A superexpressão de receptores HER-2 é anormalidade celular de grande relevância clínica no câncer de mama. Ela ocorre em aproximadamente 30% de carcinomas de mama incluindo lesões pré-neoplásicas e malignas, e está associada a prognóstico desfavorável. A hiperativação dos receptores HER-2, consequência natural de sua superexpressão, promove proliferação celular aberrante e tumorigênese. Admite-se que a ativação e envio de sinais via HER-2 possa acontecer quando estes receptores se encontram em compartimentos específicos da membrana celular, os lipid rafts. Assim, um número maior de HER-2 poderia implicar em maior quantidade de lipis rafts. Para testar essa hipótese, usamos modelo de transformação oncogênica que nos permitiu avaliar, especificamente, os efeitos da superexpressão de HER-2 e identificar a quantidade de lipid rafts. Para isso utilizamos a linhagem celular HB4a, derivada de célula epitelial luminal do tecido mamário humano normal com baixa expressão de HER-2; e a linhagem HB4aC5.2, um clone derivado da HB4a, que superexpressa receptores HER-2. Nas células HB4aC5.2, a superexpressão de HER-2 foi acompanhada pelo aumento dos lipid rafts na membrana celular, bem como, hiperativação de sinais de sobrevivência, proliferação (aumento da ativação de proteínas Akt e Erk1/2, respectivamente), e taxa de proliferação celular duas vezes mais rápida que a linhagem normal HB4a. Adicionalmente, a superexpressão de HER-2 foi associada com aumento da lipogênese celular (fenótipo lipogênico), dependente do aumento de ativação da enzima FASN e da superexpressão de DEPTOR. A FASN é responsável pela síntese de palmitato, utilizado para formação de lipid rafts. A superexpressão de DEPTOR, por modular a atividade transcricional de PPAR?, pode evitar a lipotoxicidade do excesso de palmitato. Além disso, DEPTOR, por sua capacidade em reduzir atividade do complexo mTORC1, contribui para sobrevivência celular dependente da proteína Akt. Em continuidade, consideramos, como segunda hipótese, que a desestruturação de lipid rafts poderia influenciar negativamente a ativação dos receptores HER-2. Para isso tratamos, as mesmas linhagens celulares anteriormente descritas, com ácido docosaexaenoico (DHA), um tipo de ácido graxo ômega-3. Nossos resultados mostraram que, nas células HB4aC5.2, o tratamento com DHA desestruturou os lipid rafts, inibiu a sinalização iniciada pelos receptores HER-2 ( diminuição da ativação das proteínas Akt, Erk1/2, FASN, atividade transcricional de PPAR? e expressão de DEPTOR) e reverteu o fenótipo lipogênico. Adiciona-se que essas modificações celulares e moleculares foram acompanhadas por indução significativa de morte e apoptose. As mesmas alterações não foram observadas nas células normais HB4a. Em conclusão, o presente estudo reforça a associação entre a presença de HER-2 e lipid rafts. Adicionalmente aponta que a desestruturação de lipid rafts por DHA reduz a sinalização de HER-2. Por fim, sugere que distúrbios em lipid rafts, induzidos por DHA, possam representar ferramenta útil no controle da sinalização aberrante deflagrada pelos receptores HER-2, e aponta potencial terapêutico na suplementação de DHA para quimioprevenção e tratamento do câncer de mama HER-2 positivo. / HER-2 receptor overexpression is a cellular abnormality of great clinical significance in breast cancer. It is described in approximately 30% of breast carcinomas, including preneoplasic and malignant lesions, and is associated with poor prognosis. Hyperactivation of HER-2 receptors, a natural consequence of its overexpression, promotes aberrant cell proliferation and tumorigenesis. For signal activation and transduction to occur, HER-2 must be localized in specific compartments in the cell membrane: the lipid rafts. Therefore, we hypothesize that a greater number of HER-2 receptors could indicate a greater quantity of lipid rafts. To test this, we used an oncogenic transformation model that specifically allowed assessment of the effects of HER-2 overexpression and identification of the quantity of lipid rafts: an HB4a cell line derived from normal human breast tissue luminal epithelial cells with low HER-2 expression, and an HB4aC5.2 cell line, a clone derived from HB4a that overexpresses HER-2 receptors. In the HB4aC5.2 cells, HER-2 overexpression was accompanied by an increase in lipid rafts in cell membranes as well as hyperactivation of survival signals, proliferation (increased activation of the proteins Akt and ERK1/2, respectively), and an increased rate of proliferation, compared to the normal HB4a line. In addition, HER-2 overexpression was associated with increased cellular lipogenesis (lipogenic phenotype), dependent on the increased activation of the FASN enzyme and the overexpression of DEPTOR. FASN is responsible for the synthesis of palmitate, used to synthesize lipid rafts. Overexpression of DEPTOR by modulating PPAR? transcriptional activity, may avoid lipotoxicity from excess palmitate. Moreover, DEPTOR, with its ability to reduce mTORC1 complex activity, contributes to cell survival dependent on Akt. To continue, we considered as a second hypothesis that the disruption of lipid rafts could negatively influence HER-2 receptor activation. For this, we treated the same cell lines described above with docosahexaenoic acid (DHA), a omega-3 fatty acid. Our results showed that in HB4aC5.2 cells DHA treatment disrupted the lipid rafts, inhibited signaling initiated by HER-2 receptors (reduced activation of Akt, ERK1/2, and FASN proteins, PPAR? transcriptional activity, and DEPTOR expression) and reversed the lipogenic phenotype. In addition, these cellular and molecular changes were accompanied by a significant induction of apoptosis and death. The same changes were not observed in normal HB4a cells. In conclusion, the present study reinforces the association between HER-2 presence and lipid rafts. It also indicates that the disruption of lipid rafts by DHA reduces HER-2 signaling. Finally, it suggests that DHA-induced disturbances in lipid rafts may represent a useful tool in controlling aberrant signaling triggered by HER-2 receptors, and indicate therapeutic potential in DHA supplementation for chemoprevention and treatment of HER-2 positive breast cancer.

The final thesis deals with the form and function of an educational game to be used in the 4th and 5th grades of primary school. It will deal with appropriate educational games for these pupils based on their emotional, intellectual and social development. Additionally, it will describe the method for how to categorize different kinds of educational games and how to include them in educational process. In the practical component, there is a comparison of opinions about an educational game between newly qualified and experienced teachers. The opinions of pupils and their evaluation of the specific games are also included. It includes a file of educational games as well which is based on a classification from the theoretical part.

Indiana University-Purdue University Indianapolis (IUPUI) / Cancer stem cells (CSCs) are proposed to play a major role in tumor progression, metastasis, and recurrence. The Human Epidermal growth factor Receptor 2 (HER2) gene is amplified and/or its protein product overexpressed in approximately 20% of breast cancers. HER2 overexpression is associated with increased CSCs, which may explain the aggressive phenotype and increased likelihood of recurrence for HER2+ breast cancers. Telomerase is reactivated in tumor cells, including CSCs, but has limited activity in normal tissues, providing support for the use of telomerase inhibition in anti-cancer therapy. Telomerase inhibition via an antagonistic oligonucleotide, imetelstat (GRN163L), has been shown to be effective in limiting cell growth in vitro and limiting tumor growth. Moreover, we have previously shown imetelstat can decrease metastases to the lungs, leading us to question if this is due to imetelstat targeting the CSC population. In this thesis, we investigated the effects of imetelstat on CSC and non-CSC populations of HER2+ breast cancer cell lines, as well as a triple negative breast cancer cell line, which lacks HER2 overexpression. Imetelstat inhibited telomerase activity in both CSC and non-CSC subpopulations. Moreover, imetelstat treatment alone and in combination with trastuzumab significantly reduced the CSC fraction and inhibited CSC functional ability, as shown by a significant decrease in mammosphere counts and invasive potential. Tumor growth rate was slower in combination treated mice compared to either drug alone. Additionally, there was a trend toward decreased CSC marker expression in imetelstat treated xenograft cells compared to vehicle control. The decrease in CSC marker expression we observed occurred prior to and after telomere shortening, suggesting imetelstat acts on the CSC subpopulation in telomere length dependent and independent mechanisms. Our study suggests addition of imetelstat to trastuzumab may enhance the effects of HER2 inhibition therapy.

This thesis explores the relationship between Marcel Duchamp’s oeuvre and the texts of the Comte de Lautréamont, arguing that the author’s works comprise an overlooked and undervalued source of interest and ideas for the artist. Scholars have done an extraordinary job of documenting and analyzing a number of Duchamp’s literary sources and inspirations. Their work has elucidated the roles of Raymond Roussel, Alfred Jarry, Stéphane Mallarmé, Jules Laforgue, and Jean-Pierre Brisset, among others, for Duchamp. The work of Lautréamont, however, has received proportionally little attention, despite several indications of its importance for the artist. Among the few who have proposed such a connection, none have yet offered a broadly documented or sustained argument. Other historians, generally working under the premise that Lautréamont only came to Duchamp’s attention by way of the Surrealists, have explicitly rejected the possibility that the Uruguayan-French poet had any meaningful position in Duchamp’s library prior to the Surrealist championing of the author. This thesis proposes otherwise, making the case that Lautréamont was more fundamentally important to Duchamp than yet realized. Historical documents as well as statements by the artist himself and those closest to him suggest a stronger engagement by Duchamp with the works of Lautréamont than has been previously proposed. This relationship seems to have begun by as early as 1912, well in advance of the Surrealists’ discovery of the author, and it lasted throughout Duchamp’s life. Furthermore, an examination of Duchamp’s body of work demonstrates a number of strategic and thematic resonances between artist and author that reinforce what the archival evidence suggests. These resonances should be understood as open readings, rather than exclusive readings. They are proposed as additions to the existing constellation of understanding of Duchamp’s oeuvre, rather than as foreclosures upon other ways of reading Duchamp’s body of work. / text

This thesis introduces the basic concepts of the game theory. Necessary models and solution concepts are described. Follows the summary of the computational complexity of these concepts and corresponding algorithms. Poker is formalized as one of the game theory game models. State of the art algorithms for the ex- tensive form games are explained with the application to the Poker. The thesis also introduces the Annual Computer Poker Competition and participating pro- grams. Finally, new result about the extensive form games with many actions is presented. Keywords: Game theory, Poker, Nash equilibrium, Extensive form games

The thesis deals with the historical development of computer adventure games in the Czech Republic. It focuses on the period that started in 1994 with the production of the first commercial PC game Tajemství Oslího ostrova (The Secret of Donkey Island), and ended in 1998. It also touches an earlier period and factors that influenced the production of the adventure genre in the nineties. Researched titles belong to the genre of 2D point-and-click adventure. The paper brings the analysis of the games according to the theories of game studies, context of their production, information about their producers and analysis of the feedback in the press that focused on computer games. The thesis tries to identify the common features of the first commercial PC games thanks to which the games became very popular in the nineties and also describes the obstacles that the first producers had to overcome in the post socialistic country. At nearly twenty titles the paper tries to reveal the new elements that showed in the historical development of the adventure games and also to describe the differences among monitored titles. The sources of information for the thesis were both the literature, which dealt with computer games, and the interviews with the developers, game designers and distributors who focused on the...

O objetivo do estudo foi avaliar a importância da expressão das proteínas topoisomerase II alfa (topo II) e HER-2 como fatores preditvos da resposta à quimioterapia neoadjuvante e prognóstico em pacientes com câncer de mama nos estádio clínico II e III. Pacientes e métodos: 99 pacientes receberam quimioterapia neoadjuvante com docetaxel (75mg /m²) e epirrubicina (50 mg/m²) em infusão endovenosa no dia 1 a cada 3 semanas após terem sido submetidas a biópsia incisional. Foi complementado tratamento sistêmico com quimioterapia adjuvante com CMF ou FEC de acordo com o estado axilar avaliada após a cirurgia definitiva e/ou hormonioterapia de acordo com a avaliacãodos receptores hormonais. Avaliamos a taxa de resposta ao tratamento neoadjuvante e a influência da topo II alfa e do HER-2 na taxa de resposta à quimioterapia neoadjuvante bem comona sobrevida livre de doença e sobrevida global. Também foram avaliadas a expressão dos receptores hormonais. Resultados: a taxa de resposta clínica objetiva foi de 80,8 % com 9,1 % de resposta patológica completa. A expressão da topo II alfa nao apresentou significância nas taxas de resposta ou na sobrevida das pacietnes e nao houve correlação entre a expressão desta proteína e de HER-2. A superexpressão da proteína HER-2 foi associada com uma redução significante nas taxas de sobrevida livre de doença e sobrevida global (p= 0,04 e p= 0,004, respectivamente). Conclusão: a expressão da topo II alfa não demonstrou, em nosso estudo, ser fator preditivo ou prognóstico nas pácientes submetidas a quimioterapia neoadjuvante com docetaxel e epirrubicina. / The objective of this study is to evaluate the importance of the expression of the proteins topoisomerase II alpha (topo II) and HER-2 as predictive factors to response to neoadjuvant chemotherapy and the prognosis of patients diagnosed with clinical stage II and stage III breast cancer. Patients and methods: 99 patients have received neoadjuvant chemotherapy with docetaxel (75mg /m²) and epirrubicine (50 mg/m²) through intravenous infusion on D1 q3 weeks, after submitted to pathologic specimen harvest. Systemic treatment was then complemented with CMF or FEC according to the status of axilla involvement after surgical staging and/or hormone therapy according tohormone receptor status. We evaluated the response rate to neoadjuvant treatment and the influence of topo II alpha and HER-2 expression on the response rate and disease free survival and overall survival. The expression of hormone receptors was also evaluated. Results: Objective clinical response was 78,8%, with 8,2% of complete pathological response.Topo II alpha expression did not correlate to response to chemotherapy or survival and there was no correlation between topo II alpha expression and HER-2 expression. Superexpression of HER-2 protein was associated to a significant reduction in disease free survival and overall survival (p=0,04 and p=0,004, respectively). Conclusion: topo II alpha expression did not demonstrate, in our study, to be a predictive nor prognostic factor to the patientssubmitted to neoadjuvant with docetaxel and epirrubicin.

Made available in DSpace on 2016-08-10T10:38:33Z (GMT). No. of bitstreams: 1 FLAVIA ALEIXO FERREIRA.pdf: 856261 bytes, checksum: 437e20f50936aac2d69cf7dcc15d95ed (MD5) Previous issue date: 2011-07-01 / Breast cancer is the second most frequent type of cancer worldwide and more common among women, accounting for 22% of new cases each year. These tumors appear as heterogeneous evolution and response to different treatment available whose prognostic and predictive factors guiding the therapeutic approach being used. The detection of oncogenic protein c-erbB-2 by immunohistochemistry is a prognostic factor for diagnostic, and in most cases, is associated with a worse prognosis. This study aimed to raise clinicopathological data of patients with breast cancer, as well as evaluating the expression c-erbB-2 in tumor tissue paraffin samples of these patients. Medical records of 286 female patients with breast carcinoma treated at Hospital Araújo Jorge (Association of Cancer Combat of Goiás), between 1979 and 2002 were collected and tabulated together with data from immunohistochemical detection of c-erbB protein -2. In our series the positive immunodetection of c-erbB-2 in tumor cells showed no association with conventional parameters clinicopathologics. The immunodetection of the protein c-erbB-2 did not significantly affect the survival of patients analyzed in our series, consistent with data obtained by other studies. We conclude that molecular methods should become more sensitive. / O câncer de mama é o segundo tipo mais frequente de câncer no mundo e o mais comum entre as mulheres, corresponde por 22% dos casos novos a cada ano. Esses tumores apresentam-se heterogêneos quanto a evolução e resposta às diferentes opções terapêuticas disponíveis, cujos fatores prognósticos e preditivos norteiam a conduta terapêutica a ser utilizada. A detecção da proteína oncogênica c-erbB-2 por imuno- histoquímica é um fator prognóstico auxiliar para avaliação diagnóstica e, na maioria dos casos, associa-se a um pior prognóstico. O presente estudo teve como objetivo levantar os dados clínicopatológicos de pacientes com câncer de mama, bem como avaliar a expresssão de c-erbB-2 nas amostras de tecido tumoral parafinadas dessas pacientes. Prontuários de 286 pacientes do sexo feminino com carcinoma de mama atendidas no Hospital Araújo Jorge (Associação de Combate ao Câncer em Goiás), entre 1979 e 2002, foram coletados e tabulados juntamente com os dados de imuno- histoquímica para detecção da proteína c-erbB-2. Em nossa casuística a imunodetecção positiva de c-erbB-2 nas células tumorais não demonstrou associação com os parâmetros clinicopatológicos convencionais. A imunodetecção da proteína c-erbB-2 não influenciou significativamente a sobrevida das pacientes analisadas em nossa série, condizendo com dados obtidos por outros estudos. Assim concluímos que os métodos moleculares devem se tornar mais sensíveis

Made available in DSpace on 2015-04-14T13:38:35Z (GMT). No. of bitstreams: 1 437437.pdf: 880289 bytes, checksum: 37b1f1d23d0ed82f3731dee3deda7845 (MD5) Previous issue date: 2012-01-10 / This dissertation presents the theme of the literary youth of Moacyr Scliar, focusing on the kinds of hero in these narratives. Using the literature as a methodology, it appears like the heroes of Scliar contribute to the formation of the young reader. At first, it exposes the theoretical concepts that include youth, literature and the hero. Soon after, we describe the biographical aspects of the author and the story of his youth books. As a closingm there us te analysis of the trajetory of the heroes and how is the process of humanization. The theory behind this study includes authors such as Lu?s Groppo, Edgar Morin, Jo?o Lu?s Ceccantini, Regina Zilberman, Jaime Padrino, Lutz M?ller, Carol Pearson, Joseph Campbell. The juvenile literature created by Scliar is configured as a true voyage of discovery to the extent that their heroes, complete their journeys, their mature dragons and discover themselves. The literature, therefore, appears as a means of humanizing the young hero. / Nesta disserta??o estuda-se a produ??o liter?ria juvenil de Moacyr Scliar, tendo como enfoque os tipos de her?i presentes nas narrativas. Usando como metodologia a pesquisa bibliogr?fica, verifica-se qual o perfil dos her?is e em que medida eles representam comportamentos exemplares para o leitor jovem. Num primeiro momento, exp?em-se os conceitos referentes ? juventude, ? literatura e ao her?i, a partir das reflex?es de Lu?s Groppo, Edgar Morin, Jo?o Lu?s Ceccantini, Regina Zilberman, Jaime Padrino, Lutz M?ller, Carol Pearson, Joseph Campbell. Logo ap?s, apresentam-se aspectos biogr?ficos do autor e elementos de seus livros juvenis. Como fechamento, tem-se a an?lise da trajet?ria dos her?is, ? luz de seu processo de amadurecimento. A obra juvenil criada por Scliar configura-se como uma verdadeira viagem de descobrimento, na medida em que seus her?is, ao completarem suas jornadas, vencem seus drag?es e descobrem a si mesmos. A literatura aparece, assim, como instrumento de humaniza??o do her?i jovem.

This thesis deals with factors which are important for making decisions in the game of poker. The goal is to find a way to improve players chances of success in this game. The first two chapters describe the rules of poker and the basics and presumptions of the game theory The following chapters analyze some mathematical models and assumptions for applying these models in the game. These models should find the optimal solution for individuals in decision making situations. It can be considered a static situation, where the behavior of each player is predetermined and the decision maker tries to find an appropriate strategy. It is also can be considered a dynamic situation, when all players react to each other, which heads to equilibrium solution. As a consequence of rising popularity of poker tournaments many strategy books have appeared, as well as analytic software. Nevertheless, it is and probably will remain impossible to solve all decision situations which can occur. A very important factor of success are some gamblers attitude, experience and mental skills. Mathematical knowledge, however, will become more and more important. This thesis will help to understand the basic of mathematic models and their application in poker game.