Solid organ transplantation (SOT) is considered the treatment of choice for many end-stage organ diseases. Thus far, short term results are excellent, with patient survival rates greater than 90% one year post-surgery, but there are several problems with the long term acceptance and use of immunosuppressive drugs. Hematopoietic Stem Cells Transplantation (HSCT) concerns the infusion of haematopoietic stem cells to re-establish acquired and congenital disorders of the hematopoietic system. The main side effect is the Graft versus Host Disease (GvHD) where donor T cells can cause pathology involving the damage of host tissues. Patients undergoing acute or chronic GvHD receive immunosuppressive regimen that is responsible for several side effects. The use of immunosuppressive drugs in the setting of SOT and GvHD has markedly reduced the incidence of acute rejection and the tissue damage in GvHD however, the numerous adverse side effects observed boost the development of alternative strategies to improve the long-term outcome. To this effect, the use of CD4+CD25+FOXP3+ regulatory T cells (Treg) as a cellular therapy is an attractive approach for autoimmunity disease, GvHD and limiting immune responses to allograft after transplantation. Treg have a pivotal role in maintaining peripheral immunological tolerance, by preventing autoimmunity and chronic inflammation. Results of my thesis provide the characterization and cell processing of Tregs from healthy controls and patients in waiting list for liver transplantation, followed by the development of an efficient expansion-protocol and the investigation of the impact of the main immunosuppressive drugs on viability, proliferative capacity and function of expanded cells after expansion. The conclusion is that ex vivo expansion is necessary to infuse a high Treg dose and although many other factors in vivo can contribute to the success of Treg therapy, the infusion of Tregs during the administration of the highest dose of immunosuppressants should be carefully considered.

No description available.

Due to inadequate treatments, the survival rate of adult patients with acute lymphoblastic leukemia (ALL) is still very poor. Thus there is a need to improve the efficacy of conventional therapy. In this study we evaluated the effectiveness of checkpoint kinase inhibitors (Chk-i) in single agent and in combination with different compounds conventionally used for the treatment of B-/T-ALL. We showed that Chk1 and Chk2 kinases are highly expressed and hyper-activated in tumor samples in comparison to normal tissue. On these bases we speculate that the inhibition of these kinases could mine the genetic stability and enhance cell death in ALL cells. We firstly evaluate the efficacy in single agent of the Chk1/Chk2 (PF-0477736 and LY2606368) and of the Wee1 (MK-1775) inhibitors on different cell lines and on primary cells isolated from adult B-ALL patients. We demonstrated that the inhibition of Chk1/Chk2 kinases reduces of the cell viability, activates the apoptosis and modify the expression of different elements of the G2/M checkpoint. To assess the chemo-sensitizer activity of different checkpoint kinase inhibitors, several combination studies were performed. To this purpose, LY2606368 and MK-1775 were combined with different tyrosine kinase inhibitors (imatinb, dasatinib and bosutinib) and with the purine nucleoside analogue, clofarabine. The efficacy of the combinations was not only evaluated in term of reduction of the cell viability but also in term of induction of apoptosis and induction of DNA damages. The results found were then confirmed on primary cells of B-ALL patients. Finally different class of checkpoint kinase inhibitors were combined together in order to evaluate their interaction. In our opinion the preclinical data presented in this study are the basis for a future evaluation of this class of compound in clinical trials in the treatment of adult ALL patients.

No description available.

Ce travail concerne la mise en place de plateformes professionnelles informatiques et le développement de la plate-forme SunRise pour la gestion d'une Smart City. Il s’inscrit dans le cadre du projet SunRise qui vise à transformer le campus Cité Scientifique de l'Université de Lille en une «ville intelligente et durable». Le campus est représentatif d'une petite ville de 25 000 habitants et de 100 km de réseaux urbains.Cette thèse comprend cinq parties.La première partie comprend un état de l’art concernant les Smart Cities avec ses définitions et ses composantes.La deuxième partie présente le rôle des données dans les villes intelligentes, ainsi que les dernières technologies utilisées pour la gestion des villes intelligentes. Il présente également les différentes architectures et plateformes existantes pour la gestion d'une Smart City.La troisième partie présente le démonstrateur SunRise Smart City, sur lequel s’appuie cette thèse. La partie détaille l'instrumentation du site de démonstration ainsi que le modèle SIG du démonstrateur.La quatrième partie concerne l'architecture des deux plateformes professionnelles PI System et OpenDataSoft ainsi que leur mise en place et leur utilisation pour l'analyse de la consommation d'eau.La dernière partie décrit l'architecture de la plateforme SunRise et détaille ses couches. Il présente également les étapes du développement et de l’implémentation de la plateforme. / This work concerns the implementation of professional platforms and the development of SunRise platform for managing a Smart City. It is a part of SunRise project, which aims at turning the Scientific Campus of the University of Lille into a large-scale demonstrator site of the "Smart and Sustainable City". The campus is representative to a small town of 25000 inhabitants and 100 km of urban infrastructure.This thesis includes five parts. The first part includes a literature review concerning the Smart Cities with its definitions and components. The second part presents the role of data in Smart Cities, as well as the latest technologies that are used for Smart City management. It presents also the different existing architectures and platforms for management a Smart City.The Third part presents the SunRise Smart City demonstrator, which is used as a basis for this thesis. The part details the instrumentation installed in the demo site as well as the GIS model of the demonstrator. The fourth part concerns the architecture of the two professional platforms PI System and OpenDataSoft as well as their implementation and use for the analysis of water consumption.The last part describes the architecture of the platform SunRise and details its layers. It presents also the stages of the platform development and implementation.

Estudo demográfico e social sobre a área de influência do Porto tendo por base um livro, o livro de abertura da Rua Nova no ano de 1438.

No description available.

Cette thèse est une contribution au développement d’émetteurs-récepteurs monolithiques en bande millimétrique pour réseau de capteurs sans fils. Le déploiement des réseaux de capteurs sans fils autonomes de courte portée s’oriente vers l’intelligence ambiante, modifiant la façon dont nous interagissant avec notre environnement. L’internet des objets se démocratise rapidement, avec une augmentation sans précédent des objets connectés. Ces noeuds, de plus en plus nombreux, doivent être le plus discrets et autonomes, tout en ayant des caractéristiques et performances toujours meilleures. La densification des réseaux de nœuds autonomes amplifie de surcroit les problématiques d’interférences et de multi-trajets. Le développement de capteurs en bandes millimétriques doit permettre de réduire la taille des noeuds. Notamment en réduisant les dimensions de la partie antennaire qui constitue généralement le facteur limitant l’intégration d’un système. Cette intégration sera accompagnée de solutions permettant la réduction de la consommation des capteurs. Ainsi, nous avons conçu des antennes, basées sur le principe de rayonnement des lignes à fentes progressives permettant de réduire les contraintes habituelles de conception des antennes. Les antennes sont réalisables sur des substrats de permittivité élevée et de taille réduite, et directement intégrables en technologie MMIC. Nous avons également effectuée une caractérisation expérimentale d’amplificateurs et une étude poussée de la stabilité des circuits amplificateurs en bande G. Notamment en utilisation la méthode NDF. Ceci nous a permis de concevoir un amplificateur faible bruit dont les grilles peuvent être commandées par des impulsions courte permettant la conception d’un système émetteur/récepteur très faible consommation adapté à une utilisation au sein de réseaux de capteurs autonomes sans-fils. / This thesis is a contribution to the development of transceivers for monolithic millimeter-wave wireless sensors networks. The deployment of short-range and autonomous wireless sensors networks tends towards ambient intelligence, changing the way we interact with our environment. The Internet of Things is democratizing rapidly with an unprecedented increase of connected objects. These nodes must and should become more discrete and independent, while still improving their features and performance. Moreover, the increase in nodes number constituting those networks amplifies well-known issues as interferences and indoor multipath problems. The development of sensors using millimeter-wave communications (D-band and G-band) should allow smaller nodes by reducing the antennas dimensions since the antenna is usually the technological lock in system integration. This integration will be accompanied by solutions for reducing node’s consumption. Thus, we have designed antennas, based on slot-line to reduce the usual constraints of antenna design. The antennas are well on substrates of high permittivity and small dimensions, with MMIC compatible technology. The experimental results are well consistent with the 3D electromagnetic simulation. We have also performed an experimental characterization of amplifiers and extensive study of amplifier’s stability in G-band. This study was performed using NDF method. This has allowed us to design a low noise amplifier that can be controlled by short pulses in order to realize a very low power tranceiver suitable for autonomous wireless networks-sensors.

L’objectif de ce mémoire de thèse est de mener des recherches sur l’utilisation des technologies sans contact pour la surveillance de santé structurale. Les recherches comportent des développements scientifiques et technologiques visant à bien comprendre le fonctionnement des réseaux de capteurs sans fils dans un milieu hétérogène. Tout d’abord, nos études se concentrent sur les mesures des coefficients de réflexion et de transmission des ondes électromagnétiques dans le béton. La réalisation d’une communication entre deux antennes patch noyées dans du béton a permis de confirmer l’effet de l’humidité du béton sur l’atténuation des ondes radio dans le béton. Cette analyse a conduit à l'identification des propriétés diélectriques du béton pour la fréquence 860 MHz. Ensuite, nous avons étudié l’influence des configurations des armatures du béton (emplacement des armatures, dimensions des armatures) sur les coefficients de réflexion et de transmission. Nous avons étudié et optimisé une topologie de réseaux de capteurs sans fils adéquate pour être noyée dans le béton armé. L’étude d’optimisation prend en compte les caractéristiques des nœuds de capteurs, le bilan de liaison entre un nœud de capteur communicant et le puits et la durée de vie d’un nœud. Enfin, la conception et la réalisation d’un « totem en béton armé » d’une hauteur de 3 m, a permis de valider les différentes études abordées au cours de ces travaux de thèse. Cet édifice en béton armée est un démonstrateur instrumenté par un réseau de capteurs sans fils permettant de connaitre l’évolution de la température, de l’humidité et le niveau de déformation internes du béton armé à six endroits critiques de la structure. / The objective of this thesis is to conduct research on the use of contactless technologies for structural health monitoring. The research involves scientific and technological developments to understand the functioning of wireless sensor networks in a heterogeneous environment composed of cement, aggregates, water and frames. First, our studies focus on reflection and transmission coefficients measurements of electromagnetic waves in the concrete. The realization of a communication between two Patch antennas embedded in concrete confirmed concrete moisture effect on radio waves attenuation. This analysis led to the identification of the dielectric properties of concrete at 860 MHz frequency. Later we studied the effect of various reinforced bar configurations (rebar placement, rebar radius, rebar period) on reflection and transmission coefficients. Then we studied and optimized a wireless sensor network topology to be embedded in concrete. The optimization takes into account the characteristics of sensor nodes, link budget between the communicating sensor node and the gateway and the lifespan of a node. Finally, the design and realization of a "reinforced concrete structure" of 3 m height enable to validate the different studies discussed during the thesis work. This reinforced concrete structure is an instrumented demonstrator of wireless sensor network enabling the knowledge of internal temperature, humidity and strain evolutions of a reinforced concrete in six critical areas of the structure.

PGE2 plays an important role in liver inflammation and carcinogenesis. Its metabolism is regulated by a cascade of reactions catalyzed by enzymes including COX-1/2, mPGES-1/2, 15-PGDH. Among these regulators, mPGES-1 is a cytokine-inducible enzyme mainly responsible for catalyzing terminal synthesis of PGE2, 15-PGDH catalyzes the oxidation of PGE2 to 15-keto-PGE2. In this context, we exogenously expressed mPGES-1 or 15-PGDH genes in mice hepatocytes to constitute a physiological condition ideal for evaluating PGE2 and its metabolites function in liver pathogenesis. In the first part, we developed transgenic mice with targeted expression of mPGES-1 in the liver and assessed the response of the transgenic mice to Fas-induced hepatocyte apoptosis and acute liver injury. Compared to wild type mice, the mPGES-1 Tg mice showed less liver hemorrhage, lower serum alanine transaminase and aspartate transaminase levels, less hepatic necrosis/apoptosis, and lower levels of caspase activation after intraperitoneal injection of the anti-Fas antibody Jo2. Western blotting analyses revealed increased expression and activation of the serine/threonine kinase Akt and associated anti-apoptotic molecules in the liver tissues of Jo2-treated mPGES-1 Tg mice. Pretreatment with the mPGES-1 inhibitor (MF63) or the Akt inhibitor (Akt inhibitor V) restored the susceptibility of the mPGES-1 Tg mice to Fas-induced liver injury. Our findings provide novel evidence that mPGES-1 prevents Fas-induced liver injury through activation of Akt and related signaling. This finding is consistent with previous reports of the anti-apoptotic and pro-proliferative role of PGE2. Our results suggest that induction of mPGES-1 or treatment with PGE2 may represent a potential therapeutic strategy for the prevention and treatment of Fas-associated liver injuries. In the second part, we generated transgenic mice with targeted expression of 15-PGDH in the liver and the animals were subjected to LPS/GalN-induced acute liver inflammation and injury. Compared to the wild type mice, the 15-PGDH Tg mice showed lower levels of alanine aminotransferase and aspartate aminotransferase, less liver tissue damage, less hepatic apoptosis/necrosis, less macrophage activation, and lower inflammatory cytokine production. In Kupffer cell cultures, treatment with 15-keto-PGE2 or the conditioned medium (CM) from 15-PGDH Tg hepatocyes inhibited LPS-induced cytokine production. Both 15-keto-PGE2 and the CM from15-PGDH Tg hepatocyes also up-regulated the expression of PPAR-γ downstream genes in Kupffer cells. In cultured hepatocytes, 15-keto-PGE2 treatment or 15-PGDH overexpression did not influence TNF-α-induced hepatocyte apoptosis. These findings suggest that 15-PGDH protects against LPS/GalN-induced liver injury and the effect is mediated via 15-keto-PGE2, which activates PPAR-γ in Kupffer cells and thus inhibits their ability to produce inflammatory cytokines. Accordingly, we observed that the PPAR-γ antagonist, GW9662, reversed the effect of 15-keto-PGE2 in Kupffer cell in vitro and restored the susceptibility of 15-PGDH Tg mice to LPS/GalN-induced acute liver injury in vivo. Our findings not only support the pro-inflammatory role of PGE2, but also reveal a novel anti-inflammatory role of 15-keto-PGE2. The data suggest that induction of 15-PGDH expression or utilization of a 15-keto-PGE2 analog may be therapeutic for treatment of endotoxin-associated liver inflammation/injury. Consistent with a pro-carcinogenic role for PGE2, overexpression mPGES-1 enhances growth of either HCC or cholangiocarcinoma cells, while overexpression 15-PGDH inhibits tumor cell growth in vitro. In the third part, we use a pharmacological method to induce 15-PGDH in cholangiocarcinoma tumor cells to inhibit PGE2 production. Our results indicated that treatment of human cholangiocarcinoma cells (CCLP1 and TFK-1) with ω-3 PUFA (DHA) or transfection of these cells with the Fat-1 gene (encoding Caenorhabditis elegans desaturase which converts ω-6 PUFA to ω-3 PUFA) significantly increased 15-PGDH protein level in cholangiocarcinoma cell lines. Human cholangiocarcinoma cells treated with DHA or transfected with a Fat-1 expression vector showed reduction of miRNA26a and miRNA26b (both miRNAs target 15-PGDH mRNA thus inhibiting 15-PGDH translation). Consistent with these findings, we observed that overexpression of miR26a or miR26b decreased 15-PGDH protein, reversed ω-3 PUFA-induced accumulation of 15-PGDH protein, and prevented ω-3 PUFA-induced inhibition of cholangiocarcinoma cell growth. Knockdown of 15-PGDH also attenuated ω-3 PUFA-induced inhibition of tumor cell growth. We observed that ω-3 PUFA suppressed miRNA26a and miRNA26b by inhibiting c-myc, a transcription factor that co-regulates a gene cluster comprised of miR-26a/b and carboxy-terminal domain RNA polymerase II polypeptide A small phosphatases (CTDSPs). Accordingly, overexpression of c-myc enhanced the expression of miRNA26a/b and prevented ω-3 PUFA-induced inhibition of tumor cell growth. Taken together, our results support a pro-tumorigenic role for PGE2, and suggest induction of 15-PGDH as potential way for the prevention and treatment of human cholangiocarcinoma. / 1 / LU YAO