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Application of the woodchuck animal model for the treatment of hepatitis B virus-induced liver cancer

World Journal of Gastrointestinal Oncology 2021年第6期13卷 509-535页

作者： Manasa Suresh Stephan Menne Department of Microbiology and Immunology Georgetown University Medical CenterWashingtonDC 20057United States

This review describes woodchucks chronically infected with the woodchuck hepatitis virus(WHV)as an animal model for hepatocarcinogenesis and treatment of primary liver cancer or hepatocellular carcinoma(HCC)induced by the hepatitis B virus(HBV).Since laboratory animal models susceptible to HBV infection are limited,woodchucks experimentally infected with WHV,a hepatitis virus closely related to HBV,are increasingly used to enhance our understanding of virus-host interactions,immune response,and liver disease progression.A correlation of severe liver pathogenesis with high-level viral replication and deficient antiviral immunity has been established,which are present during chronic infection after WHV inoculation of neonatal woodchucks for modeling vertical HBV transmission in humans.HCC in chronic carrier woodchucks develops 17 to 36 mo after neonatal WHV infection and involves liver tumors that are comparable in size,morphology,and molecular gene signature to those of HBV-infected patients.Accordingly,woodchucks with WHV-induced liver tumors have been used for the improvement of imaging and ablation techniques of human HCC.In addition,drug efficacy studies in woodchucks with chronic WHV infection have revealed that prolonged treatment with nucleos(t)ide analogs,alone or in combination with other compounds,minimizes the risk of liver disease progression to HCC.More recently,woodchucks have been utilized in the delineation of mechanisms involved in innate and adaptive immune responses against WHV during acute,self-limited and chronic infections.Therapeutic interventions based on modulating the deficient host antiviral immunity have been explored in woodchucks for inducing functional cure in HBV-infected patients and for reducing or even delaying associated liver disease sequelae,including the onset of HCC.Therefore,woodchucks with chronic WHV infection constitute a well-characterized,fully immunocompetent animal model for HBV-induced liver cancer and for preclinical evaluation of the safety and efficacy of new mod

关键词： woodchuck Hepatitis B virus Chronic infection Liver disease Hepatocellular carcinoma Cancer treatment

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Suitability of the woodchuck HCC as a preclinical model for evaluation of intra-arterial therapies

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Animal Models and Experimental Medicine 2020年第1期3卷 98-102页

作者： Alexander Y.Kim Joseph H.Yacoub David H.Field Byoung Uk Park Bhaskar Kallakury Kyle E.Korolowicz Stephan Menne Department of Radiology Medstar Georgetown University HospitalWashingtonDistrict of Columbia Department of Pathology and Laboratory Medicine Medstar Georgetown University HospitalWashingtonDistrict of Columbia Department of Microbiology and Immunology Georgetown University Medical CenterWashingtonDistrict of Columbia

The most commonly used preclinical models of hepatocellular carcinoma(HCC)are limited for use in testing of intra-arterial therapies such as transarterial chemoembolization and radioembolization.Issues encountered with the more commonly used animal models include dissimilarity in their disease development compared with humans and the size of the vasculature which can make intra-arterial therapy testing difficult or impossible.Here we describe the suitability of the woodchuck HCC model for testing of intra-arterial therapies.We describe the techniques for pre-embolization imaging assessment using CT and MRI,technical tips on performing angiography and embolization,and pathological assessment of treated liver.

关键词： angiography animal model hepatocellular carcinoma woodchuck

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In Vitro Anti-hepatitis B Virus Activity of 2',3'-Dideoxyguanosine

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Virologica Sinica 2018年第6期33卷 538-544页

作者： Pinghu Zhang Shuo Zhai Jinhong Chang Ju-Tao Guo Institute of Translational Medicine and Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases Yangzhou UniversityYangzhou 225001China Baruch S.Blumberg Institute Hepatitis B FoundationDoylestownPA 18902USA Qinghai Himalayan Experimental Animal Center Xining 810006China

2',3'-dideoxyguanosine(DoG) has been demonstrated to inhibit duck hepatitis B virus(DHBV) replication in vivo in a duck model of HBV infection. In the current study, the in vitro antiviral effects of DoG on human and animal hepadnaviruses were investigated. Our results showed that DoG effectively inhibited HBV, DHBV, and woodchuck hepatitis virus(WHV)replication in hepatocyte-derived cells in a dose-dependent manner, with 50% effective concentrations(EC50) of 0.3 ± 0.05, 6.82 ± 0.25, and 23.0 ± 1.5 lmol/L, respectively. Similar to other hepadnaviral DNA polymerase inhibitors,DoG did not alter the levels of intracellular viral RNA but induced the accumulation of a less-than-full-length viral RNA species, which was recently demonstrated to be generated by RNase H cleavage of pgRNA. Furthermore, using a transient transfection assay, DoG showed similar antiviral activity against HBV wild-type, 3TC-resistant rtA181 V, and adefovirresistant rtN236T mutants. Our results suggest that DoG has potential as a nucleoside analogue drug with anti-HBV activity.

关键词： HBV woodchuck hepatitis virus(WHV) Hepatitis B Antiviral Nucleoside analogues

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The Effect of Fasting on PET Imaging of Hepatocellular Carcinoma

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Journal of Cancer Therapy 2013年第2期4卷 562-567页

作者： Nathan Tenley David J. Corn Lewis Yuan Zhenghong Lee Department of Biomedical Engineering Case Western Reserve University Cleveland USA Department of Radiology University Hospitals Case Medical Center Cleveland USA.

The clinical utility of positron emission tomography (PET) imaging for liver cancer applications is not clearly defined either for diagnosis or treatment assessment. Previous clinical studies demonstrated that fluorodeoxyglucose (FDG) did not show uptake in some hepatocellular carcinoma (HCC) while acetate showed uptake. Pre-imaging fasting is required for clinical PET imaging with FDG. No studies were done to confirm the effect of fasting on acetate uptake in HCC for PET imaging. We investigated this situation with a woodchuck model of viral infection-induced HCC. Methods: Four tumor-bearing and one control woodchucks were involved in this study. They were first imaged by PET in fed state followed by another imaging session one week later when they were fasted over-night. Some animals also had FDG- PET scan that was acquired later on the same day. After imaging studies, animals were sacrificed, and their liver excised for histology. Standardized Uptake Value (SUV) was calculated using a region of interest (ROI) placed on each tumor with focal uptake. Results: Acetate showed uptake in each HCC lesion when the animals were either fasted or fed with no significant difference in SUV values (p = 0.177);some of the tumors were histologically confirmed as well-differentiated HCC while others were confirmed as moderately- or poorly-differentiated HCC;no focal uptake was found in the control animal. For the accompanying FDG scans, the uptake was detected only in animals that were fasted although the uptake pattern was different from that with acetate. Conclusion: This study provided a hint that fasting or not has little impact on PET imaging of HCC with acetate. It also confirmed prior finding regarding tumor heterogeneity that led to different tracer uptake pattern in the same tumor. Human studies are needed to validate the findings from this pre-clinical investigation.

关键词： Acetate FDG Hepatocellular Carcinoma woodchuck Positron Emission Tomography

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