Neuroblastoma is one of the most common solid tumors in patients below the age of 15. In this PhD project, the possible anti-tumor effects of the soy isoflavones on neuroblastoma cells have been investigated. A number of aspects of neuroblastoma cancer cell biology, including cell proliferation, cell cycle regulation, cell differentiation and apoptosis, intracellular signaling mechanisms, tumor invasiveness and metastatic properties, have been examined. Furthermore, novel antitumor properties of the soy isoflavones on neuroblastoma have also been quested for, hoping that through this PhD project, a better understanding of the potential anti-tumor effects of soy isoflavones on neuroblastoma cells can be obtained. In Chapter Three, we have demonstrated that the major soy isoflavones daidzein and genistein exerted potent anti-proliferative effect on murine neuroblastoma Neuro-2a (BU-1) cells. These two compounds were shown to modulate cell cycle distribution in BU-1 cells in different ways, possible through their differential effects on the expression of cell cycle regulatory proteins such as cyclins and cyclin-dependent kinase inhibitors. The anti-tumor effect of daidzein was found to be fairly specific to tumor cells, as daidzein only exhibited little, if any, direct cytotoxicity to normal murine cells such as bone marrow cells, macrophages, and thymocytes. Furthermore, the anti-proliferative effect of daidzein was unlikely to be attributed to its direct cytotoxicity to the BU-1 cells, but might be coupled with its ability to trigger the apoptosis and differentiation in the neuroblastoma cells. Our results show that daidzein could induce DNA fragmentation, ultrastructural changes, and the enrichment of cytoplasmic mono- and oligo-nucleosomes in the treated-BU-1 cells. Moreover, daidzein was shown to induce neuronal differentiation in the BU-1 cells, as indicated by morphological changes, and increased expression of the neuronal differentiation marker microtubule-associated protein-2, and acetylcholine esterase activity. In addition, we have also demonstrated that the signals of daidzein might be mediated by the estrogen receptor and nuclear factor-kappa B pathways. In Chapter Four, daidzein was shown to exert a differential an proliferative effect on three human neuroblastoma cell lines, including SK-N-DZ and SH-SY5Y. The most sensitive cell line, LA-N-1, was chosen for further mechanistic studies. It was found that daidzein-induced growth-inhibitory effect was coupled with the induction of neurite outgrowth and altered mRNA expression of the N-myc-related transcription factors. Moreover, daidzein was observed to modulate the invasiveness and metastatic properties of LA-N-1 cells, as indicated by the reduction of colony-forming ability, cell migratory ability, in vivo tumorigenicity, tumor vascularity, and angiogenic factors expression. Our results clearly suggest that the major soy isoflavone daidzein can exert its pleiotropic anti-tumor effects on both marine and human neuroblastoma cells. In Chapter Five, we isolated two stable actively proliferating subclones from the human neuroblastoma SH-SY5Y cells. We compared the sensitivities of the parental SH-SY5Y cells and the active subclones to the growth inhibition exerted by a number of conventional cancer chemotherapeutic agents and the soy isoflavone derivatives. We found that the major soy isoflavones daidzein and genistein were rather selective to the active subclones and this phenomenon was not observed with other chemotherapeutic agents. The anti-tumor action mechanisms of genistein on the most active subclone, designated as SH-SY5Y cl.6 cells, were examined in detail. It was found that genistein could induce apoptosis in SH-SY5Y cl.6 cells, as indicated by the induction of ultrastructural changes, phosphatidylserine externalization, and cytoplasmic enrichment of mono- and oligo-nucleosomes. The genistein-induced apoptosis in SH-SY5Y cl.6 cells was found to be both mitochondria and caspases-dependent, as mitochondrial membrane depolarization, cytosolic release of apoptotic mitochondrial factors and activation of caspase-3 were observed. To sum up, our results show that the major soy isoflavones, particularly daidzein and genistein, exhibit pleiotropic anti-tumor effects on both murine and human neuroblastoma cells, and they are also selective to the actively proliferating human neuroblastoma cells. (Abstract shortened by UMI.) / Lo, Fai-Hang. / "September 2007." / Adviser: Leung Kwok-Nam. / Source: Dissertation Abstracts International, Volume: 69-02, Section: B, page: 0949. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (p. 255-287). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract in English and Chinese. / School code: 1307.

by Angela Mara Bentes de Souza. / "June 2003." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (p. 176-200). / 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.

by Joseph Jao Yiu Sung. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1996. / Includes bibliographical references (p. 201-220). / 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.

by Lam Tin Lun. / "July, 2003." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (p. 308-327). / 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.

by Su Ya Lun. / "August 2003." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (p. 163-181). / 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.

Chan Ching-Man Loren. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (leaves 126-144). / Abstracts in English and Chinese. / Acknowledgement --- p.ii / Abstract --- p.iii / Table of Content --- p.vii / List of Figure --- p.ix / List of Abbreviations --- p.xii / Chapter Chapter One --- General Introduction / Chapter 1.1 --- Doxorubicin --- p.1 / Chapter 1.2 --- Antioxidants --- p.11 / Chapter 1.3 --- Flavonoids --- p.17 / Chapter 1.4 --- Protection against doxorubicin-induced cardiotoxicity by antioxidant --- p.25 / Chapter 1.5 --- Aim of research --- p.25 / Chapter Chapter Two --- Study of Cardioprotection Effect of Flavonoids Against Doxorubicin-induced Toxicity in Sprague-Dawley Rats / Chapter 2.1 --- Introduction --- p.27 / Chapter 2.2 --- Materials and Methods --- p.29 / Chapter 2.3 --- Results --- p.37 / Chapter 2.4 --- Discussion --- p.51 / Chapter ChapterThree --- Study of Effect of Flavonoids in Chemotherapy of Doxorubicinin Tumor-bearing Mice / Chapter 3.1 --- Introduction --- p.54 / Chapter 3.2 --- Materials and Methods --- p.56 / Chapter 3.3 --- Results --- p.63 / Chapter 3.4 --- Discussion --- p.80 / Chapter ChapterFour --- Study of the Effect of Flavonoids on Doxorubicin-induced Cytotoxicity on Human Tumor Cell Line and Doxorubicin-resistant Human Tumor Cell Line / Chapter 4.1 --- Introduction --- p.83 / Chapter 4.2 --- Materials and Methods --- p.86 / Chapter 4.3 --- Results --- p.94 / Chapter 4.4 --- Discussion --- p.120 / Chapter Chapter five --- Conclusion --- p.122 / References --- p.126

As diretrizes atuais no campo da saúde mental vêm apontando para a necessidade de uma construção da prática de promoção à saúde mental em que os usuários dos serviços têm participação ativa. Assim, o objetivo do presente estudo foi realizar uma avaliação, junto aos usuários em sofrimento psíquico em tratamento em um Centro de Atenção Psicossocial, sobre as atividades do projeto terapêutico elaborado para sua assistência. Como metodologia foi adotada a abordagem qualitativa, com análise de conteúdo. Para a coleta de dados foi utilizada a entrevista semi-estruturada com usuários do serviço. Nesse estudo, foi percebido que as atividades são prescritas ao usuário inicialmente, em decorrência de um quadro clínico que se manifesta e o desabilita para o enfrentamento das atividades da vida diária. Em um segundo momento, este sujeito é colocado à frente de uma série de oportunidades (recursos) que têm como objetivo auxiliá-lo a pensar em seus recursos como forma de atenuar as suas queixas. Isto consolida os preceitos da reabilitação psicossocial, que é centrado nos recursos do sujeito, valorizando sua história de vida e viabilizando a construção de novas possibilidades. A descrição da forma como os usuários elencam as atividades e seus significados fortalece a construção de um trabalho que tem um referencial sustentado no paradigma das práticas assistenciais, inclui a atenção ao sujeito, mas solicita também a inclusão do profissional técnico como participante contínuo dentro do projeto ofertado. Na análise foram atribuídos significados que permitiram concluir que o projeto terapêutico retrata o referencial teórico preconizado para a reabilitação psicossocial, subsidia este serviço, enquanto prática assistencial, fortalecendo seu vínculo com os usuários por meio das atividades e do profissional que promove essa assistência. Contudo, foi verificado também que as atividades são procedimentos que geram expectativas e angústias a ele, como também evidenciam as possibilidades, limites, e amplitudes das ações da equipe. As atividades do serviço mobilizam os sujeitos de forma positiva e de forma negativa e, nesse sentido, é necessário que os profissionais estejam motivados, por meio de supervisão, capacitação, revisão contínua de sua práxis técnica profissional, para suportarem a intensa carga de expectativa e anseio depositada pelos pacientes no desenvolver das atividades. Acreditamos que este trabalho possibilitará às equipes profissionais de instituições voltadas ao atendimento em saúde mental terem uma compreensão de suas abordagens no tratamento psiquiátrico a partir da visão de seus usuários. / Current mental health guidelines have been indicating the need to construct a mental health promotion practice in which service users participate actively. Thus, this study aimed to evaluate, among mental patients under treatment at a Psychosocial Care Center, the activities involved in the therapeutic project that was elaborated for their care. We adopted a qualitative methodology, using content analysis. Data were collected through semistructured interviews with service users. In this study, we perceived that activities are initially prescribed to these users as a result of a clinical situation that is manifested and disables them to cope with daily living activities. Next, these subjects are faced with a series of opportunities (resources), aimed at helping them think about their resources as a way of mitigating their complaints. This consolidates the principles of psychosocial rehabilitation, which is centered on the subjects’ resources, values their life history and makes it possible to construct new possibilities. The description of how users report on the activities and their meanings strengthens the construction of a service whose reference framework is supported by the paradigm of care practices and which not only includes care delivery to the subject, but also seeks to include technical professionals as continuous participants in the project that is offered. In the analysis, meanings were attributed that allowed us to conclude that the therapeutic project pictures the theoretical reference framework recommended for psychosocial rehabilitation, which supports this service as a care practice, strengthening its link with users through the activities and the professionals that provide this care. However, we also found that the activities are procedures that create expectations and anguish among users and also evidence the possibilities, limits and range of team actions. The service’s actions mobilize the subjects in a positive as well as negative way. In this sense, professionals need to be motivated through supervision, training, continuous review of their professional technical praxis, with a view to carrying the intense burden of expectations and anguish patients place on the development of the activities. We believe that this work will allow professional teams in mental health care institutions to understand their psychiatric treatment approaches from the users’ perspective.

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