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.

La réponse dynamique d’un train roulant sur une voie réelle dépend de plusieurs paramètres. Certains d’entre eux ne peuvent pas être correctement identifiés et doivent être considérés comme incertains. L’objectif de cette thèse est la construction d’un modèle probabiliste de la fatigue du rail, en considérant la géométrie de la voie et l’usure des rails comme champs aléatoires modélisés en utilisant le développement de Karhunen-Loève. Ce dernier requiert le calcul des fonctions et des valeurs propres de l’opérateur de covariance pour la représentation modale du champ. Cette étape peut devenir très coûteuse si le domaine est beaucoup plus grand que la longueur de corrélation. Pour résoudre ce problème, une adaptation de la technique est proposée. Les distributions multivariées des coefficients de projection sont identifiées à l’aide d’un développement en Chaos Polynomiaux, qui est calibré sur des données de mesures. Le rayon de courbure, l’âge du rail et la vitesse opérationnelle du train induisent des effets non stationnaires qui doivent être pris en compte dans le modèle. La validation du modèle probabiliste des quantités d’entrée est faite en comparant des données de mesure des efforts de contact roue-rail avec les résultats des simulations. Une analyse de sensibilité globale est menée sur des quantités d’intérêts dynamiques pour quantifier l’impact des irrégularités aléatoires sur la dynamique du véhicule et l’initiation à fatigue du rail. / The dynamical response of a train rolling on a real track depends on several parameters. Most of them cannot be accurately identified and have to be considered as uncertain. The aim of this thesis is the construction of a probabilistic model of the rail fatigue life considering the track geometry and the rail wear as random fields modelled with the Karhunen-Loève expansion. This latter requires the modal decomposition of the covariance operator. This step can be very expensive if the domain if much larger than the correlation length. To deal with this issue, an adaptation of the KLE, consisting in splitting the domain in sub-domains where this modal decomposition and the sample generation can be comfortably computed, is proposed. A correlation between the KLE coefficients of each sub-domain is imposed to ensure the desired correlation structure. The multivariate distributions of the random projection coefficients are characterized using a Polynomial Chaos Expansion (PCE) calibrated on measurements data of the track irregularities. The curve radius, the rail age and the train operational velocity introduce nonstationary effects that have to be taken into account to model the track. A validation of the random models is therefore performed using a set of measurements of the wheel-rail contact forces.A global sensitivity analysis is performed on some dynamical quantities of interest in order to quantify the impact of the random fields on the vehicle dynamics and the rail fatigue initiation. Since this step is computationally expensive, a PCE-based meta-modelling technique is employed to estimate the fatigue index.

Orientador: Luiz de Paula do Nascimento / Banca: Katia Lucchesi Cavalca Dedini / Banca: Gilberto Pechoto de Melo / Resumo: Neste trabalho são otimizadas rotinas computacionais de um método de estimação de rigidez de mancais de máquinas através de um processo de ajuste de modelo, utilizando a análise de sensibilidade. Este método consiste em utilizar a análise de sensibilidade dos autovalores com relação à variação da rigidez dos mancais de um rotor. A eficácia e a robustez do método são analisadas através de simulações teóricas, bem como através de dados experimentais obtidos de um rotor de rotação variável e rigidezes dos mancais ajustáveis. O modelo matemático de ajuste do sistema é desenvolvido pelo método dos elementos finitos e o método de ajuste converge empregando-se um processo iterativo. Este método de ajuste baseia-se na minimização da diferença entre autovalores experimentais e autovalores obtidos com o modelo matemático de ajuste a partir de valores de rigidez dos mancais previamente adotados. A análise é feita com o rotor em diversas velocidades de rotação para verificar a influência do efeito giroscópio, e em diversas condições de valores da rigidez dos mancais para analisar o método quando aplicado em rotores flexíveis e em rotores rígidos. O desempenho do método é analisado com resultados teóricos e experimentais. / Abstract: In this work, computational routines of estimation method of stiffness bearing of machine via a model updating process are optimized, using the sensitivity analysis. This method consists of using the eigenvalue sensitivity analysis, relating to the stiffness bearing variation of a rotor. The efficacy and the robustness of the method are analyzed through the theoretical simulations, as well as, based on the experimental data obtained of a test rotor with variable rotating speeds and adjustable bearing stiffness values. The mathematical model system is developed by the finite element method and the method of adjustment should converge employing an iterative process. The method of adjustment is based on the minimization of the difference between experimental eigenvalues and eigenvalues obtained via mathematical model from previously adopted stiffness bearing values. The analysis is made by using the rotor in different rotating speeds in order to check the influence of the gyroscopic effect, and in several conditions of the stiffness bearing values to analyze the method when applied on flexible and rigid rotors. The performance of the method is analyzed through theoretical and experimental results. / Mestre

Os efeitos deletérios do álcool sobre a gestação bem como as dificuldades para detectar o problema vêm preocupando vários pesquisadores, sendo, por isso, necessário o desenvolvimento de instrumentos de triagem apropriados para a detecção do consumo alcoólico de risco para o desenvolvimento da Síndrome Alcoólica Fetal (SAF) durante a gestação. Este estudo teve por objetivo desenvolver uma versão brasileira do T-ACE através da tradução e adaptação de seu original (SOKOL et al, 1989), bem como proceder à validação deste instrumento de acordo com as condições e características nacionais. A amostra estudada constou de 450 gestantes no terceiro trimestre de gestação, assistidas em um serviço de atendimento pré-natal do município de Ribeirão Preto - SP. Os dados foram coletados através de entrevistas individuais para aplicação do T-ACE, do estabelecimento quantitativo da história de consumo de álcool ao longo da gestação e de entrevista clínica padronizada para diagnóstico de problemas relacionados com o uso de álcool de acordo com critérios da CID 10. Foram feitos também testes de confiabilidade entre diferentes entrevistadores e confiabilidade teste/re - teste. Entre as gestantes investigadas, 100 mulheres ou 22,1% da amostra foram consideradas positivas pelo instrumento, apresentando história de consumo alcoólico de risco (>=28g). As estimativas estatísticas para expressão da validade do T-ACE com o padrão de referência CID-10 e o padrão de consumo alcoólico trimestral do terceiro trimestre aos três meses que antecederam a gestação demonstraram resultados significativos para validação do T-ACE, que mostrou-se um instrumento de alta Sensibilidade e Especificidade. Esta validação representa a disponibilização de um instrumento que pode ser aplicado em dois minutos de entrevista, sensível para o rastreamento do consumo alcoólico de risco para a SAF e apropriado para as rotinas e práticas dos serviços obstétricos. / The deleterious effects of the alcohol in the gestation as well as difficulties detecting the problem have worrying several researchers. There is a need do develop appropriate screening instruments for the detection of alcohol consumption as a risk for the Fetal Alcoholic Syndrome (SAF). This study had as objective the development of a Brazilian version of the T-ACE through the translation and adaptation of its original (SOKOL et al, 1989), as well as to proceed to the validation of this instrument in agreement with the conditions and characteristics of the Brazilian population. The studied sample consisted of 450 pregnant women in the third gestational trimester, attended in a prenatal care unit of Ribeirão Preto, São Paulo, Brazil. The data were collected through individual interviews for application of the T-ACE, with quantitative evaluation of the alcohol consumption along the gestational period. Furthermore, a standardized clinical interview was performed to diagnose problems related to the use of alcohol in agreement with ICD-10 criteria. Reliability tests among different interviewers and reliability test /re-test were made. Among the investigated pregnant women, 100 or 22,1% of the sample were considered positive for the instrument, presenting history of alcohol consumption of risk (>=28g). The statistics for validation of the T-ACE with the ICD-10 and the alcohol consumption patterns of reference, from the three months that preceded the pregnancy until the gestational third trimester, demonstrated significant and favorable results of this instrument. This validation allows the availability of a test that can be applied in two minutes of interview, sensitive for the screening of the alcohol consumption of risk for SAF and adapted for the routines and practices in prenatal care units.

There are over six million gestation sows in the United States and most of them are kept in gestation stalls. The inside environment of large livestock buildings requires advanced environmental control systems to maintain animal health and optimize animal production efficiency. The ventilation rate, inside temperature, and supplemental heating and cooling are the main control variables to manage the barn environment. About 144 barn-months of unpublished thermal data were obtained from six commercial gestation houses by the National Air Emission Monitoring Study (NAEMS). The data from this site was reviewed, corrected, and re-analyzed to improve its quality, completion, accuracy and reliability using the methods of comparison between onsite measurements and data collected from nearest weather stations, introducing corrected models to adjust the onsite data, substituting invalid and missing onsite data by weather station data and other improved methodologies. The data completeness for solar radiation, relative humidity, atmospheric pressure, outside temperature, and wind speed and direction were increased by 5.6 to 17.9%. The six NAEMS gestation barns were used to test and validate a building environmental prediction model (BEPM) based on known thermodynamic and heat transfer principles for simultaneously predicting inside temperatures and ventilation rates. The BEPM inputs included the weather, the building dimensions and materials, geographical location and building orientation, and sow herd characteristics. Predictions of ventilation rates and inside temperatures followed the expected yearly patterns as the measured NAEMS data. Four combinations of heat production rate and inside temperature submodel combinations CIGR-T, CIGR-T², US-T, and US-T² were compared and evaluated based on the root-mean-square-deviation and fitness tests to determine the best submodel combination. The average predicted and measured means of ventilation rate were 24.8 and 24.1 m³/s for NAEMS Site IA4B, 27.5 and 24.9 m³/s for Site NC4B, and 24.6 and 23.9 m³/s for Site OK4B, respectively. The average predicted and measured means of inside temperature were 20.3 and 19.7°C for IA4B, 23.3 and 22.9°C for NC4B, and 20.8 and 20.9°C for OK4B, respectively, based on their top performing submodel combinations. The overall optimal combination of four different submodels was determined to be the CIGR-T² submodel, which consisted of the CIGR International Commission of Agricultural and Biosystems Engineering heat production rate equations for sows and a second order polynomial regression of inside versus outside temperatures in the temperature control region between the minimum and maximum temperature setpoints. The CIGR-T² submodel simultaneously predicted the daily mean ventilation rate and daily mean inside temperature with good performance. The average RMSDs of the three sites for ventilation rate and inside temperature were 7.05 m³/s and 2.78°C, respectively. Sensitivity tests simulated based on the optimal BEPM (CIGR-T²) showed that annual total energy costs including electricity for powering fans and supplemental heat were influenced significantly by the minimum inside temperature setpoint, the thickness of ceiling insulation, and the minimum ventilation rate. This BEPM can be used for energy usage predictions, cooling and heating systems analysis and design, and as an important module of process-based gas emission models. It can be expanded to other livestock species (swine farrowing and finishing, egg laying operations, freestall dairy barns, etc.) by changing the heat production rate prediction submodel.

O tratamento das lesões cervicais não cariosas hipersensíveis com agentes dessensibilizantes pode ser uma opção prática e eficaz devido, principalmente, à capacidade desses produtos de obliterarem os túbulos dentinários expostos. Portanto, o objetivo deste estudo foi analisar, in vitro, o efeito quantitativo e qualitativo de cinco agentes dessensibilizantes em relação ao seu potencial de obstrução dos túbulos dentinários. Para a análise quantitativa, foram utilizados testes de condutividade hidráulica da dentina em diferentes condições experimentais. Os ensaios foram realizados na seguinte sequência experimental: na presença de smear layer (PMin); após condicionamento com ácido fosfórico a 37%, por 15 segundos (PMax); após a aplicação dos agentes dessensibilizantes e após o desafio com ácido cítrico a 6%, por um minuto. Para isso, foram selecionados 50 terceiros molares humanos hígidos não irrompidos, a partir dos quais foram confeccionados discos de dentina com espessura de 0,80 ± 1,00 mm e divididos em 5 grupos (n=10) de acordo com os diferentes agentes dessensibilizantes: Grupo 1 (Sensiactive); Grupo 2 (Sensitive Pro-Alívio); Grupo 3 (Flúor gel);Grupo 4 (Desensibilize Nano-P); e Grupo 5 (Enamel Pro@ Varnish). As medidas de condutividade hidráulica dentinária (Lp) foram analisadas através do teste ANOVA a dois critérios (p<0,05) para se determinar as diferenças intra e intergrupos. As diferenças individuais foram determinadas pelo teste Tukey, também a um nível de significância de 5%. Já a análise qualitativa foi realizada através da observação de imagens feitas através do microscópio confocal a laser (MCL). Nesse caso, foram selecionados 18 terceiros molares humanos hígidos não irrompidos, sendo que a preparação e armazenamento dos discos para as condições experimentais seguiram os mesmos passos descritos para os experimentos de condutividade hidráulica. Os espécimes foram divididos em 6 grupos, n=3, conforme os materiais experimentais estudados, e os discos divididos ao meio de modo a permitir a realização de duas fases do experimento no mesmo disco. Um grupo de discos, metade com smear layer e a outra metade condicionada com ácido fosfórico, foi utilizado como controle. Entendendo que a smear layer e o condicionamento ácido conferem padrões de superfície dentinária conhecidos, os demais grupos foram observados, apenas, com relação aos efeitos dos 5 materiais experimentais e do desafio ácido, realizados sobre a dentina condicionada. Os resultados mostraram que os agentes dessensibilizantes produziram alguma redução na Lp, exceto os Grupos 3 e 5, os quais não mostraram valores de condutividade estatisticamente diferentes da PMax. Com relação ao efeito obstrutivo pós-desafio ácido, o resultado variou entre os diferentes grupos experimentais. Apenas o Grupo 1 foi capaz de manter a mesma Lp da fase pós-tratamento. Os demais produtos apresentaram baixa resistência ao desafio ácido e resultados semelhantes entre si. A confrontação dos resultados de Lp com as imagens em MCL mostra diferentes padrões de precipitação de partículas e sugere que a deposição de cristais na superfície da dentina e no interior dos túbulos não garante o bloqueio do movimento de fluido através dos túbulos dentinários. / The treatment of hypersensitive non carious cervical lesions with desensitizing agents may be a practical and effective alternative, mainly due to the ability of these products to obliterate the exposed dentinal tubules. Therefore, the aim of this study was to investigate, in vitro, the quantitative and qualitative effect of five desensitizing agents in relation to their ability to obstruct dentinal tubules. The quantitative analysis was based on dentin hydraulic conductance tests achieved under different experimental conditions. The tests were performed in the following experimental sequence: in the presence of smear layer (PMin); after a 15-second acid etching (37% phosphoric acid- PMax); after the application of the desensitizing agents; and after a 1-minute acid challenge (6% citric acid). Fifty sound not erupted extracted human third molars were randomly selected and, from them, 0.08±1.00 mm-thickness dentine discs were obtained for distribution into 5 groups (n=10), according to the different desensitizing agents: Group 1 (Sensiactive); Group 2 (Sensitive Pro-Relief); Group 3 (Fluoride gel); Group 4 (Desensibilize Nano-P) and Group 5 (Enamel Pro@ Varnish). Dentin hydraulic conductance measures (Lp) were analyzed by two-way ANOVA (p<0.05) to determine intra and intergroup differences. Individual differences were determined by Tukey test, also at a significance level of 5%. The qualitative analysis was performed by observing images obtained from specimens via laser scanning confocal microscopy (LSCM). Here, 18 sound not erupted extracted human third molars were randomly selected and specimens preparation and storage for each experimental condition followed the same steps described for the experiments regarding dentin hydraulic conductance tests. Specimens were divided into 6 groups (n=3), according to studied materials, and each dentin disc was dimidiate to allow performing of the two phases of the experiment on the same disk. A group of discs, in which one half of each specimen showed smear layer and the other half had been acid-etched (37% phosphoric acid), acted as the control. Understanding that the presence of smear layer and that acidetching provide known dentinal patterns, other groups were observed only with respect to the effects of the 5 experimental materials and of the acid challenge, performed on conditioned dentin. Results showed that the desensitizing agents produced some reduction in Lp, except for Groups 3 and 5, which showed no statistically different conductance values of PMax. Regarding the post-acid challenge obstructive effect, results varied among different experimental groups. Only Group 1 was able to keep the same Lp of the post-treatment phase. Other products offered low resistance to acid challenge and showed similar results among them. Comparison of quantitative (Lp) and qualitative (LSCM) analyses shows different particles precipitation patterns and suggests that the deposition of crystals on the surface and into the dentinal tubules does not block fluid movement through the tubules.

The growing interest in computing structured matrix functions stems from the fact that preserving and exploiting the structure of matrices can help us gain physically meaningful solutions with less computational cost and memory requirement. The work presented here is divided into two parts. The first part deals with the computation of functions of structured matrices. The second part is concerned with the structured error analysis in the computation of matrix functions. We present algorithms applying the inverse scaling and squaring method and using the Schur-like form of the symplectic matrices as an alternative to the algorithms using the Schur decomposition to compute the logarithm of symplectic matrices. There are two main calculations in the inverse scaling and squaring method: taking a square root and evaluating the Padé approximants. Numerical experiments suggest that using the Schur-like form with the structure preserving iterations for the square root helps us to exploit the Hamiltonian structure of the logarithm of symplectic matrices. Some type of matrices are nearly structured. We discuss the conditions for using the nearest structured matrix to the nearly structured one by analysing the forward error bounds. Since the structure preserving algorithms for computing the functions of matrices provide advantages in terms of accuracy and data storage we suggest to compute the function of the nearest structured matrix. The analysis is applied to the nearly unitary, nearly Hermitian and nearly positive semi-definite matrices for the matrix logarithm, square root, exponential, cosine and sine functions. It is significant to investigate the effect of the structured perturbations in the sensitivity analysis of matrix functions. We study the structured condition number of matrix functions defined between smooth square matrix manifolds. We develop algorithms computing and estimating the structured condition number. We also present the lower and upper bounds on the structured condition number, which are cheaper to compute than the "exact" structured condition number. We observe that the lower bounds give a good estimation for the structured condition numbers. Comparing the structured and unstructured condition number reveals that they can differ by several orders of magnitude. Having discussed how to compute the structured condition number of matrix functions defined between smooth square matrix manifolds we apply the theory of structured condition numbers to the structured matrix factorizations. We measure the sensitivity of matrix factors to the structured perturbations for the structured polar decomposition, structured sign factorization and the generalized polar decomposition. Finally, we consider the unstructured perturbation analysis for the canonical generalized polar decomposition by using three different methods. Apart from theoretical aspect of the perturbation analysis, perturbation bounds obtained from these methods are compared numerically and our findings show an improvement on the sharpness of the perturbation bounds in the literature.

Orientador: Paola Castro Moraes / Coorientador: Andressa de Souza-Pollo / Banca: Alessandra Aparecida Medeiros-Ronchi / Banca: Janete Apparecida Desidério / Banca: José Geraldo Meirelles Palma Isola / Banca: Annelise Carla Camplesi dos Santos / Resumo: Lesões na pele podem resultar em feridas que, dependendo do tempo de reparação tissular podem ser classificadas como agudas ou crônicas, sendo crônicas aquelas que não apresentaram cicatrização dentro do período de quatro semanas. A ferida é contaminada por diferentes espécies bacterianas, sendo o sistema imunológico da pele o responsável por impedir que tais contaminações evoluam para infecções. No entanto, muitas vezes o quadro infeccioso é instalado, havendo necessidade de tratamento com antimicrobianos. Tendo em vista que o mau uso de antimicrobianos provoca resistência a multidrogas em estirpes bacterianas potencialmente patogênicas, este trabalho teve como objetivo identificar as bactérias prevalentes em feridas agudas e crônicas de cães por meio de sequenciamento da região 16S rRNA e testar a sensibilidade dos isolados a diferentes antimicrobianos. Para tanto, foram amostradas 20 feridas, sendo cada uma de um cão atendido no Hospital Veterinário da UNESP, Câmpus de Jaboticabal. De cada ferida foram obtidos dez isolados, os quais foram selecionados para o sequenciamento de DNA por meio de comparação entre os perfis genéticos obtidos pelo emprego de marcador molecular randômico. Foram sequenciados 74 isolados identificados como pertencentes a oito gêneros de bactérias gram-negativas, Proteus mirabilis, Escherichia coli, Pseudomonas aeruginosa, Enterobacter spp., Acinetobacter baumannii, Klebsiella spp., Kluyvera georgiana e Providencia stuartii, e três de gram-positivas,... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Skin lesions can result in cutaneous wounds that may be classified as acute or chronic depending on the period of time spent in tissue repairment. Wounds that have not healed within four weeks are generally classified as chronic. The wound is contaminated by different bacterial species and the immune system of the skin is responsible for preventing infections. Nonetheless, the infectious process is often developed and antimicrobial treatment become necessary. Considering that the misuse of antimicrobials provokes multidrug resistance in potentially pathogenic bacterial strains, this work aimed to identify prevalent bacteria in acute and chronic wounds of dogs by 16S rRNA sequencing and to test the sensitivity of the isolates to different antimicrobials. For that, 20 wounds were sampled, each one from a dog admitted at the Veterinary Hospital of UNESP, Jaboticabal, São Paulo, Brazil. From each wound ten isolates were obtained, which were selected for DNA sequencing through genetic profiles comparison by applying a random molecular marker. Seventy-five isolates were identified as belonging to eight Gram-negative bacteria genera, Proteus mirabilis, Escherichia coli, Pseudomonas aeruginosa, Enterobacter spp., Acinetobacter baumannii, Klebsiella spp., Kluyvera georgiana and Providencia stuartii, and to three gram-positive bacteria genera, Enterococcus sp., Staphylococcus spp. and Bacillus spp. Cases of dogs with acute or chronic wounds associated to more than one bacterial genus w... (Complete abstract click electronic access below) / Doutor

Le transporteur de drogues membranaire MRP1 participe à la résistance des cellules cancéreuses à la chimiothérapie lorsqu’il est surexprimé. Cette surexpression peut être exploitée afin de provoquer l’apoptose sélective de ces cellules, MRP1 devenant leur talon d’Achille : c’est l’effet de sensibilité collatérale (SC). Ainsi, le vérapamil stimule l’efflux médié par MRP1 d’un tripeptide antioxydant indispensable aux cellules, le GSH ou glutathion réduit, et provoque la mort sélective des cellules surexprimant ce transporteur. La recherche d’autres agents de SC comme le vérapamil nous a menés à l’étude de composés flavonoïdiques pouvant induire un efflux rapide et massif de GSH. Parmi ces composés, nous avons identifié un puissant agent de SC des cellules résistantes surexprimant MRP1, le dimère de flavonoïde 4e, candidat très prometteur pour de futures études in vivo. Nous avons déterminé que la surexpression de MRP1 est effectivement responsable de la SC dans les cellules cancéreuses résistantes H69AR, et que l’efflux de GSH se doit d’être massif et prolongé pour induire l’apoptose des cellules. Nous avons montré que cet efflux perturbe l’homéostasie du glutathion et l’état redox des cellules, entraînant un stress oxydatif qui participe au déclenchement de la mort cellulaire. Enfin, nous nous sommes attachés à identifier d’éventuelles cibles secondaires des agents de SC dans les cellules surexprimant MRP1, via l’initiation de l’étude de leur transcriptome et métabolome. La compréhension du mécanisme d’action de ces agents de sensibilité collatérale vise, à terme, à l’éradication des cancers résistants surexprimant MRP1 / The membrane drug transporter MRP1 is involved in the resistance of cancer cells to chemotherapy, when overexpressed. This overexpression can be exploited in order to induce the selective apoptosis of these cells, so that MRP1 becomes their Achilles’ heel: this is called Collateral Sensitivity (CS). Thus verapamil stimulates the MRP1-mediated efflux of GSH (reduced form of glutathione) that is an antioxidant tripeptide essential for cells, and induces the selective death of MRP1- overexpressing cells. Seeking for other CS agents than verapamil led to the study of flavonoid compounds able to induce a massive and rapid efflux of GSH and to the identification of a powerful CS agent of resistant cells overexpressing MRP1, i.e. flavonoid dimer 4e, which is a very promising candidate for in vivo studies. We determined that overexpression of MRP1 is indeed responsible for CS in H69AR resistant cancer cells, and that GSH efflux must be massive and protracted in order to induce cell apoptosis. We showed that this efflux disturbs glutathione homeostasis and cell redox state, which leads to an oxidative stress that is involved in triggering cell death. At last, we sought to identify possible secondary targets of CS agents in MRP1-overexpressing cells, via the initiation of transcriptomic and metabolomic studies. Understanding the mechanism of action of these Collateral Sensitivity agents aims to the eradication of resistant cancers that overexpress MRP1

Les écoulements instationnaires au-dessus de surfaces discontinues produisent d'important bruit aérodynamique. L'objectif de ce travail de thèse est l'étude aéroacoustique d'écoulement au-dessus de cavités bidimensionnelles rectangulaires, et de trouver des stratégies de réduction du bruit. Des simulations numériques directes des équations bidimensionnelles de Navier-Stokes compressibles ont été réalisées afin d'étudier l'influence des conditions initiales sur le mode d'oscillation de l'écoulement pour des cavités profonde et peu profonde. Les résultats montrent que dans le cas de cavités profondes, l'écoulement oscille selon un régime de couche de cisaillement suivant le second mode de Rossiter, et ce quelle que soit la condition initiale choisie. En revanche, dans le cas de cavités peu profondes, le régime d'oscillation observé peut être en couche de cisaillement ou bien en mode de sillage suivant la condition initiale choisie. Une analyse de sensibilité d'écoulement dans le cas de cavités profondes a été réalisé en utilisant une méthode adjointe. Les équations adjointes ont été forcées par une perturbation localisée sinusoïdale soit de la quantité de mouvement suivant x adjointe (au voisinage de la couche de cisaillement), soit de la densité adjointe (loin de la cavité). Les résultats désignent une région de l'écoulement très sensible à l'ajout de masse, et localisée au voisinage du coin supérieur amont de la cavité. Par conséquent, un actionneur de type soufflage/aspiration placé au bord d'attaque de la cavité agira sur les fluctuations de quantité de mouvement suivant x au voisinage de la couche de cisaillement et sur les fluctuations de pression au loin. / The unsteady flow over surface discontinuities produces high aerodynamic noise. The aim of this thesis is to study the aeroacoustics of two-dimensional rectangular cavities and to find strategies for noise reduction. Direct Numerical Simulation of the compressible Navier-Stokes equations is performed to investigate the influence of the initial condition on the oscillation modes in deep and shallow cavities. Results show that the deep cavity oscillates in shear layer regime at the second Rossiter mode regardless of the initial condition. On the other hand different initial conditions lead to a shear layer or wake mode in the shallow cavity case. A sensitivity analysis of the deep cavity is done by the use of adjoint methods. Local sinusoidal perturbations of x-momentum and density are applied to the adjoint equations. The results show a high sensitivity region to mass injection at the upstream corner. Therefore an actuator placed at the leading edge will modify the velocity fluctuations reaching the trailing edge and hence the pressure fluctuations in the far-field.