Résumé : Dans les maladies respiratoires chroniques, les propriétés biochimiques et mécaniques des muscles lisses des voies respiratoires (MLVR) ont été analysées, mais les modes d’action des médiateurs lipidiques endogènes dérivés des oméga-3 (époxy- ou polyhydroxy- éicosanoïdes) restent à clarifier. Mon travail de recherche a pour but de caractériser le rôle potentiel de monoacyglycéride de l’acide éicosapentaénoϊque (MAG-EPA) et de monoacylglycéride de l’acide docosahexaénoϊque (MAG-DHA) ainsi que leurs métabolites (acide 17,18-époxyéicosatétraénoϊque : 17,18-EpETE, résolvine D1 : RvD1), sur le statut inflammatoire et l’activité contractile des voies respiratoires mises en culture organoϊde avec des cytokines pro-inflammatoires. Sur des trachées de cobayes (TC) natives précontractées au U-46619 (agoniste du récepteur thromboxane prostanoϊde), le 17,18-EpETE relaxe les tissus de manière plus importante que son précurseur, le MAG-EPA. Dans les TC mises en culture pendant 3 jours, les niveaux de TNF-α ont augmenté dans les fractions microsomales par rapport aux trachées natives. Sur ces tissues cultivés et traités avec 0.3 µM 17,18-EpETE, une réduction de la sensibilité au Ca2+ a été démontrée. De plus, une diminution de niveaux de détection des P-p65-NFκB, c-fos et c-Jun a été quantifiée en présence de 17,18-EpETE et des inhibiteurs de PKC ou Rho kinase lorsque les TC sont préalablement traités par 10 ng/ml TNF-α. Les cytokines pro-inflammatoires (IL-13 et TNF-α, etc…) jouent un rôle majeur dans la physiopathologie de l’asthme. Le projet de bronchioles humaines évalue l’effet de la RvD1 et de ses précurseurs (MAG-DHA, MAG-DPA et 17(S)-HpDoHE) sur le statut inflammatoire et la bronchoréactivité, in vitro. Dans les bronchioles stimulées par l’IL-13 pendant 48 h, le MAG-DHA ainsi que ces métabolites diminuent l’activation de la voie TNF-α/NFκB et la sensibilité au Ca2+ des tissus prétraités avec l’IL-13 vers des niveaux proches des conditions contrôles. Dans les bronchioles prétraitées par le TNF-α, l’inflammation et l’hypersensibilité au Ca2+ sont abolies par 1 µM MAG-DPA. De plus, l’aspirine combinée au MAG-oméga-3 potentialise les effets inhibiteurs de ce dernier sur l’inflammation et l’hyperréactivité bronchique induite par les cytokines, tout en régulant à la hausse les niveaux de détection du GPR-32 (le récepteur de RvD1). En conclusion, les dérivés des oméga-3 à longue chaîne pourraient résoudre l’inflammation et contrer les causes de l’hyperréactivité bronchique (HRB). / Abstract : In chronic respiratory diseases, the biochemical and mechanical properties of airway smooth muscle were analyzed, but the mode of action of omega-3 derivatives (epoxy or polyhydroxy-eicosanoids) remains to be clarified. My research work aims to characterize the potential role of eicosapentaenoic acid monoacyglyceride (MAG-EPA) and docosahexaenoic acid monoacylglyceride (MAGDHA) and their bioactive metabolites (17,18-epoxyeicosatetraenoic acid: 17 18-EpETE, resolvin D1: RvD1) on the inflammatory status and the contractile activity of organcultured airway explants with pro-inflammatory cytokines. On 30 nM U-46619 (Thromboxane prostanoid receptor agonist) pre-contracted fresh guinea pig trachea, 17,18 EpETE displays a greater ability than its precursor, MAG-EPA to relax airways. In 72-h-cultured tracheal rings, TNF-α levels increase in the microsomal fractions when compared to native trachea. In cultured and pre-treated tracheal rings with 0.3 µM 17,18-EpETE, the Ca2+ hypersensitivity is alleviated in comparaison to 3 day cultured tracheal rings. In addition, the detection levels of P-NFκB, c-fos and c-Jun were abolished in the presence of 17,18-EpETE and PKC or Rho kinase inhibitors in short term-TNF-α- incubated tracheal rings. Pro-inflammatory cytokines (IL-13, TNF-α, etc…) play a major role in asthma pathophysiology. The human bronchi project evaluates the effect of RvD1 and its precursors (MAG-DHA, MAG-DPA and 17 (S)-HpDoHE) on the inflammatory status and bronchial reactivity, in vitro. In IL-13 stimulated human bronchi for 48 h, the MAG-DHA and its metabolites decrease the activation of TNF-α / NFκB pathway and blunt the Ca2+ hypersensitivity triggered by IL-13. In TNF-α-pretreated human bronchi, airway inflammation and Ca2+ hypersensitivity are reversed by 1 µM MAG-DPA. Hence, aspirin combined with MAG-omega-3 potentiate the inhibitory effects of MAG-DHA on inflammation and bronchial hyperrresponsiveness triggered by pro-inflammatory cytokines, while upregulating the GPR-32 detection levels (RvD1 receptor). In conclusion, omega-3 derivatives could counteract the causes of airway hyperrresponsiveness (AHR).

This thesis is analysing the abortion debate in Bolivia and questions a supposed contradiction of being simultaneouslyfeminist and Catholicregarding opinions on abortion. By analysing texts from three important actors in the abortion debate in Bolivia, the studyshows on what arguments and discourses that are used within the debate, as well asconsideringthe interesting role of Católicas por el Derecho a Decidir (CDD -Catholics for the Right to Decide),that isa feminist organisation fighting for a complete decriminalisation of abortion in Bolivia, but are also Catholics. The two other actors analysed are Colectivo Rebeldía as a representative of the feminist movement, and the Catholic Church asthe greatest abortion opponent. The thesis has a feminist perspective and use a critical discourse analysis in orderto provide different perspectives on the abortion debate in Bolivia. The results indicate that the rights discourse is frequently used by all three actors, although promoting different rights.Whereas the Church promotes the foetus’ right to life, the twofeminist organisations speak of rights in terms of a woman’s right to decide.The Church is using a conservative traditional language and aims to maintain status quo, whereas the feminist organisations use a variety of discourses with the objective of social transformation. Moreover, the fact that the organisation CDD is both feminist and Catholic, might not seem that contradictive when explainedwith the help of feminist theology.

The aim of my work is to analyze Czech language textbooks for foreigners in terms of inclusion and presentation of cultural studies. In the theoretical part I attempt to outline the development of Czech courses for foreigners and Czech as a foreign language, as well as summarize the current knowledge of area studies and explain their interconnectedness with the socio- cultural competence. In the second, practical part of my work, I focus on whether facts in various Czech language textbooks for foreigners are presented implicitly or explicitly, whether the facts presented in contrast with the culture are expected from the student and whether the facts in these textbooks are practiced and tested. In addition, I tried to capture the presence or absence of geographical information, historical information, information regarding cultural characteristics of the Czech and their lifestyle, information about English and its development, information regarding speech courtesy and behaviour, information regarding Czech literature, art, science, sports, Czech food, information regarding Czech politics and other possible facts. The analysis of each textbook is its assessment and the recommendation for teachers. In conclusion, I summarize all discovered knowledge regarding area studies in Czech language textbooks for...

Work deals with the causes of creation of the systems of public oversight of auditors, the regulation and functioning. Compares the surveillance systems in the Czech Republic, where the system works only since 2009, and Germany, where public oversight has been going since 2005.

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Det har blivit mer populärt att skapa 3D-modeller bland kommuner och företag idag. Det går att visualisera de flesta föremål i 3D, vilket kan skapa större tydlighet och därmed ökad förståelse. Lidköpings kommun vill kunna använda sin LiDAR-data till att visualisera byggnader samt kunna kombinera flera datalager med 3D-visualiseringar för att kunna skapa användbara karttjänster. I dagsläget finns det ingen programvara som kan skapa 3D-modeller av LiDAR-data i kommunen. Lidköpings kommun är intresserade av vilka alternativ för GIS-programvaror som finns. De programvaror som valts ut för att skapa 3D-modeller i studien är ArcGIS Pro och QGIS. ArcGIS Pro är en erkänd GIS-programvara på marknaden. Den är licensierad och kostsam. QGIS däremot är en GIS-programvara som är gratis och uppbyggd på fri källkod, vilket gör det möjligt att själv skapa algoritmer som sedan kan användas i programmet. Studien är en jämförelse mellan en programvara som är kostsam och en som är gratis. Metoden som används för att jämföra de båda programvarorna består av tre steg. Steg 1 är en programvarujämförelse, där olika påståenden ställer programvarornas kapacitet mot varandra. Steg 2 är en kontroll av lägesosäkerhet där koordinaterna av 3D-modellernas byggnadshörn jämförs med koordinater inmätta med totalstation. RMSE används för att jämföra lägesosäkerheten. Steg 3 är en visualiseringsanalys som sker igenom ett frågeformulär, vilket går ut till personer som är bekanta med GIS och 3D. Frågeformuläret ställer bilder med 3D-modeller från båda programvarorna mot varandra. Resultatet av samtliga tre steg visar, enligt metoden som har utförts, att ArcGIS Pro är den bättre programvaran. I steg 1 hade ArcGIS Pro fördelar på fem av åtta påståenden jämfört med QGIS. QGIS hade dock mindre tidsåtgång än ArcGIS Pro. I steg 2 hade ArcGIS Pro RMSE för höjd värdet; 1,617, vilket var lägre än RMSE-värdet; 1,961 i QGIS. Enligt svaren från enkäten i steg 3 bedömde ca 90 % av de svarande att ArcGIS Pro var det bättre programmet i de flesta avseenden för de avsedda ändamålen. Vissa jämförelser blev inte helt jämna. QGIS hade minst tidsåtgång för att det inte blev lika mycket felkoder som behövde undersökas som i ArcGIS Pro, även om processen för skapandet av 3D-modeller gick snabbare i ArcGIS Pro. Lägesosäkerhetsjämförelsen på höjd i ArcGIS pro var närmare de inmätta punkterna, då takmodellen skapade större tydlighet. Det blev lättare att se var taket började. I QGIS fanns det ingen takmodell, vilket gjorde det svårare att få höjden exakt. / It has become more popular to create 3D models among local governments and companies today. Now it´s possible to visualize most objects in 3D, which can give an increased understanding. The local government in Lidköping wants to be able to use their LiDAR data to visualize buildings and to combine several data layers with 3D visualizations to create useful web map services. At the present, there is no software that are able create 3D models of LiDAR data at the Local government. The local government in Lidköping is interested in testing different options for modelling in 3D. Two software packages were chosen; ArcGIS Pro and QGIS. ArcGIS Pro is a GIS software that is highly acknowledged in the market. It´s licensed and can be considered expensive. QGIS is a software that is completely free to use and uses open source code, which makes it possible to create algorithms that can then be used in the program. In this view, there will be comparison between a software that is expensive and a software that is completely free. The method used to compare the two software consists of three stages. Stage 1 is a software comparison, where the software capabilities are set against each other in different scenarios. Stage 2 is an investigation of positional accuracy where the coordinates of the 3D model's building corners are compared with coordinates measured with Total Station as reference. RMSE is used to compare positional accuracy. Stage 3 is a visualization analysis that takes place through a questionnaire answered by people who are familiar with GIS and 3D. The result of all three stages, according to the method performed, shows that ArcGIS Pro is the better software. At stage 1, ArcGIS Pro won five out of eight scenarios against QGIS, though QGIS was more time efficient than ArcGIS Pro. At stage 2, ArcGIS Pro had a RMSE value for height of 1,617, which is lower than the 1,961 RMSE value that was on QGIS. At stage 3, ArcGIS Pro had over 90% of the reply rate for most of the questions, representing that ArcGIS Pro’s images were better to visualize the different scenarios. Some comparisons were not completely even though. QGIS had better time accuracy because it did not get as much errors which needed further investigations as in ArcGIS Pro. Although ArcGIS Pro’s processes for creating 3D models were faster. The positional accuracy comparison for the building’s height shows higher accuracy between ArcGIS Pro and the Total Station’s measurements. In QGIS the 3D-modell had no roof model, which made it harder to get accurate height of the building.

Dentre as variações morfológicas possivelmente associadas ao potencial fisiológico das sementes está o tamanho do embrião. Uma das abordagens atuais da pesquisa sobre análise de imagens de sementes radiografadas é verificar até que ponto a relação entre o grau de desenvolvimento embrionário e o espaço disponível na cavidade interna da semente está associada ao desempenho da semente. Os objetivos deste trabalho foram verificar a eficiência de diferentes testes na avaliação do vigor de sementes de algodão ao longo do armazenamento, verificar a possível relação entre o espaço livre na cavidade interna e o potencial fisiológico das sementes durante o armazenamento e verificar se há relação entre o espaço livre e o desempenho de sementes de algodão. Diferentes lotes de sementes de algodão, cultivares BRS 293 e FMT 709, foram armazenados em câmara fria e seca (10 °C e 30% de UR do ar) e em ambiente natural, durante oito meses. As avaliações da germinação e do vigor (primeira contagem de germinação, germinação a baixa temperatura, envelhecimento acelerado tradicional e com solução saturada de NaCl, emergência de plântulas em campo e análise computadorizada de imagens de plântulas - SVIS®) foram realizadas a cada dois meses de armazenamento. Para avaliação do espaço livre, as sementes de cada lote foram radiografadas e analisadas por meio dos softwares Tomato Analyzer e Image-Pro® Plus. Os resultados indicaram que os testes de envelhecimento acelerado (tradicional e com solução saturada de NaCl), emergência de plântulas em campo e SVIS® (comprimento de plântulas) são adequados para avaliação do vigor de sementes de algodão, sendo o envelhecimento acelerado tradicional e as análises SVIS® (comprimento de plântulas) sensíveis para detectar redução no potencial fisiológico das sementes durante o armazenamento. No entanto, a queda do vigor das sementes de algodão não está associada ao espaço livre na cavidade interna das sementes. Contudo, há indícios de uma relação inversamente proporcional entre o espaço livre e a germinação de sementes de algodão. / One of the morphological variations usually referred as associated to seed physiological potential is the embryo size. A primary interest of image analysis of Xrayed seeds is to identify whether the ratio between the degree of embryo development and the available space in the internal seed cavity is related to seed performance. The objectives of this research were to verify the accuracy of different tests to assess the vigor of cotton seeds during storage, to check the possible relationship between the free space and cotton seed physiological potential during storage and to verify if the relationship between the free space and cotton seed performance exist. Cotton seed lots of BRS 293 and FMT 709 cultivars were stored during eight months under two environments: cold and dry chamber (10 °C and 30% relative air humidity) and laboratory non-controlled condition. Evaluations of seed germination and vigor (germination first count, cool germination, traditional and saturated salt accelerated aging, field seedling emergence and seedling imaging automated analysis - SVIS®) were performed at two months intervals during storage. Free space was evaluated in radiographed seeds from each lot using Tomato Analyzer and Image-Pro® Plus softwares. Results showed that the accelerated aging tests (traditional and with saturated NaCl), field seedling emergence and SVIS® (seedling length) are suitable for evaluate the cotton seed vigor and the traditional accelerated aging and SVIS® (seedling length) are sensitive to detect reductions in seed physiological potential during storage. However, the reduction of cotton seed vigor is not associated with the free space in the internal cavity of the seed. Nevertheless, there is evidence of an inverse relationship between the free space and germination of cotton seed.

GASPAROTTO, E.P.L. Expressão de genes e proteínas pró- e anti-apoptóticas em células precursoras da medula óssea e leucócitos do sangue periférico de pacientes portadores de policitemia vera. 2009. 185f. Tese de Doutorado. Faculdade de Ciências Farmacêuticas de Ribeirão Preto Universidade de São Paulo, Ribeirão Preto, 2009. A policitemia vera (PV) é uma doença mieloproliferativa clonal que afeta o progenitor hematopoético multipotente causando o acúmulo de eritrócitos, leucócitos e plaquetas morfologicamente normais e seus precursores, na ausência de um estímulo definido. Alterações na regulação da apoptose parece ser uma das causas do acúmulo de células eritróides sem a necessidade de eritropoetina. A mutação JAK2 V617F foi descrita como um dos eventos envolvidos na fisiopatologia das Doenças Mieloproliferativas Crônicas, sendo relacionada a um pior prognóstico. Esta mutação resulta na ativação constitutiva da enzima Janus Kinase 2 e conseqüentemente das vias de sinalização associadas ao estímulo celular mediado por citocinas e fatores de crescimento. O objetivo deste estudo foi investigar as alterações da expressão de proteínas e genes envolvidos na regulação da apoptose em pacientes com PV sem tratamento. Para tanto foi quantificada a expressão de genes e proteínas da família Bcl-2 e da via extrínseca da apoptose em células precursoras e leucócitos desses pacientes e de indivíduos saudáveis. Os leucócitos do sangue periférico de 12 pacientes e 14 controles foram obtidos pelo método de Haes-esteril. As células precursoras CD34+ destes pacientes e de 19 controles foram separadas em coluna imunomagnética. A detecção da expressão gênica e protéica das moléculas anti- e pró-apoptóticas foi realizada pelas técnicas de PCR em tempo real e Western-blot, respectivamente. Foi avaliada ainda a resistência à morte celular induzida por agentes apoptogênicos dos linfócitos dos pacientes. As células CD34+ e maduras mostraram expressão aumentada dos genes a1, mcl-1, noxa, c-flip e ciap-2. A expressão dos genes bid , bim-EL , fas e faim estava elevada e a dos genes bcl-2, bcl-xL e bax diminuída, somente nas células CD34+. Nos leucócitos, observou-se ainda maior nível de expressão do gene bok e expressão diminuída dos genes bcl-2, bcl-xL, bad, bax, faim, dr4, dr5 e trail. Os genes bcl-w, bak, bik, fasL e ciap-1 não mostraram diferença significativa na expressão em células CD34+ e leucócitos de pacientes e controles (p>0,05). Houve significância estatística nas correlações entre: expressão de dr5 e mutação JAK2 V617F; bim-EL com concentração de hemoglobina e com hematócrito; bcl-w e número de plaquetas; a1, bad, bax nas células CD34+ e bad em leucócitos com aumento do baço. Os linfócitos dos pacientes foram mais resistentes a apoptose mediada por ACT D 1uM e 5uM, ARA-C 25uM, CHX 25uM, VP-16 e VM-26 25uM. Houve correlação entre a percentagem de alelos mutados para JAK2 V617F e o perfil de resistência aos indutores de apoptose dos linfócitos dos pacientes a ACT D 1 uM e 5uM e STS 5uM. Observou-se ainda correlação estatística entre: expressão de a1 com ACT D 5 uM, CHX 50uM e ARA-C 25uM; bad com CHX 25uM e teniposídeo 25uM; bcl-2 com ACT D 5uM , CHX 50uM, STS 1uM e 5uM e VP-16 a25uM ; bid com ACT D 5uM e VM26 25uM; bik com ACT D 5uM , STS 1uM e 5uM e VM-26 25uM, ARAC 25uM e VP16 25Um; bim-EL com CHX 25uM e teniposídeo 25uM; bok com ACT D 5uM STS 1uM e 5uM, ARAC 25uM e etoposídeo 25uM; ciap-1 com ACT D 1uM e 5uM, STS 1uM e VP16 25uM; dr4 com ACT D 5uM, ARAC 25uM, VP16 a 25uM; dr5 com ACT D 5uM, STS 1uM, ARAC 25uM e VP16 25uM; faim com ACT D 5uM; mcl-1 com ARAC 25uM e STS 1uM; trail com ACT D 5uM. As proteínas A1, BAD e c-FLIP tiveram o mesmo perfil de expressão dos seus respectivos genes, contudo os níveis de expressão protéica para BCL-xL estavam aumentados e para BIM-EL diminuídos, resultados discordantes com os obtidos nas expressões gênicas. Em conjunto esses resultados sugerem que a maquinaria apoptótica está desregulada, o que poderia contribuir, pelo menos em parte, com a mieloacumulação observada no SP e MO dos pacientes com PV. / GASPAROTTO, E.P.L. Pro- and anti-apoptotic genes and proteins expression in bone marrow precursors and peripheral blood leukocytes in polycythemia vera patients. 185f. Thesis (Doctoral). Faculdade de Ciências Farmacêuticas de Ribeirão Preto Universidade de São Paulo, Ribeirão Preto, 2009. Polycythemia vera (PV) is a clonal myeloproliferative disease arising in a multipotent haematopoietic progenitor cell causing the accumulation of erythrocytes, leukocytes and platelets morphologically normal and their precursors in absence of a definable stimulus. Apoptosis deregulation seems to be one of the causes of erythroid cells accumulation without the need for erythropoietin. The JAK2 V617F mutation has been described as one of the events involved in pathophysiology of chronics myeloproliferative diseases, being related to worse prognosis. This mutation results in constitutive activation of the enzyme Janus kinase 2 and consequently of signaling pathways associated with cell stimulation mediated by cytokines and growth factors. This study aimed to investigate changes in expression of proteins and genes involved in regulation of apoptosis in PV patients without treatment. Was quantified for both gene and proteins expression of the Bcl-2 family and the extrinsic pathway of apoptosis members in precursor cells and leukocytes of patients and healthy subjects. Peripheral blood leukocytes of 12 patients and 14 controls were obtained by the Haes-sterile method. CD34+ precursor cells of these patients and 19 controls were separated by immunomagnetic column. Anti- and pro-apoptotic gene and protein expression detection was performed by real-time PCR and Western-blot techniques respectively. It also assessed the resistance to cellular death induced by apoptogenics agents in PV lymphocytes. CD34+ and mature cells showed increased expression of a1, mcl-1, noxa, c-flip and ciap-2. Gene expression of bid, bim-EL , fas e faim was high and to genes bcl-2, bcl-xL and bax diminished, only in CD34+ cells. In leukocytes, there was even greater level of expression of bok and reduced of bcl-2, bcl-xL, bad, bax, faim, dr4, dr5 and trail. Not significant difference was found to bcl-w, bak, bik, fasL and ciap-1 expression in CD34+ cells and leukocytes of patients and controls (p> 0.05). There was statistical correlation between: dr5 expression and JAK2 V617F mutation; bim-EL with hemoglobin concentration and hematócrito; bcl-w and platelets counts; a1, bad, bax in CD34+ cells and bad in leukocytes with enlarged spleen. PV lymphocytes were more resistant to apoptosis mediated by ACT D 1uM and 5uM, ARA-C 25uM, CHX 25uM, VP-16 25uM and VM-26 25uM. There was correlation between JAK2 V617F allele burden and resistance profile to apoptosis inducers in PV lymphocytes to ACT D 1uM and 5uM and STS 5uM. There was also correlation between: a1 expression with ACT D 5 uM, CHX 50uM and ARA-C 25uM; bad with CHX 25uM and teniposide 25uM; bcl-2 with ACT D 5uM, CHX 50uM, STS 1uM and 5uM and VP -16 25uM; bid with ACT D 5uM and VM-26 25uM; bik with ACT D 5uM, STS 1uM and 5uM, VM-26 25uM, ARA-C 25uM and VP-16 25uM; bim-EL with CHX 25uM and teniposide 25uM ; bok with ACT D 5uM, STS 1uM and 5uM, ARA-C 25uM and etoposide 25uM; ciap-1 with ACT D 1uM and 5uM, STS 1uM and VP-16 25uM; dr4 with ACT D 5uM, ARA-C 25uM, VP-16 25uM; dr5 with ACT D 5uM, STS 1uM, ARA-C 25uM and VP-16 25uM; faim with ACT D 5uM, mcl-1 with ARA-C 25uM and STS 1uM; trail with ACT D 5uM. The A1, BAD and c-FLIP proteins have the same profile of expression of their genes, however the levels of protein expression in BCL-xL were increased and decreased for BIM-EL, discordant results in related with the one obtained by gene expressions. Taken together these results suggest that apoptotic machinery is deregulated, which could contribute, at least in part, with myeloaccumulation observed in the SP and BM of PV patients.

Une des difficultés majeures dans le traitement des cancers est l’acquisition de résistance par les cellules tumorales vis-à-vis de la mort induite par les différentes chimiothérapies. Au sein du laboratoire, nous nous intéressons aux propriétés anti-tumorales d’un donneur de monoxyde d’azote (NO), le Glycéryl TriNitrate (GTN), fréquemment utilisé dans le traitement de l’angine de poitrine. Au cours de ce travail, nous avons étudié les mécanismes moléculaires par lesquels le GTN sensibilise les cellules tumorales de plusieurs types de cancer (colique, mammaire, prostatique) à la mort impliquant des voies de signalisation régulées par des cytokines telles que le TNFα, l’IL-6 ou encore le GDF-15.Une meilleure compréhension des mécanismes sous-jacents à l’action anti-tumorale du GTN permettrait de potentialiser son utilisation comme nouvelle thérapie anti-cancéreuse.Modèle colique : le GTN, en présence de la cytokine pro-inflammatoire TNFα, sensibilise les cellules cancéreuses coliques et mammaires à l’apoptose. Du point de vue mécanistique, le GTN induit la S-nitrosylation de cIAP1, inhibant ainsi son activité ubiquitine E3 ligase. Ce qui abroge la voie de signalisation classique NF-кB de survie cellulaire activée par la voie TNFα/TNFR1 en faveur d’une voie de signalisation pro-apoptotique.Modèle mammaire : le GTN intervient au niveau de la migration cellulaire en altérant la voie de signalisation Jak2/STAT3 activée par la cytokine pro-inflammatoire IL-6, dans un modèle de cancer du sein triple négatif. En présence de dérivés du platine (carboplatine) générant de l’IL-6, le GTN freine la migration des cellules en induisant la S-nitrosylation, et probablement l’inactivation, de la kinase Jak-2, indispensable pour l’activation de la voie.Modèle prostatique : le GTN sensibilise à la mort les cellules cancéreuses prostatiques résistantes au docétaxel en modulant le taux de deux marqueurs de résistance à cette chimiothérapie : la clusterine (CLU) et le growth differentiation factor 15 (GDF-15). Au niveau moléculaire, le GTN diminue le taux de l'isoforme cytoprotectrice soluble de la CLU (sCLU) et augmente le taux de l'isoforme cytotoxique nucléaire (nCLU) dans les cellules prostatiques résistantes au docétaxel. Plus particulièrement, en présence de GTN, nous avons établi un lien entre le GDF-15 et la modulation du taux des isoformes de la CLU. / One of the main difficulties in the treatment of cancers is the acquisition of resistance by the tumor cells vis-à-vis the death induced by the different chemotherapies. In the laboratory, we are interested in the anti-tumor properties of a nitric oxide (NO) donor, Glyceryl TriNitrate (GTN), frequently used in the treatment of angina pectoris. In this work, we investigated the molecular mechanisms by which GTN sensitizes tumor cells of several types of cancer (colonic, mammary, prostate) to death involving signaling pathways regulated by cytokines such as TNFα, IL-6 or GDF-15.A better understanding of the mechanisms underlying the GTN's anti-tumor action would make it possible to use it as a new anti-cancer therapy.Colon model: GTN, in the presence of the pro-inflammatory cytokine TNFα, sensitizes colon and mammary cancer cells to apoptosis. From a mechanistic point of view, GTN induces S-nitrosylation of cIAP1, thus inhibiting its ubiquitin E3 ligase activity. This abrogates the classical NF-κB signaling pathway of TNFα / TNFR1 activated cell survival in favor of a pro-apoptotic signaling pathway.Mammary model: GTN intervenes at the level of cell migration by altering the Jak2 / STAT3 signaling pathway activated by the pro-inflammatory cytokine IL-6, in a model of triple negative breast cancer. In the presence of platinum (carboplatin) derivatives generating IL-6, GTN inhibits cell migration by inducing S-nitrosylation, and probably inactivation, of Jak-2 kinase, essential for the activation of the way.Prostate model: GTN sensitizes prostatic prostate cancer cells to death by modulating the level of two markers of resistance to this chemotherapy: clusterin (CLU) and growth differentiation factor 15 (GDF-15). At the molecular level, GTN decreases the level of the soluble cytoprotective isoform of CLU (sCLU) and increases the level of nuclear cytotoxic isoform (nCLU) in prostatic cells resistant to docetaxel. More particularly, in the presence of GTN, we have established a link between GDF-15 and the modulation of the isoform rate of the CLU.

No description available.