Leung, Yu Tim. / Thesis submitted in: November 2006. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 103-128). / Abstracts in English and Chinese. / Thesis Committee --- p.i / Acknowledgements --- p.ii / Abstract --- p.iii / 摘要 --- p.iv / Table of Contents --- p.v / List of Tables --- p.ix / List of Figures --- p.x / Abbreviations --- p.xiii / Chapter 1. --- Introduction / Chapter 1.1 --- Flower herbal teas --- p.1 / Chapter 1.2 --- R. rugosa --- p.3 / Chapter 1.2.1 --- The phytochemistry of R. rugosa --- p.3 / Chapter 1.3 --- Secondary metabolites --- p.4 / Chapter 1.4 --- Classification of secondary metabolites --- p.6 / Chapter 1.5 --- Phenolic compounds --- p.6 / Chapter 1.5.1 --- Phenylpropanoid compounds --- p.6 / Chapter 1.5.2 --- Lignins --- p.7 / Chapter 1.5.3 --- Coumarins --- p.7 / Chapter 1.5.4 --- Stilbenes --- p.8 / Chapter 1.5.5 --- Tannins --- p.8 / Chapter 1.5.6 --- Flavonoids --- p.9 / Chapter 1.6 --- Oxidative Stress --- p.13 / Chapter 1.6.1 --- Diseases related to ROS --- p.13 / Chapter 1.6.2 --- Significant chemical or biochemical conversion of ROS --- p.14 / Chapter 1.6.3 --- Sources of ROS --- p.15 / Chapter 1.7 --- Natural dietary antioxidants --- p.15 / Chapter 1.7.1 --- Vitamin C --- p.15 / Chapter 1.7.2 --- Vitamin E --- p.16 / Chapter 1.7.3 --- Carotenoids --- p.16 / Chapter 1.7.4 --- Phenolic compounds --- p.16 / Chapter 1.8 --- Cancinogenesis --- p.17 / Chapter 1.9 --- Cell cycle --- p.18 / Chapter 1.9.1 --- Cell cycle of eukaryotic cells --- p.18 / Chapter 1.9.2 --- Checkpoints of cell cycle --- p.18 / Chapter 1.10 --- Cancer cell lines --- p.19 / Chapter 1.11 --- The growth phases of cancer cell lines --- p.20 / Chapter 1.12 --- Antiproliferative effects of phenolic compounds --- p.21 / Chapter 1.13 --- Genotoxicity of phenolic compounds --- p.22 / Chapter 1.14 --- Objectives --- p.23 / Chapter 2. --- Methods and Materials / Chapter 2.1 --- Extraction of active substances --- p.40 / Chapter 2.2 --- Determination of antioxidant activities TEAC assay --- p.40 / Chapter 2.3 --- Determination of hydroxy 1 radical scavenging activity by the deoxyribose assay --- p.41 / Chapter 2.4 --- Determination of phenolic contents by Folin´ؤCiocalteu assay --- p.43 / Chapter 2.5 --- Determination of total flavonoid by aluminum chloride colorimetric method --- p.43 / Chapter 2.6 --- Determination of oxidative DNA damage by comet assay --- p.44 / Chapter 2.7 --- Cell lines propagation --- p.49 / Chapter 2.8 --- Determination of antiproliferative activities by MTT assay (colorimetric) --- p.50 / Chapter 2.9 --- Determination of antiproliferative activities by BrdU labeling assay --- p.52 / Chapter 2.10 --- Cell cycle analysis by flow cytometry --- p.55 / Chapter 2.11 --- Determination of genotoxicity by SOS chromotest --- p.57 / Chapter 3. --- Results / Chapter 3.1 --- Dermination of antioxidant activities by TEAC assay --- p.59 / Chapter 3.1.1 --- Trolox Standard Reference --- p.59 / Chapter 3.1.2 --- TEAC of the seven flower extracts --- p.59 / Chapter 3.2 --- Hydroxyl radical scavenging activity by deoxyribose assay --- p.60 / Chapter 3.3 --- Determination of phenolic contents by Folin´ؤCiocalteu assay --- p.60 / Chapter 3.4 --- Determination of total flavonoids by colorimetirc aluminium chloride assay --- p.61 / Chapter 3.5 --- "The Inter-correlation between the antioxidant activities, total phenolic and flavonoid contents of flower extraction powders" --- p.61 / Chapter 3.6 --- Determination of oxidative DNA damage by comet assay --- p.62 / Chapter 3.7 --- Determination of antiproliferative activities by MTT assay --- p.63 / Chapter 3.7.1 --- Antiporoliferative activities on HepG2 --- p.63 / Chapter 3.7.2 --- Antiproliferative activities on MCF7 --- p.63 / Chapter 3.7.3 --- IC50 of R. rugosa extract on both HepG2 and MCF7 --- p.64 / Chapter 3.8 --- "The Inter-correlation between antioxidant activities, total phenolic contents, flavonoid contents, and the antiproliferative activities of flower extraction Powders" --- p.64 / Chapter 3.9 --- Determination of DNA synthesis by BrdU labeling analysis --- p.65 / Chapter 3.10 --- Cell cycle analysis by flow cytometry --- p.65 / Chapter 3.11 --- Determination of genotoxicity by SOS chromotest --- p.66 / Chapter 4. --- Discussions / Chapter 4.1 --- Extraction method --- p.90 / Chapter 4.2 --- Comparison of TEAC of the dry flowers with other foods --- p.90 / Chapter 4.3 --- Correlation between ABTS+ and hydroxyl scavenging ability of flower extraction powder --- p.91 / Chapter 4.4 --- Comparison of phenolic contents of the fry flowers with other foods --- p.92 / Chapter 4.5 --- Correlation between total phenolic contents and flavonoid contents of flower Eextraction powders --- p.92 / Chapter 4.6 --- "Correlation between total phenolic, flavonoid content and antioxidant activities of flower extraction powders" --- p.93 / Chapter 4.7 --- Factors affecting the antioxidant power besides total phenolic contents --- p.94 / Chapter 4.8 --- Synergistic effect of phenolic compounds --- p.94 / Chapter 4.9 --- Toxicity of drinking flower herbal tea --- p.95 / Chapter 4.10 --- Recommended dose of flower herbal teas --- p.96 / Chapter 4.11 --- Antiproliferative activities of flower extracts by MTT assay --- p.97 / Chapter 4.12 --- Antiproliferation activities of flower extraction Powders by Brdu labeling assay --- p.98 / Chapter 4.13 --- Protective effects of flower extraction powder on oxidative DNA damage determined by comet assay --- p.99 / Chapter 4.14 --- Cell cycle analysis --- p.100 / Chapter 4.15 --- Further Studies --- p.101 / Chapter 5. --- Conclusion --- p.102 / Chapter 6. --- References --- p.103

Tang Sze-Wan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (leaves 104-118). / Abstracts in English and Chinese. / Abstract --- p.i / Abstract (Chinese) --- p.iii / Acknownledgement --- p.iv / List of Abbreviations --- p.v / List of Tables --- p.vii / List of Figures --- p.viii / Table of Contents --- p.xi / Chapter Chapter 1 - --- Introduction / Chapter 1.1 --- Trichosanthes spp --- p.1 / Chapter 1.1.1 --- Use of Trichosanthes --- p.2 / Chapter 1.1.2 --- Trichosanthin --- p.2 / Chapter 1.1.3 --- Karasurin --- p.5 / Chapter 1.1.4 --- Ribosome Inactivating Proteins --- p.6 / Chapter 1.1.5 --- Immunosuppresion --- p.7 / Chapter 1.1.6 --- Anti-Cancer Activity --- p.8 / Chapter 1.1.7 --- Miscellaneous Uses --- p.8 / Chapter 1.2 --- Cancer --- p.9 / Chapter 1.2.1 --- Oncogenes --- p.10 / Chapter 1.2.2 --- Tumor-Suppressor Genes --- p.11 / Chapter 1.2.3 --- Stability Genes --- p.12 / Chapter 1.2.4 --- Types of Cancer --- p.13 / Chapter 1.2.5 --- Cancer Therapy --- p.13 / Chapter 1.2.6 --- Apoptosis --- p.14 / Chapter 1.3 --- Chronic Myelogenous Leukemia (CML) --- p.17 / Chapter 1.3.1 --- Philadelphia Chromosome and BCR-ABL gene --- p.18 / Chapter 1.3.2 --- Treatment of CML --- p.20 / Chapter 1.4 --- Dendritic Differentiation of LC976 on K-562 --- p.20 / Chapter 1.4.1 --- Dendritic Cells --- p.21 / Chapter 1.4.2 --- Cancer Vaccine Development of Leukemia --- p.22 / Chapter 1.4.3 --- Dendritic differentiation of K-562 cells --- p.23 / Chapter 1.5 --- Perspective of the Project --- p.23 / Chapter Chapter 2 - --- Materials and Methods / Chapter 2.1 --- Materials / Chapter 2.1.1 --- Chemicals and Reagents --- p.25 / Chapter 2.1.2 --- Bioassay Kits --- p.26 / Chapter 2.1.3 --- Human Cell Lines --- p.26 / Chapter 2.1.4 --- Lab Wares and Equipments --- p.28 / Chapter 2.2 --- Extraction of LC9 --- p.76 / Chapter 2.2.1 --- Chemical Properties of the Lead Compound --- p.28 / Chapter 2.2.2 --- Crude Extraction of Trichosanthes sp --- p.29 / Chapter 2.2.3 --- Purification by Reversed-Phase Column --- p.29 / Chapter 2.2.4 --- Lyophilization and Preparation of LC976 --- p.31 / Chapter 2.3 --- Anti-Proliferation Effect of LC976 on Human Cell Lines / Chapter 2.3.1 --- Maintenance of Cell Lines --- p.32 / Chapter 2.3.2 --- MTT Assay --- p.32 / Chapter 2.3.3 --- BrdU Cell Proliferation ELISA --- p.34 / Chapter 2.4 --- Apoptosis Induction on K-5 --- p.62 / Chapter 2.4.1 --- PI Staining --- p.35 / Chapter 2.4.2 --- Annexin V-FITC FACS Analysis --- p.36 / Chapter 2.4.3 --- Caspase Activation --- p.37 / Chapter 2.5 --- Effect on Normal Human Lymphocytes / Chapter 2.5.1 --- Preparation of Human Normal Lymphocytes --- p.38 / Chapter 2.5.2 --- MTT Cell Viability Assay --- p.38 / Chapter 2.5.3 --- PI Staining --- p.39 / Chapter 2.5.4 --- Annexin V-FITC FACS Analysis --- p.39 / Chapter Chapter 3 - --- Results / Chapter 3.1 --- Extraction of LC976 --- p.40 / Chapter 3.2 --- LC976 Inhibited Proliferation of Human Cell Lines / Chapter 3.2.1 --- MTT Assay --- p.41 / Chapter 3.2.2 --- BrdU Cell Proliferation ELISA --- p.52 / Chapter 3.3 --- LC976 Induced Apoptosis in K-562 Cells / Chapter 3.3.1 --- PI Staining --- p.63 / Chapter 3.3.2 --- Annexin V-FITC FACS Analysis --- p.70 / Chapter 3.3.3 --- Caspase Activation --- p.73 / Chapter 3.4 --- Effect on Normal Human Lymphocytes / Chapter 3.4.1 --- MTT Cell Viability Assay --- p.76 / Chapter 3.4.2 --- PI Staining --- p.78 / Chapter 3.4.3 --- Annexin V-FITC FACS Analysis --- p.82 / Chapter Chapter 4 - --- Discussion / Chapter 4.1 --- Extraction of LC976 --- p.85 / Chapter 4.2 --- LC976 Inhibited Proliferation of Human Cell Lines / Chapter 4.2.1 --- MTT Assay --- p.86 / Chapter 4.2.2 --- BrdU Cell Proliferation ELISA --- p.88 / Chapter 4.3 --- LC976 induced Apoptosis in K-562 Cells / Chapter 4.3.1 --- PI Staining --- p.90 / Chapter 4.3.2 --- Annexin V-FITC Analysis --- p.95 / Chapter 4.3.3 --- Caspase Activation --- p.96 / Chapter 4.4 --- Effect on Normal Human Lymphocytes / Chapter 4.4.1 --- MTT Cell Viability Assay --- p.98 / Chapter 4.4.2 --- PI Staining --- p.99 / Chapter 4.4.3 --- Annexin V-FITC FACS Analysis --- p.100 / Chapter 4.5 --- Conclusion --- p.103 / Reference --- p.104

Li Lok Yee Mandy. / "June 2004." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (p. 155-165). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Apesar de existir novas técnicas e múltiplas alternativas terapêuticas para o câncer de próstata localmente avançado, esta enfermidade se constitui em um grande problema de saúde pública mundial, resultando em índices significativos de morbidade e mortalidade, gerando desta forma um desafio para urologistas e oncologistas. Existem múltiplas e bem sucedidas estratégias de tratamento da doença localizada, tais como: a prostatectomia radical, a radioterapia externa conformacional, a braquiterapia e a crioablação. Em contraste, o tratamento da doença metastática e localmente avançada, freqüentemente necessita da alguma forma de bloqueio hormonal. Não existe consenso em vários aspectos da terapia hormonal para tumores localmente avançados tais como: o tipo de bloqueio androgênico a ser usado, terapia hormonal precoce ou tardia, associação com outras modalidades terapêuticas e o uso de bloqueio intermitente. Foi realizada uma revisão crítica deste tipo de tratamento, bem como as indicações atuais de bloqueio hormonal nos tumores de próstata localmente avançado. Não existem estudos prospectivos e randomizados que comparem as diversas formas de tratamento cirúrgico versus radioterápico do câncer de próstata localmente avançado. A hormonioterapia adjuvante à prostatectomia radical, na doença localmente avançada, parece reduzir a progressão tumoral bioquímica, porém, não há estudo que evidencie melhora na sobrevida livre de metástase ou na sobrevida global. O bloqueio androgênico neoadjuvante à prostatectomia radical aumenta a proporção dos pacientes com doença órgão-confinada e margens cirúrgicas negativas, porém sem efeito nas taxas de falha bioquímica do tratamento. A terapia hormonal adjuvante à radioterapia em pacientes portadores de câncer de próstata localmente avançado oferece vantagens na sobrevida global. A terapia hormonal neoadjuvante à radioterapia, em estudos multicêntricos e randomizados, resulta em melhor controle local do tumor bem como prolonga a sobrevida doença-específica. Não há, porém evidência de melhora na sobrevida global. O tratamento por tempo prolongado com bloqueadores hormonais adjuvante à radioterapia mostrou-se superior em relação à sobrevida global e sobrevida livre de doença quando comparado a um período curto de bloqueio, principalmente em pacientes com tumores indiferenciados (Gleason 8-10). Os análogos LHRH, orquiectomia ou o dietilestilbestrol se mostraram como opções de monoterapia, igualmente eficazes, para os pacientes que iniciam terapia hormonal de primeira linha, no tratamento da doença localmente avançada. Não existe evidência que justifique o bloqueio androgênico máximo como terapia hormonal de primeira linha ao invés de monoterapia. Existem vantagens potenciais na qualidade de vida e nos custos do tratamento quando realizada a ablação intermitente, mas a sua eficácia a longo prazo necessita ser confirmada / Despite new techniques and multiple therapeutic alternatives, locally advanced prostate cancer is a serious public health problem, resulting in significant morbidity and mortality rates, that remains a great challenge for urologists and oncologists. Several therapeutic strategies to treat localized prostate cancer have been successful such as conformational external beam radiation therapy, brachytherapy and cryoablation. In contrast, treatment of metastatic and locally advanced tumors may often involve androgenic suppression. However, there are no consensus on several aspects of hormonal therapy for locally advanced tumors such as the type of antiandrogenic drug to be used, early versus delayed hormonal therapy, association with other therapeutic modalities and the use of intermittent blockade. We set out to critically review important aspects and current indications of hormonal blockade in the locally advanced prostate tumors. There are no prospective and randomized study that compares current forms of surgical treatment versus radiation therapy of locally advanced prostate cancer. After radical prostatectomy, adjuvant hormonal therapy in the locally advanced disease reduces biochemical failure rates, although no benefit has been shown regarding metastatic free survival or overall suvival. Neoadjuvant androgen blockade enhances the proportion of patients with organ-confined disease and negative surgical margins but no benefit is seen regarding biochemical free recurrence. Neoadjuvant hormonal therapy to the radiotherapy improves local tumor control as well as it prolongs the diseasespecific survival, although there are no survival advantage. Adjuvant hormonal therapy offers overall survival advantage in patients with locally advanced prostate cancer treated with radiotherapy Long term adjuvant hormonal blockade offers survival benefit for patients with high Gleason score (8-10). LHRH analogues, bilateral orquiectomy and dietilestilbestrol were shown are equally effective as adjuvant therapy for patients with locally disease advanced. There are evidences that maximum androgenic blockade are not more efficient than monotherapy. Potential quality of life and costs advantages of intermittent ablation could be considered an alternative treatment for this group of patient

Considerada como uma nova estratégia no direcionamento de fármacos para tecidos lesionados, a LDE é uma nanopartícula lipídica que se concentra em locais inflamatórios com altas taxas de proliferação celular, como lesões ateroscleróticas, e é usada em modelos experimentais e no homem. Docetaxel (DTX), agente quimioterápico antiproliferativo, ainda não foi explorado no tratamento da aterosclerose. Coelhos New Zealand brancos machos foram alimentados com ração enriquecida com 1% de colesterol para induzir aterosclerose ao longo do período experimental de 8 semanas. Após 4 semanas, os animais foram tratados semanalmente com LDE-DTX (n =9) com dose de 1 mg/kg e.v. ou apenas com LDE (grupo Controle, n =9). O consumo de ração e os perfis lipídico, hematológico e ponderal foram avaliados durante o protocolo nos tempos basal, 4 semanas e final. Após a eutanásia, foram realizadas análises morfológicas e Western blot das aortas. Como esperado, o colesterol total aumentou aproximadamente 42 vezes em ambos os grupos quando comparados os períodos basal e final. Houve diminuição no número de hemácias entre os períodos basal e final em ambos os grupos, aparentemente não relacionada ao tratamento. Os animais não apresentaram toxicidade renal e hepática. A área de lesão macroscópica nas aortas do grupo LDE-DTX foi aproximadamente 80% menor em relação ao Controle e a área de placa na região do arco aórtico foi 86% menor no grupo tratado com LDE-DTX quando comparado ao Controle. Em relação aos fatores inflamatórios, a expressão proteica de CD68 foi 64% menor no grupo tratado com LDE-DTX quando comparado ao grupo Controle. MCP-1 foi 84% menor no grupo tratado com LDEDTX e o TNF-alfa foi 44% menor no grupo tratado, quando comparados ao grupo Controle. A expressão proteica de interleucina IL-1beta e do NFkB foram cerca de 60% menores no grupo tratado assim como a IL-6, que foi 79% menor, ambos comparados ao grupo Controle. O fator de von Willebrand foi cerca de 30% menor no grupo tratado com LDE-DTX comparado ao Controle. Os fatores próapoptóticos apresentaram menor expressão no grupo LDE-DTX: a caspase 3 foi 82% menor em comparação ao Controle, caspase 9 e Bax, cerca de 50% menor que o controle bem como o fator anti-apoptótico Bcl-2. A expressão proteica dos colágeno I e III também foi menor no grupo LDE-DTX. Comparados ao controle, a expressão proteica de MMP-2 e MMP-9 foram cerca de 70% menores no grupo LDE-DTX. O marcador de proliferação celular PCNA foi 41% menor no grupo LDE-DTX em comparação com o grupo Controle. O tratamento com a associação LDE-DTX mostrou-se eficaz, uma vez que os coelhos tratados apresentaram uma área menor da lesão aterosclerótica, menor inflamação, morte celular e proliferação na aorta quando comparado ao grupo Controle / Considered as a new strategy of targeting drugs to injured tissues, LDE, a lipid core nanoparticle concentrates on inflammatory sites with high cell proliferation rates, as atherosclerotic lesions, and it is used as a vehicle for drugs in experimental models and in humans. Docetaxel (DTX), an antiproliferative chemotherapeutic agent has not been explored yet in the treatment of atherosclerosis. New Zealand white male rabbits were fed with 1% cholesterol diet throughout the 8-week experimental period to induce atherosclerosis. After 4 weeks, the animals were treated weekly with LDE-DTX (n=9) at a dose of 1mg/kg i.p. or only with LDE (Control group, n=9). We evaluated feed intake, lipid, hematological, and weight profiles during the protocol at baseline, 4 weeks and post-treatment. After euthanasia was performed morphological analysis and Western blot of the aorta. As expected, total cholesterol increased 42-fold in both groups comparing baseline to post-treatment. There was a decrease in red blood cells number in both groups but it is probably not treatment-related. There was no hepatic and renal treatment-related toxicity. The macroscopic lesion area in the aortas of LDE-DTX was approximately 80% smaller compared to Control and the morphometry of the aortic arch was 86% smaller in LDE-DTX group compared to Control group. Regarding inflammatory factors, CD68 was 64% lower in LDEDTX group comparing to Control group. MCP-1 was 84% in LDE-DTX group and TNF-alpha was 44% lower in the treated group comparing to Control group. The protein expression of IL-1beta and NFkB were about 60% lower in the LDE-DTX group as well as IL-6 that was 79% lower, both compared to Control group. The von Willebrand factor was about 30% lower in LDE-DTX group compared to Control group. The pro-apoptotic factors showed lower expression in LDE-DTX group: caspases 3 was 82% lower compared to control and caspases 9 and Bax were about 50% than Control group as well as the anti-apoptotic factor Bcl-2. The protein expression of collagen I and III were lower in LDE-DTX group. Compared to control, the protein expression of MMP-2 and MMP-9 were about 70% lower in the LDE-DTX group compared to Control group. The cell proliferation marker PCNA was 41% lower in LDE-DTX group compared to Control group. Treatment with LDE-DTX association proved to be effective since the treated rabbits had a smaller area of the atherosclerotic lesion, lower inflammation, cell death and proliferation in the aorta when compared to Control group

No presente estudo realizou-se a análise custo-efetividade das terapias antineoplásicas IFL (irinotecano, 5-fluorouracil e leucovorin) e IFL+BV (IFL associado ao bevacizumabe) empregado no tratamento do câncer colorretal metastático em primeira linha. Estimou o custo direto de medicamentos, materiais e recursos humanos. A efetividade dos protocolos foi medida pela proporção de pacientes livre de progressão de doença. Os dados relativos aos custos de materiais e medicamentos foram obtidos a partir de tabelas de preços que regulamentam o mercado hospitalar. Os dados concernentes à efetividade foram obtidos através da literatura científica. Utilizou-se o modelo de análise de decisão para estimar o custo total da terapia antineoplásica. Os resultados mostraram que o protocolo IFL apresentou a melhor relação custo-efetividade durante todo o tempo de seguimento, ou seja, o menor custo por unidade de efetividade, que no 10º mês foi de R$ 180.619,46. A análise de sensibilidade mostrou que esta conclusão foi robusta. Essas análises farmacoeconômicas apontaram que a seleção do protocolo antineoplásico depende do custo e efetividade, mas, sobretudo da relação custo-efetividade que permite saber o custo estimado por unidade de sucesso. / In this paper a cost–effectiveness analyses was done of the antineoplasics therapies IFL (irinotecan, 5- fluorouracil and leucovorin) and IFL + BV (IFL associated to bevacizumab) used as metastatic colorectal cancer as first line treatment. It has estimated the cost of medications, materials and human resources. The effectiveness of the protocols was measured through the proportion of patients that were free from the illness progression. Data regarding material cost and medication were obtained by price tables that regulate Hospital market. Data relating to effectiveness were obtained through scientific literature. We utilized the decision analysis model to estimate the total cost of the antineoplasics therapy. The results showed that the IFL protocol presented a better cost–effectiveness relationship during the whole period following, that is, the lowest cost per effectiveness units, that on the 10th Month was R$ 180.619,46. The sensitivity analysis showed that this conclusion was strong. These pharmacoeconomic analyses pointed to the fact that antineoplasics protocol selection depends on cost and effectiveness, but, above all on the cost–effectiveness relation which allows us to know the estimated cost per successful unit.

The purpose of this research is to validate various forms of mathematical modeling of glioblastoma multiforme (GBM) expressed as differential equations, numerically. The first work was involved in the numerical solution of the reaction-convection model, efficacy of which is expressed in terms of survival time. It was calculated using simple numerical scheme for the standard-of-care treatment in clinics which includes surgery followed by the radiation and chemotherapy. Survival time using all treatment options increased significantly to 57 weeks compared to that of surgery close to 14 weeks. It was also observed that survival time increased significantly to 90 weeks if tumor is totally resected. In reaction-diffusion model using simple numerical scheme, tumor cell density patterns due to variation in patient specific tumor parameters such as net proliferation rate and diffusion coefficient were computed. Significant differences were observed in the patterns while using dominant diffusion and proliferation rate separately. Numerical solution of the tumor growth model under the anti-angiogenic therapy revealed some impacts in optimum tumor growth control however it was not significant. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2016. / FAU Electronic Theses and Dissertations Collection

TRAIL has been widely investigated as an anti-cancer agent due to its high efficacy in vitro and its safety to normal cells. However, TRAIL-based agents only showed modest effect in clinical studies because of TRAIL resistance. In addition to apoptosis, TRAIL has also been reported to promote pro-survival signalings, cell migration and metastasis. One of the current strategies in the development of TRAIL-based therapeutics focuses on the search of sensitizing agents that help overcome TRAIL resistance without increasing harm to normal cells. / This study reports a novel combination of TRAIL and 4-methylumbelliferone (4-MU) which can kill HeLa cells and HepG2 cells synergistically without cytotoxicity to Hs68 non-tumorigenic cells. This combination also effectively inhibited cancer cell proliferation and potentiated apoptosis by accumulation of tBid, down-regulation of anti-apoptotic proteins and inhibition of Akt. More importantly, 4-MU could suppress the recovery of HeLa cells from TRAIL-induced apoptosis, a process previously implicated to be associated with cancer relapse and tumor heterogeneity. This study has provided solid evidences substantiating further research on TRAIL-4-MU combination. / 腫瘤壞死因子相關凋亡誘導配體 (TRAIL) 在體外實驗中有良好抗癌作用，且不會傷害正常細胞，使之得到廣泛研究，成為近年熱門的新抗癌分子。然而TRAIL 在臨床實驗中並沒有顯著抗癌功效，一般認為人體腫瘤細胞對TRAIL 具有耐藥性。研究文獻亦指出，除了細胞凋亡外，TRAIL亦會誘發細胞存活機制、促進細胞移行及癌細胞轉移。目前，對於TRAIL相關藥品抗癌作用的研究有幾個大方向，其中之一就是尋找良好的增敏分子。良好的增敏分子應能夠增力癌細胞對TRAIL的敏感性，對抗癌細胞對TRAIL的耐藥性，同時不能殺傷正常細胞。 / 本研究揭示了一個全新的抗癌藥物聯合。當TRAIL聯合4-甲基伞形酮(4-MU)能產生協同作用，殺傷HeLa癌細胞和HepG2癌細胞而不會傷害Hs68正常細胞。此組合能有效抑制癌細胞生長，並透過增加tBid蛋白表達、減少抗凋亡蛋白表達及抑制Akt來促進細胞凋亡。更為重要的是，4-MU能抑制HeLa癌細胞自TRAIL誘導凋亡的恢復和逆轉。而癌細胞凋亡逆轉一般被視為與癌症復發及腫瘤多樣性有關。本研究提供了實質證據，支持對TRAIL-4-MU組合的後續研究。 / Wu, Hoi Yan. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2015. / Includes bibliographical references (leaves 90-107). / Abstracts also in Chinese. / Title from PDF title page (viewed on 05, October, 2016). / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

by Lawrence Chi-ming Chiu. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1994. / Includes bibliographical references (leaves 142-151). / Abstract --- p.i / Acknowledgments --- p.iv / Table of Contents --- p.v / List of Figures --- p.vii / List of Tables --- p.xi / List of Abbreviations --- p.xii / Chapter Chapter 1: --- Introduction / Chapter 1.1 --- Polysaccharide-peptide (PSP ) --- p.1 / Chapter 1.2 --- Paracetamol (APAP ) --- p.6 / Chapter 1.2.1 --- Metabolism of APAP --- p.9 / Chapter 1.2.2 --- Mechanisms of APAP toxicity --- p.11 / Chapter 1.2.3 --- Factors influencing the hepatotoxicity of APAP --- p.17 / Chapter 1.3 --- Aim of the present study --- p.23 / Chapter Chapter 2: --- Studies on the effects of PSP on APAP-hepatotoxicity and glutathione levels / Chapter 2.1 --- Introduction --- p.25 / Chapter 2.2 --- Materials and methods --- p.30 / Chapter 2.3 --- Results / Chapter 2.3.1 --- The effects of PSP on APAP-induced hepatotoxicity --- p.41 / Chapter 2.3.2 --- The acute and sub-chronic effects of PSP on glutathione in rats --- p.45 / Chapter 2.4 --- Discussions --- p.66 / Chapter Chapter 3: --- Studies on the effects of PSP on the covalent binding and metabolism of APAP / Chapter 3.1 --- Introduction --- p.79 / Chapter 3.2 --- Materials and methods --- p.85 / Chapter 3.3 --- Results / Chapter 3.3.1 --- The effects of PSP on the covalent binding of radiolabelled paracetamol (14C-APAP ) in vitro --- p.102 / Chapter 3.3.2 --- The effects of PSP on the metabolism of APAP --- p.107 / Chapter 3.4 --- Discussions --- p.119 / Chapter Chapter 4: --- Conclusion --- p.137 / References --- p.142

Li Ka Wai Kay. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references. / Abstracts in English and Chinese. / ACKNOWLEDGEMENTS --- p.i / ABSTRACT (ENGLISH/CHINESE) --- p.ii / TABLE OF CONTENTS --- p.viii / LIST OF FIGURES --- p.xii / LIST OF APPENDICES --- p.xiii / Chapter 1 --- INTRODUCTION --- p.1 / Chapter 1.1 --- Gastric carcinomas --- p.1 / Chapter 1.1a --- Epidemiology --- p.1 / Chapter 1.1b --- Classification --- p.2 / Chapter 1.1c --- TNM staging --- p.3 / Chapter 1.1d --- Prognosis --- p.4 / Chapter 1.1e --- Etiology --- p.6 / Chapter 1.1f --- Genetic alteration in gastric cancer --- p.10 / Chapter 1.2 --- Treatment --- p.16 / Chapter 1.2a --- "Surgery, chemotherapy, and others" --- p.16 / Chapter 1.2b --- Response rate of treatments in previous studies --- p.18 / Chapter 1.2c --- Chemotherapeutic Drugs --- p.21 / Chapter 1.2c (1) --- 5-fluorouracil (5-FU) --- p.22 / Chapter 1.2c (2) --- cis-diamminedichloroplatinum (Cisplatin) --- p.23 / Chapter 1.2c (3) --- Doxorubicin (Adriamycin) --- p.23 / Chapter 1.2c (4) --- Daunorubicin --- p.25 / Chapter 1.2c (5) --- Epirubicin --- p.25 / Chapter 1.2d --- Toxicity of chemotherapeutic drugs --- p.26 / Chapter 1.2d (1) --- Side effects of 5-FU --- p.26 / Chapter 1.2d (2) --- "Side effects of anthracyc lines (adriamycin, daunobicin, epuirbicin)" --- p.27 / Chapter 1.2d (3) --- Side effects of cisplatin --- p.28 / Chapter 1.3 --- Mechanisms of drug resistance --- p.28 / Chapter 1.3a --- Drug resistance --- p.28 / Chapter 1.3b --- P-glycoprotein (MDR1 gene) --- p.29 / Chapter 1.3c --- p53 tumor suppressor gene --- p.35 / Chapter 1.4 --- Chemosensitivity testing --- p.40 / Chapter 1.4a --- Original of chemosensitivity testing --- p.40 / Chapter 1.4b --- Non-clonogentic assay --- p.40 / Chapter 1.4c --- Clonogenic assay --- p.42 / Chapter 2 --- AIM OF MY STUDY --- p.44 / Chapter 3 --- MATERIALS AND METHODS --- p.45 / Chapter 3.1 --- Patients --- p.45 / Chapter 3.2 --- Tumor collection and handling procedure --- p.46 / Chapter 3.2a --- Large tumor tissue from gastrectomy --- p.46 / Chapter 3.2b --- Pseudo-biopsies --- p.47 / Chapter 3.3 --- Chemosensitivity testing --- p.48 / Chapter 3.3a --- Cell Plating --- p.48 / Chapter 3.3b --- Drug testing --- p.49 / Chapter 3.4 --- Chemosensitivity analysis --- p.50 / Chapter 3.5 --- Conformational sensitive gel electrophoresis analysis (CSGE) and single strand conformational polymorphism (SSCP) --- p.51 / Chapter 3.5a --- Preparation of genomic DNA --- p.51 / Chapter 3.5b --- PCR condition for CSGE analysis --- p.51 / Chapter 3.5c --- Scanning PCR products by CSGE --- p.52 / Chapter 3.5d --- PCR condition for SSCP analysis --- p.53 / Chapter 3.5e --- Scanning PCR products by SSCP --- p.53 / Chapter 3.6 --- Reverse transcription-polymerase chain reaction (RT-PCR) for multi-drug drug resistance (MDR1) gene --- p.54 / Chapter 3.6a --- Isolation of RNA --- p.54 / Chapter 3.6b --- cDNA synthesis --- p.55 / Chapter 3.6c --- PCR primers --- p.55 / Chapter 3.6d --- Optimalization of PCR condition for MDR1 gene expression --- p.56 / Chapter 3.6e --- PCR of β2-m gene --- p.57 / Chapter 3.6f --- PCR of MDR1 gene and analysis of its expression --- p.57 / Chapter 3.7 --- Immunohistochemistry --- p.58 / Chapter 3.7a --- Immunostaining by DO-7 --- p.58 / Chapter 3.7b --- lmmunohistochemistochemical analysis of p53 protein expression --- p.59 / Chapter 3.8 --- Statistics --- p.59 / Chapter 4. --- RESULTS --- p.60 / Chapter 4.1 --- Chemosensitivity testing --- p.60 / Chapter 4.1a --- Tests completed --- p.60 / Chapter 4.1b --- Number of cases tested for each drug --- p.60 / Chapter 4.1c --- 〇D reading of the background samples --- p.60 / Chapter 4.1d --- Dose-dependent response curve --- p.61 / Chapter 4.1e --- Unique IC50 for each tumor in each drug test --- p.61 / Chapter 4.1f --- Wide distribution of ic50 for anti-tumor drugs --- p.61 / Chapter 4.1g --- Chemosensitivity and tumor histologic type --- p.63 / Chapter 4.1h --- Correlation of ic50 with tumor stage --- p.63 / Chapter 4.2 --- Immunohistochemical staining of p53 protein (DO-7) --- p.64 / Chapter 4.2a --- p53 protein accumulation in samples --- p.64 / Chapter 4.2b --- Correlation of p53 IHC expression and chemosensitivity --- p.64 / Chapter 4.3 --- SSCP and CSGE --- p.65 / Chapter 4.3a --- Detection of abnormal band movement --- p.65 / Chapter 4.3b --- Correlation of p53 mutations with chemosensitivity --- p.66 / Chapter 4.3c --- Concordance between IHC and SSCP/CSGE --- p.66 / Chapter 4.4 --- MDR1 gene expression --- p.67 / Chapter 4.4a --- MDR1 gene expression in normal and tumors --- p.67 / Chapter 4.4b --- Correlation of MDR1 expression and chemosensitivity --- p.68 / Chapter 4.5 --- Pseudobiopsies --- p.68 / Chapter 5 --- DISCUSSION --- p.70 / Chapter 5.1 --- p53 analysis of the tumors --- p.70 / Chapter 5.1a --- Immunohistochemistry versus mutational analysis --- p.70 / Chapter 5.1b --- Methods of mutational analysis --- p.73 / Chapter 5.1c --- Comparing IHC results with previous findings --- p.77 / Chapter 5.1d --- Comparing SSCP/ CSGE results with previous findings --- p.78 / Chapter 5.1e --- Correlation of IHC and SSCP/CSGE results --- p.81 / Chapter 5.2 --- MDR1 expression --- p.85 / Chapter 5.2a --- Methods for detecting MDR1 expression --- p.85 / Chapter 5.2b --- Comparing MDR1 expression results with published data --- p.88 / Chapter 5.2c --- Correlation between chemosensitivity and MDR1 gene expression --- p.92 / Chapter 5.3 --- Chemosensitivity testing --- p.94 / Chapter 5.3a --- Chemosensitivity testing method --- p.94 / Chapter 5.3b --- The chemosensitivity results --- p.102 / Chapter 5.3c --- Chemosensitivity and MDR1 expression --- p.108 / Chapter 5.3d --- Chemosensitivity and p53 immunohistochemical expression… --- p.110 / Chapter 5.3e --- Chemosensitivity and p53 mutations --- p.112 / Chapter 5.3f --- Limitation of this study --- p.115 / Chapter 5.3g --- Pseudobiopsies and large tumor samples --- p.118 / Chapter 6. --- conclusions --- p.121 / figures / appendices / references