{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T02:33:22Z","timestamp":1784169202053,"version":"3.55.0"},"reference-count":67,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T00:00:00Z","timestamp":1692835200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["R01AA021510"],"award-info":[{"award-number":["R01AA021510"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Although alcohol is a well-known causal factor associated with liver diseases, challenges remain in inducing liver fibrosis in experimental rodent models. These challenges include rodents\u2019 natural aversion to high concentrations of alcohol, rapid alcohol metabolism, the need for a prolonged duration of alcohol administration, and technical difficulties. Therefore, it is crucial to establish an experimental model that can replicate the features of alcoholic liver fibrosis. The objective of this study was to develop a feasible rat model of alcoholic liver fibrosis that emulates human drinking patterns and combines low-dose chemicals within a relatively short time frame. We successfully developed an 8-week rat model of alcoholic liver fibrosis that mimics chronic and heavy drinking patterns. Rats were fed with a control liquid diet, an alcohol liquid diet, or alcohol liquid diet combined with multiple binges via oral gavage. To accelerate the progression of alcoholic liver fibrosis, we introduced low-dose carbon tetrachloride (CCl4) through intraperitoneal injection. This model allows researchers to efficiently evaluate potential therapeutics in preclinical studies of alcoholic liver fibrosis within a reasonable time frame.<\/jats:p>","DOI":"10.3390\/biom13091293","type":"journal-article","created":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T10:06:48Z","timestamp":1692871608000},"page":"1293","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Establishment of a Rat Model of Alcoholic Liver Fibrosis with Simulated Human Drinking Patterns and Low-Dose Chemical Stimulation"],"prefix":"10.3390","volume":"13","author":[{"given":"Chien-Yu","family":"Lin","sequence":"first","affiliation":[{"name":"Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evanthia","family":"Omoscharka","sequence":"additional","affiliation":[{"name":"Department of Pathology, University Health\/Truman Medical Center, School of Medicine, University of Missouri-Kansas City, 2301 Holmes Street, Kansas City, MO 64108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanli","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Cheng","sequence":"additional","affiliation":[{"name":"Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1002\/hep.32531","article-title":"Alcohol use disorder in community management of chronic liver diseases","volume":"77","author":"Leggio","year":"2023","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.cld.2012.08.002","article-title":"Alcohol metabolism","volume":"16","author":"Cederbaum","year":"2012","journal-title":"Clin. Liver Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1053\/j.gastro.2011.09.002","article-title":"Alcoholic liver disease: Pathogenesis and new therapeutic targets","volume":"141","author":"Gao","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"173","DOI":"10.5009\/gnl16477","article-title":"Pathophysiology and Management of Alcoholic Liver Disease: Update 2016","volume":"11","author":"Stickel","year":"2017","journal-title":"Gut Liver"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.mam.2007.10.001","article-title":"Alcohol induced hepatic fibrosis: Role of acetaldehyde","volume":"29","author":"Mello","year":"2008","journal-title":"Mol. Asp. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"495156","DOI":"10.1155\/2013\/495156","article-title":"The effect of inflammatory cytokines in alcoholic liver disease","volume":"2013","author":"Kawaratani","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"193","DOI":"10.3389\/fphys.2012.00193","article-title":"Acute alcohol-induced liver injury","volume":"3","author":"Massey","year":"2012","journal-title":"Front. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1007\/s00204-015-1543-4","article-title":"Experimental models of liver fibrosis","volume":"90","author":"Yanguas","year":"2016","journal-title":"Arch. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"G182","DOI":"10.1152\/ajpgi.00361.2018","article-title":"Combination of CCl4 with alcoholic and metabolic injuries mimics human liver fibrosis","volume":"317","author":"Brol","year":"2019","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"883","DOI":"10.3748\/wjg.v26.i9.883","article-title":"Role of alcohol in pathogenesis of hepatitis B virus infection","volume":"26","author":"Ganesan","year":"2020","journal-title":"World J. Gastroenterol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"81","DOI":"10.4254\/wjh.v4.i3.81","article-title":"Alcoholic liver disease","volume":"4","author":"Bruha","year":"2012","journal-title":"World J. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ghosh Dastidar, S., Warner, J.B., Warner, D.R., McClain, C.J., and Kirpich, I.A. (2018). Rodent Models of Alcoholic Liver Disease: Role of Binge Ethanol Administration. Biomolecules, 8.","DOI":"10.3390\/biom8010003"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.alcohol.2012.08.004","article-title":"Rodent models of alcoholic liver disease: Of mice and men","volume":"46","author":"Schrum","year":"2012","journal-title":"Alcohol"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/nprot.2012.014","article-title":"Mouse intragastric infusion (iG) model","volume":"7","author":"Ueno","year":"2012","journal-title":"Nat. Protoc."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.jhep.2020.04.011","article-title":"Animal models for liver disease\u2014A practical approach for translational research","volume":"73","author":"Nevzorova","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1828","DOI":"10.1111\/acer.13840","article-title":"The Lieber-DeCarli Diet\u2014A Flagship Model for Experimental Alcoholic Liver Disease","volume":"42","author":"Guo","year":"2018","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nprot.2013.032","article-title":"Mouse model of chronic and binge ethanol feeding (the NIAAA model)","volume":"8","author":"Bertola","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Chiang, D.J., Roychowdhury, S., Bush, K., McMullen, M.R., Pisano, S., Niese, K., Olman, M.A., Pritchard, M.T., and Nagy, L.E. (2013). Adenosine 2A receptor antagonist prevented and reversed liver fibrosis in a mouse model of ethanol-exacerbated liver fibrosis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0069114"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.jhep.2018.03.011","article-title":"A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer","volume":"69","author":"Tsuchida","year":"2018","journal-title":"J. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4091","DOI":"10.3748\/wjg.v22.i16.4091","article-title":"Adult mouse model of early hepatocellular carcinoma promoted by alcoholic liver disease","volume":"22","author":"Ambade","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1111\/j.1365-2559.2010.03609.x","article-title":"The relationship between liver disease stage and liver fibrosis: A tangled web","volume":"57","author":"Germani","year":"2010","journal-title":"Histopathology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1900046","DOI":"10.1002\/adtp.201900046","article-title":"Targeted Delivery of an siRNA\/PNA Hybrid Nanocomplex Reverses Carbon Tetrachloride-Induced Liver Fibrosis","volume":"2","author":"Jain","year":"2019","journal-title":"Adv. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1021\/mp9000469","article-title":"TGF-beta1 gene silencing for treating liver fibrosis","volume":"6","author":"Cheng","year":"2009","journal-title":"Mol. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1080\/01926230490465874","article-title":"Relationships between organ weight and body\/brain weight in the rat: What is the best analytical endpoint?","volume":"32","author":"Bailey","year":"2004","journal-title":"Toxicol. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5063","DOI":"10.3748\/wjg.v24.i45.5063","article-title":"Alcoholic liver disease: Utility of animal models","volume":"24","author":"Hao","year":"2018","journal-title":"World J. Gastroenterol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1293\/tox.2017-0038","article-title":"Increased hepatic inflammation in a normal-weight mouse after long-term high-fat diet feeding","volume":"31","author":"Toita","year":"2018","journal-title":"J. Toxicol. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Schomaker, S., Potter, D., Warner, R., Larkindale, J., King, N., Porter, A.C., Owens, J., Tomlinson, L., Sauer, J.M., and Johnson, K. (2020). Serum glutamate dehydrogenase activity enables early detection of liver injury in subjects with underlying muscle impairments. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0229753"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1093\/toxsci\/kft009","article-title":"Assessment of emerging biomarkers of liver injury in human subjects","volume":"132","author":"Schomaker","year":"2013","journal-title":"Toxicol. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1136\/bmj.2.6101.1508","article-title":"Glutamate dehydrogenase: A reliable marker of liver cell necrosis in the alcoholic","volume":"2","author":"Lieber","year":"1977","journal-title":"Br. Med. J."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Teschke, R. (2018). Alcoholic Liver Disease: Alcohol Metabolism, Cascade of Molecular Mechanisms, Cellular Targets, and Clinical Aspects. Biomedicines, 6.","DOI":"10.3390\/biomedicines6040106"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1136\/gut.2005.084475","article-title":"An appraisal of the histopathological assessment of liver fibrosis","volume":"55","author":"Standish","year":"2006","journal-title":"Gut"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1002\/hep.1840200228","article-title":"The role of tumor necrosis factor-alpha in acute endotoxin-induced hepatotoxicity in ethanol-fed rats","volume":"20","author":"Hansen","year":"1994","journal-title":"Hepatology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6655","DOI":"10.3748\/wjg.14.6655","article-title":"Innate immune reactivity of the liver in rats fed a choline-deficient L-amino-acid-defined diet","volume":"14","author":"Kawaratani","year":"2008","journal-title":"World J. Gastroenterol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.bpg.2011.02.005","article-title":"Mechanisms of hepatic fibrogenesis","volume":"25","author":"Lee","year":"2011","journal-title":"Best Pract. Res. Clin. Gastroenterol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.livres.2017.05.003","article-title":"Silencing of alpha-complex protein-2 reverses alcohol- and cytokine-induced fibrogenesis in hepatic stellate cells","volume":"1","author":"Liu","year":"2017","journal-title":"Liver Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1111\/j.1440-1746.2006.04149.x","article-title":"Expression of Ki-67, transforming growth factor beta1, and B-cell lymphoma-leukemia-2 in liver tissue of patients with chronic liver diseases","volume":"21","author":"Piekarska","year":"2006","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4974","DOI":"10.3748\/wjg.v13.i37.4974","article-title":"Alcohol-induced steatosis in liver cells","volume":"13","author":"Donohue","year":"2007","journal-title":"World J. Gastroenterol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Hyun, J., Han, J., Lee, C., Yoon, M., and Jung, Y. (2021). Pathophysiological Aspects of Alcohol Metabolism in the Liver. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115717"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1177\/0023677215571192","article-title":"The carbon tetrachloride model in mice","volume":"49","author":"Scholten","year":"2015","journal-title":"Lab. Anim."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1016\/j.biocel.2011.06.010","article-title":"The roles of ER stress and P450 2E1 in CCl4-induced steatosis","volume":"43","author":"Lee","year":"2011","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/S0741-8329(02)00204-5","article-title":"Liver disease in alcohol abusers: Clinical perspective","volume":"27","author":"Diehl","year":"2002","journal-title":"Alcohol"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"27","DOI":"10.21608\/ejhm.2002.18854","article-title":"Protective effects of garlic oil against liver damage induced by combined administration of ethanol and carbon tetrachloride in rats","volume":"6","author":"Khalifa","year":"2002","journal-title":"Egypt. J. Hosp. Med."},{"key":"ref_43","first-page":"401","article-title":"Hepatoprotective effects of Arctium lappa Linne on liver injuries induced by chronic ethanol consumption and potentiated by carbon tetrachloride","volume":"9","author":"Lin","year":"2002","journal-title":"J. Biomed. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/0270-9139(91)90246-R","article-title":"Hepatic fibrosis and cirrhosis after chronic administration of alcohol and \u201clow-dose\u201d carbon tetrachloride vapor in the rat","volume":"13","author":"Hall","year":"1991","journal-title":"Hepatology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1111\/j.1440-1746.1994.tb01719.x","article-title":"The pathology of liver injury induced by the chronic administration of alcohol and \u2018low-dose\u2019 carbon tetrachloride in Porton rats","volume":"9","author":"Hall","year":"1994","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Kojima-Yuasa, A., Goto, M., Yoshikawa, E., Morita, Y., Sekiguchi, H., Sutoh, K., Usumi, K., and Matsui-Yuasa, I. (2016). Protective effects of hydrolyzed nucleoproteins from salmon milt against ethanol-induced liver injury in rats. Mar. Drugs, 14.","DOI":"10.3390\/md14120232"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/s00726-004-0105-5","article-title":"Betaine or taurine administration prevents fibrosis and lipid peroxidation induced by rat liver by ethanol plus carbon tetrachloride intoxication","volume":"27","author":"Erman","year":"2004","journal-title":"Amino Acids"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1016\/j.fct.2010.02.006","article-title":"Protective effect of fermented sea tangle against ethanol and carbon tetrachloride-induced hepatic damage in Sprague-Dawley rats","volume":"48","author":"Lee","year":"2010","journal-title":"Food Chem. Toxicol."},{"key":"ref_49","first-page":"28","article-title":"Hepatoprotective effect of a polyherbal formulation (Ayush-Liv. 04) against ethanol and CCl4 induced liver damage in rats","volume":"25","author":"Narayanasamy","year":"2005","journal-title":"Anc. Sci. Life"},{"key":"ref_50","first-page":"347","article-title":"Qualitative study on the Kupffer cells in the liver of ethanol- and carbon tetrachloride-treated rats","volume":"90","author":"Lautenschlager","year":"1982","journal-title":"Acta Pathol. Microbiol. Scand. Ser. C Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.taap.2016.09.011","article-title":"A mouse model of alcoholic liver fibrosis-associated acute kidney injury identifies key molecular pathways","volume":"310","author":"Furuya","year":"2016","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1053\/j.gastro.2017.09.022","article-title":"MicroRNA 122, Regulated by GRLH2, Protects Livers of Mice and Patients from Ethanol-Induced Liver Disease","volume":"154","author":"Satishchandran","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_53","first-page":"237","article-title":"Modeling liver fibrosis in rodents","volume":"117","author":"Constandinou","year":"2005","journal-title":"Methods Mol. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3456","DOI":"10.3892\/or.2016.5167","article-title":"Overexpression of PCBP2 contributes to poor prognosis and enhanced cell growth in human hepatocellular carcinoma","volume":"36","author":"Zhang","year":"2016","journal-title":"Oncol. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/j.1751-2980.2010.00468.x","article-title":"Pathogenesis of alcoholic liver disease: Interactions between parenchymal and non-parenchymal cells","volume":"12","author":"Cohen","year":"2011","journal-title":"J. Dig. Dis."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.livres.2022.01.001","article-title":"Immune cells in alcohol-related liver disease","volume":"6","author":"Xu","year":"2022","journal-title":"Liver Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1002\/hep.22034","article-title":"Liver: An organ with predominant innate immunity","volume":"47","author":"Gao","year":"2008","journal-title":"Hepatology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1369\/0022155415627681","article-title":"TGF-beta\/SMAD Pathway and Its Regulation in Hepatic Fibrosis","volume":"64","author":"Xu","year":"2016","journal-title":"J. Histochem. Cytochem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.alcohol.2007.04.008","article-title":"Liver regeneration is suppressed in alcoholic cirrhosis: Correlation with decreased STAT3 activation","volume":"41","author":"Horiguchi","year":"2007","journal-title":"Alcohol"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.it.2015.02.008","article-title":"Overcoming T cell exhaustion in infection and cancer","volume":"36","author":"Pauken","year":"2015","journal-title":"Trends Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nrgastro.2015.200","article-title":"Immunology in the liver\u2014From homeostasis to disease","volume":"13","author":"Heymann","year":"2016","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1053\/j.gastro.2014.11.041","article-title":"Blockade of PD1 and TIM3 restores innate and adaptive immunity in patients with acute alcoholic hepatitis","volume":"148","author":"Markwick","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3322","DOI":"10.3748\/wjg.v17.i28.3322","article-title":"Immunostaining of PD-1\/PD-Ls in liver tissues of patients with hepatitis and hepatocellular carcinoma","volume":"17","author":"Wang","year":"2011","journal-title":"World J. Gastroenterol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5538","DOI":"10.4049\/jimmunol.169.10.5538","article-title":"Expression of programmed death 1 ligands by murine T cells and APC","volume":"169","author":"Yamazaki","year":"2002","journal-title":"J. Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.3389\/fimmu.2018.02077","article-title":"Clinicopathologic Significance and Prognostic Value of Programmed Cell Death Ligand 1 (PD-L1) in Patients with Hepatocellular Carcinoma: A Meta-Analysis","volume":"9","author":"Li","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"7333","DOI":"10.1158\/1078-0432.CCR-17-0950","article-title":"Characterization of the Immune Microenvironment in Hepatocellular Carcinoma","volume":"23","author":"Yarchoan","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1158\/1078-0432.CCR-08-1608","article-title":"Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma","volume":"15","author":"Gao","year":"2009","journal-title":"Clin. Cancer Res."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/9\/1293\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:38:01Z","timestamp":1760128681000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/9\/1293"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,24]]},"references-count":67,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["biom13091293"],"URL":"https:\/\/doi.org\/10.3390\/biom13091293","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,24]]}}}