In the past two decades, a growing interest in alternative energy resources as a replacement to the non-renewable resources used now days. These alternatives include geothermal energy which can be used to generate power and reduce the demands on energy used to heat and cool buildings. Ground-coupled ventilation system is one of the many applications of the geothermal energy that have a lot of attention in the early 80's and 90's but all designs of the system where based on single case situations. On the other hand, computational fluid dynamics tools are used to simulate heat and fluid flow in any real life situation. They start to develop rapidly with the fast development of computers and processors. These tools provide a great opportunity to simulate and predict the outcome of most problems with minimum loss and better way to develop new designs. By using these CFD tools in GCV systems designing procedure, energy can be conserved and designs going to be improved. The main objective of this study is to find and develop a CFD modeling strategy for GCV systems. To accomplish this objective, a case study must be selected, a proper CFD tool chosen, modeling and meshing method determined, and finally running simulations and analyzing results. All factors that affect the performance of GCV should be taken under consideration in that process such as soil, backfill, and pipes thermal properties. Multiple methods of simulation were proposed and compared to determine the best modeling approach. / Master of Science

L'adenocarcinoma ductal de pàncrees és un càncer molt agressiu que actualment representa la quarta causa de mort per càncer als països occidentals. Les teràpies clàssiques, basades en la resecció quirúrgica, la radioteràpia i el tractament amb quimioteràpics com la gemcitabina, no són efectives en la gran majoria del pacients. En aquests darrers anys s'està estudiant l'aplicació de la teràpia gènica com a teràpia alternativa o adjuvant per al tractament d'aquesta neoplàsia. Una aproximació important és la que es basa en la transferència del gen de la timidina quinasa del virus Herpes simplex tipus 1 (TK) i l'administració de la pro-droga ganciclovir (GCV). Un dels atractius que presenta aquest sistema TK/GCV és que disposa d'un mecanisme amplificador de la mort cel·lular, que va més enllà d'eliminar la cèl·lula tumoral modificada genèticament amb el gen TK i que es coneix com l'efecte adjacent. S'ha proposat, que aquest efecte podria ser degut al trànsit dels metabòlits tòxics del GCV a través dels canals intercel·lulars que formen les unions gap.En aquesta tesi hem realitzat una caracterització de l'expressió de les molécules constitutives de les unions gap, les connexines, en l'adenocarcinoma de pàncrees; i hem estudiat el seu paper en l'eficàcia de dues estratègies terapèutiques basades en l'administració de compostos anàlegs de nucleòsids: el sistema suïcida TK/GCV i el quimioteràpic gemcitabina. S'ha estudiat també la possible contribució de l'E-cadherina, element clau de les unions adherents epitelials, en l'efecte citotòxic d'aquestes teràpies i amb especial èmfasi en el sistema TK/GCV.

Made available in DSpace on 2015-03-03T15:32:43Z (GMT). No. of bitstreams: 1 IvanildoFP_DISSERT.pdf: 6193808 bytes, checksum: 2b4b204c68da306ef20f2a99dc91d9c9 (MD5) Previous issue date: 2013-09-20 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / In general, an inverse problem corresponds to find a value of an element x in a suitable vector space, given a vector y measuring it, in some sense. When we discretize the problem, it usually boils down to solve an equation system f(x) = y, where f : U Rm ! Rn represents the step function in any domain U of the appropriate Rm. As a general rule, we arrive to an ill-posed problem. The resolution of inverse problems has been widely researched along the last decades, because many problems in science and industry consist in determining unknowns that we try to know, by observing its effects under certain indirect measures. Our general subject of this dissertation is the choice of Tykhonov?s regulaziration parameter of a poorly conditioned linear problem, as we are going to discuss on chapter 1 of this dissertation, focusing on the three most popular methods in nowadays literature of the area. Our more specific focus in this dissertation consists in the simulations reported on chapter 2, aiming to compare the performance of the three methods in the recuperation of images measured with the Radon transform, perturbed by the addition of gaussian i.i.d. noise. We choosed a difference operator as regularizer of the problem. The contribution we try to make, in this dissertation, mainly consists on the discussion of numerical simulations we execute, as is exposed in Chapter 2. We understand that the meaning of this dissertation lays much more on the questions which it raises than on saying something definitive about the subject. Partly, for beeing based on numerical experiments with no new mathematical results associated to it, partly for being about numerical experiments made with a single operator. On the other hand, we got some observations which seemed to us interesting on the simulations performed, considered the literature of the area. In special, we highlight observations we resume, at the conclusion of this work, about the different vocations of methods like GCV and L-curve and, also, about the optimal parameters tendency observed in the L-curve method of grouping themselves in a small gap, strongly correlated with the behavior of the generalized singular value decomposition curve of the involved operators, under reasonably broad regularity conditions in the images to be recovered / Problemas inversos, usualmente recaem em resolver alguma equa??o do tipo f(x) = b, onde cada equa??o fi(x) = bi pode ser pensada como uma medida de um dado x a ser recuperado. Usualmente s?o mal postos, no sentido de corresponderem a equa??es que podem n?o ter solu??o exata, podem ainda ter muitas solu??es, ou ainda, o que ? o mais comum, ter solu??es muito inst?veis a ru?dos na obten??o de b. H? v?rias formas de regularizar a obten??o de solu??es de tais problemas e a mais popular seria a de Tykhonov, que corresponde a: Minimizar ||f(x) b||2 + l ||L(x x0) ||2 (I) A regulariza??o pretendida corresponde a se escolher o operador l, de tal forma que o problema I tenha solu??es est?veis com perturba??es em b e que aproximem solu??es do problema de m?nimos quadrados usual, no caso de se fazer l 0. O primeiro termo de (I) representa o ajuste aos dados e o segundo termo penaliza a solu??o de forma a regularizar o problema e produzir uma solu??o est?vel a ru?dos. Se l = 0, isto significa que estamos procurando uma solu??o de quadrados m?nimos para o problema, o que usualmente ? insuficiente para problemas mal postos. O termo de regulariza??o adicionado introduz um vi?s na solu??o ao penalizar o ajuste com um termo adicional. Se L for a identidade, por exemplo, isto significa que estamos apostando que a solu??o estaria relativamente pr?xima de x0. Se L for o operador gradiente, estamos apostando que a solu??o x ? razoavelmente suave. Nas aplica??es, L usualmente ? escolhido como um operador adaptado ao problema estudado e de forma se valer de informa??es a priori dispon?veis sobre as solu??es procuradas. A escolha do par?metro l > 0 ? crucial neste m?todos, pelo fato que se l ? excessivo, isto tende a enfraquecer excessivamente o ajuste aos dados, induzindo um ajuste da solu??o ? x0. Se l for pequeno demais a regulariza??o pretendida acaba n?o acontecendo e a solu??o do problema (I) usualmente acaba ficando muito inst?vel e contaminada por ru?dos. H? v?rias t?cnicas dispon?veis na literatura para tal escolha, sobretudo se f ? uma fun??o linear f(x) = Ax. O objetivo da disserta??o ? o de estudar algumas destas t?cnicas de ajuste do par?metro l no caso de operadores discretizados, vale dizer, x no Rn. Em especial, destacamos os m?todos de ajuste do par?metro l reconhecidos na literatura como L-curve, GCV e m?todo da discrep?ncia, e objetiva-se comparar estes m?todos em testes feitos com a transformada de Radon e tendo como regularizador um operador de derivada de primeira ordem. Os resultados dos testes realizados revelam pontos interessantes na rela??o entre os diferentes estimadores para o par?metro de regulariza??o e que sugerem um aprofundamento te?rico al?m do escopo desta disserta??o

Deux différents types de vecteurs, les nanocapsules lipidiques (LNC) et les systèmes multimodulaires (MMS) ont été développés pour l'administration par voie systémique de deux types d'acides nucléiques, l'ADN et les petits ARN à interférence (siRNA). Ces vecteurs sont formulés à base de complexes d'acides nucléiques et de lipides cationiques (lipoplexes) qui ont été soit encapsulés au coeur des LNC, soit recouverts de stabilisateurs stériques afin de former des MMS. Une partie du travail a consisté à développer des vecteurs de siRNA et à les caractériser par des méthodes physico-chimiques. En fonction du lipide cationique utilisé, jusqu'à 65% de siRNA ont pu être encapsulés dans les LNC, en présentant des caractéristiques appropriées pour une administration par voie systémique. La seconde partie a consisté à approfondir la caractérisation des vecteurs d'ADN et à analyser leur profil de distribution en utilisant de l'imagerie par fluorescence in vivo. Chez la souris saine, les vecteurs d'ADN ont présenté des profils de biodistribution spécifiques à leur composition. Sur deux modèles tumoraux (gliome sous-cutané et mélanome), les vecteurs ayant un temps de circulation prolongé ont également montré une co-localisation intéressante avec les cellules tumorales. Afin de mettre en évidence l'efficacité de ces vecteurs, un plasmide codant pour la tymidine kinase du virus herpes simplex (HSV-tk) a été encapsulé et administré. Puis un traitement par le ganciclovir (GCV) basé sur l'approche par gène suicide a été effectué. Les premiers résultats sont concluants, montrant une baisse de croissance tumorale après quelques jours de traitement aussi bien dans le modèle de gliome que dans celui du mélanome. Ces résultats indiquent que ces outils sont prometteurs pour une variété d'applications en thérapie génique.

El sistema TK/GCV es, problamente, la estrategia suicida mejor caracterizada hasta el momento. No obstante, se desconocen muchos aspectos relacionados con su mecanismo de acción. Con el objetivo de indentificar condicionantes de la respuesta TK/GCV, realizamos un estudio comparativo de la expresión de genes y de las vías de señalización que se activan en células sensibles y en células resistentes al tratamiento. Así, pudimos asociar la actividad de la quinasa Chk1, y la expresión de genes involucrados en el control del ciclo celular, con una mayor respuesta al sistema suicida. Así mismo, determinamos que la combinación de TK/GCV con el inhibidor de Chk1 UCN-01 produce un efecto antagónico en las células sensibles a TK/GCV. Por otro lado, la terapia combinada capaz de lisar las células e inducir muerte celular por fosforilación de GCV, en un único agente (ICOVIR11), resultó en una potenciación de sus efectos citotóxicos, permitiendo la compensación de la pérdida de potencia secundaria al uso de un promotor selectivo de tumor. Más aún, la expresión de TK como gen tardío de ICOVIR11,permitió la monitorización in vivo y de manera no invasiva, de la actividad TK y la replicación viral. / Although extensively characterized, the paradigmatic suicide system TK/GCV conceals the details of its ultimate mechanism of action. In order to shed some light on this issue, we conducted a series of experiments with resistant and sensitive cell lines, allowing us to identify cell cyclerelated genes that are deregulated in cells with induced resistance to TK/GCV. In addition, the association of Chk1 activation with a greater sensitivity to TK/GCV, pointed out the relevance of the cell cycle status at the moment of receiving the treatment, and its control in response to genotoxic insults. Treatment with a Chk1 inhibitor induced, in sensitive cells, an antagonistic effect on TK/GCV cytotoxicity. On the other hand, single-agent combination therapy of TK/GCV with adenoviral lysis resulted in enhanced cytotoxicity. In this setting the expression of TK as a late gene in an oncolytic adenovirus minimized the loss of potency associated to the conditioning of viral replication. On top of that, TK expression allowed for in vivo, real time, non-invasive monitoring of viral replication in mice, and was used to analyze the effects of treatment schedule on treatment outcome.

Diffusion-weighted magnetic resonance imaging (MRI) has allowed unprecedented non-invasive mapping of brain neural connectivity in vivo by means of fiber tractography applications. Fiber tractography has emerged as a useful tool for mapping brain white matter connectivity prior to surgery or in an intraoperative setting. The advent of high angular resolution diffusion-weighted imaging (HARDI) techniques in MRI for fiber tractography has allowed mapping of fiber tracts in areas of complex white matter fiber crossings. Raw HARDI images, as a result of elevated diffusion-weighting, suffer from depressed signal-to-noise ratio (SNR) levels. The accuracy of fiber tractography is dependent on the performance of the various methods extracting dominant fiber orientations from the HARDI-measured noisy diffusivity profiles. These methods will be sensitive to and directly affected by the noise. In the first part of the thesis this issue is addressed by applying an objective and adaptive smoothing to the noisy HARDI data via generalized cross-validation (GCV) by means of the smoothing splines on the sphere method for estimating the smooth diffusivity profiles in three dimensional diffusion space. Subsequently, fiber orientation distribution functions (ODFs) that reveal dominant fiber orientations in fiber crossings are then reconstructed from the smoothed diffusivity profiles using the Funk-Radon transform. Previous ODF smoothing techniques have been subjective and non-adaptive to data SNR. The GCV-smoothed ODFs from our method are accurate and are smoothed without external intervention facilitating more precise fiber tractography. Diffusion-weighted MRI studies in amyotrophic lateral sclerosis (ALS) have revealed significant changes in diffusion parameters in ALS patient brains. With the need for early detection of possibly discrete upper motor neuron (UMN) degeneration signs in patients with early ALS, a HARDI study is applied in order to investigate diffusion-sensitive changes reflected in the diffusion tensor imaging (DTI) measures axial and radial diffusivity as well as the more commonly used measures fractional anisotropy (FA) and mean diffusivity (MD). The hypothesis is that there would be added utility in considering axial and radial diffusivities which directly reflect changes in the diffusion tensors in addition to FA and MD to aid in revealing neurodegenerative changes in ALS. In addition, applying adaptive smoothing via GCV to the HARDI data further facilitates the application of fiber tractography by automatically eliminating spurious noisy peaks in reconstructed ODFs that would mislead fiber tracking.