published_or_final_version / Medicine / Master / Doctor of Medicine

published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

Background: Hepatocellular carcinoma is one of the most fatal diseases worldwide. Liver transplantation dramatically improved the survival rate of HCC patients. However, tumor recurrence remains a huge threat to HCC patients without any promising curative treatment. Chemotherapy, as one of the potential treatments to recurrent HCC, did not show any significant effect either. Objective: We aim to investigate the role of interferon-gamma inducible protein 10 (IP10) in acute-phase liver graft injury induced late-phase cisplatin resistance after liver transplantation and to explore the underlying mechanism. Furthermore, a potential adjuvant therapy was expected to be identified to sensitize cisplatin treatment in HCC. Materials and methods: A rat orthotopic liver transplantation model was established with applying whole or small-for-size (50%) graft. Afterwards, a rat hepatoma cell (MH7777) was injected via portal vein to generate recurrent tumor. The expressions of genes linked to multi-drug resistance and graft injury were compared between tumors developed after liver transplantation using small and whole grafts. IP10 expression was further validated in clinical samples from two cohorts of patients including HCC patients with hepatectomy and HCC patients with liver transplantation. The extracellular and intracellular roles of IP10 were examined in vitro by using IP10 recombinant protein and IP10 stable transfectants in HCC cell lines. The correlation between IP10 expression and tumor growth was investigated in three in vivo nude mice models including a subcutaneous model, an orthotopic model and ischemia reperfusion injury model. The underlying mechanism was further explored in vitro, in vivo and in clinical samples. IP10 neutralizing antibody was employed as an adjuvant therapy to identify its effect on sensitizing cisplatin treatment in HCC. Results: The expressions of multidrug resistant genes were significantly up-regulated in liver and tumor from small-for-size group in rat liver transplantation model. IP10 was selected as the potential target for its constantly higher expression in liver and tumor tissues in small-for-size group. In clinical studies, IP10 was overexpressed in around 45% HCC patients with hepatectomy. The expression of circulating IP10 well correlated with tumor recurrence and small graft ratio in HCC patients after liver transplantation. In in vitro studies, it was demonstrated that overexpression of IP10 could significantly promote HCC cell proliferation either in short term or in long term cisplatin administration. In in vivo studies, subcutaneous and orthotopic nude mice models showed that the overexpression of IP10 have significant correlations with larger tumor volume and less tumor necrosis after cisplatin treatment. In mechanism studies, IP10 overexpression was found to be well correlated with the activation of endoplasmic reticulum (ER) stress signaling pathways in vitro and further validated in vivo models and in clinical specimens. IP10 neutralizing antibody was identified as a potential therapy which could sensitize cisplatin treatment in vitro and in vivo. Conclusions: The high expression of IP10 was identified in two cohorts of clinical samples and showed significant correlations with tumor recurrence. Graft injury induced IP10 overexpression could significantly increase cisplatin resistance after liver transplantation via ER stress signaling pathways. IP10 neutralizing antibody may be applied as an alternative treatment for recurrent HCC after liver transplantation. / published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

Autopsy liver material from patients having died of chronic liver disease, cirrhosis, hepatocellular carcinoma (HCC) and causes unrelated to liver diseases was examined by dot blot hybridisation for the presence of HBV DNA. The results indicate that of the patients with chronic liver disease 6/9 were positive for HBV DNA in the liver tissue; of the patients with HCC 3/4 were positive for HBV DNA; of the patients with cirrhosis 4/4 showed the presence of HBV DNA in the liver. Thus by this technique 13/17 (76%) of these patients, all of whom were HBsAg positive, were shown to have HBV DNA present in liver tissue. However, autopsy liver samples were found to be unsuitable for Southern blot hybridisation. Biopsy liver/tumour tissue was examined for the presence of integrated or non-integrated HBV DNA by Southern blot analysis using the enzymes Eco R1 and Hind 111. 5/5 patients who were both HBsAg and HBeAg positive had extrachromosomal HBV DNA and 2/5 also showed the presence of integrated HBV DNA. 3/4 patients who were HBsAg positive and HBeAg negative had extrachromosomal HBV DNA and all three also had integrated HBV DNA. One control patient was negative for both markers and also for Southern blot hybridisation with the HBV DNA probe. These results support the hypothesis that HBV is a factor in the development of HCC, and indicate that the dot blot hybridisation method would be suitable for routine evaluation of patients with chronic liver disease or cirrhosis. / Thesis (M. Med.)-University of Natal, Durban, 1987.

No description available.

Bibliography: leaves 331-381 / xxiv, 381 leaves : ill ; 31 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, 1986

Thesis (Ph. D.)--University of Alabama at Birmingham, 2007. / Title from first page of PDF file (viewed Feb. 7, 2008). Includes bibliographical references (p. 114-133).

Thesis (Ph. D.)--University of Hong Kong, 2008. / Also available in print.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.