Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Submitted by Kamila Costa (kamilavasconceloscosta@gmail.com) on 2015-06-15T22:12:07Z No. of bitstreams: 1 Dissertacao-Wheidima C de Melo.pdf: 2703087 bytes, checksum: e6e1c33a03cbfdb7ab483f0f6f9e6dc7 (MD5) / Approved for entry into archive by Divisão de Documentação/BC Biblioteca Central (ddbc@ufam.edu.br) on 2015-06-16T15:15:11Z (GMT) No. of bitstreams: 1 Dissertacao-Wheidima C de Melo.pdf: 2703087 bytes, checksum: e6e1c33a03cbfdb7ab483f0f6f9e6dc7 (MD5) / Approved for entry into archive by Divisão de Documentação/BC Biblioteca Central (ddbc@ufam.edu.br) on 2015-06-16T15:16:09Z (GMT) No. of bitstreams: 1 Dissertacao-Wheidima C de Melo.pdf: 2703087 bytes, checksum: e6e1c33a03cbfdb7ab483f0f6f9e6dc7 (MD5) / Made available in DSpace on 2015-06-16T15:16:09Z (GMT). No. of bitstreams: 1 Dissertacao-Wheidima C de Melo.pdf: 2703087 bytes, checksum: e6e1c33a03cbfdb7ab483f0f6f9e6dc7 (MD5) Previous issue date: 2014-06-27 / Não Informada / Traditionally, electromyographic signals are compressed to one-dimensional techniques, which are specifically developed for this purpose. However, some studies have shown that the compression of biological signals such as images, via its pre-processing and rearrangement on a two-dimensional array, can lead to good results. The present work an investigation of the compression electromyographic signals like images, three main contributions: the use of new encoders, the development of new pre-processing techniques and modification of the coding core of a specific compressor, so that existing redundancies are better exploited. With respect to the pre-processing of the signal, two new techniques are introduced: ordering a percentage difference and targeting similarity which have the potential to increase the performance of encoded pictures. Optionally for compression of electromyographic signals, propose to the high efficiency video coding encoder, which features state of the art in video compression. Furthermore, an investigation of the paradigm that uses recurrence multiscale standards, known as multidimensional multiscale parser, is also presented. In summary, the encoder adapts to working with the biological signal by replacing its prediction techniques to improve the exploitation of redundancy, the result of which is termed Bio-MMP. The experiments performed with real electromyographic signals show that the proposed techniques are effective, providing better results than the state of the art in the literature. / Tradicionalmente, sinais eletromiográficos são comprimidos com técnicas unidimensionais, que são desenvolvidas especificamente para esse fim. No entanto, alguns trabalhos têm demonstrado que a compressão de sinais biológicos como imagens, através do seu pré-processamento e rearranjo em uma matriz bidimensional, pode levar a bons resultados. O presente trabalho apresenta uma investigação sobre a compressão de sinais eletromiográficos como imagens, com três principais contribuições: a utilização de novos codificadores, o desenvolvimento de novas técnicas de pré-processamento e a modificação do núcleo de codificação de um compressor específico, de modo que as redundâncias existentes sejam melhor exploradas. No que diz respeito ao pré-processamento do sinal, duas novas técnicas são introduzidas: a ordenação por diferença percentual e a segmentação por similaridade, que apresentam o potencial de aumentar o desempenho do codificados de imagens. Como opção para compressão de sinais eletromiográficos, propõem-se o codificador high efficiency video coding, que apresenta o estado da arte em compressão de vídeo. Além disso, uma investigação do paradigma que utiliza recorrência de padrões multiescalas, conhecido como multidimensional multiscale parser, também é apresentada. Em resumo, adapta-se o codificador para trabalhar com o sinal biológico, através da substituição das suas técnicas de predição, de modo a melhorar a exploração de redundâncias, cujo resultado é denominado de MMP-Bio. Os experimentos realizado com sinais eletromiográficos reais mostram que as técnicas propostas são eficazes, proporcionando resultados superiores ao estado da arte presente na literatura.

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This thesis explores the relevant impact of three influences - policy, personality and opportunity - on New Zealand governments since 1996. The Mixed Member Proportional electoral system (MMP) was adopted by New Zealand for the 1996 general election. The various coalition government arrangements since then have been analysed using a series of case studies of identified events during coalitions’ crucial pre-election, formation, duration and termination stages. The roles assumed by, or perceived of, small parties have been important as have the actions of the pivotal party in each government. My interest in this topic springs from my service as an Alliance MP. I was an Alliance party list Member of Parliament during the 45th and 46th Parliaments (1996-2002). Systems theory was relied upon as the methodology with which to study relevant political processes. Key informant interviews and participant observation were the main research methods. This research investigates the traits, apparent in the coalitions formed from 1996 until 2002, which contributed to each government’s continuation or termination. Each stage reflected the parties’ competing interests as argued by theorists such as Muller and Strøm. Wolfgang Muller and Kaare Strøm knitted together theoretical approaches and concluded that politicians are motivated by competing goals. This seminal work provides the theoretical guideline for explaining events in New Zealand and was adopted as a framework to develop this research. Coalitions faced policy shocks, adverse polls and other critical events during the three coalition governments included in this study. Politicians adapted the formal and informal constraints. In this way, they attempted to strengthen the attributes of both the Parliaments and Cabinet to ensure that they were robust enough to withstand adverse incidents. Politicians’ ambitions fluctuated between seeking office, policy objectives or electoral support depending upon the circumstances of the time. Stable and durable coalitions, as desired by the 1986 Royal Commission on the Electoral System, were those where the relevant parties’ leadership enjoyed positive relationships with each other. However, parties could not be considered to be unitary actors. Intra-party relationships were important factors. Intra-party dissension contributed to inter-party conflict and vice versa. Governments that were terminated earlier than constitutionally required suffered from deteriorating intra-party and/or inter-party relationships. The crucial component identified as an important consideration for the success or otherwise of any coalition government can be summed up as that pertaining to ‘relationship issues’ as affected by policy, personality and opportunity.

<p>Angiogenesis, de novo synthesis of blood vessels from the pre-existing vasculature, is required both during embryonic development and in pathophysiological conditions. In particular, tumor growth needs new capillary vessels in order to both deliver oxygen and nutrients and to remove toxin and metabolites. Growth of most solid tumors would be restricted to a microscopic size in the absence of neovascularization. Angiogenesis ensues as a result of a shift in the balance between pro- and anti-angiogenic molecules.</p><p>Histidine-rich glycoprotein (HRGP) is a heparin-binding plasma protein. We showed that HRGP inhibits endothelial cell migration and adhesion to vitronectin. As a consequence, HRGP attenuates growth and vascularization of mouse model tumors. The anti-angiogenic effect of HRGP is mediated by the central histidine/proline (His/Pro)-rich domain, which must be released from the parent molecule to exert its effect. A 35-amino acid residue peptide denoted HRGP330, derived from the His/Pro-rich domain, was identified as a minimal active anti-angiogenic domain of HRGP. HRGP330 induces disruption of molecular interactions required for cell motility, such as the integrin-linked kinase/paxillin complex. Moreover, HRGP330 inhibits VEGF-induced tyrosine phosphorylation of α-actinin, a focal adhesion kinase (FAK) substrate. Consequently, the motility of endothelial cells is arrested. By use of a signal transduction antibody array, we identified FAK, paxillin and growth factor receptor-bound 2 (Grb2) as tyrosine phosphorylated in HRGP330-treated cells. We confirmed that HRGP targets focal adhesions in endothelial cells, thereby disrupting the cytoskeletal organization and the ability of endothelial cells to assemble into vessel structures. A critical role of FAK in HRGP-inhibition of angiogenesis was validated using a FAK inhibitor, geldanamycin, which allowed rescue of endothelial cell actin rearrangement.</p><p>We identified another potential mechanism in the HRGP/HRGP330 anti-angiogenic effects, exerted through regulation of tumor-associated macrophages (TAMs). HRGP/HRGP330 treatment led to reduced TAM infiltration, which in turn caused a marked decrease in VEGF and MMP-9 levels in the tumor. </p><p>Taken together, our present studies show that HRGP/HRGP330 target endothelial cell adhesion, migration, focal adhesions, and furthermore, that HRGP is involved in regulation of macrophage infiltration.</p>

Angiogenesis, de novo synthesis of blood vessels from the pre-existing vasculature, is required both during embryonic development and in pathophysiological conditions. In particular, tumor growth needs new capillary vessels in order to both deliver oxygen and nutrients and to remove toxin and metabolites. Growth of most solid tumors would be restricted to a microscopic size in the absence of neovascularization. Angiogenesis ensues as a result of a shift in the balance between pro- and anti-angiogenic molecules. Histidine-rich glycoprotein (HRGP) is a heparin-binding plasma protein. We showed that HRGP inhibits endothelial cell migration and adhesion to vitronectin. As a consequence, HRGP attenuates growth and vascularization of mouse model tumors. The anti-angiogenic effect of HRGP is mediated by the central histidine/proline (His/Pro)-rich domain, which must be released from the parent molecule to exert its effect. A 35-amino acid residue peptide denoted HRGP330, derived from the His/Pro-rich domain, was identified as a minimal active anti-angiogenic domain of HRGP. HRGP330 induces disruption of molecular interactions required for cell motility, such as the integrin-linked kinase/paxillin complex. Moreover, HRGP330 inhibits VEGF-induced tyrosine phosphorylation of α-actinin, a focal adhesion kinase (FAK) substrate. Consequently, the motility of endothelial cells is arrested. By use of a signal transduction antibody array, we identified FAK, paxillin and growth factor receptor-bound 2 (Grb2) as tyrosine phosphorylated in HRGP330-treated cells. We confirmed that HRGP targets focal adhesions in endothelial cells, thereby disrupting the cytoskeletal organization and the ability of endothelial cells to assemble into vessel structures. A critical role of FAK in HRGP-inhibition of angiogenesis was validated using a FAK inhibitor, geldanamycin, which allowed rescue of endothelial cell actin rearrangement. We identified another potential mechanism in the HRGP/HRGP330 anti-angiogenic effects, exerted through regulation of tumor-associated macrophages (TAMs). HRGP/HRGP330 treatment led to reduced TAM infiltration, which in turn caused a marked decrease in VEGF and MMP-9 levels in the tumor. Taken together, our present studies show that HRGP/HRGP330 target endothelial cell adhesion, migration, focal adhesions, and furthermore, that HRGP is involved in regulation of macrophage infiltration.

In systemic sclerosis (SSc), interstitial lung disease (ILD) and engagement of the vascular system lead to increased morbidity and mortality. The aim of this thesis was to elucidate, in a consecutively included cohort of SSc (limited and diffuse) patients (n = 33), the T cell cytokine profile driving the disease in ILD and to explore the role of matrix metalloproteinase 9 (MMP-9) and its inhibitor: tissue inhibitor of metalloproteinase 1 (TIMP-1) in the extracellular matrix (ECM) degrading process leading to fibrous scarring and honey combing. Moreover, to characterize the role of nitric oxide (NO) in vascular engagement. Peripheral arterial changes cause Raynaud’s phenomenon and digital ulcers. Nitric oxide (NO) a main inducer of vasodilation is produced by endothelial nitric oxide synthase (eNOS) in response to changes in blood flow or by inflammatory cytokine inducible (i) NOS. In the vascular smooth muscle cell (VSMC) NO activates guanylate cyclase to produce cGMP, causing relaxation. We showed elevated plasma nitrate, a degradation product of NO, and increased urinary excretion of nitrate and cGMP. Plasma nitrate correlated with elevated levels of endothelial adhesion molecules: endothelial (E) selectin and vascular adhesion molecule 1, indicating that the activated endothelium is the site of NO synthesis by iNOS. Endothelial staining for E-selectin and the finding of iNOS and eNOS in SSc skin biopsies supported this notion. In SSc increased vascular stiffness may limit the NO vasodilatory effects. We found normal endothelium-dependent (i.e. flow mediated (FMD%)) and endothelium-independent (i.e. nitroglycerin-induced (NTG%)) vasodilation in the brachial artery. Radial arterial wall stiffness measured as maximum increase in pulse pressure (dP/dtmax) was increased. FMD% and especially NTG% correlated negatively and dP/dtmax positively to measures of endothelial inflammation: plasma- nitrate and adhesion molecule levels. Thus inflammatory vascular wall changes may interfere with dilation as may the presence of nitrate tolerance. We found elevated alveolar MMP-9 in both its pro- and active form in ILD. The levels correlated to decline in lung capacity, pointing at a causal relation. We suggest that neutrophils secrete MMP-9, which may degrade collagen IV, (the main constituent of basal membranes), collagen V, gelatins, proteoglycans and elastin. MMP-9 activity is partly regulated by the binding of pro- and active form to TIMP-1. Alveolar TIMP-1, which even stimulates fibroblast ECM synthesis, was increased independent of ILD. The inflammatory process in ILD is orchestrated by activated T helper (h) lymphocytes. We found a mixed Th1/Th2 reaction in SSc alveolar T cells expressing messenger for interferon gamma (Th1), IL-6 and IL-10 (both Th2). No particular cytokine mRNA profile distinguished alveolar T cells in ILD. Neutrophils invaded the bronchial epithelium, which seemed otherwise inert as levels of inflammatory cytokine sensitive transcription factors and their nuclear translocation tended to be low. The neutrophil recruitment pathway is uncertain as chemoattractants and endothelial adhesion molecules were normally expressed. In conclusion, MMP-9 probably causes degradation of lung tissue in ILD and may represent a future therapeutic target. Alveolar T cells show a mixed Th1/Th2 cytokine profile independent of ILD. Neutrophils invade the bronchial epithelium. Activated endothelium produces increased amounts of NO and adhesion molecules and the level of activation influences brachial arterial FMD% and NTG% and radial arterial compliance. Nitrate tolerance may be present.

Le développement d'une nouvelle sonde dite " activity-based probe " pour réaliser la détection de formes actives de protéases appartenant à la famille des protéases à zinc de la matrice (MMP) a été réalisé dans ce travail, en partant d'un inhibiteur phosphinique puissant des MMP dans lequel a été introduit un groupement photoactivable de type diazérine. Ce composé se révèle un inhibiteur puissant de plusieurs MMP avec des affinités nanomolaires. Ce composé incubé avec différentes MMP est par ailleurs capables de modifier de façon covalente un grand nombre de MMP au niveau de leur site actif, avec des rendements de modification variant de plus de 50% à 11%, selon la nature des MMP. En ayant choisi comme moyen de détection la radioactivité, nous démontrons qu'avec cette nouvelle sonde qu'il est possible de détecter des formes actives de MMP avec des sensibilités de l'ordre de la femtomole dans des systèmes modèles de protéomes complexes. Appliquée à l'analyse de lavages broncho alvéolaires de souris traitées par voie pulmonaire avec des nanoparticules pour induire une réponse inflammatoire, cette nouvelle sonde permet de mettre en évidence la présence de formes actives du domaine catalytique de la MMP-12, une métalloprotéase à zinc exprimée par les macrophages, mais pas dans les animaux contrôles. En revanche l'analyse de carotides humaines de patients souffrant d'athérosclérose ne nous pas conduit avec cette sonde à la détection de formes actives de MMP. Malgré ce résultat, il est à noter que la détection de forme active de MMP dans un fluide pathologique est une première dans ce domaine. Cette sonde étant validée pour sa capacité à détecter des formes actives de MMP, elle permettra dans l'avenir de tester d'autres fluides pathologiques d'origine humaine ou bien des extraits de tissu comme des tumeurs pour lesquels les MMP pourraient être des marqueurs de ces pathologies.

Prostate cancer is the most common cancer in men, with the incidence rapidly increasing in Europe over the past two decades. Reliable biomarkers for prostate cancer are currently unavailable. Thus, there is an urgent need for improved biomarkers to diagnose prostate cancer at an early stage and to determine the best treatment options. Higher expression of transforming growth factor-β (TGFβ) has been reported in patients with aggressive cancer. TGFβ is a multifunctional cytokine that acts as a tumor suppressor during early tumor development, and as a tumor promoter at later stages of cancer. TGFβ signals through the canonical Smad or non-Smad cascade via TGFβ type II and type I receptors. The TGFβ signaling cascade is regulated by various post-translational modifications of its key components. The present investigation aimed to identify a potential function of TRAF6 in TGFβ-induced responses in prostate cancer. The first two articles of this thesis unveil the proteolytic cleavage of TGFβ type I receptor (TβRI), and the biological importance of the liberated TβRI intracellular domain (TβRI-ICD) in the nucleus. We found that tumor necrosis factor receptor-associated factor 6 (TRAF6) polyubiquitinates TβRI, which leads to cleavage of TβRI by tumor necrosis factor alpha converting enzyme (TACE) in a protein kinase C zeta (PKCζ)-dependent manner. Following ectodomain shedding, TβRI undergoes a second cleavage by presenilin 1 (PS1), which liberates TβRI-ICD. TβRI-ICD translocates to the nucleus, where it regulates its own expression as well as expression of the pro-invasive gene Snail1, thereby promoting invasion. We further found that TβRI-ICD associates with Notch intracellular domain (NICD) to drive expression of the pro-invasive gene Snail1, as well as Notch1 ligand Jag1. The third article provides evidence that TRAF6 promotes Lys63-linked polyubiquitination of TβRI at Lys178 in a TGFβ-dependent manner. TβRI polyubiquitination was found to be a prerequisite for TβRI nuclear translocation, and thus for regulation of the genes involved in cell cycle, differentiation, and invasion of prostate cancer cells. In the fourth article we investigated the role of the pro-invasive gene Snail1 in TGFβ-induced epithelial-to-mesenchymal transition (EMT) in prostate cancer cells.

Wound healing and carcinogenesis are defined as complex, adaptive processes which are controlled by intricate communications between the host and the tissue microenvironment. A number of phenotypic similarities are shared by wounds and cancers in cellular signaling and gene expression. Radiotherapy is the second most effective modality of cancer treatment after surgery and can be used, either alone or in combination with chemotherapy. Recent findings suggest that radiotherapy apart from tumor cell death also rapidly and persistently modifies the tissue microenvironment. These modifications affect cell phenotype, tissue metabolism, bidirectional exchanges and signaling events between cells. The complex interactions between stromal cells and cancer cells are of immense interest and in The First Part of My Thesis, I tried to explore the crosstalk between stromal and carcinoma cells in response to radiotherapy by genetic modulation of the stroma and irradiation. We found that fibroblasts, irrespective of their RhoB status, do not modulate intrinsic radiosensitivity of TC-1 but produce diffusible factors able to modify tumor cell fate. Then we found that Wt and RhoB deficient fibroblasts stimulated TC-1 migration through distinct mechanisms respectively, TGF-β1 and MMP-mediated. We also found that co-irradiation of fibroblasts and TC-1 abrogated the pro-migratory phenotype by repression of TGF-β and MMP secretion. This result is highly relevant to the clinical situation and suggests that conversely to, the current view; irradiated stroma would not enhance carcinoma migration and could be manipulated to promote anti-tumor immune response. Secondly, our in vivo experiments, tends to confirm the in vitro data showing that irradiated tumor bed does not stimulate tumor growth and escape. Our results also challenges the view that irradiated stroma would promote migration of carcinoma cells as we show that independently from their genotype co-irradiation of fibroblasts and carcinoma cells repressed carcinoma cell migration and confirmations studies are currently performed in vivo. The Third Part of My Project, was dedicated to investigate the effect on CTC release after radiotherapy. Consistently with the results reported after surgery , the number of CTC increases in the blood stream after radiotherapy probably due to radiation-induced vascular injury induced or/and by EMT induction in tumor cells but these cells seemed to be entrapped into the cardiac cavity. The significance of these CTC to metastatic development is still under investigation but there is evidence for a metastasis-promoting effect of RT from animal studies.Thus the microenvironment can exert antagonist stimulatory or inhibitory effects on malignant cells.