Background and Objective: Severe inflammation resulted from small-for-size liver graft injury provides favorable environment for tumor growth. The oxidative stress not only accelerates the inflammatory response, but also stimulates the proliferation of cancer cells. Therefore, attenuating oxidative stress after liver surgery may not only ameliorate liver injury, but also suppress tumor growth and metastasis. Glutathione peroxidase 3 (GPx3) is an anti-oxidant which has been reported to be down-regulated in several types of cancer. Here, we aimed to investigate the clinical significance of GPx3 and characterize the role of GPx3 in liver graft injury and hepatocellular carcinoma (HCC). Furthermore, we intended to explore the therapeutic value of GPx3 using hiPSC-MSCs as a delivery vehicle in hepatic ischemia-reperfusion injury and HCC. Materials and methods: To investigate the clinical significance of GPx3, the HCC patients underwent liver transplantation (106 recipients) or hepatectomy (113 patients) were recruited to study the correlation of GPx3 with clinical parameters. To explore the mechanism of GPx3 in liver graft injury, simulated IR injury model and rat liver transplantation model were applied. To examine the effect of GPx3 on HCC, rGPx3 administration and forced-expression of GPx3 within HCC cells were performed in vitro and in vivo. To explore the therapeutic value of GPx3, engineered hiPSC-MSCs delivering GPx3 was established and applied in mice hepatic IR injury model and nude mice liver cancer model. Results: I. The role of GPx3 in graft injury. The intra-graft GPx3 expression was significantly down-regulated in small-for-size graft accompanied with severe graft injury in a rat liver transplantation model. Clinically, the lower plasma GPx3 was mainly observed in the recipients with small-for-size liver graft. Furthermore, the lower plasma GPx3 significantly correlated with higher tumor recurrence post-transplantation. The down-regulation of GPx3 was associated with hepatic senescence in small-for-size graft. GPx3 treatment delivered by hiPSC-MSCs could significantly ameliorated hepatic IR injury through inhibition of macrophages activation followed by decreased production of ROS, TNFα and IL-1. II. The role of GPx3 in HCC. Down-regulation of GPx3 in liver tumor was observed in half of HCC patients (56/113). It significantly correlated with advanced pTNM stage (P = 0.024), presence of venous infiltration (P =0.043) and high AFP level (P = 0.006). The one year (P = 0.038) and five year (P = 0.019) recurrence rate were significantly higher in the patients with lower GPx3 expression. In functional study, rGPx3 administration and over-expression of GPx3 significantly suppressed proliferation and invasiveness of HCC cells in vitro and in vivo. The tumor suppressive activity of GPx3 was mediated by inhibition of EMT through Erk-NFκB-SIP1 pathway. The GPx3 treatment delivered by hiPSC-MSCs could significantly inhibit proliferation of MHCC97L. Conclusions: I. Down-regulation of GPx3 was associated with small-for-size graft injury. Low circulating GPx3 at early phase after transplantation predicted higher tumor recurrence of HCC recipients. II. Down-regulation of GPx3 indicated poor prognosis of HCC patients. GPx3 suppressed tumor growth and invasiveness by inhibition of EMT through Erk-NFκB-SIP1 pathway. III. Engineered hiPSC-MSCs delivering GPx3 may possess therapeutic value in liver graft injury and HCC. / published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / toc / Surgery / Master / Master of Philosophy

published_or_final_version / abstract / toc / Surgery / Master / Master of Philosophy

published_or_final_version / Pathology / Master / Master of Philosophy

The Best MPhil Thesis in the Faculties of Dentistry, Engineering, Medicine and Science (University of Hong Kong), Li Ka Shing Prize / published_or_final_version / Pathology / Master / Master of Philosophy

Intensity modulated radiotherapy (IMRT) can potentially increase the dose delivered to liver tumours while sparing normal tissues from dose. More complex IMRT, with more modulation of the radiation beam is more susceptible to geometric and dosimetric uncertainties than simpler radiotherapy plans. Simple breath-hold liver IMRT using few radiation beam segments (<30) was investigated in 27 patients to determine the quality of treatment in terms of tumour dose coverage and normal tissue sparing as compared to index IMRT using >30 segments. In all 27 plans number of segments was reduced to <30 without compromising tumour coverage or normal tissue dose constraints, at the expense of dose conformity. Delivered tumour and normal tissue dose did not differ statistically between IMRT plans when accounting for treatment residual geometric error. This research supports considering the use of simple IMRT for treatment of liver cancer, except when loss of dose conformation is undesirable (i.e. very high doses).

Thesis (Ph. D.)--University of Hong Kong, 2007. / Also available in print.

Class of 2012 Abstract / Specific Aims: To evaluate associations between hospital and patient characteristics and mortality and economic outcomes. Included records were of adult patients age 18 years or older with a diagnosis of primary or disseminated liver cancer. Methods: This study was a retrospective cohort design that utilized emergency department discharge records from the Agency for Healthcare Research and Quality (AHRQ) Healthcare Cost and Utilization Project (HCUP) National Emergency Department Sample (NEDS). Generalized linear models were used for analyses to assess outcomes of mortality and total charges. Logistic regression was utilized for mortality; gamma regression with log-link was utilized for charges. Main Results: Overall, 239,895 adult records were included in the study with diagnoses of ICD-9 155.x or 197.7. Total charges for all records were over $8.23 billion in 2009. The average age of the case was 65.07 (±13.8) years with 48.7% being female. Mortality (either in the ED or hospital) was 11.1% (n=26,701). The mean length of stay was 6.47 (±6.05) days. Charges for each record were $42,874.50 (±53,956.34). Increased mortality was associated the most with hospital teaching status and primary payer. Increased charges were associated with hospitals located in the Western region. Conclusions: The differences in clinical outcomes were primarily from different payers and economical outcomes differed greatly by the Western region hospital location. Data taken from the nationally-representative investigation reveals that primary and disseminated liver cancer still remains a clinical high burden-of-illness with an 11.1% mortality rate and total charges approaching $10.3 billion dollars.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19227号 / 医博第4026号 / 新制||医||1011(附属図書館) / 32226 / 京都大学大学院医学研究科医学専攻 / (主査)教授 小川 誠司, 教授 坂井 義治, 教授 松原 和夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy