1,721,651 research outputs found
Blockade of chemokine (C-X-C motif) receptor 4 for the inhibition of hepatocellular carcinoma metastasis
No full textpublished_or_final_versionSurgeryDoctoralDoctor of Philosoph
The effect of AMN107 on hepatocellular carcinoma
No full textpublished_or_final_versionabstractSurgeryMasterMaster of Philosoph
Identification of brain-derived neurotrophic factor (BDNF) as a novel angiogenic factor in tumor angiogenesis
No full textpublished_or_final_versionSurgeryDoctoralDoctor of Philosoph
SPARC and SPARC-like 1 are associated with tumor angiogenesis in hepatocellular carcinoma
No full textpublished_or_final_versionabstracttocSurgeryMasterMaster of Philosoph
Antitumor and vascular disrupting effects of ombrabulin in hepatocellular carcinoma
No full textHepatocellular Carcinoma (HCC) the fifth most common cancer and the third leading cause of death among cancer worldwide. Curative treatments such as liver resection and liver transplantation are generally used in treating early-stage HCC patients. However, only 10% to 30% of HCC patients are eligible for the surgery, which is due to the asymptomatic characteristic of HCC, most HCC patients are diagnosed at late stage. Palliative treatment such as TAE, TACE and Sorafenib provide them options to maintain their quality of life and extend their survival. Nevertheless, current treatments provides limited benefits to them as efficacy remains unsatisfactory. Therefore, there is a great need to develop new palliative treatments and explore new agents for the treatment of HCC.
The aim of this study is to investigate the efficacy of a new therapeutic agent, Ombrabulin, in the treatment of HCC. Angiogenesis in HCC has been well-studied for many years as many studies proved that angiogeneisis plays an important role in the progression and development of HCC. Angiogenesis can also affect the prognosis and efficacy of treatments in HCC. As a result, antiangiogenesis and vascular disrupting agents have become new target in the therapaies of HCC. Ombrabulin is a synthetic vascular disrupting agent, which can inhibit tubulin polymerization in endothelial cells, causing cytoskeleton disorganization in endothelial cells. Endothelial cells will then detach from the basement membrane and eventually lead to vascular shutdown. This study demonstrated for the first time that Ombrabulin could selectively inhibit human umbilical vein endothelial cell (HUVEC) growth in vitro; particularly the early-form of HUVEC, which represent immature endothelial cell in neovasculature. Furthermore, this study also demonstrated the antiangiogenic effect of Ombrabulin on endothelial cells. By F-actin staining, it was shown that Ombrabulin caused changes in HUVECs morphology, which supported that Ombrabulin could lead to distortion in cytoskeleton.
In vivo study demonstrated the early effect and long term effect of Ombrabulin. For the first part of the in vivo study, Nude mice were treated with single-dose of Ombrabulin for one week. Hoechst 33342, anti-CD34 staining and PCNA staining were carried out to study the functional effect of Ombrabulin and the combination effect with Sorafenib in vivo. Mice treated with Ombrabulin resulted in decreased blood perfusion, microvessel density and tumor cell proliferation, and tumor necrosis was also observed. In the combination with Sorafenib, it did not show synergistic effect in both tumor cell proliferation and microvessel density.
For the second part of the in vivo study, nod scid mice were treated with multiple doses of Ombrabulin for three weeks to study the long term effect of Ombrabulin. Mice treated with Ombrabulin resulted in significantly smaller tumor size, demonstrating its antitumor efficacy in HCC. Furthermore, combination treatment of Sorafenib and Ombrabulin in vivo could enhance the efficacy of the treatment of HCC.
In conclusion, Ombrabulin has vascular disrupting and antitumor effects, which could efficiently suppress HCC tumor growth in vivo. These results suggest that Ombrabulin could be a promising vascular disrupting agent in treating HCC. Combination with sorafenib should be further explored in clinical studies to demonstrate the synergistic antitumor effects in HCC patients.published_or_final_versionSurgeryMasterMaster of Philosoph
Phenotypic and genotypic epidemiological studies of Hong Kong Chinese patients with hereditary breast cancer
No full textBreast cancer is the most common cancer in women in most part of the world. Although there are multiple risk factors which have been reported to be related to breast factors, by far one of the highest risk of breast cancer is the inheritance of the BRCA1 and BRCA2 cancer susceptibility genes. The lifetime risk of breast cancer can be as high as 60-80% for BRCA mutation carriers. As the breast cancer epidemiology and genetic predisposition is increasingly understood, it transpires that ethnic differences exist. Although variations of genetic factors may play a role, the reasons for these differences remain unclear. Most published data are Caucasian based and there are limited publications on hereditary breast cancer in Asians available to date.
This thesis hypothesizes that due to the known differences in genetic predisposition in different ethnic groups, it is likely that the mutation spectrum of BRCA mutations and breast cancer characteristics of Hong Kong Chinese, a relatively unexplored cohort, will differ to that of Caucasians. Moreover, the ancestors of local Hong Kong population migrated from Mainland China of which majority were from Southern China. They then remained in Hong Kong and populated and hence similar to smaller countries such as Iceland and Poland where founder mutations are identified, it is likely that a founder mutation will be present. Lastly due to different cultural differences and availability of screening facilities, management options of those found to carry the BRCA mutation may differ to that of other countries.
The aims of this study are as follows
1) Perform a comprehensive genetic and phenotypic analysis using Full Gene Sequencing and Multiplex ligation-dependent probe amplification (MLPA) testing of Hong Kong Chinese cohort or breast cancer patients/families who are clinically high risk and to develop a registry to collect data related to this study.
2) To identify the spectrum of BRCA mutation in Hong Kong.
3) To report, any novel mutations, founder mutations, large rearrangements and deletions (using MLPA) if any are found.
4) If founder mutations are present, to develop a fasting and cheaper technique so that rapid screening can be offered.
5) To identify the choice of management in this high risk cohort.
A total of 451 clinically high-risk breast and /or ovarian cancer patients from 1 March 2007 to 28 February 2011 were recruited. Based on sequencing results, 59 (13.1%) deleterious BRCA gene mutations were identified: 24 (41%) were in BRCA1 and 35 (59%) in BRCA2. Of the 59 deleterious mutations, 22 (37%) were novel mutations, 8 were BRCA1 and 14 were BRCA2 mutations. Eight recurrent mutations were identified of which four were proven to be founder mutations. These results showed that both BRCA1 and BRCA2 mutations account for a substantial proportion of hereditary breast/ovarian cancer in Sothern Chinese population. By using MLPA, four patients with large genomic rearrangement were identified and one of whom has a de novo BRCA1 mutation encompassing exons 1 to 12 deletion. Such mutations are rare and this de novo mutation has not been previously reported. Moreover another novel BRCA2 variant of unknown significance (c.7806-9T>G), a splice-site intronic mutation, was recharacterized to be pathogenic due to clinical suspicion based on its co-segregation. High Resolution Melting Technique in performing rapid screening for the founder mutations was developed and tested on a further cohort confirming the possibility of the use of founder mutations screening technique in future. Finally, concerning the management choice of BRCA mutation carriers undertaken in Chinese, BRCA mutation carriers in our cohort are more likely to choose intensive surveillance as an option of risk management rather than prophylactic interventions.
In summary, this study provides valuable information on mutation spectrum of BRCA1 and BRCA2 in Southern Chinese population. Identifications founder mutations and knowledge of its prevalence in this Chinese population provides important information both to genetic counselling and risk assessment as well as to development of a cost-effective screening strategy. Furthermore, our study on the choice of management of mutation carriers allows us to have a baseline for development of future studies of psychological impact of genetic testing and management related to genetic testing, so that these high risk families can be better supported.published_or_final_versionSurgeryDoctoralDoctor of Philosoph
Local and systemic effects of hepatic radiofrequency ablation in animal models
No full textpublished_or_final_versionabstracttocSurgeryDoctoralDoctor of Philosoph
Blockade of hypoxia inducible factor-1α sensitizes hepatocellular carcinoma to hypoxia and chemotherapy
No full textpublished_or_final_versionabstractSurgeryDoctoralDoctor of Philosoph
Identification of miR-106b over-expression in metastatic hepatocellular carcinoma by using the orthotopic animal model
No full textpublished_or_final_versionSurgeryDoctoralDoctor of Philosoph
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