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Evaluation préclinique de trois nouvelles stratégies de radiosensibilisation pharmacologique : modulation de p53/Mdm2, perturbation de la dynamique des microtubules et ciblage de MET/Aurora B / Preclinical assessment of three novel strategies for radiosensitization : modulation of p53/Mdm2, disruption of microtubules dynamics, and targeting of MET/Aurora BChargari, Cyrus 24 March 2014 (has links)
Les résultats insuffisants de la radiochimiothérapie conventionnelle ont motivé l’évaluation de nouvelles cibles afin de moduler la radiosensibilité tumorale: voies intrinsèques impliquées dans la réponse aux rayonnements ionisants, vascularisation tumorale, stroma non vasculaire. A travers cette thèse, nous avons évalué trois nouvelles stratégies de radiosensibilisation pharmacologique. Nous avons d’abord étudié en association à la radiothérapie l’intérêt de la modulation de l’axe p53/Mdm2 par le JNJ26854165, un inhibiteur de la dégradation de p53 par le protéasome. Les résultats in vitro et in vivo dans des xénogreffes sous-cutanées de cancers bronchiques non à petites cellules (CBNPC) montrent que cette stratégie permet d’améliorer significativement l’efficacité de la radiothérapie. Nous avons également rapporté des résultats encourageants in vitro dans plusieurs lignées cellulaires tumorales avec un nouvel agent antivasculaire ciblant la tubuline, l’EHT 6706. Cette stratégie augmentait l’efficacité de l’irradiation et potentialisait l’effet antiprolifératif de certains agents de chimiothérapie conventionnelle. Enfin, le développement le plus abouti a consisté en l’évaluation de l’association d’un triple inhibiteur de MET/AXL/FGFR en association à l’irradiation in vitro et dans des modèles de CBNPC implantés en xénogreffes sous-cutanées, mais également sous forme de tumeurs pulmonaires orthotopiques. Cet agent pharmacologique potentialisait l’efficacité de la radiothérapie dans des lignées ne surexprimant pas MET. Il est apparu que l’activité de la drogue faisait intervenir, au moins partiellement, l’inhibition de l’activité d’acteurs de la cytocinèse. Ces trois évaluations, qui s’inscrivent dans la recherche translationnelle, montrent l’importance de la recherche préclinique pour les études d’association aux rayonnements ionisants. Seul un développement préclinique rationnel permettra de faire émerger de nouveaux standards dans le domaine de la biomodulation pharmacologique de la radiosensibilité tumorale. / Insufficient results of conventional chemoradiation have encouraged assessment of new targets for radiosensitization: intrinsic cellular pathways involved in radiation response, tumor angiogenesis, and nonvascular stroma. We have investigated these three strategies for pharmacological radiosensitization. First, we examined the usefulness of targeting p53/Mdm2 pathway in combination with irradiation. In vitro and in vivo results obtained in non-small cell lung carcinoma (NCSLC) showed that this strategy was promising for enhancing radiation efficacy. We also found encouraging results within several cell lines with a novel vascular disrupting agent targeting tubulin. This strategy enhanced radiation effects and also increased the antiproliferative effects of various chemotherapeutics. Finally, the most advanced preclinical development was obtained with a novel MET/AXL/FGFR inhibitor, which improved effectiveness of radiation therapy in vitro and in subcutaneous and orthotopic models of non MET-dependent cell cancer lines. This effect was not only related to an inhibition of stroma/cancer cell interactions, as it probably involved activity toward actors of cytocinesis. These studies, which are part of translational research, highlight the importance of preclinical investigations in the area of radiation research. Only rationale preclinical development will allow new standards to emerge for pharmacological modulation of tumor radiosensitivity.
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Avaliação morfoquantitativa e ultraestrutural da cartilagem do processo condilar da mandíbula e da sincondrose basioccipital de ratos Wistar subnutridos e suplementados com resveratrol / Morphoquantitative and ultrastructural evaluation of the mandibular condylar cartilage and basioccipital synchondrosis of Wistar rats subjected to protein undernutrition and supplementation with resveratrolPereira, Joice Naiara Bertaglia 30 September 2015 (has links)
A subnutrição é uma doença causada pela ingestão inadequada e/ou insuficiente de energia ou de outras biomoléculas, que pode comprometer o crescimento e o desenvolvimento dos tecidos. Em conjunto, a cartilagem do processo condilar da mandíbula e a sincondrose basioccipital representam os dois centros efetivos do crescimento craniofacial, que depende, dentre outros, de fatores locais como a produção do fator de crescimento semelhante à insulina I (IGF-I) e seu receptor (IGF-IR). Alterações tanto no peptídeo quanto no receptor estão associadas a graves atrasos no crescimento e desenvolvimento ósseo. Dentre os nutrientes alternativos com a capacidade de promoção da recuperação nutricional, destaca-se o resveratrol, um polifenol contido na uva e derivados que pode promover a melhora do crescimento através de propriedades osteogênicas, além de atuar como condroprotetor. Assim, a presente pesquisa teve por objetivo avaliar os efeitos da subnutrição proteica na cartilagem do processo condilar da mandíbula (PC) e na sincondrose basioccipital (SBo) de ratos, bem como os processos de renutrição e suplementação com resveratrol nos períodos pré-púbere (21 dias) e púbere (60 dias). Os grupos nutrido (N) e subnutrido (S) foram formados por filhotes cujas mães receberam dieta normoproteica e hipoproteica, respectivamente, desde o período de acasalamento; ao completarem 21 dias de vida extrauterina, época determinada para o desmame, os filhotes foram eutanasiados. A partir do 22° dia de vida, filhotes dos grupos N e S foram mantidos com as respectivas dietas até o 60° dia de vida quando constituíram, respectivamente, os grupos NN e SS. Dois grupos considerados renutridos foram formados por animais do grupo S, que a partir do 22° dia passaram a receber, o primeiro, a dieta normoproteica com 20% de caseína (grupo RN), e o segundo, a dieta normoproteica acrescida de resveratrol (RRv). A cartilagem do PC e a SBo foram processadas através das técnicas histológicas rotineiras e posteriormente submetidas às colorações da HE, Picrossíruis e Safranina-O, para a evidenciação dos componentes celular e colágeno e imunohistoquímica para a marcação de células reativas ao IGF-I e IGF-IR. Os aspectos ultraestruturais também foram analisados através da microscopia eletrônica de transmissão. Os resultados mostraram que a subnutrição foi capaz de alterar os componentes da matriz extracelular (MEC), acarretando em modificações na secreção das fibrilas colágenas e acúmulo de proteoglicanas nos tecidos; diminuição do número de células imunorreativas ao IGF-I e IGF-IR na cartilagem do PC e atraso no crescimento ósseo endocondral, comprovado através das avaliações quantitativas e morfométricas, em ambos os tecidos. A renutrição com dieta normal foi parcialmente eficaz na recuperação dos parâmetros avaliados, e pode ter provocado uma diminuição da capacidade de resposta celular ao IGF-I. Os efeitos condroprotetores do resveratrol foram fundamentados através da recuperação dos componentes da MEC e organelas dos condrócitos e uma possível diminuição da insensibilidade ao IGF-I; o atraso no crescimento ósseo endocondral foi minimizado através do seu potencial osteogênico (mais acentuado na SBo). Muito embora a recuperação dos tecidos não tenha ocorrido totalmente, diante dos dados apresentados, pode-se afirmar que a suplementação de resveratrol na dieta auxiliou de forma mais efetiva no restabelecimento dos parâmetros afetados pela subnutrição do que somente a recuperação proteica com dieta normal / Undernutrition is a disease caused by inadequate and / or insufficient intake of energy or other biomolecules, which can compromise growth and development of tissues. Together, the mandibular condylar cartilage and basioccipital synchondrosis represent the two effective centers of craniofacial growth, which depends of the factors such as the local production of insulin like growth factor I (IGF-I) and receptor (IGF-IR). Changes in both the peptide and receptor are associated with serious delays in growth and bone development. Among the alternative nutrients to the promotion capacity of nutritional recovery, there is resveratrol, a polyphenol contained in grapes and derivatives that can promote improved growth through osteogenic properties, besides acting as chondroprotective. Thus, the present study aimed to evaluate in rats the effects of protein undernutrition in the mandibular condylar cartilage and basioccipital synchondrosis, as well renutrition and supplementation with resveratrol in pre pubertal periods (21 days) and pubertal (60 days). The nourished groups (N) and undernourished (S) were formed by young whose mothers received normal protein and hypoproteic diet respectively since the breeding season; to complete 21 days of extra-uterine life, given time to weaning, puppies were euthanized. From the 22nd day of life, puppies from N and S groups were kept with their diets until the 60th day of life when constituted, respectively, NN and SS groups. Two groups considered re-nourished were formed by the S group, which from day 22 began receiving, the first, the normal protein diet with 20% casein (RN group), and the second, the normal protein diet plus of resveratrol (RRv). The cartilage of PC and SBo were processed through routine histological techniques, and then subjected to HE, Sirius red and Safranin-O staining for the disclosure of cellular components and collagen and immunohistochemistry for marking cells responsive to IGF-I and IGF-IR. The ultrastructural aspects were also analyzed by transmission electron microscopy. The results showed that undernutrition was able to change the components of the extracellular matrix (ECM) leading to changes in the secretion of collagen fibrils and proteoglycans accumulation in the tissues; decrease in the number of immunoreactive cells to IGF-I and IGF-IR in PC cartilage and delayed endochondral bone growth, confirmed by quantitative and morphometric analysis in both tissues. Renutrition with normal diet was partially effective in recovering the parameters evaluated, and may have caused a decrease in cell responsiveness to IGF-I. The chondroprotective effects of resveratrol were founded by recovering the ECM components and organelles of chondrocytes and a possible decrease in the insensitivity to IGF-I; the delay in endochondral bone growth was minimized by osteogenic potential (more pronounced in SBo). Although the tissue recovery has not fully occurred, the resveratrol supplementation in the diet helped more effectively in restoring the parameters affected by undernutrition than just protein recovery with normal diet
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Constru??es metaf?ricas de vida e morte: cogni??o, cultura e linguagemSantos, Ricardo Yamashita 16 September 2011 (has links)
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Previous issue date: 2011-09-16 / En esta investigaci?n, tratamos de poner de relieve los aspectos cognitivos y culturales que subyacen a las met?foras en el lenguaje. Partimos de la premisa de que nuestra comprensi?n a cerca del mundo se construye socio-cognitivamente, sendo la met?fora un elemento clave de esta construcci?n. Por lo tanto, tenemos la intenci?n de mirar debajo de la teor?a de la Teor?a Cognitiva de la Met?fora, visto desde el an?lisis del poema Morte e Vida Severina, de Jo?o Cabral de Melo Neto, la met?fora de la vida y muerte, infer?veis en el corpus forma patrones discursivos, llamado por nosotros como el Construccionismo del Bloques. Estas met?foras se encuentran en el nivel conceptual de nuestro lenguaje, emitido por modelos cognitivos idealizados, y mostrar las relaciones entre la lengua, la cultura y la cognici?n. Vemos una red de integraci?n que implica la met?fora primaria llamada, elaborado a partir de los esquemas y los dominios conceptuales y met?foras congruentes, con la participaci?n de la noci?n de marco. / Nesta pesquisa, buscamos evidenciar os aspectos cognitivos e culturais subjacentes ?s met?foras presentes em um corpus liter?rio. Partimos da premissa de que nosso entendimento acerca do mundo ? constru?do sociocognitivamente, sendo a met?fora um elemento-chave dessa constru??o. Desse modo, pretendemos, sob o olhar te?rico da Teoria Cognitiva da Met?fora, constatar, a partir da an?lise do poema Morte e Vida Severina, de Jo?o Cabral de Melo Neto, que as met?foras de VIDA e MORTE, infer?veis no corpus em quest?o, formam Padr?es Discursivos, denominados por n?s como Blocos Construcionais. Tais met?foras est?o no n?vel conceptual de nossa linguagem, formuladas atrav?s de Modelos Cognitivos Idealizados, e evidenciam as inter-rela??es entre linguagem, cultura e cogni??o. Percebemos uma rede de integra??o que envolve as chamadas met?foras prim?rias, formuladas a partir de esquemas e dom?nios conceptuais, e as met?foras congruentes, que envolvem a no??o de frame.
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Análise de conforto térmico em áreas abertas no município de Ourinhos - SP / Analysis of thermal comfort in open areas in OurinhosAna Claudia Carfan 05 July 2011 (has links)
Uma das conseqüências do aumento da população urbana e da modificação da paisagem é a alteração do clima local, criando um clima típico denominado clima urbano. Entender o clima urbano e buscar soluções para amenizar a influência de áreas construídas no clima de uma cidade é de grande interesse para a melhoria na qualidade de vida. Os modelos microclimáticos podem ser de grande utilidade no planejamento de cidades. Estes podem fornecer diretrizes para o planejamento arquitetônico, altura de edifícios, disposição de ruas e localização de áreas verdes trazendo um aumento do conforto térmico e dispersão de poluentes. O município de Ourinhos-SP está localizado no Sudoeste do Estado de São Paulo e faz divisa com o Estado do Paraná. Possui um clima do tipo subtropical, com inverno seco e verão chuvoso. O objetivo deste trabalho é analisar o clima urbano e o conforto térmico no município de Ourinhos, tendo para isso o modelo tridimensional ENVI-met como ferramenta principal de simulação das variáveis meteorológicas. Esse modelo possibilita a análise da temperatura do ar, umidade relativa do ar, direção e velocidade do vento além dos índices de conforto térmico PMV (Predicted Mean Vote) e PPD (Predicted Percentage of Dissatisfied) tendo por base a configuração da cidade. Efetuaram-se simulações para três áreas no município de Ourinhos, sendo duas no interior da área urbana e uma área suburbana. As simulações ocorreram para os dias 10/06/2009, inverno na região e dia 15/02/2010, situação de verão. Para o ponto situado no centro da cidade realizou-se, além da situação real, três simulações distintas alterando a estrutura através do aumento da altura das edificações, através da retirada das edificações da quadra central e instalação de um parque com vegetação rasteira e árvores e por meio da rotação da planta baixa da área urbano denso de 76º, onde a avenida principal antes com orientação NNO/SSE passa a ter orientação L/O. Pode-se observar que o modelo simula com razoável precisão as temperaturas obtidas em comparação aquelas medidas nas estações e através do coeficiente de determinação obteve-se que estes são significativos. Estes estudos mostraram que existe uma forte correlação entre a parte física da cidade (ruas, edificações e vegetação) e o conforto térmico humano. A situação de conforto para o verão e inverno é bastante diferenciada. Na análise dos índices de conforto PMV e PPD, no inverno somente a área urbano permeável não apresentou nenhuma área dentro dos limites de conforto estipulado pela norma ISSO 7730. No verão, a área urbano denso para a situação real e com aumento das edificações e a área expansão urbana apresentaram reduzidas áreas de conforto. As demais áreas, tanto no inverno quanto no verão apresentaram-se desconfortáveis. As propostas de modificação feitas, neste trabalho, não foram suficientes para mitigar o desconforto térmico das áreas urbanas abertas. / The increasing urban population and the modification of the landscape bring forth one consequence, the local climate change, developing a typical urban climate, known as urban climate. Understanding the urban climate and seek solutions to mitigate the influence of the buildings in the environment in a city is of great interest for improving the quality of life. The microclimatic models can be very useful in planning the cities. They can provide guidelines for the architectural planning, building heights, street layout and location of green areas by bringing in an increase in thermal comfort and pollutant dispersion. Ourinhos county is located in the southwestern state of Sao Paulo and is bordered by the state of Parana. It has a subtropical type climate with dry winter and rainy summer. This study aims to analyze the urban climate and thermal comfort in the city, using on this purpose the three-dimensional model ENVI-met as a main tool for simulation of meteorological variables. This model enables the researcher to analyze the temperature, relative humidity, wind direction, wind intensity and the thermal comfort indices PMV (Predicted Mean Vote) and PPD (Predicted Percentage of Dissatisfied) based on the configuration of the city. We carried out simulations in three areas in Ourinhos, two within the urban area and another in a suburban area. The simulations occurred at 10/06/2009, winter days in the region and 15/02/2010, the summer situation. The simulations took place at the center of the city, besides the actual situation, three different simulations, altering the structure by increasing the height of buildings, through the removal of buildings from the central block, a park with trees and creepers and by turning the ground floor of dense urban area of 76º, where the main avenue with prior oriented NNW / SSE direction is replaced by E / O. As observed, the model explains well the temperature obtained by comparison with those in the stations. Through the coefficient of determination it was found that these are significant. These studies showed that There is a strong correlation between the physical part of the city (streets, buildings and vegetation) and human thermal comfort. Summer and winter comfort situation is very different. Analyzing the comfort indices PMV and PPD in the winter, only the permeable urban area did not show any area within the comfort limits stipulated by ISO standard 7730. In summer, the dense urban area onto the actual situation and the increase of buildings and urban expansion area showed little comfort zones. The remaining areas, in both winter and summer were uncomfortable. Proposed changes made in this work were not enough to alleviate the discomfort of urban open areas.
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Avaliação morfoquantitativa e ultraestrutural da cartilagem do processo condilar da mandíbula e da sincondrose basioccipital de ratos Wistar subnutridos e suplementados com resveratrol / Morphoquantitative and ultrastructural evaluation of the mandibular condylar cartilage and basioccipital synchondrosis of Wistar rats subjected to protein undernutrition and supplementation with resveratrolJoice Naiara Bertaglia Pereira 30 September 2015 (has links)
A subnutrição é uma doença causada pela ingestão inadequada e/ou insuficiente de energia ou de outras biomoléculas, que pode comprometer o crescimento e o desenvolvimento dos tecidos. Em conjunto, a cartilagem do processo condilar da mandíbula e a sincondrose basioccipital representam os dois centros efetivos do crescimento craniofacial, que depende, dentre outros, de fatores locais como a produção do fator de crescimento semelhante à insulina I (IGF-I) e seu receptor (IGF-IR). Alterações tanto no peptídeo quanto no receptor estão associadas a graves atrasos no crescimento e desenvolvimento ósseo. Dentre os nutrientes alternativos com a capacidade de promoção da recuperação nutricional, destaca-se o resveratrol, um polifenol contido na uva e derivados que pode promover a melhora do crescimento através de propriedades osteogênicas, além de atuar como condroprotetor. Assim, a presente pesquisa teve por objetivo avaliar os efeitos da subnutrição proteica na cartilagem do processo condilar da mandíbula (PC) e na sincondrose basioccipital (SBo) de ratos, bem como os processos de renutrição e suplementação com resveratrol nos períodos pré-púbere (21 dias) e púbere (60 dias). Os grupos nutrido (N) e subnutrido (S) foram formados por filhotes cujas mães receberam dieta normoproteica e hipoproteica, respectivamente, desde o período de acasalamento; ao completarem 21 dias de vida extrauterina, época determinada para o desmame, os filhotes foram eutanasiados. A partir do 22° dia de vida, filhotes dos grupos N e S foram mantidos com as respectivas dietas até o 60° dia de vida quando constituíram, respectivamente, os grupos NN e SS. Dois grupos considerados renutridos foram formados por animais do grupo S, que a partir do 22° dia passaram a receber, o primeiro, a dieta normoproteica com 20% de caseína (grupo RN), e o segundo, a dieta normoproteica acrescida de resveratrol (RRv). A cartilagem do PC e a SBo foram processadas através das técnicas histológicas rotineiras e posteriormente submetidas às colorações da HE, Picrossíruis e Safranina-O, para a evidenciação dos componentes celular e colágeno e imunohistoquímica para a marcação de células reativas ao IGF-I e IGF-IR. Os aspectos ultraestruturais também foram analisados através da microscopia eletrônica de transmissão. Os resultados mostraram que a subnutrição foi capaz de alterar os componentes da matriz extracelular (MEC), acarretando em modificações na secreção das fibrilas colágenas e acúmulo de proteoglicanas nos tecidos; diminuição do número de células imunorreativas ao IGF-I e IGF-IR na cartilagem do PC e atraso no crescimento ósseo endocondral, comprovado através das avaliações quantitativas e morfométricas, em ambos os tecidos. A renutrição com dieta normal foi parcialmente eficaz na recuperação dos parâmetros avaliados, e pode ter provocado uma diminuição da capacidade de resposta celular ao IGF-I. Os efeitos condroprotetores do resveratrol foram fundamentados através da recuperação dos componentes da MEC e organelas dos condrócitos e uma possível diminuição da insensibilidade ao IGF-I; o atraso no crescimento ósseo endocondral foi minimizado através do seu potencial osteogênico (mais acentuado na SBo). Muito embora a recuperação dos tecidos não tenha ocorrido totalmente, diante dos dados apresentados, pode-se afirmar que a suplementação de resveratrol na dieta auxiliou de forma mais efetiva no restabelecimento dos parâmetros afetados pela subnutrição do que somente a recuperação proteica com dieta normal / Undernutrition is a disease caused by inadequate and / or insufficient intake of energy or other biomolecules, which can compromise growth and development of tissues. Together, the mandibular condylar cartilage and basioccipital synchondrosis represent the two effective centers of craniofacial growth, which depends of the factors such as the local production of insulin like growth factor I (IGF-I) and receptor (IGF-IR). Changes in both the peptide and receptor are associated with serious delays in growth and bone development. Among the alternative nutrients to the promotion capacity of nutritional recovery, there is resveratrol, a polyphenol contained in grapes and derivatives that can promote improved growth through osteogenic properties, besides acting as chondroprotective. Thus, the present study aimed to evaluate in rats the effects of protein undernutrition in the mandibular condylar cartilage and basioccipital synchondrosis, as well renutrition and supplementation with resveratrol in pre pubertal periods (21 days) and pubertal (60 days). The nourished groups (N) and undernourished (S) were formed by young whose mothers received normal protein and hypoproteic diet respectively since the breeding season; to complete 21 days of extra-uterine life, given time to weaning, puppies were euthanized. From the 22nd day of life, puppies from N and S groups were kept with their diets until the 60th day of life when constituted, respectively, NN and SS groups. Two groups considered re-nourished were formed by the S group, which from day 22 began receiving, the first, the normal protein diet with 20% casein (RN group), and the second, the normal protein diet plus of resveratrol (RRv). The cartilage of PC and SBo were processed through routine histological techniques, and then subjected to HE, Sirius red and Safranin-O staining for the disclosure of cellular components and collagen and immunohistochemistry for marking cells responsive to IGF-I and IGF-IR. The ultrastructural aspects were also analyzed by transmission electron microscopy. The results showed that undernutrition was able to change the components of the extracellular matrix (ECM) leading to changes in the secretion of collagen fibrils and proteoglycans accumulation in the tissues; decrease in the number of immunoreactive cells to IGF-I and IGF-IR in PC cartilage and delayed endochondral bone growth, confirmed by quantitative and morphometric analysis in both tissues. Renutrition with normal diet was partially effective in recovering the parameters evaluated, and may have caused a decrease in cell responsiveness to IGF-I. The chondroprotective effects of resveratrol were founded by recovering the ECM components and organelles of chondrocytes and a possible decrease in the insensitivity to IGF-I; the delay in endochondral bone growth was minimized by osteogenic potential (more pronounced in SBo). Although the tissue recovery has not fully occurred, the resveratrol supplementation in the diet helped more effectively in restoring the parameters affected by undernutrition than just protein recovery with normal diet
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Ligations chimiques : synthèse d'inhibiteurs extracellulaires de la signalisation HGF/SF-MET / Chemical Ligation Synthesis of extracellular inhibitors of HGF/SF-MET signalling pathwayBesret, Soizic 20 April 2011 (has links)
Les peptides constituent une famille de biomolécules dont l’utilisation dans différents domaines thérapeutiques (cancer, diabète, sida) s’est fortement développée ces dernières années. Le défi pour les chimistes consiste à y accéder grâce à de nouvelles méthodes fiables et efficaces. La première partie de notre travail a d’abord été orientée vers le développement deux méthodes de ligations non natives efficaces et complémentaires de celles existant. La première méthode, appelée ligation thiocarbamate, permet d’obtenir des peptides alkylthiocarbamate avec de très bons rendements, alors que la seconde, appelée ligation azaGly, aboutit à la formation d’un azaGlypeptide. La seconde partie de cette thèse traite de la conception et synthèse de nouveaux peptides susceptibles d’inhiber la signalisation HGF/SF-MET. Le récepteur à activité tyrosine kinase MET et son ligand, l’HGF/SF (Hepatocyte Growth Factor/Scattor Factor), sont des cibles de choix pour une thérapie anti-cancéreuse. La ligation thiocarbamate, précédemment décrite, et la ligation thioéther plus classique ont été utilisées pour préparer une chimiothèque de peptides sulfonatés d’inhiber cette signalisation de façon extracellulaire. La capacité de liaison des composés de la chimiothèque avec le domaine extracellulaire de MET a été évaluée grâce à la technologie biopuces. L’activité biologique (tests MTT, d’activité kinase) des meilleurs produits a été ensuite évaluée. / Use of peptides as biomolecules have been extensively applied to various therapeutic fields (cancer, diabetes, AIDS). The challenge for chemists consists in development of new reliable and efficient strategies. Our work especially focused on the conception of two innovative non native chemical ligations bringing an additionnal asset to the existing state of the art.The first ligation, i.e. thiocarbamate ligation, affords alkylthiocarbamate peptides with remarkable yields. Regarding the second one, the azaGly ligation allows the straightforward synthesis of azaGlypeptides. On the other hand, this thesis deals with the design of new peptides suitable to inhibit the signaling pathway of the tyrosine–kinase MET receptor and its ligand HGF/SF (Hepatocyte Growth factor/Scattor factor). Indeed interfering with MET signaling appears to be a promising therapeutic approach.The thiocarbamate ligation disclosed previously along with a classical thioether ligation have been employed for the chemical library design of sulfonated peptids in order to inhibit extracellular interactions. Binding activities assessment of the chemical libray toward the MET extracellular domain has been achieved using a microarray technology. Biological activities (MTT tests and kinase activity) have also been investigated.
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Nanocomposites à base d'argile et de surfactants polymérisables (surfmers) : synthèse et propriétés / Nanocomposites based on clay and plymerizable surfactants (surfmers) : synthesis and propertiesBenbayer, Chahinez 27 May 2014 (has links)
Le travail présenté dans ce mémoire de thèse porte sur la préparation de nouveaux nanocomposites polystyrène-argile en utilisant des argiles modifiées par divers tensioactifs cationiques polymérisables fluorés. Des systèmes de référence ont aussi été envisagés en utilisant des tensioactifs classiques de structure proche de celles des surfmers (surfmers et tensioactifs hydrocarbonés) et ce, afin de mettre en évidence le rôle joué par le groupement polymérisable et l’atome de fluor sur la structure et les propriétés des nanocomposites obtenus. Les propriétés de surface des tensioactifs ont été étudiées en termes de CMC, tensions de surface et enthalpies de micellisation de Gibbs afin d’évaluer le comportement en solution de ces tensioactifs. Ces tensioactifs ont été par la suite utilisés pour modifier une montmorillonite sodée via un processus d’échange cationique. Les organoargiles ainsi obtenues ont été caractérisées par IR, ATG et DRX. Les données DRX obtenues sont en faveur d’un alignement de la majorité des surfmers fluorés en bicouche La préparation des nanocomposites polystyrène-argile contenant diverses quantités d’organoargiles variant de 1 à 15% en utilisant la technique de polymérisation radicalaire en masse ou en solution, a montré l’effet positif de l’introduction d’une chaîne fluorée et d’une fonction polymérisable sur la stabilité thermique des nanocomposites. Des morphologies exfoliées ont été obtenues pour la majorité des nanocomposites fluorés préparés. Une relation structure-propriétés de surface et propriétés thermique a été établie sur la base des analyses ATG, DRX et TEM/MEB. / The work presented in this thesis focuses on the preparation of new polystyrene-clay nanocomposites using fluorinated polymerizable cationic surfactants as modifiers. Reference systems have also been proposed using conventional surfactants of similar structure than surfmers. The main objective is to highlight the role of the polymerizable group and the fluorine atoms on the structure and the properties of the obtained nanocomposites. The surface properties of surfactants were studied in terms of CMC, surface tensions and Gibbs enthalpies of micellization to evaluate the solution behavior of these surfactants. These surfactants were subsequently used to modify a sodium montmorillonite via cation exchange process. The resultant organoclays were characterized by IR, TGA and XRD analysis. XRD data are in favor of an alignment of the majority of fluorinated surfmers to form a bilayer structure while conventional surfactants tend to form a pseudotrimolecular layer. Determination of surfmer reactivity ratios by NMR was used to predict the behavior of these derivatives in radical copolymerization with styrene. Preparation of polystyrene-clay nanocomposite containing various amounts of organoclays from 1 to 15 wt% by radical polymerization process in bulk or solution, showed the positive effect of the introduction of fluorinated chain and polymerizable functional group on thermal stability of nanocomposites. Exfoliated morphologies were obtained for the majority of the fluorinated nanocomposite. A structure-surface and thermal properties relationship was established on the basis of TGA, XRD and TEM / SEM analysis.
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Transgéline dans la carcinogénèse colorectale induite par MetChampagne, Audrey January 2015 (has links)
Plusieurs évidences cliniques et expérimentales soutiennent un rôle important de la dérégulation du récepteur à activité tyrosine kinase (RTK) Met dans l’étiologie et la progression du cancer colorectal (CCR). En effet, Met contrôle plusieurs fonctions biologiques nécessitant une étroite régulation telles que la prolifération, la survie cellulaire, la migration et l’invasion. Lorsqu’une forme constitutivement active de Met, Tpr-Met, est exprimée dans des cellules épithéliales intestinales (CEI), celles-ci se transforment et acquièrent des pouvoirs oncogéniques. Par des analyses de protéomique quantitative, notre équipe a démontré que la transformation induite par Tpr-Met dans les CEI était accompagnée d’une modulation des niveaux de protéines impliquées dans la régulation du cytosquelette, incluant une diminution de 31,2 fois de transgéline (TAGLN). Étant une protéine régulant plusieurs processus cellulaires de par sa capacité à réorganiser le cytosquelette d’actine, nous avons émis l’hypothèse que la perte de TAGLN dans le CCR serait due à la suractivation du récepteur Met et que celle-ci contribuerait aux fonctions oncogéniques de Met.
Nos travaux de recherche indiquent, pour la première fois, que Met régule négativement la protéine TAGLN de façon dépendante et indépendante de MEK, notamment par le recrutement des protéines Shc et Grb2 aux résidus tyrosine du récepteur. De plus, par la réexpression de TAGLN dans les CEI transformées par Tpr-Met, nous démontrons que la perte de TAGLN contribue aux fonctions oncogéniques de Met, telles que la croissance au-delà de la confluence et en indépendance d’ancrage, la migration, ainsi que la croissance de tumeurs in vivo chez la souris. De plus, cette étude valide cliniquement la corrélation inverse entre l’expression de Met et de TAGLN dans le CCR. Étonnamment, à des faibles niveaux d’expression de MET, l’expression de TAGLN est corrélée de façon négative avec la survie des patients. Au contraire, à des hauts niveaux de MET, l’expression de TAGLN ne permet pas une stratification des patients selon leur pronostic de survie.
En conclusion, nous démontrons que le RTK Met régule négativement TAGLN. Cependant, chez les patients où cette régulation n’a pas lieu, l’expression de MET protègerait ceux-ci d’un mauvais pronostic. Cette étude suggère que les niveaux de TAGLN et de MET pourraient représenter des biomarqueurs permettant d’identifier en clinique les patients atteints de CCR susceptibles de bénéficier de thérapies ciblant le récepteur Met.
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La double face de la protéine SOCS1 dans la carcinogenèse colorectaleTobelaim, William Sam January 2014 (has links)
Historiquement, SOCS1 a été décrite comme une protéine capable de réguler négativement la signalisation induite par les cytokines. Dès lors, un vif engouement s’est porté sur cette protéine quant à un probable rôle de suppresseur de tumeur, notamment grâce à ses fonctions anti-inflammatoires. De surcroit, son expression est fréquemment perdue dans de nombreux cancers des suites de phénomènes épigénétiques. Récemment, il a même été démontré que SOCS1 pouvait rentrer en complexe protéique avec le suppresseur de tumeur P53, et était requis pour son activité transcriptionnelle. Finalement, notre laboratoire a participé à démontrer que SOCS1 inhibait la signalisation et les fonctions du récepteur MET dans les hépatocytes. Étant donné l’influence bien connue de l’inflammation, de l’épigénétique, de P53 et de MET dans le cancer colorectal (CCR), nous avions émis l’hypothèse que SOCS1 agirait en tant que suppresseur de tumeur dans le CCR. Dans la présente étude, nous avons modulé l’expression de SOCS1 dans un modèle cellulaire de progression tumorale colique, soit les cellules CT36 et CT26. Puis, les caractéristiques biologiques dites cancéreuses de ces lignées ont été évaluées in-cellulo et in-vivo. Contre toute attente, nos résultats révèlent une action pro-tumorale menée par SOSC1 dans le CCR. La surexpression de SOCS1 dans les cellules CT26 provoque une augmentation de la croissance cellulaire, de la survie sans ancrage à la matrice extracellulaire et de la capacité à former des tumeurs in vivo. Et à l’inverse, sa diminution, par ARN interférent, provoque chez les cellules CT36 une baisse de ces mêmes fonctions cancéreuses. Au niveau moléculaire, nous avons validé que SOCS1 conservait bien son aptitude à inhiber les voies de signalisation des cytokines et du récepteur MET ainsi qu’à promouvoir l’activité de p53. Nous avons aussi identifié que SOCS1 diminue l’expression des protéines STAT1, P21cip/kip, et de la protéine adaptatrice P66SHC. En conclusion, ce travail de recherche révèle, pour la première fois, que l’expression de SOCS1 favoriserait le développement de certains CCR. Les protéines STAT1, P21 cip/kip et P66SHC étant connues pour être impliquées dans des processus antiprolifératifs et pro-apoptotiques, leurs régulations négatives par SOCS1 pourraient en être les raisons.
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Die ontwikkeling van 'n skaal vir die bepaling van die houding van eerstejaarstudente aan Afrikaansmediumuniversiteite teenoor die natuurwetenskap en natuurwetenskaplikes / Stephanus Johannes NelNel, Stephanus Johannes January 1978 (has links)
Proefskrif--PU vir CHO
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