n activates N-myc2, the mechanisms previously described to be involved in N-myc2 activation do not appear to properly account for activation in this subset of WHV integrations. Available data suggest that activation of N-myc2 by WHV integration in b3n might be mediated by the S/MAR located near the WHV insertion. Copyright 1999 Academic Press. d]Bilbao, R. Gerolami, R. Bralet, M. P. Qian, C. Tran, P. L. Tennant, B. Prieto, J. Brechot, C.rTransduction efficacy, antitumoral effect, and toxicity of adenovirus-mediated herpes simplex virus thymidine kinase/ ganciclovir therapy of hepatocellular carcinoma: the woodchuck animal modelECancer Gene Therapym 20007o5  657-62*Adenoviridae/ge [Genetics] Animal Antiviral Agents/tu [Therapeutic Use] Antiviral Agents/to [Toxicity] Apoptosis Carcinoma, Hepatocellular/me [Metabolism] *Carcinoma, Hepatocellular/th [Therapy] Combined Modality Therapy Cytomegalovirus/en [Enzymology] Disease Models, Animal *Ganciclovir/tu [Therapeutic Use] Ganciclovir/to [Toxicity] *Gene Therapy/mt [Methods] Genetic Vectors Lac Operon Liver/me [Metabolism] Liver Neoplasms, Experimental/me [Metabolism] *Liver Neoplasms, Experimental/th [Therapy] Marmota Necrosis Promoter Regions (Genetics) *Simplexvirus/en [Enzymology] Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. *Thymidine Kinase/ge [Genetics] *Transduction, Genetic beta-Galactosidase/bi [Biosynthesis] Gene therapy for hepatocellular carcinoma (HCC) has shown some promise, but its evaluation requires relevant experimental models. With this aim, we present an evaluation of the interest of using the woodchuck model of HCC to assess in vivo gene transfer efficiency. We tested the transduction efficacy of the adenoviral vectors directing lacZ gene product expression under the control of the cytomegalovirus and alpha-fetoprotein (AFP) regulatory sequences. We have also investigated whether an adenoviral cytomegalovirus-thymidine kinase (Tk) vector might induce an antitumoral effect in this model. Our results demonstrate that with direct intratumoral and intrahepatic arterial injections, transduction of a significant proportion of tumor cells occurred even in large HCC nodules. Furthermore, due to intra-arterial anastomoses, direct intratumoral injection led to transduction of some noninjected HCC nodules. Moreover, direct intratumoral injection of a herpes simplex virus-1 Tk-encoding vector induced, on ganciclovir administration, a significant antitumoral effect in the two animals evaluated. However, in one animal, massive hepatic failure occurred due to Tk expression in nontumor cells. These results emphasize the need to target the expression of the Tk gene to tumor cells using a hepatoma-specific promoter such as AFP promoter. However, we showed that, in vivo, lacZ expression as driven by the AFP promoter was extremely low, thus emphasizing some potential pitfalls when using this approach. Altogether, our data stress the need to test gene therapy-based strategies in such in vivo animal models of HCC and evaluate gene transduction, expression, and biological activity, as well as its potential toxicity.  @ " $&%#? the woodchuck seems to be ideal for studying the effect of antiviral treatment and immunotherapy on the outcome of hepadnavirus infection and on survival. The median life expectancy of experimentally infected, chronic WHV carriers is approximately 29 months, and almost all develop HCC. New types of prophylaxis or therapy can be":4Gerin, J. L. Cote, P. J. Korba, B. E. Tennant, B. C.6/Hepadnavirus-induced liver cancer in woodchucksa Review$Cancer Detection & Preventionn 1989142  227-9-Animal Hepadnaviridae *Liver Neoplasms/mi [Microbiology] *Marmota/mi [Microbiology] *Sciuridae/mi [Microbiology] Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S.LEWoodchuck hepatitis virus (WHV), a member of the Hepadnaviridae, is closely related to hepatitis B virus (HBV) in its virus structure, genetic organization, and mechanism of replication. As with HBV in man, persistent WHV infection is common in natural woodchuck populations and is associated with chronic hepatitis and hepatocellular carcinoma (HCC). In 1980, a program was initiated to develop the woodchuck as an experimental model of hepadnavirus infection and disease. The experimental studies have established that WHV causes HCC in woodchucks. Chronic WHV carriage as an outcome of experimental infection is a function of animal age at time of exposure, virus dose, and, possibly, virus strain. Almost all (97%) chronic carriers developed histologically confirmed HCC within 3 years; no HCC developed in uninfected animals held concurrently in the same laboratory setting. The model has application to studies of the underlying mechanisms of hepadnavirus-induced hepatocarcinogenesis and to the development of prophylactic and therapeutic strategies of disease control. [References: 18]%# Snyder, R.L. 1985The laboratory woodchuckLab Anim14 20-32;\UAnimal Husbandry. Common HCC, Aortic Dissection, Pyelonephritis, Cerebral Hemorrhage.t$Snyder R, David D, Christian J 19614-Seasonal Changes in the weights of woodchucksJ Mammal42297-312:3Describes methodology for determining woodchuck ageTennant, B. C. 2001HAAnimal models of hepadnavirus-associated hepatocellular carcinomaoClinics in Liver Disease5l1t 43-68\Nice review of HBV-related viruses in woodchucks, other animals. Includes details of woodchuck HCC and of mechanisms of HBV oncogenesis.Animal Antiviral Agents/tu [Therapeutic Use] *Carcinoma, Hepatocellular/et [Etiology] *Disease Models, Animal *Hepatitis B/co [Complications] *Hepatitis B Virus, Woodchuck *Liver Neoplasms/et [Etiology] Mice Mice, Transgenic Support, U.S. Gov't, P.H.S.VPAnimal models of hepatitis B virus infection have been valuable for determining the mechanisms of hepadnavirus replication, for studies of pathogenesis, and for investigations of viral hepatocarcinogenesis. The woodchuck model also seems to be useful in the discovery and development of antiviral drugs to treat HBV infection and for testing new forms of immunotherapy. In particular, the woodchuck seems to be ideal for studying the effect of antiviral treatment and immunotherapy on the outcome of hepadnavirus infection and on survival. The median life expectancy of experimentally infected, chronic WHV carriers is approximately 29 months, and almost all develop HCC. New types of prophylaxis or therapy can be evaluated under controlled experimental conditions, in a relevant animal model, and within a reasonable time frame. [References: 245] ReviewYoung, R. A. Sims, E. A. 1979:4The woodchuck, Marmota monax, as a laboratory animal Laboratory Animal Scienced296\ 770-80|Describes animal care and colony development. Frequent atherosclerosis, aneursym, aortic rupture, CVA in captive woodchucks.Animal *Animal Husbandry/mt [Methods] *Animals, Laboratory Body Weight Breeding Hibernation Housing, Animal *Marmota/ph [Physiology] *Rodentia/ph [Physiology] Seasons Support, U.S. Gov't, P.H.S.The woodchuck or groundhog (Marmota monax) has been used as a biomedical model for studies of obesity and energy balance, endocrine and metabolic function, central nervous system control mechanisms and cardiovascular, cerebrovascular and neoplastic disease. Methods of care of a woodchuck colony, techniques for handling, restraint, anesthesia, blood sampling and breeding were developed.>7E:\References\Articles\lab animal science 79 29 770.pdf .(Dandri, M. Schirmacher, P. Rogler, C. E.Woodchuck hepatitis virus X protein is present in chronically infected woodchuck liver and woodchuck hepatocellular carcinomas which are permissive for viral replication-Journal of Virologyy 1996708i5246-54 Animal *Carcinoma, Hepatocellular/me [Metabolism] Carcinoma, Hepatocellular/pa [Pathology] Carcinoma, Hepatocellular/vi [Virology] *Gene Products, tax/bi [Biosynthesis] *Hepatitis B/me [Metabolism] Hepatitis B/pa [Pathology] Hepatitis B/vi [Virology] *Hepatitis B Virus, Woodchuck/ph [Physiology] *Liver Neoplasms, Experimental/me [Metabolism] Liver Neoplasms, Experimental/pa [Pathology] Liver Neoplasms, Experimental/vi [Virology] Marmota Mice Support, U.S. Gov't, P.H.S. *Virus ReplicationThe woodchuck hepatitis virus (WHV) X gene (WHx) is required for infectivity of WHV in woodchucks, and the gene encodes a broadly acting transcription factor. Several lines of evidence from cell culture and transgenic mice suggest that X proteins can promote hepatocarcinogenesis. To determine whether WHx-encoded proteins are present during persistent infection and hepatocellular carcinoma (HCC) in woodchucks, we surveyed livers and HCCs from a panel of WHV carrier woodchucks for the presence of WHx by utilizing an immunoprecipitation-Western blot (immunoblot) procedure. We detected a single 15.5-kDa WHx gene product in 100% of the persistently infected livers but not in livers from animals which had recovered from acute infection or in those of uninfected woodchucks. Analysis of HCCs revealed that all of the tumors which contained WHV replication intermediates were also positive for WHx. In contrast, WHx was undetectable in HCCs which did not contain replicative intermediates. Subcellular localization studies detected WHx in the cytoplasm but not in the nuclei of primary woodchuck hepatocytes. Comparative immunoprecipitation experiments revealed that there were 4 X 10(4) to 8 X 10(4) molecules of WHx per primary woodchuck hepatocyte. Four lines of WHx transgenic mice did not develop HCC spontaneously. However, when one line was treated with diethylnitrosamine, the occurrence of precancerous lesions was enhanced compared with that in diethylnitrosamine-treated nontransgenic controls. The apparent absence of WHx in some woodchuck HCCs indicates that WHx may not be required to maintain the tumor phenotype, whereas its presence in all persistently infected livers leaves open the possibility that it plays a role in hepatocarcinogenesis.V & $Ponzetto A, Forzani Br 1991`ZAnimal models of hepatocellular carcinoma: hepadnavirus-induced liver cancer in woodchucks Italian J Gastroenterology23 491-3\>8Hepatomas in all infected woodchucks within 17-36 monthsD>Popper, H. Roth, L. Purcell, R. H. Tennant, B. C. Gerin, J. L.<6Hepatocarcinogenicity of the woodchuck hepatitis virusVOProceedings of the National Academy of Sciences of the United States of AmericaU 19878439 866-7081Animal *Hepatitis Viruses/py [Pathogenicity] Hepatitis, Viral, Animal/mi [Microbiology] Hepatitis, Viral, Animal/pa [Pathology] *Liver Neoplasms, Experimental/mi [Microbiology] Liver Neoplasms, Experimental/pa [Pathology] *Marmota/mi [Microbiology] *Sciuridae/mi [Microbiology] Support, U.S. Gov't, P.H.S.sDuring investigations of the evolution of experimental laboratory infections of woodchucks (Marmota monax) with the woodchuck hepatitis virus (WHV), eight hepatocellular carcinomas (HCC) were observed, six in newborns and two in young adult animals, all within 17-36 months after infection. The absence of an external cocarcinogenic effect in the well-monitored woodchucks indicates the carcinogenicity of WHV and suggests the same for the genetically and biologically similar human hepatitis B virus (HBV). Laboratory infections of woodchucks with two strains of WHV, not reported here in detail, resembled human and chimpanzee HBV infections histologically and serologically. In these studies, eight woodchucks became carriers of surface antigen of WHV for greater than 1 year. All eight woodchucks developed HCC, indicating a 100% risk of HCC in experimentally infected chronic WHV antigen carriers, which is analogous to the high risk of HCC in human hepatitis B surface antigen carriers. Histologically, the absence of cirrhosis in the examined pericarcinomatous tissue permits recognition of gradual transition from normal parenchyma to neoplastic nodules to HCC of rising anaplasia, indicating a continuum of increasingly more malignant neoplastic stages, as known for chemical carcinogenesis. The HCC developed in carrier woodchucks infected as newborns with only minor, if any, hepatitic changes but is associated with antigen-carrying hepatocytes and sometimes with hyperplastic nodules. This stage was preceded in infected adults by an early, acute, weeks-long hepatitis coinciding with the appearance of surface antigen. These findings are also analogous to typical HBV infection in human newborns and young adults, respectively. At the time of HCC development in all animals with adequate histologic material, an acute recent necroinflammation appeared around the tumor, associated with abnormal hematopoietic cells around and within the tumor. A promoting role in carcinogenesis of this necroinflammation of yet unestablished pathogenesis is being postulated, to be confirmed by determination of the status of the WHV DNA in the HCC and by prospective histologic study of the inflammatory reaction.Putzer, B. M. Stiewe, T. Rodicker, F. Schildgen, O. Ruhm, S. Dirsch, O. Fiedler, M. Damen, U. Tennant, B. Scherer, C. Graham, F. L. Roggendorf, M.Large nontransplanted hepatocellular carcinoma in woodchucks: treatment with adenovirus-mediated delivery of interleukin 12/B7.1 genes.(Journal of the National Cancer Institute 2001936  472-9H*Adenoviridae Animal *Antineoplastic Agents/ad [Administration & Dosage] *Antineoplastic Agents/pd [Pharmacology] *Carcinoma, Hepatocellular/dt [Drug Therapy] Carcinoma, Hepatocellular/im [Immunology] Carcinoma, Hepatocellular/pa [Pathology] Carcinoma, Hepatocellular/vi [Virology] Genetic Vectors Hepatitis, Viral, Animal/co [Complications] *Immunotherapy/mt [Methods] Interferon Type II/an [Analysis] *Interleukin-12/ad [Administration & Dosage] Interleukin-12/ge [Genetics] *Interleukin-12/pd [Pharmacology] *Liver Neoplasms/dt [Drug Therapy] Liver Neoplasms/im [Immunology] Liver Neoplasms/pa [Pathology] Liver Neoplasms/vi [Virology] Marmota Support, Non-U.S. Gov'trlBACKGROUND: Cytokine-based gene therapy strategies efficiently stimulate immune responses against many established transplanted tumors, leading to rejection of the tumor. In this study, we investigated the therapeutic potential of cancer immunotherapy in a clinically more relevant model, woodchucks with primary hepatocellular carcinomas induced by woodchuck hepatitis virus. METHODS: Large (2-5 cm), established intrahepatic tumors were given an injection once with 1 x 10(9) plaque-forming units of AdIL-12/B7.1, an adenovirus vector carrying genes for murine interleukin 12 and B7.1, or of AdEGFP, the control virus, and regression of the tumors was then monitored. Five animals were used in total. RESULTS: In four tumor-bearing animals, the antitumor response was assessed by autopsy and histologic analysis within 1-2 weeks after treatment. In all animals treated with AdIL-12/B7.1 therapy versus AdEGFP therapy, we observed substantial tumor regression (P =.006; two-sided unpaired Student's t test) accompanied by a massive infiltration of T lymphocytes. These tumors also contained increased levels of CD4(+) and CD8(+) T cells and interferon gamma (IFN gamma). In continuously growing tumor nodules given an injection of the control virus or in nontumoral liver, no such effects (i.e., tumor regression and increased levels of CD4(+) and CD8(+) T cells and IFN gamma) were detected. In the fifth animal, monitored for long-term antitumor efficacy by magnetic resonance imaging (MRI) after intratumoral vector administration by MRI guidance, the tumor was almost completely eliminated (> or = 95%) 7 weeks after treatment. CONCLUSION: Adenovirus vector-based immunotherapy appears to be an effective treatment of large nontransplanted (orthotopic) tumors that acquire malignant characteristics in a stepwise process, reflecting the real-world scenario of hepatocellular carcinoma in humans.JDRivkina, M. Cote, P. J. Robinson, W. S. Tennant, B. C. Marion, P. L.Absence of mutations in the p53 tumor suppressor gene in woodchuck hepatocellular carcinomas associated with hepadnavirus infection and intake of aflatoxin B1Carcinogenesis 199617122689-94thb*Aflatoxin B1/to [Toxicity] Animal *Carcinogens/to [Toxicity] *Carcinoma, Hepatocellular/et [Etiology] Carcinoma, Hepatocellular/ge [Genetics] DNA, Viral/an [Analysis] Exons *Genes, p53 *Hepatitis B/co [Complications] *Hepatitis B Virus, Woodchuck *Liver Neoplasms/et [Etiology] Liver Neoplasms/ge [Genetics] Marmota *Mutation Support, U.S. Gov't, P.H.S.Infection with hepadnaviruses and exposure to aflatoxin B1 (AFB1) are considered major risk factors in the development of hepatocellular carcinoma (HCC) in humans and in animals. A high rate of mutations in the p53 tumor suppressor gene in hepatocellular carcinomas of predominantly hepatitis B virus (HBV) carrier patients has been recently related to dietary aflatoxin. Another member of the hepadnavirus family, the woodchuck hepatitis virus (WHV), infects woodchucks in a manner similar to that of HBV in humans. Therefore, it was of particular interest to determine whether the p53 gene in woodchuck HCCs associated with hepadnavirus infection and with exposure to AFB1 is affected in the same manner as in human HCCs. By direct PCR-sequencing, we analyzed exons 4-9 of the p53 gene in 13 HCCs from 12 woodchucks (two uninfected, ten WHV carriers). Six WHV carrier and two uninfected woodchucks were treated with AFB1. None of the analyzed HCC samples exhibited mutations, either in p53 gene exons 4-9, or in splicing donor-acceptor sites. The present data are consistent with our previous study that indicated a low rate of p53 mutations in HCCs of AFB1-treated ground squirrels, either infected or not infected with ground squirrel hepatitis virus, and in WHV carrier woodchucks not exposed to AFB1. Overall, our findings indicate that in woodchucks and in ground squirrels exposure to aflatoxin may affect the development of p53 mutations less than in humans. l`ZFourel, G. Trepo, C. Bougueleret, L. Henglein, B. Ponzetto, A. Tiollais, P. Buendia, M. A.^WFrequent activation of N-myc genes by hepadnavirus insertion in woodchuck liver tumoursd see comments Nature 1990 347i 6290 294-8sAmino Acid Sequence Animal Base Sequence Cloning, Molecular DNA, Viral/ge [Genetics] Enhancer Elements (Genetics)/ge [Genetics] Exons *Gene Expression *Hepadnaviridae/ge [Genetics] Human Introns Liver Neoplasms, Experimental/ge [Genetics] *Liver Neoplasms, Experimental/mi [Microbiology] Marmota/ge [Genetics] Marmota/mi [Microbiology] *Marmota Molecular Sequence Data Nucleic Acid Hybridization Polymerase Chain Reaction *Proto-Oncogene Proteins/ge [Genetics] Proto-Oncogene Proteins c-myc RNA Splicing Rats Sciuridae/ge [Genetics] Sciuridae/mi [Microbiology] *Sciuridae Sequence Homology, Nucleic Acid Support, Non-U.S. Gov't Transcription, Genetic Transfectiond The recent finding of c-myc activation by insertion of woodchuck hepatitis virus DNA in two independent hepatocellular carcinoma has given support to the hypothesis that integration of hepatitis B viruses into the host genome, observed in most human and woodchuck liver tumours, might contribute to oncogenesis. We report here high frequency of woodchuck hepatitis virus DNA integrations in two newly identified N-myc genes: N-myc1, the homologue of known mammalian N-myc genes, and N-myc2, an intronless 'complementary DNA gene' or 'retroposon' that has retained extensive coding and transforming homology with N-myc. N-myc2 is totally silent in normal liver, but is overexpressed without genetic rearrangements in most liver tumours. Moreover, viral integrations occur within either N-myc1 or N-myc2 in about 20% of the tumours, giving rise to chimaeric messenger RNAs in which the 3' untranslated region of N-myc was replaced by woodchuck hepatitis virus sequences encompassing the viral enhancer. Insertion sites were clustered in a short sequence of the third exon that coincides with a retroviral integration hotspot within the murine N-myc gene, recently described in T-cell lymphomas induced by murine leukaemia virus. Thus, comparable mechanisms, leading to deregulated expression of N-myc genes, may operate in the development of tumours induced either by hepatitis virus or by nonacute retroviruses in rodents. Activation of myc genes by insertion of hepadnavirus DNA now emerges as a common event in the genesis of woodchuck hepatocellular carcinoma. vGouillat, C. Manganas, D. Zoulim, F. Vitrey, D. Saguier, G. Guillaud, M. Ain, J. F. Duque-Campos, R. Jamard, C. Praves, M. Trepo, C. 1997leWoodchuck hepatitis virus-induced carcinoma as a relevant natural model for therapy of human hepatoma*Journal of Hepatologyk266o1324-30t>8WHV+ animals. 70% of 44 with tumors by ultrasound over 30months (others died without tumors). 5 excluded due to poor health or multifocal tumors. Describes surgical and anesthetic technique. 3 woodchucks without tumor on exlap. Performed Bx, resection, PEI or laser. Describes path extensively. 10 died in post-op period. All 4 survivors in resection group developed recurrence away from resection and died between 10-18months. All local ablation underwent resection after 1 month. PEI showed between 5 and 50% necrosis. The 1 animal with laser had complete necrosis.Animal Carcinoma, Hepatocellular/pa [Pathology] *Carcinoma, Hepatocellular/su [Surgery] Carcinoma, Hepatocellular/us [Ultrasonography] *Carcinoma, Hepatocellular/ve [Veterinary] Disease Models, Animal Hepatitis B/pa [Pathology] *Hepatitis B/ve [Veterinary] *Hepatitis B Virus, Woodchuck Human Liver Neoplasms/pa [Pathology] *Liver Neoplasms/su [Surgery] Liver Neoplasms/us [Ultrasonography] *Liver Neoplasms/ve [Veterinary] Marmota Support, Non-U.S. Gov'tBACKGROUND: Eastern American woodchuck (Marmota monax), naturally infected with woodchuck hepatitis virus, a virus similar to human hepatitis B virus, develops liver cancer with a high prevalence. AIMS: The aim of this work was to assess Marmota monax as a model of human hepatocellular carcinoma, especially to assess new potential adjuvant therapies after surgical resection. METHODS: Forty-four woodchuck hepatitis virus-infected animals were regularly screened by ultrasound examination from the age of 18 months and for a 30-month period. One or more liver tumors were diagnosed in 31 animals (70%). Five of them with multifocal tumor or poor general status were considered unsuitable for surgery. The other 26 were operated on. At laparotomy no tumor was found in three. RESULTS: The 18 liver tumors studied were hepatocellular carcinomas, grossly and microscopically similar to human hepatocellular carcinoma. Peritumoral parenchyma studied in 13 specimens was always non-cirrhotic but adequate staining demonstrated patterns of fibrosis in four cases. Clear evidence of chronic active hepatitis, periportal hepatitis and steatosis were demonstrated in five, seven and one of the 13 specimens, respectively. Tumors were treated by tumorectomy in eight animals, by alcoholization in seven and by laser photocoagulation in one. A simple tumor biopsy was performed in the other seven. Ten animals died postoperatively. All the survivors in the tumorectomy group died from tumor recurrence within 10-18 months after surgery. CONCLUSIONS: It is concluded that woodchuck hepatitis virus-induced liver carcinoma is a natural model of human hepatocellular carcinoma with similar pathology and natural history, including early ultrasonic detection and tumor recurrence after resection. Tumor excision is feasible in this animal model, which now provides the basis for assessment of new potential adjuvant therapies for human hepatocellular carcinoma in an attempt to reduce the high recurrence rate after surgical resection in humans.82E:\References\Articles\J hepatology 97 26 1324.pdfD>Hsu, T. Y. Fourel, G. Etiemble, J. Tiollais, P. Buendia, M. A.ZSIntegration of hepatitis virus DNA near c-myc in woodchuck hepatocellular carcinoma  Gastroenterologia Japonica 199025Suppl 2  43-8Animal Carcinoma, Hepatocellular/et [Etiology] Carcinoma, Hepatocellular/ge [Genetics] Carcinoma, Hepatocellular/ve [Veterinary] *DNA, Viral/ge [Genetics] Gene Expression Genes, myc *Hepatitis B Virus/ge [Genetics] Hepatitis B Virus/py [Pathogenicity] Liver Neoplasms/et [Etiology] Liver Neoplasms/ge [Genetics] Liver Neoplasms/ve [Veterinary] Lysogeny/ge [Genetics] Marmota RNA, Viral/ge [Genetics] Restriction Mappingn0)A total of 33 hepatocellular carcinomas, induced in woodchucks by chronic infection with woodchuck hepatitis virus (WHV), a virus closely related to the human hepatitis B virus, were analyzed for the state of viral DNA, the expression of viral genes and of different cellular proto-oncogenes. Low levels of viral replication and presence of integrated viral forms including sequences of the enhancer element, appeared as a general rule in these tumors. Enhanced expression of one or more of the nuclear protooncogenes: c-myc, N-myc, c-fos, c-jun and jun-B was frequently observed. In two hepatomas, elevated expression and allelic alterations of c-myc were subsequent to integration of WHV DNA near the c-myc coding domain. The viral strategy for insertional activation of c-myc in these tumors appeared basically identical to that of mammalian retroviruses in T-cell lymphomas of mice and rats. Whether insertional mutagenesis of different oncogenes may be more generally linked to liver oncogenesis induced by WHV and hepatitis B viruses remains to be determined.