Submitted by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2016-02-19T13:06:21Z No. of bitstreams: 1 Leandro de Oliveira Cedraz Concentrações... 2015.pdf: 1784489 bytes, checksum: 5639169c6995e05270cd7c552e5ccb71 (MD5) / Approved for entry into archive by Ana Maria Fiscina Sampaio (fiscina@bahia.fiocruz.br) on 2016-02-19T13:06:35Z (GMT) No. of bitstreams: 1 Leandro de Oliveira Cedraz Concentrações... 2015.pdf: 1784489 bytes, checksum: 5639169c6995e05270cd7c552e5ccb71 (MD5) / Made available in DSpace on 2016-02-19T13:06:35Z (GMT). No. of bitstreams: 1 Leandro de Oliveira Cedraz Concentrações... 2015.pdf: 1784489 bytes, checksum: 5639169c6995e05270cd7c552e5ccb71 (MD5) Previous issue date: 2015 / Fundação Oswaldo Cruz, Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / INTRODUÇÃO: O vírus linfotrópico das células T humano tipo 1 (HTLV-1) é endêmico na Bahia e está associado com doenças graves, como a Paraparesia Espástica Tropical/Mielopatia associada ao HTLV-1 (HAM/TSP) e a Dermatite Infecciosa associada ao HTLV-1 (DIH). Escassos trabalhos tem sido reportados com a avaliação de citocinas e quimiocinas em indivíduos jovens infectados pelo HTLV-1 e não existem dados sobre a manifestação simultânea DIH e HAM/TSP na faixa infanto-juvenil. OBJETIVO: Avaliar as concentrações plasmáticas de citocinas e quimiocinas na infecção pelo HTLV-1 em indivíduos infanto-juvenis. MÉTODO: Foram incluídos 61 indivíduos portadores do HTLV-1 distribuídos nos grupos Portadores assintomáticos, pacientes com a DIH, pacientes com DIH/HAM/TSP, pacientes com a HAM/TSP e 20 indivíduos saudáveis sem a infecção pelo HTLV-1, todos na faixa infanto-juvenil. As concentrações plasmáticas foram comparadas através do método de Elisa e de Cytometric Bead Array (CBA). As análises estatísticas foram realizadas com o GraphPad Prism 6.1 através do teste Mann Whitney para comparação das medianas e pelo teste Wilcoxon para comparação das amostras pareadas, e a avaliação das correlações pelo coeficiente de Spearman. RESULTADOS: As citocinas IL-2, IL-6 estiveram em maiores concentrações em todos os grupos de portadores do HTLV-1. Os indivíduos saudáveis apresentaram menores concentrações de IFN-γ que o grupo de indivíduos portadores assintomáticos e o grupo de pacientes com a DIH, além de menores concentrações de IL-4 e IL-10 quando comparado com os indivíduos infectados, contudo apenas a IL-10 esteve em concentrações diferentes nos indivíduos com o vírus. Os indivíduos saudáveis apresentaram maiores concentrações da quimiocina CCL-22. Portadores assintomáticos e pacientes com a DIH apresentaram menores concentrações de IL-1β quando comparados com indivíduos saudáveis. Os portadores assintomáticos apresentaram menores concentrações da IL-17 que os indivíduos não infectados. Os pacientes com a DIH/HAM/TSP apresentaram maiores concentrações para a IL-1β, quando comparado com o grupo de pacientes com a DIH e com o grupo de pacientes com a HAM/TSP, além de menores concentrações da quimiocina CCL-27. O grupo HAM/TSP apresentou menores concentrações de IL-8 que os grupos DIH e DIH/HAM/TSP. A carga proviral foi menor no grupo dos portadores assintomáticos, seguidos do grupo de pacientes com DIH, e do grupo de pacientes de DIH que também manifestaram HAM/TSP, já o grupo de pacientes com a HAM/TSP apresentaram cargas provirais menores que o grupo DIH e o grupo DIH/HAM/TSP. Apenas a IL-8 e IL-10 apresentaram correlações fracas com a carga proviral. Na remissão da DIH, houve maiores concentrações da CCL-27, enquanto o TNF-α esteve em maiores concentrações no momento em que o paciente apresentou a DIH/HAM/TSP. CONSIDERAÇÕES FINAIS: Na infecção pelo HTLV-1 na faixa infanto-juvenil ocorre uma desregulação imunológica acompanhada de um mecanismo imunomodulador. Nos portadores assintomáticos, parece existir um maior equilíbrio entre a resposta pro e anti-inflamatória. A manifestação de DIH e da HAM/TSP, parece estar relacionada com um maior desequilíbrio entre a resposta imunológica, e nos pacientes com a DIH/HAM/TSP esta resposta parece sofrer influência de mecanismos da comanifestação. / INTRODUCTION: The lymphotropic virus of cells T human type 1 (HTLV ) is endemic in Bahia and it is associated with serious diseases such as Tropical Spastic Paraparesis/associated myelopathy with HTLV-1 and Infectious Dermatitis associated with HTLV -1 (IDH). Very little work has been reported with the evaluation of cytokines and chemokines in the IDH and there has been no data on the manifestation simultaneous IDH and HAM\TSP in children and youth range. OBJECTIVE: To evaluate the plasma concentrations of cytokines and chemokines in HTLV-1 infection in children and young individuals. METHOD: We included 61 individuals HTLV-1 spread in groups Asymptomatic Carriers, patients with IDH, patients with IDH/HAM/TSP, patients with HAM/TSP and 20 healthy individuals without HTLV-1, all in children's range. Plasma concentrations were compared using the ELISA method and Cytometric Bead Array (CBA). Statistical analyzes were performed using GraphPad Prism 6.1 using the Mann Whitney test to compare the medians and the Wilcoxon test for comparison of paired samples, and evaluation of correlations by Spearman coefficient. RESULTS: The cytokines IL-2 and IL-6 concentrations were higher in all groups of patients with HTLV-1. Healthy individuals showed lower concentrations of IFN-γ to the group of asymptomatic individuals and the group of patients with IDH, in addition to lower concentrations of IL-4 and IL-10 when compared to infected individuals, but only IL-10 was in different concentrations in subjects with the virus. Healthy individuals showed higher concentrations of the chemokine CCL-22. Asymptomatic carriers and patients with IDH had lower IL-1β levels in comparison with healthy subjects. Asymptomatic carriers had lower IL-17 concentrations that Healthy individuals. Patients with IDH/HAM/TSP had higher concentrations of IL-1β compared with the group of patients with the IDH and the group of patients with HAM/TSP, and lower concentrations of CCL-27 chemokine. The HAM/TSP group had lower IL-8 concentrations of the IDH and IDH/HAM/TSP groups. The proviral load was lower in asymptomatic patients, followed by the group of patients with IDH, and the group of IDH patients also expressed HAM/TSP, the group of patients with HAM/TSP had lower proviral loads that the IDH group and IDH/HAM/TSP group. As IL-8 and IL-10 exhibit weak correlation with proviral load. In Remission IDH, there were higher concentrations of CCL-27, while TNF-α was higher concentrations at the time the patient showed IDH/HAM/TSP. CONCLUSIONS: In the HTLV-1 infection in children and young occurs an immune dysregulation accompanied of an immunomodulatory mechanism. In asymptomatic patients, there seems to be a greater balance between the response pro and anti-inflammatory. The manifestation of IDH and HAM/TSP seems to be related to a greater imbalance between the immune response, and in patients with IDH/HAM/TSP this answer seems to be influenced by mechanisms of co-expression mechanisms.

Made available in DSpace on 2015-04-11T13:53:06Z (GMT). No. of bitstreams: 1 Emadina Soares.pdf: 751137 bytes, checksum: 886ccfba52ad365c98aac821abae47ef (MD5) Previous issue date: 2010-05-04 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / primeiro aconteceu no período áureo da borracha e o segundo na implantação da Zona Franca de Manaus e do seu Polo Industrial. O crescimento acelerado exerce uma forte pressão na infra-estrutura existente da cidade, uma vez que a população necessita de mínimas condições para uma boa vivência urbana, bem como disponibilidade de serviços e equipamentos urbanos. O surgimento de assentamentos desordenados, sem o devido controle, ocasionou uma cidade com problemas, tais como: carência de infra-estrutura básica, água encanada, energia, esgoto, asfalto e serviços públicos essenciais. O Programa das Nações Unidas para o Desenvolvimento (PNUD) é a entidade das Nações Unidas que tem a missão de promover mudança e conectar países à experiências, conhecimentos e recursos, apontando soluções que se consiga sociedades e Nações fraternas e socialmente justas. O Índice de Desenvolvimento Humano (IDH) é uma ferramenta do PNUD que sintetiza o nível de sucesso atingido pela sociedade no atendimento a três necessidades básicas e universais do ser humano: acesso ao conhecimento (dimensão educação), direito a uma vida longa e saudável (dimensão longevidade) e direito a um padrão de vida digno (dimensão renda). A construção de indicadores socioeconômicos tem como principal finalidade permitir uma análise da dinâmica das coletividades em seus vários aspectos, proporcionando, dessa forma, subsídios para a avaliação e estabelecimento de objetivos e prioridades. Esta dissertação intitulada O que revelaram os Índices de Desenvolvimento Humano na Cidade de Manaus , está delimitada à Cidade de Manaus, no período 1991- 2000 e tem como objetivo geral investigar as características qualitativas e quantitativas dos Índices de Desenvolvimento Humano (IDH), 1991-2000. Quanto aos os objetivos específicos, passa-se a enumerá-los: Verificar alguns dos melhores Índices de Desenvolvimento Humano (IDH) do Brasil e no exterior; examinar os melhores e os piores Índices de Desenvolvimento Humano (IDH) entre os municípios do Estado do Amazonas; analisar as Unidades de Desenvolvimento Humano (UDHs) do município de Manaus, bem como os IDHMs desta capital. Trata-se de uma revisão de literatura com finalidades descritivas, explicativas e analíticas

Submitted by Eduardo Silva (teneduardo14@gmail.com) on 2018-10-12T15:01:22Z No. of bitstreams: 2 Dissertação de Mestrado de Eduardo Pereira.pdf: 5174790 bytes, checksum: 393d879b505f281b87469f4a5364db4c (MD5) Carta de Encaminhamento.pdf: 193860 bytes, checksum: f3437c09a5b0ce71c490d4a343d04d5f (MD5) / Approved for entry into archive by Geografia PPG (ppgeog@ufam.edu.br) on 2018-10-13T03:27:49Z (GMT) No. of bitstreams: 2 Dissertação de Mestrado de Eduardo Pereira.pdf: 5174790 bytes, checksum: 393d879b505f281b87469f4a5364db4c (MD5) Carta de Encaminhamento.pdf: 193860 bytes, checksum: f3437c09a5b0ce71c490d4a343d04d5f (MD5) / Approved for entry into archive by Divisão de Documentação/BC Biblioteca Central (ddbc@ufam.edu.br) on 2018-10-15T13:24:52Z (GMT) No. of bitstreams: 2 Dissertação de Mestrado de Eduardo Pereira.pdf: 5174790 bytes, checksum: 393d879b505f281b87469f4a5364db4c (MD5) Carta de Encaminhamento.pdf: 193860 bytes, checksum: f3437c09a5b0ce71c490d4a343d04d5f (MD5) / Made available in DSpace on 2018-10-15T13:24:52Z (GMT). No. of bitstreams: 2 Dissertação de Mestrado de Eduardo Pereira.pdf: 5174790 bytes, checksum: 393d879b505f281b87469f4a5364db4c (MD5) Carta de Encaminhamento.pdf: 193860 bytes, checksum: f3437c09a5b0ce71c490d4a343d04d5f (MD5) Previous issue date: 2018-07-20 / This study sought to relate effective military police in the year 2016 with population resident in the 62 municipalities of Amazonas, with the human-HDI index of the censuses of 1991 and 2010 and the police occurrences of thefts, thefts, bodily injuries, Rapes and homicides between the years 2014, 2015 And 2016. Recognizing that there is a close relationship between human development, crime and resident populations. It broke out of the Hypothesis that there are relations between police occurrences, military police coverage, social indicators and human development in the municipalities of the state of Amazonas. The police occurrence data of the five natures previously mentioned, and the resident populations were related through the geographic Information system – SIG, which provided maps of studies: On the amount of occurrences, on the Relation of inhabitants by military police, on index of human development. The study used scatter charts to observe the evolution of human development indicators education, income and longevity. And also, the distribution of police occurrences, the relationship between inhabitants by crime, the military police coverage in the municipalities of Amazonas. The municipalities were evidenced as to the evolution of the HDI and which presented more police occurrences, which presented greater relation of inhabitants for crime, which municipalities presented the smallest and largest police coverage. The study showed that greater human development is synonymous with greater crime in the municipalities of Amazonas. This study will further research that links human development and police occurrences. / Este estudo buscou relacionar efetivo policial militar no ano de 2016, com população residente nos 62 municípios do Amazonas, com o índice de desenvolvimento humano - IDH dos censos de 1991 e 2010 e as ocorrências policiais de furtos, roubos, lesões corporais, estupros e homicídios entre os anos de 2014, 2015 e 2016. Reconhecendo que há uma relação próxima entre desenvolvimento humano, criminalidade e as populações residentes, partiu-se da hipótese de que há relações entre as ocorrências policiais, cobertura policial militar, indicadores sociais e de desenvolvimento humano nos municípios do Estado do Amazonas. Os dados de ocorrências policiais das cinco naturezas anteriormente mencionadas, e, as populações residentes foram relacionadas através do Sistema de Informações Geográficas – SIG, que proporcionou mapas de estudos sobre a quantidade de ocorrências, sobre a relação de habitantes por policial militar, sobre índice de desenvolvimento humano. O estudo utilizou gráficos de dispersão, para observar a evolução dos indicadores de desenvolvimento humano educação, renda e longevidade. E, ainda, a distribuição das ocorrências policiais, a relação entre habitantes por crime, a cobertura policial militar nos municípios do Amazonas. Foram evidenciados os municípios quanto à evolução do IDH e quais apresentavam maior quantidade de ocorrências policiais, quais apresentavam maior relação de habitantes por crime, quais municípios apresentavam as menores e maiores coberturas policiais. O estudo mostrou que maior desenvolvimento humano é sinônimo de maior criminalidade nos municípios do Amazonas. Este estudo enseja futuras pesquisas, que relacionem desenvolvimento humano e ocorrências policiais. / Este estudo tem como base as relações de desenvolvimento humano, ocorrências policiais, cobertura Policial Militar e populações residentes nos municípios do Estado do Amazonas.

La leucémie lymphoïde chronique (LLC) est le cancer hématologique le plus fréquent du monde occidental et est caractérisée par une évolution clinique hétérogène :certains patients vivent plusieurs décennies sans symptôme alors que pour d'autres le besoin de traitements est rapide et voient leur survie globale raccourcie. Il est dès lors primordial de savoir à quel type d’évolution le patient sera confronté afin d’adapter au mieux le suivi de la maladie et la précocité ou non du traitement. Ces dernières années, la génétique a mis en évidence des aberrations chromosomiques et des mutations spécifiques récurrentes dans cette maladie mais le domaine de l'épigénétque est encore peu étudié.L'épigénétique étudie les processus induisant des modifications réversibles et héritables de l’ADN sans altérer la séquence en acides nucléiques. La méthylation de l'ADN, les modifications post-traductionnelles des histones, l'interférence par ARN et l'hydroxyméthylation de l'ADN sont les mécanismes qui induisent ces modifications et ont un impact sur l'expression génique. Dans ce travail, nous traitons des histones désacétylases et des gènes TET et IDH impliqués dans l'hydroxyméthylation de l'ADN.Au cours de ce travail, nous avons dressé le profil d'expression des 18 isoenzymes HDAC dans des lymphocytes B de patients atteints de LLC. Nous avons observé une surexpression globale de celles-ci par rapport à des cellules B saines. Nous avons également démontré que HDAC3, 6, SIRT2, 3 et 6 sont corrélés avec le pronostic pour la survie sans traitement ou la survie globale. Quelques isoenzymes sélectionnées par des analyses multivariées (HDAC6, 7, 10 et SIRT3, 5 et 6) ont été combinées pour générer un score HDAC qui s'est avéré être un facteur pronostic puissant divisant significativement notre cohorte (P<0,0001).L'activité enzymatique globale des HDAC fut par la suite étudiée. Elle fut très significativement corrélée avec les deux types de survie et particulièrement avec la survie sans traitement où elle s'impose comme un facteur indépendant. Les patients avec une haute activité présentent une survie globale médiane de 137 mois alors qu'elle est supérieure à 376 mois pour une faible activité (P<0,0001). De fait elle nous permet de raffiner le pronostic en mettant en évidence des sous-groupes au sein de patients catégorisés par des facteurs pronostiques classiques.Enfin, nous nous sommes penchés sur l'hydroxyméthylation de l'ADN et les gènes associés à ce phénomène (TET et IDH) qui, pour certains, voient leur expression dérégulée dans les cellules leucémiques. TET2 et IDH1 prédisent significativement la survie sans traitement, les patients présentant une haute expression de ces gènes ayant une médiane de survie sans traitement plus grande (111 mois) que les autres (78 mois). De plus, l'expression de TET1 est diminuée alors que celle de TET3 et IDH2 est augmentée dans les lymphocytes B de patients lorsque ceux-ci sont cultivés en présence de cellules stromales mésenchymateuses, des acteurs du microenvironnement. Cependant, ces dérégulations d'expression ne sont pas associées à une modification du taux globale d'hydroxyméthylation de l'ADN.Ce travail met en avant une association évidente entre les gènes HDAC, TET et IDH et le pronostic des patients relevant dès lors la pertinence des changements épigénétiques dans la progression de la LLC. / Doctorat en Sciences biomédicales et pharmaceutiques (Médecine) / info:eu-repo/semantics/nonPublished

No description available.

Syftet med kunskapsöversikten var att specificera vad motivationsarbete kan innebära i undervisningen i idrott och hälsa (IDH). För att undersöka detta har vi använt oss av två frågeställningar: På vilka sätt påverkar lärarens undervisning elevernas motivation i ämnet idrott och hälsa? Hur identifieras aspekter av motivation inom idrott och hälsa? Metoden som används i studien är systematisk informationssökning av olika forskningsartiklar. Vi har använt olika databaser för att få fram olika artiklar, exempelvis ERIC via EBSCO, Sportdiscus och Education Research Complete (ERC). Vi har avgränsat våra sökningar där artiklarna ligger inom årtalen 2000–2023, samt är peer-review. Resultatet av våra 12 källor visar att lärarens undervisning har stor påverkan för elevernas motivation i ämnet IDH. Det blev även tydligt att motivation har stor påverkan vad gäller elevers aktivitetsnivåer och att läraren kan styra över detta. En slutsats vi kom fram till var att läraren har en nyckelroll vad gäller att motivera sina elever och att betydelsen av motivation är avgörande när det kommer till delaktighet. Genom att exempelvis testa nya förhållningssätt, strategier och justera aktivitetsnivåerna är det möjligt att motivera sina elever.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23780号 / 医博第4826号 / 新制||医||1057(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 村川 泰裕, 教授 武藤 学, 教授 滝田 順子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

In acute myeloid leukemia (AML), between 15-20% of all patients harbor a somatic mutation in the isocitrate dehydrogenase 1 or 2 gene (IDH1 and IDH2). Therefore, these mutations are among the common ones in AML. However, the prognostic significance of mutated IDH in AML patients remains controversial. Several research groups reported distinct outcomes within specific patient subsets depending on the biological and clinical context. Additionally, the prognostic impact seems to be depended by the co-mutations, the specific location of the mutation (i.e., regarding the hotspot locations IDH1 R132, IDH2 R140, and IDH2 R172) as well as the applied treatment. Today, allogeneic hematopoietic stem cell transplantation (HSCT) remains the consolidation therapy with the highest chance of sustained remission for most younger and older AML patients. Even though many IDH mutated AML patients are consolidated by HSCT and several trials testing IDH inhibitors in a maintenance setting are active, very little data are available on the influence of IDH mutations at diagnosis and as measurable residual disease (MRD) marker in the HSCT context. The first aim of our study was to study the frequency of IDH mutations and assess their associations with other biological and pretreatment markers. In our cohort of 292 AML patients, who all received an HSCT for consolidation, we identified somatic IDH mutations in 70 (24%) patients. IDH1 mutations were found in 11.4% of the patients, all of which were R132 substitutions. Regarding mutations in the IDH2 gene, we identified 8.9% and 5.1% patients harboring a R140 or a R172 substitution, respectively. Generally, IDH mutated patients did not differ significantly from IDH wild type patients in our set regarding their biological characteristics with the exception that IDH mutated patients had significant higher bone marrow blasts at diagnosis. When we analyzed the mutational landscape of our cohort, we found that IDH mutated patients more frequently also harbored DNMT3A mutations, while RUNX1 mutations and TP53 mutations were found in lower frequencies. For the diagnostic bone marrow variant allele fractions (VAFs) associated with the three IDH mutation types, we observed a mutation specific pattern. While IDH2 R140 mutations clustered around a median VAF of about 50%, the VAFs for IDH1 R132 and IDH2 R172 mutations at diagnosis were significantly lower by median but showed a wider distribution. Next, we aimed to examine the prognostic value of different IDH1 and IDH2 mutations in AML patients that receive a consolidating allogeneic HSCT. Here, we observed no differences in the cumulative incidence of relapse (CIR), event-free survival (EFS), and overall survival (OS) according to the IDH mutational status at diagnosis. This also held up when we analyzed the three mutations, i.e., IDH1 R132, IDH2 R140, and IDH2 R172 mutations separately. Also in multivariable analyses, the diagnostic IDH mutation status did not significantly associate with outcomes after HSCT. However, we also analyzed the prognostic impact in the context of the ELN2017 classification and observed a distinct prognostic impact of the IDH mutations. With respect to outcome following HSCT consolidation in the ELN2017 Favorable-risk group, IDH mutation status did not influence outcomes. In the ELN2017 Intermediate-risk group, IDH mutated patients had an increased relapse rate compared to IDH wild-type patients. Nevertheless, this did not translate into significant shorter EFS or OS. Within the ELN2017 Adverse-risk group, IDH mutated patients had a lower CIR and by trend longer OS and EFS. The final major objective of our study was to analyze the role of IDH mutations as MRD marker in AML patients in CR prior to an allogeneic HSCT. In our cohort, 44 mutated patients had material for IDH mutation status detection on MRD level using digital droplet PCR (ddPCR) at HSCT available. DdPCr is a novel method that allows absolute quantification of gene mutations and/or expression without the necessity of standard curves. We established an assay that allows the quantification of IDH1 and IDH2 mutations with very high sensitivity and specificity. Of the 44 patients, 33 (75%) had detectable IDH MRD. The ddPCR based IDH mutation MRD positive patients were differently distributed (IDH1 R132: 65%; IDH2 R140: 94%; IDH2 R172: 44%). Interestingly, the VAFs at HSCT were much lower in IDH1 R132 (median 0.17%) and IDH2 R172 (median 0.20%) compared to IDH2 R140 (median 11.6%). Looking for association between IDH MRD status at HSCT and outcome, we observed a strong relapse association of IDH1 R132 positivity or IDH2 R172 positivity. Patients that were MRD positive for IDH1 R132 or IDH2 R172 mutations also had a shorter - though not significant - EFS and OS. Thus, clinically, the elimination of persisting IDH mutations – especially of IDH1 R132 and IDH2 R172 – before HSCT could be an important milestone towards a cure for these patients. On the other hand, IDH2 R140 MRD positivity at HSCT did not associate significantly with the CIR, EFS, and OS. Together with the previous mentioned finding of a higher VAF at diagnosis, we speculated that in our cohort, IDH2 R140 mutations behaved more like a clonal hematopoiesis-related aberrations.:Inhalt/Content Bibliographische Beschreibung/Bibliographic Description 1 Referat/Abstract 2 Einleitung/Introduction 3 Acute myeloid leukemia 3 Epidemiology 3 Clinical presentation and pathogenesis 3 Diagnostic workup and classification 3 Risk stratification and treatment 6 2022 European LeukemiaNet genetic risk classification 6 Standard Treatment 7 Measurable Residual Disease 10 Isocitrate Dehydrogenase 1 and 2 mutations 11 Definition 11 Pathology and Epidemiology 12 IDH mutations as prognostic markers 12 IDH inhibitors 13 Publikation/Publication 15 Zusammenfassung/Summary 22 Perspektive/Outlook 26 Literaturverzeichnis/References 27 Anlage/Supplemental Material 36 Referenz der Publikation/Reference of the Publication 55 Erklärung über den wissenschaftlichen Anteil des Promovenden 56 Erklärung über eigenständige Abfassung der Arbeit 58 Lebenslauf/Curriculum Vitae 59 Publikationen/Publications 61 Erst- und Letztautorschaften/First and Last authorship 60 Ko-Autorschaften/Co authorship 61 Reviews 66 Danksagung/Acknowledgments 67

Made available in DSpace on 2014-06-11T19:23:37Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-11-03Bitstream added on 2014-06-13T20:27:57Z : No. of bitstreams: 1 garbin_ig_me_mar.pdf: 994173 bytes, checksum: 9fd069ced756b3a1d543e62a8e6737ca (MD5) / O objetivo desta dissertação consiste em traçar o perfil sul-americano de cumprimento das decisões da Corte Interamericana (Corte IDH). Partindo da revisão teórica na área do Direito e das Relações Internacionais, bem como dos pressupostos básicos de funcionamento do sistema interamericano, ao medir o cumprimento das decisões interamericanas pretende-se observar se o monitoramento da performance dos Estados, por parte do próprio sistema regional, proporciona melhores índices de cumprimento. A análise empírica dos atos decisórios prolatados pelo Tribunal, em sede de jurisdição contenciosa, no período de 01/01/2004 a 23/03/2009, abarca um universo de 24 casos. A metodologia de mensuração aplicada se baseia no método de Hillebrecht (2009b), que consiste no cálculo porcentual e multinivelar de cumprimento das decisões da Corte IDH. Espera-se que os dados e evidências encontrados possam ajudar a aprimorar as informações sobre a observância dos direitos humanos na América do Sul e, com isso, contribuir com o diálogo sobre o processo de efetivação dos direitos internacionalmente declarados / The aim of this dissertation is to trace the south-american profile of compliance with the Interamerican Court (Corte IDH) rulings. Departing from the theoretical review in Law and in International Relations, as well as from the basic presuppositions of the Inter-american system functioning, by measuring compliance with inter-american rulings it aims to observe if monitoring states performance, by the regional system itself, can contribute to better levels of compliance. The empirical analysis of the ruling acts issued by the Tribunal on contentious jurisdiction, during 01/01/2004 to 23/03/2009, undertakes a universe of 24 cases. The measurement methodology is based on Hillebrecht´s approach (2009b), which consists of the percentage and multi-level calculation of compliance with the Court rulings. We hope that the found data and evidence might help improve the information on observance of human rights in South America and, therefore, might contribute with the dialogue over the process of effectivation of the internationally declared rights

Les gènes de l'isocitrate déshydrogénase (IDH) sont mutés dans 70 à 80 % des gliomes de bas grade. Les enzymes mutantes IDH qui en résultent présentent une activité de gain de fonction, produisant du R-2-hydroxyglutarate (R-2-HG), appelé oncométabolite en raison de son accumulation anormale dans les tumeurs et de ses activités oncogéniques potentielles. Parmi les caractéristiques du cancer telles que la reprogrammation métabolique et épigénétique, le stress réplicatif et la stabilité du génome ont été peu caractérisés dans les cancers IDH-mutants. Par conséquent, cette étude vise à étudier l'impact de l'accumulation de R-2-HG sur la réplication de l'ADN et sa contribution au stress réplicatif dans les cancers IDH-mutants. Nous avons étudié la dynamique de la fourche de réplication dans des astrocytes humains normaux et confirmé les résultats dans d'autres lignées cellulaires normales et cancéreuses. Nous avons constaté que le traitement exogène par l'octyl-R-2-HG entravait la progression de la fourche de réplication et retardait par conséquent l'achèvement de la phase S. L'évaluation des niveaux de phosphorylation des protéines RPA, CHK1 et H2AX a révélé que la réponse classique au stress réplicatif (RSR) n'était pas activée. Un état cellulaire dans lequel la réplication de l'ADN est altérée sans activation de la RSR a notamment été décrit dans la littérature comme résultant de l'activation de la réponse au stress intégré (ISR). Cependant, l'activation de la RSI dans les cancers mutants IDH n'est pas bien étudiée. En évaluant les marqueurs d'activation de la RSI, tels que la phosphorylation de l'eIF2α et les niveaux de protéines ATF4, nous avons montré que l'octyl-R-2-HG activait la RSI. De plus, le blocage de l'ISR a partiellement sauvé la fourche de réplication et la progression de la phase S. Nous avons répliqué cette étude oncométrique. Nous avons reproduit ce défaut de réplication de l'ADN lié à l'oncométabolite ainsi que l'effet de sauvetage partiel de l'ISRIB lors de l'induction de la surexpression du gène IDH mutant. Nos résultats indiquent que la production de R-2-HG associée à la mIDH peut inhiber la dynamique normale de réplication de l'ADN via la signalisation ISR. / The isocitrate dehydrogenase (IDH) genes are mutated in 70-80% of low-grade gliomas. The resulting IDH mutant enzymes exhibit gain-of-function activity, producing R-2-hydroxyglutarate (R-2-HG), which is referred to as an oncometabolite due to its abnormal accumulation in tumours and potential oncogenic activities. Among the hallmarks of cancer such as metabolic and epigenetic reprogramming, replicative stress and genome stability have been poorly characterized in IDH-mutant cancer. Therefore, this study aims to investigate the impact of R-2-HG accumulation on DNA replication and its contribution to replicative stress in IDH-mutant cancers. We investigated replication fork dynamics in normal human astrocytes and confirmed the results in other normal and cancer cell lines. We found that exogenous treatment with octyl-R-2-HG impaired replication fork progression and consequently delayed S-phase completion. Assessment of RPA, CHK1 and H2AX protein phosphorylation levels revealed that the classical Replicative Stress Response (RSR) was not activated. Among others, a cell state in which DNA replication was impaired without activation of the RSR has been described in the literature as a result of activation of the Integrated Stress Response (ISR). However, ISR activation in IDH-mutant cancers is not well studied. Hence, by assessing ISR activation markers such as eIF2α phosphorylation and ATF4 protein levels, we showed that octyl-R-2-HG activated ISR. Moreover, blocking ISR partially rescued the replication fork and S-phase progression. We replicated this oncometabolite-related DNA replication defect as well as ISRIB’s partial rescue effect upon induction of mutant IDH gene overexpression. Our results indicate that mIDH-associated R-2-HG production possibly inhibits normal DNA replication dynamics via ISR signalling.