Zugl.: Münster (Westfalen), Univ., Diss., 2009

Universiẗat, Diss., 2004--Bonn. / Erscheinungsjahr an der Haupttitelstelle: 2003.

Thyroid carcinoma is the most common endocrine malignant neoplasia. Differentiated thyroid carcinomas (DTC), represent more than 90% of all thyroid carcinomas and comprise the papillary (PTC) and follicular thyroid carcinomas (FTC) subtypes. Anaplastic thyroid carcinoma (ATC) corresponds to less than 5% of all thyroid tumors. The etiology of DTC is not fully understood. Several genetic events have been implicated on differentiated thyroid tumorigenesis. Point mutations in BRAF and RAS genes and RET/PTC rearrangements are observed in about 70% of PTC cases. Follicular carcinomas commonly harbor RAS mutations and PAX8-PPARJ rearrangements. Anaplastic carcinomas may harbor a wide set of genetic alterations, as in genes encoding effectors in the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinases (PI3K) and G-Catenin signaling pathways. These distinct genetic alterations are able to activate constitutively several signaling pathways as MAPK, PI3K and G-Catenin, which have been implicated on thyroid cancer development and progression. In this context, the evaluation of the specific oncogenes, as well as the knowledge of their effects on thyroid carcinomas can provide important information about the disease presentation, prognosis and therapy, through the development of specific tyrosine kinase targets. Particularly in this review, we explore the main genetic alterations observed in follicular cell-derived thyroid carcinomas as well as the molecular mechanisms involved in thyroid tumors development and progression.

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Thyroid carcinoma is the most common endocrine malignant neoplasia. Differentiated thyroid carcinomas (DTC), represent more than 90% of all thyroid carcinomas and comprise the papillary (PTC) and follicular thyroid carcinomas (FTC) subtypes. Anaplastic thyroid carcinoma (ATC) corresponds to less than 5% of all thyroid tumors. The etiology of DTC is not fully understood. Several genetic events have been implicated on differentiated thyroid tumorigenesis. Point mutations in BRAF and RAS genes and RET/PTC rearrangements are observed in about 70% of PTC cases. Follicular carcinomas commonly harbor RAS mutations and PAX8-PPARJ rearrangements. Anaplastic carcinomas may harbor a wide set of genetic alterations, as in genes encoding effectors in the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinases (PI3K) and G-Catenin signaling pathways. These distinct genetic alterations are able to activate constitutively several signaling pathways as MAPK, PI3K and G-Catenin, which have been implicated on thyroid cancer development and progression. In this context, the evaluation of the specific oncogenes, as well as the knowledge of their effects on thyroid carcinomas can provide important information about the disease presentation, prognosis and therapy, through the development of specific tyrosine kinase targets. Particularly in this review, we explore the main genetic alterations observed in follicular cell-derived thyroid carcinomas as well as the molecular mechanisms involved in thyroid tumors development and progression.

Iguape é um dos municípios do litoral sul paulista que teve muita importância na história do Brasil Colonial. Conheceu o auge com o ciclo do arroz, quando o rio Ribeira de Iguape era o principal meio de transporte e o porto às suas margens um dos mais importantes do País. Depois veio o declínio, conseqüência da abertura do Valo Grande e do assoreamento de seu porto. E, por fim, veio o isolamento numa das regiões mais pobres do Estado de São Paulo, o Vale do Ribeira. Iguape é o ponto 334 indicado por Antenor Nascentes para a pesquisa da realidade dialetal brasileira. O presente estudo objetiva registrar amostras desse verdadeiro dialeto caiçara, bolsão de tupinismos, arcaísmos e variantes lexicais peculiares. Procurou-se arrolar as lexias mais utilizadas na região não somente para lançá-las num mapa. Além de fazer o tratamento quantitativo dos dados, com o apoio das noções de estatística lexical de Muller, privilegiou-se a abordagem dos aspectos semântico-lexicais, com base em Pottier e Rastier, partindo da concepção de norma de Coseriu. Com base nos procedimentos teórico-metodológicos da Geolingüística da atualidade, aplicaram-se as questões da área Corpo Humano do Questionário semântico-lexical do Projeto ALiB, versão 2001, em três pontos do município de Iguape Icapara, Rocio e Jairê, a doze sujeitos, quatro de cada ponto, dos dois gêneros e em duas faixas etárias, quais sejam, de 18 a 30 anos (primeira faixa) e de 66 anos em diante (segunda faixa). A partir das respostas obtidas nas entrevistas, elaboraram-se dezesseis cartogramas, que espelham a variação diatópica de cunho lexical. Ainda em consonância com os preceitos da Geolingüística moderna, que alia sua metodologia às da Sociolingüística, compondo um quadro pluridimensional, mostrou-se o quadro da diversidade lingüística local. Em suma, o trabalho faz o registro da realidade lingüística desta parte muito pequena do Brasil, mas de grande importância para os estudos geolingüísticos, antes que esses falares se percam, quer pela ação homogeneizadora dos meios de comunicação de massa, quer pelas próprias forças centrífugas da língua. / Iguape is one of the cities on the southern coast of São Paulo State that had great importance in the History of colonial Brazil. It had its days of glory during the rice plantation period, when Ribeira de Iguape River was the main means of transportation and the port on its banks was one of the most important in the country. Later, decline came as a consequence of the opening of Valo Grande and the aggradation of its port. Finally, it became isolated in one of the poorest areas of the São Paulo State, the Ribeira Valley. Iguape is point number 334, as indicated by Antenor Nascentes, for the research of the Brazilian dialectal reality. The present work aims at registering samples of this truly \"caiçara\" dialect, in a region of \"tupinisms\", archaisms and peculiar lexical variants. We intended not only to place the lexias used in the area on a map, but also to list the most frequent ones. Besides doing quantitative treatment to data, based on Muller\'s notions of Lexical Statistics, we have focused in approaching the semantic-lexical aspects, based on Pottier and Rastier and starting from Coseriu\'s notion of norm. Based on present Geolinguistics theoretical-methodological procedures, we have applied the questions from area \"Human Body\" in the semantic-lexical Questionnaire of Project AliB, version 2001, in three points of the city of Iguape - namely Icapara, Rocio e Jairê -, to twelve subjects, four in each point, from both genders and belonging to two age groups, between 18 to 30 (first group) and older than 66 (second group). From the answers obtained in interviews, we have elaborated sixteen cartograms, which reflect the diatopic variation on lexical basis. Still in consonance with the principles of modern Geolinguistics, which allies its methodology to the one used in Sociolinguistics, forming a pluridimensional framework, we have showed the picture of local linguistic diversity. In summary, this work registers the linguistic reality of this very small part of Brazil, which has great importance to geolinguistic studies, before the loss of these speeches, be it by the homogenizing effect of mass media or by language\'s own centrifugal forces.

O presente estudo tem por objetivo registrar a variação dialetal no léxico do município de Guiratinga-MT. Para isto utilizou-se do Questionário Semântico-Lexical do projeto ALiB, versão 2001, na recolha in loco do corpus, a qual se deu em conformidade com os princípios metodológicos da Geolinguística atual, em três pontos do município: a sede e dois distritos.Na sede foram entrevistados 05 homens e 05 mulheres em cada uma das quatro faixas etárias estabelecidas: acima de 65 anos, 50/64 anos, 35/49 anos e 20/34 anos; no distrito 1, Alcantilado, entrevistaram-se 02 homens e 02 mulheres em cada faixa etária; no distrito 2, Vale Rico, os sujeitos entrevistados foram 03 homens e 03 mulheres, também naquelas faixas etárias. Os dados obtidos a partir dessas respostas estão em tabelas nas quais consideram ponto linguístico, faixa etária, gênero e frequência absoluta e relativa de acordo com as noções de estatística lexical de Muller. Ao final de cada área semântica expõem-se as lexias mais frequentes em histogramas, e a seguir se dão as análises, privilegiando a abordagem semântico-lexical, com base em Rastier semas inerentes e aferentes , a partir da concepção de norma de Coseriu. Enfim, a pesquisa apresenta a realidade linguística de um pequeno município do centro-oeste do Brasil, antes que ela se perca pela ação natural de dinâmica e mutabilidade da própria língua ou por questões denominadas homogeneizadoras. / The present study has as aim to register the lexical dialectal variation of Guiratinga-MT; In order to reach that objective, the Semantics-Lexical Questionnaire, of the ALiB project, version 2001, was used during the collection of corpus in loco, according to the current Geolinguistics methodological principles, in three sites: the headquarter (the town) and two districts. In the headquarter, 5 men and 5 women from each of the following age categories were interviewed: over 65 years old, 50/64 years old, 35/49 years old and 20/34 years old; in the first district, Alcantilado, 2 men and 2 women of those age categories were interviewed. The obtained data are in tables which consider linguistics point, age, gender, and, absolute and relative frequency, in accordance to Mullers lexical statistics notion. At the end of each semantical field, the most frequent lexis were exposed in histograms, followed by analysis, granting the semantical lexical approach, based on Rastier inherent and afferent semas from the model conception of Coseriu. Finally, the study presents the linguistics reality of a small town in the Brazilian Midwest, before it disappears because of the natural action of dynamics and changeability of the own language, or because of homogenizing matters.

O presente estudo tem por objetivo registrar a variação dialetal no léxico do município de Guiratinga-MT. Para isto utilizou-se do Questionário Semântico-Lexical do projeto ALiB, versão 2001, na recolha in loco do corpus, a qual se deu em conformidade com os princípios metodológicos da Geolinguística atual, em três pontos do município: a sede e dois distritos.Na sede foram entrevistados 05 homens e 05 mulheres em cada uma das quatro faixas etárias estabelecidas: acima de 65 anos, 50/64 anos, 35/49 anos e 20/34 anos; no distrito 1, Alcantilado, entrevistaram-se 02 homens e 02 mulheres em cada faixa etária; no distrito 2, Vale Rico, os sujeitos entrevistados foram 03 homens e 03 mulheres, também naquelas faixas etárias. Os dados obtidos a partir dessas respostas estão em tabelas nas quais consideram ponto linguístico, faixa etária, gênero e frequência absoluta e relativa de acordo com as noções de estatística lexical de Muller. Ao final de cada área semântica expõem-se as lexias mais frequentes em histogramas, e a seguir se dão as análises, privilegiando a abordagem semântico-lexical, com base em Rastier semas inerentes e aferentes , a partir da concepção de norma de Coseriu. Enfim, a pesquisa apresenta a realidade linguística de um pequeno município do centro-oeste do Brasil, antes que ela se perca pela ação natural de dinâmica e mutabilidade da própria língua ou por questões denominadas homogeneizadoras. / The present study has as aim to register the lexical dialectal variation of Guiratinga-MT; In order to reach that objective, the Semantics-Lexical Questionnaire, of the ALiB project, version 2001, was used during the collection of corpus in loco, according to the current Geolinguistics methodological principles, in three sites: the headquarter (the town) and two districts. In the headquarter, 5 men and 5 women from each of the following age categories were interviewed: over 65 years old, 50/64 years old, 35/49 years old and 20/34 years old; in the first district, Alcantilado, 2 men and 2 women of those age categories were interviewed. The obtained data are in tables which consider linguistics point, age, gender, and, absolute and relative frequency, in accordance to Mullers lexical statistics notion. At the end of each semantical field, the most frequent lexis were exposed in histograms, followed by analysis, granting the semantical lexical approach, based on Rastier inherent and afferent semas from the model conception of Coseriu. Finally, the study presents the linguistics reality of a small town in the Brazilian Midwest, before it disappears because of the natural action of dynamics and changeability of the own language, or because of homogenizing matters.

Iguape é um dos municípios do litoral sul paulista que teve muita importância na história do Brasil Colonial. Conheceu o auge com o ciclo do arroz, quando o rio Ribeira de Iguape era o principal meio de transporte e o porto às suas margens um dos mais importantes do País. Depois veio o declínio, conseqüência da abertura do Valo Grande e do assoreamento de seu porto. E, por fim, veio o isolamento numa das regiões mais pobres do Estado de São Paulo, o Vale do Ribeira. Iguape é o ponto 334 indicado por Antenor Nascentes para a pesquisa da realidade dialetal brasileira. O presente estudo objetiva registrar amostras desse verdadeiro dialeto caiçara, bolsão de tupinismos, arcaísmos e variantes lexicais peculiares. Procurou-se arrolar as lexias mais utilizadas na região não somente para lançá-las num mapa. Além de fazer o tratamento quantitativo dos dados, com o apoio das noções de estatística lexical de Muller, privilegiou-se a abordagem dos aspectos semântico-lexicais, com base em Pottier e Rastier, partindo da concepção de norma de Coseriu. Com base nos procedimentos teórico-metodológicos da Geolingüística da atualidade, aplicaram-se as questões da área Corpo Humano do Questionário semântico-lexical do Projeto ALiB, versão 2001, em três pontos do município de Iguape Icapara, Rocio e Jairê, a doze sujeitos, quatro de cada ponto, dos dois gêneros e em duas faixas etárias, quais sejam, de 18 a 30 anos (primeira faixa) e de 66 anos em diante (segunda faixa). A partir das respostas obtidas nas entrevistas, elaboraram-se dezesseis cartogramas, que espelham a variação diatópica de cunho lexical. Ainda em consonância com os preceitos da Geolingüística moderna, que alia sua metodologia às da Sociolingüística, compondo um quadro pluridimensional, mostrou-se o quadro da diversidade lingüística local. Em suma, o trabalho faz o registro da realidade lingüística desta parte muito pequena do Brasil, mas de grande importância para os estudos geolingüísticos, antes que esses falares se percam, quer pela ação homogeneizadora dos meios de comunicação de massa, quer pelas próprias forças centrífugas da língua. / Iguape is one of the cities on the southern coast of São Paulo State that had great importance in the History of colonial Brazil. It had its days of glory during the rice plantation period, when Ribeira de Iguape River was the main means of transportation and the port on its banks was one of the most important in the country. Later, decline came as a consequence of the opening of Valo Grande and the aggradation of its port. Finally, it became isolated in one of the poorest areas of the São Paulo State, the Ribeira Valley. Iguape is point number 334, as indicated by Antenor Nascentes, for the research of the Brazilian dialectal reality. The present work aims at registering samples of this truly \"caiçara\" dialect, in a region of \"tupinisms\", archaisms and peculiar lexical variants. We intended not only to place the lexias used in the area on a map, but also to list the most frequent ones. Besides doing quantitative treatment to data, based on Muller\'s notions of Lexical Statistics, we have focused in approaching the semantic-lexical aspects, based on Pottier and Rastier and starting from Coseriu\'s notion of norm. Based on present Geolinguistics theoretical-methodological procedures, we have applied the questions from area \"Human Body\" in the semantic-lexical Questionnaire of Project AliB, version 2001, in three points of the city of Iguape - namely Icapara, Rocio e Jairê -, to twelve subjects, four in each point, from both genders and belonging to two age groups, between 18 to 30 (first group) and older than 66 (second group). From the answers obtained in interviews, we have elaborated sixteen cartograms, which reflect the diatopic variation on lexical basis. Still in consonance with the principles of modern Geolinguistics, which allies its methodology to the one used in Sociolinguistics, forming a pluridimensional framework, we have showed the picture of local linguistic diversity. In summary, this work registers the linguistic reality of this very small part of Brazil, which has great importance to geolinguistic studies, before the loss of these speeches, be it by the homogenizing effect of mass media or by language\'s own centrifugal forces.

La variante d’histone H2AZ joue un rôle important dans l’activation de la transcription, la prolifération cellulaire, le développement et la différentiation. H2AZ orne les promoteurs de la majorité des gènes, mais les mécanismes de bases de cette localisation sont inconnus. La compréhension de l’assemblage et du désassemblage du nucléosome passe par la caractérisation de la dynamique du nucléosome et des chaperonnes d’histones. L’objectif de ma thèse était d’identifier des chaperonnes spécifiques impliqués dans la dynamique de H2AZ en utilisant une approche de protéomique. Pour élucider les mécanismes de déposition/éviction de H2AZ, j’ai purifié le complexe prénucléosomale de H2AZ et j’ai caractérisé toutes les protéines associées. J’ai trouvé que Anp32e fait partie du complexe p400/TIP60 qui est présumée pour être responsable de l’échange d’H2AZ sur la chromatine. Anp32e présente une spécificité pour le dimère H2AZ-H2B, car il n’interagit pas avec le dimère H2A-H2B. L’interaction est accomplie au niveau d’une petite région dans le domaine d’ancrage sur H2AZ et au niveau d’un nouveau domaine ZID sur Anp32e. Finalement, j’ai montré que la suppression d’Anp32e entraine : un défaut dans la dé-répression des gènes dont l’expression est contrôlée par une hormone et une accumulation sur les promoteurs de ces derniers. Dans l’ensemble ces résultats identifient Anp32e comme une nouvelle chaperonne de la variante d’histoneH2AZ impliquée dans l’éviction de H2AZ chez les mammifères. / The histone variant H2AZ has emerged as a key regulator of chromatin function and plays an essential role in transcriptional activation, cell proliferation, development, and differentiation. H2AZ marks nucleosomes flanking the promoters of most genes, but the mechanistic basis for this localization is unknown. A mechanistic understanding of nucleosome assembly/disassembly requiresa detailed knowledge of nucleosome thermodynamics and histone chaperones. The aim of my thesis was to identify specific chaperone involved in H2AZ dynamic by using biochemical and proteomic strategies. To elucidate the mechanism of H2AZ deposition/eviction, I purified the prenucelosomal H2AZ complex and characterized in details the interacting protein partners. I found that Anp32e is a member of the presumed H2A.Z histone-exchange complex p400/TIP60. Bacterially expressed Anp32e binds only to the H2AZ/H2B dimers but not to the H2A/H2B. Anp32e interacts with a short region of the docking domain of H2A.Z. The binding occurred through a novel Anp32e motif, termed ZID. Finally, I show that down regulation of Anp32e interferes with both the de-repression of hormone dependent genes and H2A.Z removal from their promoter. Our data identified Anp32e as a novel mammalian H2AZ chaperone invoved in H2AZ eviction.