De nombreux gènes suppresseurs de tumeurs sont inactivés par hyperméthylation dans les cancers. Cette inactivation serait en partie initiée par la protéine, MBD2 (Methyl-CpG-Binding Domain protein 2). Cette protéine recrute au niveau de séquences méthylées des complexes enzymatiques capables de modifier la structure chromatinienne et crée ainsi des régions fonctionnellement inactives. Dès lors, ce répresseur apparaît être une cible potentielle pour combattre le cancer. Dans cette perspective, rechercher les cibles de MBD2 et comprendre sa capacité à contrôler l’expression génique semblent cruciales. Au cours de deux études gènes candidats, nous avons pu démontrer (i) une réelle spécificité de cible du répresseur méthylationdépendant MBD2 pour les loci hTERT et pS2/TFF1 ; et (ii) un nouveau rôle de la protéine MBD2 en tant que modulateur de l’expression génique. De plus, les actions antagonistes entre le répresseur MBD2 et le trans-activateur naturel du gène pS2, le récepteur aux oestrogènes α, ont été explorées. Puis, l’analyse globale des profils de distribution de MBD2, de la méthylation de l’ADN, ainsi que de l’ARN polymérase II, sur puce promoteur a montré que MBD2 possède toutes les caractéristiques d’un répresseur trancriptionnel méthylation-dépendant. En effet, 74% des promoteurs fixés par MBD2 sont méthylés et cette liaison est associée dans 65% des cas à une répression transcriptionnelle. / In the past few years, several clinical trials have shown that targeting DNA methylation machinery might be of interest in cancer therapy to restore tumor suppressor genes expression and inhibit tumor growth. The Methyl-CpG-Binding Domain protein 2 (MBD2) is an important constituent of the DNA methylation machinery since this protein is directly involved in the mediation of the epigenetic signal. Moreover, MBD2 seems to show some gene specificity, its inhibition reactivate a limited number of genes. Taken together these data suggest that MBD2 represents potential new target in cancer therapy and, therefore, new insights on MBD2 specificities are, in this context, of importance. To this end, we have developed two different approaches: a candidate genes analysis and a genome-wide analysis, using ChIP-on-chip method, in order to map MBD2 binding sites. The candidate gene approaches are strongly in favour of the “one gene – one MBD” hypothesis, at least for the genes analyzed. Indeed, our results indicate that MBD2 is specifically and directly involved in the transcriptional repression of hTERT and pS2/TFF1 genes. Furthermore, a new role of MBD2 in the fine-scale modulation of these genes was demonstrated, and the antagonist actions between MBD2 and the natural trans-activator of pS2 gene, the estrogen α, were explored. Genome wide distribution of MBD2 binding sites, DNA Methylation profiles, and silencing potential, showed that the MBD2 is a real methylation-dependant transcriptional repressor: 74% of the MBD2 binding promoters are methylated and 65% silenced.

Pour croître et proliférer, les cellules cancéreuses de la prostate activent des voies de signalisation dépendantes des androgènes. L'intervention thérapeutique en première ligne du cancer de la prostate (CaP) s'appuie donc d’abord sur le blocage de l'axe androgènes-récepteur aux androgènes (RA) mais rapidement, les patients développent des tumeurs résistantes (CRPC, Castration Resistant Prostate Cancer).Les récepteurs à activité tyrosine kinase de la famille ErbB semblent jouer un rôle dans cette résistance, en particulier le récepteur ErbB3. En effet, l'inactivation des voies en aval d'ErbB1 et ErbB2, en association avec les anti-androgéniques n'empêche pas la progression vers l'hormono-indépendance, et une accumulation nucléaire d'ErbB3 est observée dans les CRPC en même temps que la voie PI3K-Akt est réactivée.Dans ce contexte, nous avons validé l'expression d'une isoforme nucléaire ErbB380kDa chez les patients et dans des lignées hormono-sensible (LNCaP) et hormono-résistante (PC3). Par ChIP-on-chip, nous avons isolé 353 promoteurs cibles communs aux deux lignées, 245 spécifiques à la lignée LNCaP et 925 à la lignée PC3, et montré qu'ErbB380kDa est un co-régulateur transcriptionnel des gènes étudiés, parmi lesquels GATA2. L'analyse in silico de ces promoteurs révèle des sites de liaison pour les facteurs de transcription GATA2 et MZF1 au niveau des régions liant ErbB380kDa. Un complexe nucléaire GATA2-MZF1-ErbB380kDa est retrouvé dans les cellules LNCaP et PC3.Des travaux récents montrent que GATA2 s'associe au RA pour réguler l'expression de gènes et qu'il pourrait être participer à la dissémination métastatique dans le CaP.Nos résultats suggèrent qu'ErbB380kDa pourrait jouer un rôle régulateur, en amont de GATA2, dans les processus de résistance et l'apparition de métastases. Cette isoforme nucléaire insensible aux traitements actuels apparaît donc comme une cible privilégiée pour le ciblage thérapeutique. / Prostate cancer (PCa) is dependent on androgens and functional androgen-receptor (AR) for growth and proliferation. Androgen-directed therapy is used at the first stages of the disease but cancer cells frequently become resistant (CRPC) by inappropriate reactivation of AR activity. As ErbB receptors are expressed in PCa cells, therapies aiming at inactivate the pathways downstream have been tested in advanced prostate cancers alongside hormone-based therapy. Still, a significant proportion of CRPC treated by ErbB1/2 inhibitors resist to treatment. ErbB3 could be responsible for this failure through both its unexpected nuclear localization and the reactivation of the PI3K-Akt pathway in those advanced tumors.We have described a nuclear ErbB380kDa isoform, expressed in hormone-sensitive (LNCaP) and hormone-resistant (PC3) PCa cell lines that accumulates in the nucleus of tumor cells during cancer progression. ChIP-on-chip experiments led us to characterize 353 target promoters binding ErbB380kDa in both cell lines; 245 promoters specific to LNCaP and 925 specific to PC3 cells, among which the promoter of GATA2. We show that ErbB380kDa functions as a transcriptional co-regulator for the studied genes, potentially through its interaction with transcription factors. In silico analysis revealed binding sites for GATA2 and MZF1 transcription factors on the target promoters, and a complex GATA2-MZF1-ErbB380kDa has been found in LNCaP and PC3 cells. Recent publications have reported a role for GATA2 in the regulation of RA responsive-genes and in metastatic spreading. We propose that ErbB380kDa could act, upstream of GATA2, to induce resistance mechanisms and facilitate cancer progression. Thus, ErbB380kDa emerges as a putative target for the development of new therapies in prostate cancer.

In order to carry out the complicated computation inside the high performance computing (HPC) systems, tens to hundreds of parallel processor chips and physical wires are required to be integrated inside the multi-chip package module (MCM). The physical wires considered as the electrical interconnects between the processor chips, however, have the challenges on placements and routings because of the unequal progress between the semiconductor and I/O size reductions. The primary goal of the research is to overcome package design challenges - providing a hybrid computing architecture with implemented 60 GHz antennas as the high efficient wireless interconnect which could generate over 10 Gbps bandwidth on the data transmissions. The dissertation is divided into three major parts. In the first part, two different performance metrics, power loss required to be recovered (PRE) and wireless link budget, on evaluating the antenna's system performance within the chip to chip wireless interconnect are introduced to address the design challenges and define the design goals. The second part contains the design concept, fabrication procedure and measurements of implemented 60 GHz broadband antenna in the application of multi-chip data transmissions. The developed antenna utilizes the periodically-patched artificial magnetic conductor (AMC) structure associated with the ground-shielded conductor in order to enhance the antenna's impedance matching bandwidth. The validation presents that over 10 GHz -10 dB S11 bandwidth which indicates the antenna's operating bandwidth and the horizontal data transmission capability which is required by planar type chip to chip interconnect can be achieved with the design concept. In order to reduce both PRE and wireless link budget numbers, a 60 GHz two-element array in the multi-chip communication is developed in the third part. The third section includes the combined-field analysis, the design concepts on two-element array and feeding circuitry. The simulation results agree with the predicted field analysis and demonstrate the 5dBi gain enhancement in the horizontal direction over a single 60 GHz AMC antenna to further reduce both PRE and wireless link budget numbers.

Low-loss off-chip interconnects are required for energy-efficient communication in dense microprocessors. To meet these needs, air cavity parallel plate and microstrip lines with copper conductors were fabricated on an FR-4 epoxy-fiberglass substrate using conventional microelectronics manufacturing techniques. Copper transmission lines were separated by a composite dielectric of air and Avatrel 2000P and by a dielectric layer of air only. The composite dielectric lines were characterized to 10 GHz while the all air dielectric lines were characterized to 40 GHz. The transmission line structures showed loss as low 1.5 dB/cm at 40 GHz with an effective dielectric constant below 1.4. These novel structures show low loss in the dielectric due to the reduced relative permittivity and loss tangent introduced by the air cavity. Transmission line structures with a composite dielectric were built by coating the sacrificial polymer poly(propylene carbonate) (PPC) over a copper signal line, encapsulating with an overcoat polymer, electroplating a ground line, and decomposing PPC to form an air cavity. The signal and ground wires were separated by a layer of 15 µm of air and 20 µm of Avatrel 2000P. Air cavity formation reduced dielectric constant more than 30 percent and loss of less than 0.5 dB/cm was measured at 10 GHz. Residue from PPC decomposition was observed in the cavity of composite dielectric structures and the decomposition characteristics of PPC were evaluated to characterize the residue and understand its formation. Analysis of PPC decomposition based on molecular weight, molecular backbone structure, photoacid concentration and vapor pressure, casting solvent, and decomposition environment was performed using thermogravimetric analysis and extracting kinetic parameters. Novel interaction of copper and PPC was observed and characterized for the self-patterning of PPC on copper. Copper is dissolved from the surface during PPC spincoating and interacts with the polymer chains to improve stability. The improved thermal stability allows selective patterning of PPC on copper. Decomposition characteristics, residual metals analysis, and diffusion profile were analyzed. The unique interaction could simplify air-gap processing for transmission lines. Inorganic-organic hybrid polymers were characterized for use as overcoat materials. Curing characteristics of the monomers and mechanical properties of the polymer films were analyzed and compared with commercially available overcoat materials. The modulus and hardness of these polymers was too low for use as an air-gap overcoat, but may be valuable as a barrier layer for some applications. The knowledge gained from building transmission line structures with a composite dielectric, analyzing PPC decomposition, interaction with copper, and comparison of hybrid polymers with commercial overcoats was used to build air-gap structures with improved electrical design. The ground metal was separated from the signal only by air. The signal wire was supported from above using 60 µm of Avatrel 8000P as an overcoat. Structures showed loss of less than 1.5 dB/cm at 40 GHz, the lowest reported value for a fully encapsulated transmission line structure.

De nombreux gènes suppresseurs de tumeurs sont inactivés par hyperméthylation dans les cancers. Cette inactivation serait en partie initiée par la protéine, MBD2 (Methyl-CpG-Binding Domain protein 2). Cette protéine recrute au niveau de séquences méthylées des complexes enzymatiques capables de modifier la structure chromatinienne et crée ainsi des régions fonctionnellement inactives. Dès lors, ce répresseur apparaît être une cible potentielle pour combattre le cancer. Dans cette perspective, rechercher les cibles de MBD2 et comprendre sa capacité à contrôler l'expression génique semblent cruciales. Au cours de deux études gènes candidats, nous avons pu démontrer (i) une réelle spécificité de cible du répresseur méthylationdépendant MBD2 pour les loci hTERT et pS2/TFF1 ; et (ii) un nouveau rôle de la protéine MBD2 en tant que modulateur de l'expression génique. De plus, les actions antagonistes entre le répresseur MBD2 et le trans-activateur naturel du gène pS2, le récepteur aux oestrogènes α, ont été explorées. Puis, l'analyse globale des profils de distribution de MBD2, de la méthylation de l'ADN, ainsi que de l'ARN polymérase II, sur puce promoteur a montré que MBD2 possède toutes les caractéristiques d'un répresseur trancriptionnel méthylation-dépendant. En effet, 74% des promoteurs fixés par MBD2 sont méthylés et cette liaison est associée dans 65% des cas à une répression transcriptionnelle.

Dissertation/Thesis / Masters Thesis Electrical Engineering 2015

L'électronique de puissance d'aujourd'hui s'inscrit dans un contexte environnemental où l'économie d'énergie est au centre des préoccupations. La traduction technologique d'une telle problématique sera, pour l'électronicien, la recherche de structures de conversion optimisant à la fois le rendement, la fiabilité et la qualité de l'énergie absorbée ou produite. Cet effort d'optimisation énergétique ne saurait être satisfaisant sans une recherche d'adaptation matérielle aux applications industrielles ou domestiques visées (avion tout électrique, éclairage...). C'est dans ce contexte que se situe ce travail de thèse, visant à chercher des solutions innovantes en terme de package de convertisseurs statiques satisfaisant les exigences de ces nouveaux secteurs d'exploitation, dans lesquels la miniaturisation, la fiabilité ou encore l'immunité aux perturbations CEM sont déterminants.

Notch signaling plays a key role in development, tissue homeostasis, and cancer. High expression levels of Notch signaling components are associated with aggressive disease and poor patient prognosis in breast cancer. Mesenchymal‐epithelial transition factor (MET) is a receptor tyrosine kinase with an established prognostic significance correlating with poor disease outcome in breast cancer patients as a result of high metastatic rate. We performed expression array analysis to identify candidate Notch target genes; we identified and validated MET as a target of NOTCH1 signaling in breast cancer. We found that NOTCH1 knockdown significantly reduces MET promoter activity, as well as expression levels of MET transcript and protein. The mechanism of NOTCH1 regulation of MET expression will be the focus of future work. To further identify candidate target genes of NOTCH1 signaling, we generated and validated a NOTCH1 antibody for use in chromatin immunoprecipitation experiments.

Notch signaling plays a key role in development, tissue homeostasis, and cancer. High expression levels of Notch signaling components are associated with aggressive disease and poor patient prognosis in breast cancer. Mesenchymal‐epithelial transition factor (MET) is a receptor tyrosine kinase with an established prognostic significance correlating with poor disease outcome in breast cancer patients as a result of high metastatic rate. We performed expression array analysis to identify candidate Notch target genes; we identified and validated MET as a target of NOTCH1 signaling in breast cancer. We found that NOTCH1 knockdown significantly reduces MET promoter activity, as well as expression levels of MET transcript and protein. The mechanism of NOTCH1 regulation of MET expression will be the focus of future work. To further identify candidate target genes of NOTCH1 signaling, we generated and validated a NOTCH1 antibody for use in chromatin immunoprecipitation experiments.

No description available.