In recent times, there has been an increasing interest in adaptive designs for clinical trials. As opposed to conventional designs, adaptive designs allow flexible design adaptation in the middle of a trial based on accumulated data. Although various models have been developed using both frequentist and Bayesian perspectives, relative statistical performances of adaptive designs are somewhat controversial and little is known about those of Bayesian adaptive designs. Most comparison studies also focused on single experimental treatment rather than multiple experimental treatments. In this report, both frequentist and Baysian adaptive designs were compared in terms of statistical power by a simulation study, assuming the situation when multiple experimental treatments are tested in multiple stages. The designs included in the current study are group sequential design (frequentist), adaptive design based on combination tests (frequentist), and Bayesian adaptive design (Bayesian). Based upon the results under multiple scenarios, the Bayesian adaptive design showed the highest power, and the design based on combination tests performed better than group sequential designs when proper interim adaptation could be conducted to increase power. / text

Breast cancer is the most common malignancy diagnosed among women and is the first cause of neoplastic death in women globally. In the last decade our understanding of breast cancer biology has increased and led to the development of a number of targeted therapies, one of which is targeting the cell apoptosis pathway. One of the new targeting pathways under investigation, which was found to be involved in both cell apoptosis and cell proliferation processes, is the sphingolipid signalling pathway. The sphingolipid pathway represents a group of intracellular and extracellular bioactive lipid molecules, including ceramide, ceramide- 1-phosphate, sphingosine, and sphingosine-1-phosphate (S1P). In my research, I focused on the role S1P plays in breast cancer and its potential application as a therapeutic agent. I examined the effects of S1P on the apoptosis, proliferation, and cytotoxicity of different types of breast cancer cell lines in vitro. In addition, I evaluated the effect of both low and high doses of S1P when co-administrated with anticancer drugs commonly used in breast cancer treatment in vitro and in vivo. Moreover, I studied the S1P cellular distribution following exogenous administration. My results demonstrate that S1P can selectively induce apoptosis in breast cancer cells without harming normal breast cells and that S1P is more effective against aggressive breast cancer cells. Another major finding of my study is that S1P can increase the efficacy of chemotherapies against human breast cancer cells. Although S1P cannot directly substitute the current chemotherapies, S1P may function as a good candidate for combination therapy. Furthermore, my work showed that the pro-apoptotic and anti-proliferative effect of S1P is correlated with its intracellular action and that chronic exposure of exogenous S1P in vivo is not toxic to the major organs. Certainly, S1P inclusion in breast cancer treatment modalities may decrease the morbidity and mortality of breast cancer patients and improve clinical outcomes. Further investigations are required to understand the mechanism by which S1P induces apoptosis and inhibits cell proliferation.

Several wild-type poxviruses have emerged as potential oncolytic viruses (OVs), including orf virus (OrfV), and vaccinia virus (VV). Oncolytic VVs have been modified to include attenuating mutations that enhance their tumour selective nature, but these mutations also reduce overall viral fitness in cancer cells. Previous studies have shown that a VV (Western Reserve) with its E3L gene replaced with the E3L homologue from, OrfV (designated VV-E3LOrfV), maintained its ability to infect cells in vitro, but was attenuated compared to its parental VV in vivo. Our goal was to determine the safety and oncolytic potential VV-E3LOrfV, compared to wild type VV and other attenuated recombinants. VV-E3LOrfV, was unable to replicate to the same titers and was sensitive to IFN compared to its parental virus and other attenuated VVs in normal human fibroblast cells. The virus was also less pathogenic when administered in vivo. Viral replication, spread and cell killing, as measures of oncolytic potential in vitro, along with in vivo efficacy, were also observed.. The Parapoxvirus, OrfV has been shown to have a unique immune-stimulation profile, inducing a number of pro-inflammatory cytokines, as well as potently recruiting and activating a number of immune cells. Despite this unique profile, OrfV is limited in its ability to replicate and spread in human cancer cells. Various strategies were employed to enhance the oncolytic efficacy of wild-type OrfV. A transient transfection/infection screen was created to determine if any of the VV host-range genes (C7L, K1L, E3L or K3L) would augment OrfV oncolysis. Combination therapy, including the use of microtubule targeting agents, Viral Sensitizer (VSe) compounds and the addition of soluble VV B18R gene product were employed to see if they also enhance OrfV efficacy. Unfortunately, none of the strategies mentioned were able to enhance OrfV.

Thesis is focused on a combination game of football as a way of consecutive offensive and also on the way of defending in this game style. It is based on both theoretical sources and original research conducted in the club SK Slavia Prague and also on the analysis of Champions League matches from year 2011. The outcomes of this thesis will be found in use as a source of information for practice trainers. Key words: Football, combination, offensive phase, defending, pass

The human visual system gathers information about three-dimensional object shape from a wide range of sources. How effectively we can use these sources, and how they are combined to form a consistent and accurate percept of the 3D world is the focus of much research. In complex scenes inter-reflections of light between surfaces (mutual illumination) can occur, creating chromatic illumination gradients. These gradients provide a source of information about 3D object shape, but little research has been conducted into the capabilities of the visual system to use such information. The experiments described here were conducted with the aim of understanding the influence of chromatic gradients from mutual illumination on 3D shape perception. Psychophysical experiments are described that were designed to investigate: If the human visual system takes account of mutual illumination when estimating 3D object shape, and how this might occur; How colour shading cues are integrated with other shape cues; The relative influence on 3D shape perception of achromatic (luminance) shading and chromatic shading from mutual illumination. In addition, one chapter explores a selection of mathematical models of cue integration and their applicability in this case. The results of the experiments suggest that the human visual system is able to quickly assess and take account of colour mutual illuminations when estimating 3D object shape, and use chromatic gradients as an independent and effective cue. Finally, mathematical modelling reveals that the chromatic gradient cue is likely integrated with other shape cues in a way that is close to statistically optimal.

The method of combination p-values from multiple tests is the foundation for some studies like meta-analysis and detection of signal. There are tremendous methods have been developed and applied like minimum p-values, Cauchy Combination, goodness-of-fit combination and Fisher’s combination. In this paper, I tested their ability to detect signals which is related to real case in biology to find out significant single-nucleotide polymorphisms (SNPs). I simulated p-values for SNPs logistics regression model and test 7 combination methods’ power performance in different setting conditions. I compared sparse or dense signals, dependent or independent and combine them in gene-level or pathway-level. One method based on Fisher’s combination called Omni-TFisher is ideal for most of the situations. Recent years, genome-wide association studies (GWASs) focused on BMD-related SNPs at gene significance level. In this paper I used Omni-TFisher to analyses real data on haplotype blocks. As a result, haplotype blocks can find more SNPs in non-coding and intergeneric regions than gene-based and save computational complexity. It finds out not only known genes, but also other genes need further verification.

A combinação de algoritmos tem despertado interesse para melhorar o desempenho de filtros adaptativos. Esse método consiste em combinar linearmente as saídas de dois filtros operando em paralelo com passos de adaptação diferentes para se obter um filtro com conver- gência rápida e um erro quadrático médio em excesso (EMSE - excess mean squared error) reduzido. Nesse contexto, foi proposta a combinação afim de dois algoritmos LMS (least-mean square), cujo parâmetro de mistura não fica restrito ao intervalo [0, 1] e por isso é considerada como uma generalização da combinação convexa. Neste trabalho, a combinação afim de dois algoritmos LMS é estendida para os algoritmos supervisionados NLMS (normalized LMS) e RLS (recursive least squares) e também para equalização autodidata, usando o CMA (constant modulus algorithm). Foi feita uma análise em regime da combinação afim desses algoritmos de forma unificada, considerando entrada branca ou colorida e ambientes estacionários ou não- estacionários. Através dessa análise, verificou-se que a combinação afim de dois algoritmos da mesma família pode apresentar uma redução de EMSE de até 3 dB em relação ao EMSE de seus filtros componentes e conseqüentemente ao EMSE da combinação convexa. Para garantir que a estimativa combinada seja pelo menos tão boa quanto a do melhor filtro componente, foram propostos e analisados três novos algoritmos para adaptação do parâmetro de mistura. Utilizando resultados da análise desses algoritmos em conjunto com os resultados da análise de transitório de filtros adaptativos, analisou-se o comportamento transitório da combinação afim. Através de simulações, observou-se uma boa concordância entre os resultados analíticos e os de simulação. No caso de equalização autodidata, também foi proposta uma combinação de dois equalizadores CMA com inicializações diferentes. Verificou-se através de simulações que em alguns casos a combinação afim é capaz de evitar a convergência para mínimos locais da função custo do módulo constante. / In order to improve the performance of adaptive filters, the combination of algorithms is receiving much attention in the literature. This method combines linearly the outputs of two filters operating in parallel with different step-sizes to obtain an adaptive filter with fast convergence and reduced excess mean squared error (EMSE). In this context, it was proposed an affine combination of two least-mean square (LMS) filters, whose mixing parameter is not restricted to the interval [0, 1]. Hence, the affine combination is a generalization of the convex combination. In this work, the affine combination of two LMS algorithms is extended to the supervised algorithms NLMS (normalized LMS) and RLS (recursive least squares), and also to blind equalization, using the constant modulus algorithm (CMA). A steady-state analysis of the affine combination of the considered algorithms is presented in a unified manner, assuming white or colored inputs, and stationary or nonstationary environments. Through the analysis, it was observed that the affine combination of two algorithms of the same family can provide a 3 dB EMSE gain in relation to its best component filter and consequently in relation to the convex combination. To ensure that the combined estimate is at least as good as the best of the component filters, three new algorithms to adapt the mixing parameter were proposed and analyzed. Using the analysis results of these algorithms in conjunction with the results of the transient analysis of adaptive filters, the transient behavior of the affine combination was analyzed. Through simulations, a good agreement between analytical and experimental results was always observed. In the blind equalization case, a combination of two CMA equalizers with different initializations was also proposed. The simulation results suggest that the affine combination can avoid local minima of the constant modulus cost function.

O propósito desta tese foi investigar as operações de fusões e aquisições - F&A, uma subárea do que se denomina \"combinação de negócios\", observadas entre firmas brasileiras no período de 2002 a 2006, em que ao menos uma delas (firma \"bidder\" ou firma \"target\") fosse listada na Bovespa. Não foram amostradas fusões e aquisições celebradas entre firmas sob um mesmo controle, excluindo dessa forma as incorporações reversas. Foram amostrados 101 anúncios (1º Fato Relevante arquivado) envolvendo 104 operações, totalizando R$ 223,7 bilhões, ou 66,86% do universo que integrou o ranking da ANBID de 2002 a 2006. Duas técnicas foram utilizadas: o estudo de eventos por retornos ao redor dos anúncios e o estudo de eventos amparado por métricas contábeis. Para fins de amostragem, além da base de dados da ANBID, foi utilizada a base da Economática, a base da \"Melhores e Maiores\" e o sistema IPE da CVM/Bovespa. As evidências empíricas e os testes estatísticos conduziram à conclusão de que o anúncio das operações de fusão e aquisição criou expectativas de maximização de valor para os acionistas das firmas combinadas. Contudo, para os acionistas das firmas \"target\", na ocorrência de uma OPA, com a possibilidade da tensão durante o processo de definição do prêmio de controle a ser pago a acionistas não controladores, especialmente se investidores institucionais como fundos de pensão integram o grupo de não controladores, o anúncio das operações de fusão e aquisição foi precificado de modo diferenciado entre ações ordinárias e preferenciais, causando no mercado uma reação similar à hipótese da miopia, um fenômeno peculiar no ambiente brasileiro. A Contabilidade, por seu turno, não corroborou as expectativas médias do mercado no que concerne às possíveis sinergias advindas da combinação de firmas amostradas. Vale dizer que a medição da performance por métricas contábeis não foi influenciada pelo \"big bath\" tampouco por múltiplas aquisições efetivadas por firmas \"bidder\". Os resultados econométricos sugerem a necessidade de se proceder a um teste de \"impairment\" para averiguar a substância econômica de ágios. Por fim, em se tratando dos efeitos sobre os preços das operações não efetivadas e anunciadas (\"unsuccessful takeovers\"), as evidências empíricas indicam que o mercado de capitais brasileiro ajusta tempestivamente os papéis das firmas combinadas, em linha com o que prescreve a hipótese do mercado eficiente na sua forma semi-forte. / The aim of this thesis was the investigation of Mergers and Acquisitions - M&A, a subset of what is named \"business combination\", observed among Brazilian firms from 2002 to 2006, which at least one of them (bidder firm or target firm) was listed in Bovespa. Mergers and Acquisitions - M&A among firms under the same group of control were not sampled, which means that special transactions usually named \"incorporações reversas\" were not considered in the sample. There have been sampled 101 announcements (1st Fato Relevante filed) involving 104 M&A, totalizing R$ 223,7 billion, or 66,86% of the universe that took part in ANBID ranking from 2002 to 2006. Two techniques were used: the event studies on returns before and after M&A announcements and the event studies on accounting based measures. For sampling purposes, besides ANBID database, Economática database, \"Melhores e Maiores\" database and IPE system from CVM/Bovespa were used. The empirical evidences and the statistical tests led to the conclusion that the announcement of M&A transactions raised expectations of value maximization to the shareholders of the firms combined. Nonetheless, for the target firm shareholders, in the occurrence of a tender offer, with the possibility of a tension during the process of defining the control premium to be paid to minorities, specially if institutional investors such as pension funds take part in the minority group, the announcement of M&A transactions was priced differently among common and preferential shares, causing in the market a reaction alike to the myopia hypothesis, a particular phenomena in Brazil. Accounting, it must be pointed out, did not corroborate the average expectations of the market related to synergies associated with the combination of firms sampled. It must be mentioned that the measurement of the performance based on accounting based measures was not influenced by \"big bath\" neither by multiple acquisitions done by bidder firms. The econometric results suggest the necessity of adopting impairment test to check the economic substance of goodwill. Last, concerning the price effects of the unsuccessful takeover transactions announced, the empirical evidences indicate that the Brazilian stock market timely adjusts the stock prices of the combined firms, which is coherent with the efficient market hypothesis in the semi-strong form.

A leucemia linfóide aguda (LLA) é a neoplasia hematológica mais comum na infância e representa uma doença heterogênea em relação à biologia e ao prognóstico e seu tratamento consiste principalmente em quimioterapia. Apesar dos avanços no tratamento, cerca de 20% dos pacientes apresentam recaída da doença e/ou óbito indicando a necessidade de terapias diferenciadas para esse grupo. Recentemente, drogas epigenéticas como inibidores de DNA metiltransferases (iDNMTs) tem mostrado efeitos anti-neoplásicos promissores para o tratamento de diversos tipos de neoplasias incluindo a LLA. Nos tumores, a hipermetilação gênica é encontrada em vários genes, incluindo genes de reparo do DNA, reguladores do ciclo celular e apoptose. Sendo assim, drogas desmetilantes estão sendo apontadas como promissores agentes para o tratamento do câncer. A Zebularina (ZB) é um iDNMT análogo de citidina que inibe a metilação do DNA. Esta droga tem mostrado resultados animadores para o tratamento de diversas neoplasias, incluindo glioblastoma, leucemia mielóide aguda, câncer de mama, próstata e outros. O objetivo deste trabalho foi avaliar os efeitos do tratamento com a ZB, associada ou não à quimioterápicos, em linhagens celulares pediátricas de LLA, por meio de ensaios funcionais como proliferação celular, capacidade clonogênica, apoptose e ciclo celular. Além disso, foi analisada a capacidade desmetilante da droga e a expressão dos genes DNMT1, DNMT3a e DNMT3b após o tratamento com a ZB. A ZB inibiu a proliferação celular de maneira dose e tempo-dependente e agiu sinergicamente quando combinada com o MTX em ambas as linhagens. Ela também diminuiu a capacidade clonogênica e aumentou a taxa de apoptose nas duas linhagens estudadas. Além disso, o tratamento com ZB causou uma parada na fase S do ciclo celular na linhagem ReH. A ZB foi capaz de desmetilar parcialmente o gene AhR e reduzir a expressão dos genes DNMT1, DNMT3a e DNMT3b. Todos os dados encontrados no presente trabalho sugerem que as drogas desmetilantes podem ser interessantes agentes para o tratamento da LLA pediátrica. / Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in childhood and represents a heterogeneous disease regarding its biology and prognosis. Its treatment consists mainly of chemotherapy. Despite advances in treatment, about 20% of patients experience disease recurrence and/or death indicating the need for differentiated therapies for this group. Recently, epigenetic drugs such as DNA methyltransferases inhibitors (iDNMTs) has shown antineoplastic and promising results for several types of tumors including ALL. Gene hypermethylation is found in several genes in tumors cells, including genes responsible for DNA repair, cell cycle and apoptosis regulators. Therefore, demethylating agents may be promising agents for cancer treatment. Zebularine (ZB) an iDNMT is a cytidine analogue that inhibits DNA methylation. This drug has shown promising results for the treatment of many cancers, including glioblastoma, acute myeloid leukemia, breast and prostate cancer and others. The aim of this study was to evaluate the effects of ZB treatment, associated or not with chemotherapeutic agents, in childhood ALL cell lines through functional tests such as cell proliferation, clonogenic capacity, apoptosis and cell cycle. In addition, we examined the demethylating ability of ZB and the expression of DNMT1, DNMT3a and DNMT3b genes after treatment with this agent. ZB inhibited cell proliferation in a dose- and time-dependent manner and showed synergistic effects when combined with MTX in both cell lines. ZB treatment also reduced clonogenic capacity and increased the number of apoptotic cells in both cell lines studied. Furthermore, treatment with ZB caused an S phase cell cycle arrest in ReH cell line. ZB was able to partially demethylate AhR gene and reduce the expression of genes DNMT1, DNMT3a and DNMT3b. These results suggest that demethylating drugs may be interesting agents for the treatment of childhood ALL.

O cérebro humano é formado por um conjunto de neurônios de diferentes tipos, cada um com sua especialidade. A combinação destes diferentes tipos de neurônios é um dos aspectos responsáveis pelo desempenho apresentado pelo cérebro na realização de várias tarefas. Redes Neurais Artificiais são técnicas computacionais que apresentam um modelo matemático inspirado no sistema nervoso e que adquirem conhecimento através da experiência. Uma alternativa para melhorar o desempenho das Redes Neurais Artificiais é a utilização de técnicas de Combinação de Classificadores. Estas técnicas de combinação exploram as diferenças e as semelhanças das redes para a obtenção de resultados melhores. Dentre as principais aplicações de Redes Neurais Artificiais está o Reconhecimento de Padrões. Neste trabalho, foram utilizadas técnicas de Combinação de Classificadores para a combinação de Redes Neurais Artificiais em problemas de Reconhecimento de Padrões. / The human brain is formed by neurons of different types, each one with its own speciality. The combination of theses different types of neurons is one of the main features responsible for the brain performance in severa! tasks. Artificial Neural Networks are computation technics whose mathematical model is based on the nervous system and learns new knowledge by experience. An alternative to improve the performance of Artificial Neural Networks is the employment of Classifiers Combination techniques. These techniques of combination explore the difference and the similarity of the networks to achieve better performance. The main application of Artificial Neural Networks is Pattern Recognition. In this work, Classifiers Combination techniques were utilized to combine Artificial Neural Networks to solve Pattern Recognition problems.