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Glioblastoma is the most common and lethal malignant brain tumor with a survival rate of 14.6 months and a tumor recurrence rate of ninety percent. Two key causes for glioblastomas grim outcome derive from the lack of applicable prognostic markers and effective therapeutic targets. By employing a loss of function RNAi screen in glioblastoma cells we found a list of 20 kinases that can be considered glioblastoma survival kinases. These survival kinases which we term as survival kinase genes, (SKGs) were investigated to find prognostic markers as well as therapeutic targets for glioblastoma. Analyzing these survival kinases in The Cancer Genome Atlas patient database, we found that CDCP1, CDKL5, CSNK1𝜀, IRAK3, LATS2, PRKAA1, STK3, TBRG4, and ULK4 genes could be used as prognostic markers for glioblastoma with or without temozolomide chemotherapeutic treatment as a covariate. For the first time, we found that patients with increased levels of NEK9 and PIK3CB mRNA expression had a higher probability of recurrent tumors. We also discovered that expression of CDCP1, IGF2R, IRAK3, LATS2, PIK3CB, ULK4, or VRK1 in primary glioblastoma tumors was associated with tumor recurrence prognosis. To note, of these recurrent prognostic candidates, PIK3CB expression in recurrent tumor tissue had much higher expression compared to primary tissue. Further investigation in the PI3K pathway showed a strong correlation with recurrence rate, days to recurrence and survival emphasizing the role of PIK3CB in tumor recurrence in glioblastoma. In efforts to find effective therapeutic targets for glioblastoma we used SKGs as potential candidates. We chose the serine/threonine kinase, Casein Kinase 1 Epsilon (CSNK1𝜀) as a target for glioblastoma because multiple shRNAs targeted this gene in our loss of function screen and multiple commercially available inhibitors of this gene are available. Casein kinase 1 epsilon protein and mRNA expression were investigated using computational tools. It was revealed that CSNK1𝜀 expression has higher expression in glioblastoma than normal tissue. To further examine this gene we knocked down (KD) or inhibited CSNK1𝜀 in glioblastoma cells lines and noticed a significant increase in cell death without any significant effect on normal cell lines. KD and inhibition of CSNK1𝜀 in cancer stem cells, a culprit of tumor recurrence, also revealed limited self-renewal and proliferation in cancer stem cells and a significant decrease in cell survival without affecting normal stem cells. Further analysis of downstream effects of CSNK1𝜀 knockdown and inhibition indicate a significant increase in the protein expression of β-catenin (CTNNB1). We found that CSNK1𝜀 KD activated β-catenin, which increased GBM cell death, but can be rescued using CTNNB1 shRNA. Our survival kinase screen, computational analyses, patient database analyses and experimental methods contributed to the discovery of novel prognostic markers and therapeutic targets for glioblastoma. / Ph. D.

In the present study, the author builds upon the single degree of freedom ice-structure interaction model initially proposed by Matlock, et al. (1969, 1971). The model created by Matlock, et al. (1969, 1971), assumed that the primary response of the structure would be in its fundamental mode of vibration. In order to glean a greater physical understanding of ice-structure interaction phenomena, it was critical that this study set out to develop a multi-mode forced response for the pier when a moving ice floe makes contact at a specific vertical pier location. Modal analysis is used in which the response of each mode is superposed to find the full modal response of the entire length of a pier subject to incremental ice loading. This incremental ice loading includes ice fracture points as well as loss of contact between ice and structure. In this model, the physical system is a bottom supported pier modeled as a cantilever beam. The frequencies at which vibration naturally occurs, and the mode shapes which the vibrating pier assumes, are properties which can be determined analytically and thus a more precise picture of pier vibration under ice loading is presented. Realistic conditions such as ice accumulation on the pier modeled as a point mass and uncertainties in the ice characteristics are introduced in order to provide a stochastic response. The impact of number of modes in modeling is studied as well as dynamics due to fluctuations of ice impact height as a result of typical tidal fluctuations. A Poincaré based analysis following on the research of Karr, et al. (1992) is employed to identify any periodic behavior of the system response. Recurrence plotting is also utilized to further define any existing structure of the ice-structure interaction time series for low and high speed floes. The intention of this work is to provide a foundation for future research coupling multiple piers and connecting structure for a comprehensive ice-wind-structural dynamics model. / Master of Science

INTRODUÇÃO: Aproximadamente 50% dos pacientes com tumor colorretal apresentam metástase hepática e a hepatectomia é o procedimento terapêutico de escolha. Discutem-se diversos fatores prognósticos, entre eles a margem cirúrgica é um fator sempre recorrente, pois não existe consenso da distância mínima necessária entre o nódulo metastático e a linha de secção hepática. Alguns autores identificaram que a margem cirúrgica maior que 1cm é um fator de melhor prognóstico com maior sobrevida e menor recidiva. Contudo, outros estudos demonstram resultados semelhantes entre pacientes com margens cirúrgicas maiores que 1cm, exíguas e até mesmo microscopicamente acometidas. Essas controvérsias conduzem à idéia de que outros fatores biológicos possam estar envolvidos na fisiopatologia de recorrência. Assim sendo, é de grande importância a avaliação da relação das margens cirúrgicas de ressecções hepáticas de metástases de câncer colorretal com a sobrevida e recidiva da doença. OBJETIVOS: Avaliar as margens cirúrgicas e o tipo de borda tumoral nas ressecções de metástases hepáticas de câncer colorretal e sua correlação com recidiva local e sobrevida. MÉTODOS: Estudo retrospectivo, baseado na revisão dos prontuários de 91 pacientes submetidos à ressecção de metástases hepáticas de neoplasia colorretal, durante o período compreendido entre janeiro de 2000 e dezembro de 2009. Revisão histopatológica prospectiva de todos os casos com aferição da menor margem cirúrgica e classificação das bordas tumorais como expansiva ou infiltrativa. RESULTADOS: Não houve diferença estatística nas taxas de recidiva e no tempo de sobrevivência global entre as margens livres e acometidas, assim como não houve diferença entre as margens subcentimétricas e maiores de 1cm. A sobrevida livre de doença dos pacientes com margens microscopicamente acometidas foi significativamente menor do que os pacientes com margens livres (p=0,002). A análise multivariada identificou o tipo de borda infiltrativa como fator de risco para recidiva (0,05). A sobrevida livre de doença foi significativamente menor nos pacientes com borda infiltrativa em comparação com os tumores com bordas expansivas (p=0,05). CONCLUSÕES: As ressecções de metástase hepática com margens livres de doença, independentemente da distância da margem, não influencia na recidiva tumoral (hepática ou extra-hepática) ou sobrevida do paciente. A borda tumoral do tipo infiltrativa foi fator de risco para recidiva / INTRODUCTION: Approximately 50% of patients with colorectal cancer have liver metastases and hepatectomy is the therapeutic procedure of choice. Surgical margin is an ever-recurring discussed prognostic factor, because there is no consensus of the minimum required distance between the metastatic nodule and the liver section line. Some authors reported surgical margin larger than 1 cm as a better prognosis factor ensuring longer survival rates and lower recurrence. However, other studies showed similar outcomes among patients with surgical margins larger than 1 cm, narrow margins and even microscopically affected ones. These controversies led the idea that other biological factors may be involved in the pathophysiology of recurrence. Therefore, it is valuable to assess the relationship between surgical margins of liver resection for colorectal cancer metastases with survival and recurrence. OBJECTIVES: To evaluate the surgical margins size and tumors growth pattern of colorectal liver metastases and its correlation with local recurrence and survival. METHODS: A retrospective study based on review of medical records of 91 patients undergoing resection of colorectal liver metastases during the period between January 2000 and December 2009. In addition, we undertook a detailed pathologic analysis of each pathological specimen with record of the closest surgical margins and tumors growth pattern classification as pushing or infiltrative. RESULTS: There was no statistical difference in recurrence rates and overall survival time between positive or negative margins, as well as no difference between the margins of 1cm width or more with subcentimeter margins. The disease-free survival of patients with microscopically positive margins was significantly lower than patients with negative margins (p = 0.002). Multivariate analysis identified infiltrative tumor growth pattern as a risk factor for recurrence (p=0.05). Disease-free survival was significantly lower in patients with infiltrative growth pattern compared to tumors with expansive margins (p = 0.05). CONCLUSIONS: Colorectal liver metastases resection with negative margins, regardless of width, has no influence on recurrence (hepatic or extrahepatic), neither on patient survival. The infiltrative tumor growth pattern type was a risk factor for recurrence

Made available in DSpace on 2016-01-26T12:51:30Z (GMT). No. of bitstreams: 1 margaretearticobaptista_tese.pdf: 3014770 bytes, checksum: a4b4de19204259991aae1ec3ae61a0aa (MD5) Previous issue date: 2011-10-07 / In the last 30 years, the increasing health care expenditures resulted in an outburst of studies aimed at new proposals on the methodological evaluation of health services. With the aid of computing, several studies have been developed with the purpose of analyzing nonlinear and complex systems. The most outstanding among those methods was the Recurrence Plot, first described by Erickman et al. (1987).Objectives: To analyze the temporal behavior of the weekly amount of admissions by some nosologic groups (Appendix Diseases, Bacterial Diseases, Neoplastic Disease, and Acute Coronary Syndrome), which has occurred over a decade, through Recurrence Plots and Poincaré Recurrence Plots, as well as checking whether the systems are presenting a periodic, chaotic, or random behavior pattern. Material and Methods: The database containing all hospitalizations recorded at the Hospital de Base Regional Medical School Foundation (FUNFARME) of Sao Jose do Rio Preto, a teaching hospital, from January 1, 1998 to December 31, 2007 was peered into a microscope. As a reference to classify all these admissions, the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) was used. The Microsoft Office Excel 2003® was the software used to arrange the data into columns. The admissions were systematically set to the right array, such as day, month, and year. They were arranged into columns according to the uniform criteria of identification of the epidemiological weeks. The recurrence graphs and the respective quantitative analyses of recurrence were developed with the aid of the Visual Recurrence Analysis (VRA) software, which is freely available on the Internet. To perform the comparison among the behavior patterns, mathematical models of time series for random behavior pattern, series time for chaotic behavior pattern, series times for periodic behavior pattern, and series time for linear behavior pattern were constructed. And it has also been performed a comparison between the Recurrence Plots and the Quantitative Analysis of Recurrence with clinical cases of specific groups (young, adult, child, premature newborn, and brain death).Results: It has become clear that the number of weekly admissions for diseases of the appendix has had a tendency over the years from a random behavior pattern. In hospitalizations due to bacterial diseases, there was a chaotic behavior pattern and the neoplastic diseases showed a chaotic behavior pattern tending to a linear behavior pattern. Hospitalizations because of Acute Coronary Syndrome presented a predominantly linear behavior pattern. Conclusions: The visual aspects of Recurrence Plot and Poincaré Recurrence plot exhibited different patterns when comparing quantities of admissions of certain nosologic groups over a decade. The quantitative analysis of recurrence that was useful in classifying the behavior pattern of the quantities of admissions is likely to constitute a useful tool of evaluation and decision making regarding hospital administration. / Nos últimos trinta anos, o crescimento dos gastos com a atenção médica resultou numa expansão dos estudos voltados para novas propostas metodológicas sobre avaliação dos serviços de saúde. Com a utilização da informática, vários estudos têm sido desenvolvidos para análise de sistemas complexos e não lineares, destacando-se, entre esses métodos, os gráficos de recorrência, descritos pela primeira vez por Erickman et al. (1987). Objetivos: Analisar o comportamento temporal da quantidade semanal de internações por alguns grupos nosológicos (Doenças do Apêndice, Doenças Bacterianas, Doenças Neoplásicas e por Síndrome Coronária Aguda) ocorridas ao longo de uma década, por meio de Gráficos de Recorrência e Gráficos de Poincaré e verificar se são sistemas que apresentam comportamentos periódicos, aleatórios ou caóticos. Material e Método: Foi avaliado o banco de dados contendo todas as internações no Hospital de Base da Fundação Faculdade Regional de Medicina de São José do Rio Preto, no período de 01 de janeiro de 1998 a 31 de dezembro de 2007. Como referência para classificação dessas internações, utilizou-se a Décima Revisão da Classificação Internacional de Doenças e de Problemas Relacionados à Saúde (CID 10). Foi utilizado o programa Microsoft Office Excel 2003 para a tabulação dos dados. As internações foram ordenadas em dia, mês, ano e tabuladas, seguindo o critério uniforme de identificação das semanas epidemiológicas. Os gráficos de recorrência e respectiva análise quantitativa foram construídos com o auxílio do software Visual Recurrence Analysis (VRA), disponível gratuitamente na Internet. Para realizar a comparação de padrões de comportamentos foram construídos modelos matemáticos de séries temporais aleatória, caótica, periódica e linear. E também foi realizada comparação entre Gráficos de Recorrência e Análise Quantitativa da Recorrência com casos clínicos de grupos específicos (jovem adulto, criança, Recém- nascido prematuro e morte cerebral). Resultados: Evidenciou-se que a quantidade de internações semanal por doenças do apêndice tiveram uma tendência ao longo dos anos de comportamento aleatório. Nas internações por doenças bacterianas houve comportamento caótico e as internações por doenças neoplásicas apresentaram um comportamento caótico tendendo a linear. As internações por Síndrome Coronária Aguda apresentaram predominantemente comportamento linear, Conclusões: Os aspectos visuais dos Gráficos de Recorrência e de Poincaré exibiram padrões diferentes na comparação entre quantidades de internações de determinados grupos nosológicos ao longo de uma década. A análise quantitativa da recorrência que auxiliou na classificação do comportamento das quantidades de internações e pode constituir-se em ferramenta útil de avaliação e tomada de decisão em administração hospitalar.

O transplante de fígado é definido como a terapêutica de escolha para as doenças hepáticas em estágio terminal. Por muitos anos, o sucesso deste procedimento foi mensurado pelas taxas de mortalidade e a freqüência de complicações nas anastomoses biliares e complicações infecciosas. No entanto, mais recentemente um novo foco de preocupação voltou-se para a avaliação da qualidade de vida no grupo de pacientes transplantados. Os benefícios do transplante hepático sobre a qualidade de vida dos pacientes é um evento já demonstrado previamente em alguns estudos que utilizaram questionários genéricos de avaliação de qualidade de vida. A qualidade de vida em saúde também pode ser acessada através de questionários específicos, como o LDQOL (Liver Disease Quality of Life). Este é um instrumento voltado especificamente para sintomas relacionados às doenças hepáticas, desenvolvido nos Estados Unidos e recentemente traduzido para o Português e adaptado culturalmente para à população brasileira. Objetivo Aplicar este novo instrumento na população de pacientes em lista de espera de transplante de fígado e naqueles submetidos a transplante, reavaliando diferentes aspectos da qualidade de vida destes pacientes e avaliando o impacto da recidiva da doença de base após o transplante hepático. Método: Foram aplicados os questionários LDQOL e SF?36 a 126 pacientes em acompanhamento ambulatorial regular no Serviço de Transplante e Cirurgia do Fígado do Hospital das Clínicas da Universidade de São Paulo, dos quais 65 eram pacientes cirróticos em lista de espera de transplante de fígado e 61 deles eram pacientes submetidos a transplante hepático há pelo menos 6 meses e no máximo há 60 meses. Também foi aplicado o questionário SF-36 a um grupo de doadores de sangue sadios, pareados por sexo e idade e que funcionou como grupo controle. As avaliações, realizadas a partir da formação destes 3 grupos, incluiram a comparação da qualidade de vida entre cirróticos e transplantados, a comparação entre indivíduos saudáveis e portadores de hepatopatia e a influência de outros aspectos como etiologia da doença hepática, escore do MELD, classificação de Child-Pugh, presença de co-morbidades, tempo decorrido do transplante e efeito da recidiva da doença hepática sobre a qualidade de vida do paciente transplantado. O método estatístico aplicado foi o teste de Mann- Whitney. Resultados: As pontuações atingidas para os pacientes em lista de transplante hepático para mensuração da qualidade de vida foram significantemente mais baixas do que aquelas atingidas pelo grupo controle. Na comparação entre cirróticos com MELD <= 15 e cirróticos com MELD > 15, tanto o SF-36 como o LDQOL mostraram pior qualidade de vida nos pacientes com MELD mais elevado. A comparação entre indivíduos antes e depois do transplante evidenciou melhor qualidade de vida no grupo de pacientes transplantados. Isto ficou evidenciado tanto pelo LDQOL como SF-36. No grupo de pacientes pré-transplante, o questionário LDQOL mostrou maior comprometimento da qualidade de vida naqueles pacientes com cirrose por VHC, quando comparado a outras etiologias, enquanto o SF-36 não teve a mesma acurácia em demonstrar esta diferença. Nos pacientes transplantados, a recidiva da hepatite C determina comprometimento da qualidade de vida, quando avaliados pelo LDQOL, mas não pelo SF-36. Conclusões: O uso de um instrumento de medida de qualidade de vida - o LDQOL - pôde demonstrar, com maior acurácia, o seu comprometimento nos pacientes cirróticos, a melhora observada nos pacientes transplantados e o impacto negativo da recidiva da hepatite C no pós-transplante. / Liver transplantation has been established as the standard treatment for patients with end stage liver disease and for many years the outcomes of its procedure has been measured as mortality rates and biliary and infectious complications. More recently a new issue has been raised and many studies have been changing the focus to analyze the health related quality of life among the population of transplanted patients. A positive effect of liver transplantation on health-related quality of life (HRQOL) has been documented in many studies using generic instruments. Health-related quality of life can also be assessed with specific instruments, as the Liver Disease Quality of Life(LDQOL), a questionnaire targeted to symptoms of hepatic disease, that has been recently translated to Portuguese and culturally adapted to Brazilian population. Our aim was to reevaluate different aspects of HRQOL before and after liver transplantation with this new instrument, and determinate the impact of liver disease recurrence after the surgical procedure. Methods: The LDQOL and SF-36 questionnaires were applied to 126 patients at the Service of Transplant and Liver Surgery of Clinical Hospital of University of São Paulo, 65 of them on the transplant waiting list and 61 of them after 6 to 60 months of liver transplantation. It was also analyzed the quality of life, by using the SF-36 questionnaire, of health blood donors, paired by sex and age, to serve as control group. Multiple comparisons were made concerning etiology of cirrhosis, co-morbidities, MELD scores, time elapsed of transplant, recurrence of liver disease after liver transplantation, using the Mann-Whitney test. Results: HRQOL scores for patients waiting for transplantation were significantly lower than those for the control group. Patients with MELD scores > 15 showed worse healthrelated quality of life than patients with MELD scores <= 15, both with SF-36 and LDQOL. When the group of transplanted patients was compared with patients before transplant, an improvement of HRQOL was found in the transplanted group with both SF-36 and LDQOL. Quality of life in pretransplant patients was found to be worse in those with cirrhosis due to hepatitis C than in those with cirrhosis due to other etiologies; the reduction in quality of life was found to be greater using LDQOL than using SF-36. Transplanted patients with recurrence of hepatitis C had worse HRQOL when measured with LDQOL, but not with SF-36. Conclusions: LDQOL, a specific instrument for measuring quality of life is more reliable than SF-36 in showing quality of life impairment. A deterioration in health-related quality of life after recurrence of hepatitis C could be observed with LDQOL.

In this thesis we study the zeros and asymptotics of sequences that satisfy linear recurrence relations with generally nonconstant coefficients. By the theorem of Skolem-Mahler-Lech, the set of zero terms of a sequence that satisfies a linear recurrence relation with constant coefficients taken from a field of characteristic zero is comprised of the union of finitely many arithmetic progressions together with a finite exceptional set. Further, in the nondegenerate case, we can eliminate the possibility of arithmetic progressions and conclude that there are only finitely many zero terms. For generally nonconstant coefficients, there are generalizations of this theorem due to Bézivin and to Methfessel that imply, under fairly general conditions, that we obtain a finite union of arithmetic progressions together with an exceptional set of density zero. Further, a condition is given under which one can exclude the possibility of arithmetic progressions and obtain a set of zero terms of density zero. In this thesis, it is shown that this condition reduces to the nondegeneracy condition in the case of constant coefficients. This allows for a consistent definition of nondegeneracy valid for generally nonconstant coefficients and a unified result is obtained. The asymptotic theory of sequences that satisfy linear recurrence relations with generally nonconstant coefficients begins with the basic theorems of Poincaré and Perron. There are some generalizations of these theorems that hold in greater generality, but if we restrict the coefficient sequences of our linear recurrences to be polynomials in the index, we obtain full asymptotic expansions of a predictable form for the solution sequences. These expansions can be obtained by applying a transfer method of Flajolet and Sedgewick or, in some cases, by applying a bivariate method of Pemantle and Wilson. In this thesis, these methods are applied to a family of binomial sums and full asymptotic expansions are obtained. The leading terms of the expansions are obtained explicitly in all cases, while in some cases a field containing the asymptotic coefficients is obtained and some divisibility properties for the asymptotic coefficients are obtained using a generalization of a method of Stoll and Haible.

Made available in DSpace on 2014-06-11T19:25:31Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-02-19Bitstream added on 2014-06-13T20:53:31Z : No. of bitstreams: 1 abud_cv_me_rcla.pdf: 2091525 bytes, checksum: f8a3b24150a2a718ad53ff294a3c6844 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Procuramos nesta dissertação, entender e desenvolver estudos relacionados com o movimento de trajetórias caóticas num sistema dinâmico não linear. Esses estudos, envolvem uma abordagem sobre a quantificação de recorrências de trajetórias a uma região e sobre o transporte no espaço de fases. Nós escolhemos como modelo o bilhar anular em duas configurações: primeiramente com as fronteiras estáticas e posteriormente, uma dependência temporal (pulsante) e introduzida. Inicialmente reproduzimos os resultados sobre aprisionamentos para caso do bilhar estático, existentes na literatura, a fim de ganharmos experiência para estudar o sistema pulsante. Nesse caso, a topologia dos dois planos de fases possíveis constituídos de variáveis canônicas, apesar de bastante complexas, apresentaram resultados interessantes. Os principais resultados obtidos foram: a observação de regiões de aprisionamentos nos dois planos de fases conectadas entre si; a aceleração de Fermi caracterizada por vários regimes anômalos; ( uma explicação para a diferença desses regimes e dada por aprisionamentos no plano do bilhar) e a evolução do espaço de fases, dito geométrico, que tende a se recuperar conforme a velocidade relativa partícula-fronteira aumenta. Estudamos ainda os efeitos de dissipação no sistema pulsante através de colisões inelásticas. Os resultados indicam que qualquer dissipação desse tipo, independente da magnitude, é suficiente para saturar o crescimento de energia. Porém, em situações especiais essa mesma dissipação pode ser usada para que na média o sistema ganhe energia. / We reach in this dissertation, understand and develop studies related to the motion of the chaotic trajectories in a non-linear dynamical system. These studies require an approach on the quanti cation of the recurrences of trajectories to a region and on the transport in the phase space. We choose as a model the annular billiard with two con gurations: rstly with the static boundaries and next, a time-dependent (pulsating)is introduced. Initially we reproduced some results about stickiness in the static case in order to gain experience to study the pulsating system. In such case the topology of the two possible phase space of canonical variables, showed interesting results. The main results were: the observation of sticky regions in both connected phase spaces; the Fermi acceleration characterized by di erent anomalous regimes ( an explanation to this diferent regimes is given by the stickiness on the billiard plane) and the evolution of the phase space, called geometric, which tends to be recovered as the relative velocity particle-boundary increases. We also studied the e ects of dissipation in the pulsating system through inelastic collisions. The results show that this kind of dissipation, regardless of its magnitude, is enough to saturate the energy growth. However, in special situations the mean average of the system can increase with the introduction of inelastic collisions.