Thesis (M.H.A.)--University of Michigan, 1971.

Thesis (M.S.)--University of Michigan, 1991.

Thesis (M.B.A.)--University of Hong Kong, 1996. / Includes bibliographical references (leaf 136-147).

Thesis (M. Ed.)--University of Hong Kong, 1993.

Thesis (M.Ed.)--University of Hong Kong, 1993. / Also available in print.

Thesis (Ph. D.)--University of Michigan, 2004. / Includes bibliographical references (leaves 100-102).

Thesis (Ph. D.)--Princeton University, 1994. / Includes bibliographical references.

Thesis (M.S.)--University of Michigan, 1991.

Es gliomes sont des tumeurs cérébrales associées à une mortalité élevée. Le glioblastome multiforme (GBM) est la forme la plus fréquente des tumeurs cérébrales primaires. Malgré une prise en charge thérapeutique optimale constituée d'une chirurgie, d'une radiochimiothérapie concomitante et d'une chimiothérapie adjuvante, la survie médiane est de 15 mois. Ceci s'explique surtout par le potentiel infiltratif de ces tumeurs. Il est donc difficile de réaliser une exérèse chirurgicale totale, ce qui entraine une récidive quasi-systématique avec l'apparition de chimiorésistance. Ces phénomènes de résistances associés à une importante toxicité des molécules cytotoxiques mettent en évidence l'importance de rechercher de nouvelles stratégies thérapeutiques. Parmi ces dernières, les anticorps monoclonaux thérapeutiques sont très prometteurs, leurs actions ciblées limitent la toxicité au niveau du tissu sain. Cependant ces nouvelles thérapies manquent cruellement de suivi. L'apparition d'effets secondaires graves remet en cause leur intérêt. C'est pourquoi ces nouvelles thérapies, bien qu'efficaces, doivent être contrôlées par l'intermédiaire de biomarqueurs compagnons ce qui permettrait une meilleure efficience de la molécule. Le bevacizumab en est un bon exemple, de par une pharmacocinétique interindividuelle variable (de 11 à 50 jours) et une absence d'adaptation de la posologie on constate l'apparition d'effets secondaires (phlébite, hémorragie) qui entrainent l'arrêt du traitement. Or, ces effets secondaires pourraient être limités par un simple suivi de la concentration sérique de bevacizumab. De plus, dans le cas particulier des GBM, la présence de la barrière hémato-encéphalique (BHE) nécessite de développer de nouvelles stratégies pour favoriser une meilleure biodistrubution de molécules au niveau de la tumeur cérébrale. De ce fait, nous avons étudié l'efficacité d'un contournement de la BHE mécanique par une administration localisée directement dans la tumeur. Et dans cette étude préclinique, une amélioration significative de la médiane de survie des animaux ayant eu un traitement par CED (Convection Enhanced Delivery) par rapport à une administration intrapéritonéale. Enfin, dans le but de proposer une technique innovante de criblage de biomarqueurs compagnons, nous avons mis en place une stratégie innovante de marquage isotopique in vivo afin d'étudier la dynamique du protéome tumoral en réponse au traitement. Cette stratégie, déjà validée, est en cours de transfert chez l'homme dans l'étude du métabolisme des GBM. / Gliomas are brain tumors associated with important mortality. Glioblastoma multiforme (GBM) is the most frequent of primary brain tumors. Despite an optimal therapeutic management consists that includes surgery, radiotherapy plus concomitant and adjuvant chemotherapy, the median survival is 15 months. This, is mainly due to the presence of infiltrative tumor cells that hamper total surgical excision, and leads to relapse with the emergence of drug resistance. This highlights the importance of seeking new therapeutic strategies.Of these, therapeutic monoclonal antibodies are very promising. Their targeted actions limit the toxicity to healthy tissue. However, these new therapies are desperately short of monitoring. The appearance of serious side effects is a present challenge to their use. In consequences, these targeted therapies, even effective, have to be controlled via companion’s biomarkers that would provide better monitoring of the molecule. Bevacizumab is a good illustration for the existence of interindividual pharmacokinetic variability (11 to 50 days). In addition to its effect on the therapy efficiency, this inte variability must be also considered for side effects (phlebitis, hemorrhage) that lead to failure of treatment. However, these side effects could be limited by a simple monitoring of serum concentration of bevacizumab.Moreover, in the specific case of GBM, the action to the blood-brain barrier (BBB) requires the development of new strategies to promote a better bio-distribution of molecules in the brain tumor. Therefore, we investigated the effectiveness of a mechanical bypass of BBB in experimental brain tumors by a localized administration directly in the tumor. In this preclinical study, a significant improvement in median survival of animals treated with convection-enhanced delivery (CED) versus intraperitoneal administration was demonstrated.Finally, in order to offer an innovative technique of companion’s biomarkers screening, we have implemented an isotope labeling in vivo in order to study the dynamics of the proteome in tumor response to treatment. This strategy has already been released and is being transferred in humans in the study of the metabolism of GBM.

Submitted by VALÉRIA RIVEIRO (valclemos@hotmail.com) on 2016-12-21T13:41:47Z No. of bitstreams: 1 Versão final dissertação_Valéria Riveiro.pdf: 3531559 bytes, checksum: 4348a5f3abd70d3fbd922350b7d40eed (MD5) / Approved for entry into archive by Janete de Oliveira Feitosa (janete.feitosa@fgv.br) on 2016-12-27T12:00:00Z (GMT) No. of bitstreams: 1 Versão final dissertação_Valéria Riveiro.pdf: 3531559 bytes, checksum: 4348a5f3abd70d3fbd922350b7d40eed (MD5) / Made available in DSpace on 2017-01-03T17:23:28Z (GMT). No. of bitstreams: 1 Versão final dissertação_Valéria Riveiro.pdf: 3531559 bytes, checksum: 4348a5f3abd70d3fbd922350b7d40eed (MD5) Previous issue date: 2016-12-05 / The current scenario of a huge economic uncertainty, the speed of technological changes and the high competitiveness of companies in the reinsurance market present a great challenge for organizations in this sector that are looking for effective alternatives to ensure their survival. In this context, the importance of trust in leadership could be questioned as the main intangible asset that can generate a strategic differential and help the leaders of the researched company to understand the best practices to increase the retention of their talents. The surveyed company is considered a large 'aquarium' of skilled people in its industry and the loss of talent would pose a serious problem, which could threaten the sustainability of the business. Proactively, this research focused on the investigation of turnover intention as a variable capable of predicting how intensely an employee plans to leave the organization in the short term. Therefore, the main objective of this case study is t to understand the relationship between the trust in leadership and the intention of turnover of employees in the company surveyed. For this purpose, a bibliographic survey was initially carried out on the themes of turnover, trust, leadership and talents that originated the hypotheses tested. The research was typified as a quasi-experiment because it sought to identify if the intention of turnover occurred differently between the group of employees considered as talents and the other employees of the control group, selected according to the Mahapick technique that guaranteed pairing between the treated group and the control group. Afterwards, the questionnaires made available electronically were Managerial Trust (MT), Behavioral Trust Inventory (BTI), Multifactor Leadership Questionnaire (MLQ) and Turnover Intention (IT) in order to obtain data for analysis. The sample used had 48 respondents and the data obtained were statistically analyzed through modeling of structural equations. As a main result, this research showed that there are no significant differences between the intention of turnover of the talent group and the control group. In addition, it has been observed that transformational leadership reduces turnover intention while passive leadership has the opposite effect. Finally, organizational trust acts as a mediator in the relationship with transformational leadership, significantly reducing turnover intention. / O cenário atual de maior incerteza econômica, a velocidade das mudanças tecnológicas e a alta competitividade entre as empresas no mercado de resseguros trazem um grande desafio para as organizações desse setor, que buscam alternativas eficazes para assegurar a sua sobrevivência. Nesse contexto questiona-se a importância da confiança na liderança enquanto principal ativo intangível que pode gerar um diferencial estratégico e ajudar os líderes da empresa pesquisada a compreender quais são as melhores práticas para aumentar a retenção de seus talentos. A empresa pesquisada é considerada um grande 'aquário' de mão de obra especializada em seu setor de atuação e a perda de talentos representaria um grave problema, que poderia ameaçar a sustentabilidade dos negócios. De forma proativa, esta pesquisa se debruçou na investigação da intenção de turnover como variável capaz de prever com que intensidade um empregado planeja deixar a organização no curto prazo. Portanto, o objetivo principal deste estudo de caso é compreender a relação entre a confiança na liderança e a intenção de turnover dos empregados na empresa pesquisada. Para tanto, inicialmente foi realizado um levantamento bibliográfico sobre os temas intenção de turnover, confiança, liderança e talentos que originaram as hipóteses testadas. A pesquisa foi tipificada como quase experimento porque buscou identificar se a intenção de turnover ocorria de maneira diferenciada entre o grupo de empregados considerados talentos e os demais empregados do grupo de controle, selecionados de acordo com a técnica Mahapick que garantiu pareamento entre o grupo tratado e o grupo de controle. Na sequência, foram aplicados os questionários disponibilizados eletronicamente Managerial Trust (MT), Behavioral Trust Inventory (BTI), Multifactor Leadership Questionnaire (MLQ) e Turnover Intention (TI), a fim de obter os dados para análise. A amostra utilizada teve 48 respondentes e os dados obtidos foram analisados estatisticamente via modelagem de equações estruturais. Como principal resultado, esta pesquisa mostrou que não existem diferenças significativas entre a intenção de turnover do grupo de talentos e do grupo de controle. Além disso, observou-se que a liderança transformacional reduz a intenção de turnover enquanto a liderança passiva tem efeito contrário. Por fim, a confiança organizacional atua como mediadora na relação com a liderança transformacional reduzindo de maneira significante a intenção de turnover.