{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:11:43Z","timestamp":1792001503778,"version":"4.4.0"},"reference-count":46,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2021,8,9]],"date-time":"2021-08-09T00:00:00Z","timestamp":1628467200000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P42 ES005948"],"award-info":[{"award-number":["P42 ES005948"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 ES015241"],"award-info":[{"award-number":["R01 ES015241"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Protocols"],"published-print":{"date-parts":[[2021,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Human hepatocellular carcinoma (HCC) develops most often as a complication of fibrosis or cirrhosis. Although most human studies of HCC provide crucial insights into the molecular signatures of HCC, they seldom address its etiology. Mouse models provide essential tools for investigating the pathogenesis of HCC, but the majority of rodent cancer models do not feature liver fibrosis. Detailed here is a protocol for an experimental mouse model of HCC that arises in association with advanced liver fibrosis. The disease model is induced by a single injection of\n                    <jats:italic>N<\/jats:italic>\n                    \u2010nitrosodiethylamine (DEN) at 2 weeks of age followed by repeated administration of carbon tetrachloride (CCl\n                    <jats:sub>4<\/jats:sub>\n                    ) from 8 weeks of age for up to 14 consecutive weeks. A dramatic potentiation of liver tumor incidence is observed following administration of DEN and CCl\n                    <jats:sub>4<\/jats:sub>\n                    , with 100% of mice developing liver tumors at 5 months of age. This model has been employed for studying the molecular mechanisms of fibrogenesis and HCC development, as well as for cancer hazard\/chemotherapy testing of drug candidates. \u00a9 2021 Wiley Periodicals LLC.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Basic Protocol<\/jats:bold>\n                    : The DEN and CCl\n                    <jats:sub>4<\/jats:sub>\n                    \u2010induced mouse model of fibrosis and inflammation\u2010associated hepatocellular carcinoma\n                  <\/jats:p>","DOI":"10.1002\/cpz1.211","type":"journal-article","created":{"date-parts":[[2021,8,9]],"date-time":"2021-08-09T16:06:41Z","timestamp":1628525201000},"source":"Crossref","is-referenced-by-count":47,"title":["The DEN and CCl\n                    <sub>4<\/sub>\n                    \u2010Induced Mouse Model of Fibrosis and Inflammation\u2010Associated Hepatocellular Carcinoma"],"prefix":"10.1002","volume":"1","author":[{"given":"Takeki","family":"Uehara","sequence":"first","affiliation":[{"name":"Strategic Development Department Shionogi &amp; Co.  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor P.","family":"Pogribny","sequence":"additional","affiliation":[{"name":"National Center for Toxicological Research U.S. Food and Drug Administration  Jefferson Arkansas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Rusyn","sequence":"additional","affiliation":[{"name":"Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences Texas A&amp;M University  College Station Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,9]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201013\u20102107"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jviscsurg.2010.12.012"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204\u2010012\u20100931\u20102"},{"key":"e_1_2_5_5_1","first-page":"9","article-title":"Strain and species differences in susceptibility to liver tumour induction","volume":"51","author":"Bannasch P.","year":"1983","journal-title":"IARC Scientific Publications"},{"key":"e_1_2_5_6_1","first-page":"553","article-title":"Thioacetamide hepatocarcinogenesis","volume":"71","author":"Becker F. F.","year":"1983","journal-title":"Journal of the National Cancer Institute"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575\u2010018\u20100033\u20106"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.98106619"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/1055\u20109965.EPI\u201011\u20100643"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.09.053"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.28610"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.02.007"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.00171"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminoncol.2012.05.002"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1177\/1535370219898141"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304\u20103835(86)90008\u2010X"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00525556"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2007.04.061"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1934"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2004.09.014"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20100030\u20101247135"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471\u2010230X\u201010\u201079"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1080\/01926230252824770"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.01.025"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12253\u2010010\u20109296\u20100"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365\u20102613.2009.00656.x"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1177\/0192623309351726"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.9193247"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1177\/0192623309351892"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.22860"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2010.213"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.04.014"},{"key":"e_1_2_5_33_1","first-page":"75","article-title":"Some histological methods: Trichrome stainings and their preliminary technique","volume":"12","author":"Masson P. J.","year":"1929","journal-title":"Teaching Methods"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1097\/MCG.0b013e318291f237"},{"key":"e_1_2_5_35_1","volume-title":"Prudent practices in the laboratory: Handling and disposal of chemicals","author":"National Research Council","year":"2005"},{"key":"e_1_2_5_36_1","volume-title":"12th report on carcinogens","author":"National Toxicology Program","year":"2011"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1006\/exmp.2002.2434"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.3727\/105221618X15205148413587"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.08.017"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2019.12.030"},{"key":"e_1_2_5_41_1","first-page":"345","article-title":"Histochemical and microchemical changes in experimental cirrhosis and hepatoma formation in mice by carbon tetrachloride","volume":"11","author":"Stowell R. E.","year":"1951","journal-title":"Cancer Research"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00210\u2010020\u201001973\u20104"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1080\/10520290500138372"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfs342"},{"key":"e_1_2_5_45_1","first-page":"4253","article-title":"Kinetics of diethylnitrosamine hepatocarcinogenesis in the infant mouse","volume":"43","author":"Vesselinovitch S. D.","year":"1983","journal-title":"Cancer Research"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.170"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2008.12.006"}],"container-title":["Current Protocols"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpz1.211","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpz1.211","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/currentprotocols.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpz1.211","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T10:35:25Z","timestamp":1692614125000},"score":1,"resource":{"primary":{"URL":"https:\/\/currentprotocols.onlinelibrary.wiley.com\/doi\/10.1002\/cpz1.211"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8]]},"references-count":46,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2021,8]]}},"alternative-id":["10.1002\/cpz1.211"],"URL":"https:\/\/doi.org\/10.1002\/cpz1.211","archive":["Portico"],"relation":{},"ISSN":["2691-1299","2691-1299"],"issn-type":[{"value":"2691-1299","type":"print"},{"value":"2691-1299","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8]]},"article-number":"e211"}}