Molecular mechanisms in the development and progression of thyroid carcinomas are still not fully understood. In the present thesis the highly malignant anaplastic thyroid carcinoma (ATC) was used to study regulation of apoptosis and tumor interstitial fluid pressure (IFP). Addition of a natural estrogen metabolite, 2-Methoxyestradiol (2-ME), induced a G2/M cell cycle arrest and apoptosis in five out of six human ATC cell lines. Treatment with 2-ME induced DNA-fragmentation as well as activation of caspase-3. Inhibitors of JNK and p38 MAPKs activity decreased the effect of 2-ME suggesting involvement in the induction of apoptosis. Solid tumors have an elevated IFP. High IFP forms or reflects a barrier for exchange of molecules between microvessels and surrounding tissue. The mechanisms for the generation of the high IFP were investigated using a specific TGF-β inhibitor in an ATC model in athymic mice. Tumor IFP was lowered in TGF-β inhibitor-treated compared to control mice. Affymetrix microarray analysis showed a decreased expression of macrophage-associated genes in treated tumors. Furthermore, the number and activity of tumor-associated macrophages was reduced after TGF-β inhibition. A decreased protein leakage together with an increased coverage of α-smooth-muscle actin (SMA)-expressing cells indicated vessel normalization. An adjuvant treatment with the TGF-β inhibitor resulted in an increased treatment efficacy of doxorubicin. Thus, TGF-β inhibitor-treatment suggests improved microvessel function which results in a lowering of tumor IFP and increased tumor drug uptake. To create a model for specific inactivation of genes in the thyroid, a transgenic mouse with a thyrocyte-specific expression of Cre recombinase was generated. The thyroglobulin promoter together with an inducible Cre recombinase (creERT2) was used. Two transgenic founder lines were identified expressing cre mRNA solely in the thyroid. Functional activity of the CreERT2 protein was demonstrated by using a ROSA26-LacZ reporter mouse.

Idiopathic Normal Pressure Hydrocephalus (INPH) is a condition affecting gait, cognition and continence. Radiological examination reveals enlarged ventricles of the brain. A shunt that drains CSF from the ventricles to the abdomen often improves the symptoms. Much research on INPH has been focused on identifying tests that predict the outcome after shunt surgery. As part of this quest, there are attempts to find measurement methods of intracranial parameters that are valid, reliable, tolerable and safe for patients. Today's technologies for intracranial pressure (ICP) measurement are invasive, often requiring a burr-hole in the skull. Recently, a method for non-invasive ICP measurements was suggested: the Pulsatile Index (PI) calculated from transcranial Doppler data assessed from the middle cerebral artery. In this thesis the relation between PI and ICP was explored in INPH patients during controlled ICP regulation by lumbar infusion. The confidence interval for predicted ICP, based on measured PI was too large for the method to be of clinical utility. In the quest for better predictive tests for shunt success in INPH, recent studies have shown promising results with criteria based on cardiac related ICP wave amplitudes. The brain ventricular system, and the fluid surrounding the spinal cord are in contact. In this thesis it was shown that ICP waves could be measured via lumbar subarachnoid space, with a slight underestimation. One of the cardinal symptoms of hydrocephalus is cognitive impairment. Neuropsychological studies have demonstrated cognitive tests that are impaired and improve after shunt surgery in INPH patients. However, there is currently no standardized test battery and different studies use different tests. In response, in this thesis a fully automated computerized neuropsychological test battery was developed. The validity, reliability, responsiveness to improvement after shunt surgery and feasibility for testing INPH patients was demonstrated. It was also demonstrated that INPH patients were impaired in all subtests, compared to healthy elderly.

High interstitial fluid pressure (IFP) in tumours is recognized as a barrier to drug delivery resulting in reduced efficacy. High IFP impedes the normal process of convective fluid flow (CFF) from blood vessels into the interstitium. The aim of this study was to develop an in vitro model that could be used to measure CFF and to study its effects on drug delivery. The model consists of a transwell cell culture insert which supports the growth of multicell layers (MCL) on collagen coated membranes. A graduated tube is inserted into the transwell and a pressure gradient is applied across the membrane by raising the volume of medium in the tube above that of the bottom chamber. CFF is determined by measuring the weight of medium in the bottom chamber as a function of time. CFF was inversely proportional to MCL thickness and 41.1±3.6µm thick MCL has completely stopped CFF. Using a physiologically relevant hydrostatic pressure of 28mmHg, a CFF of 21µL/min was recorded using a DLD-1 MCL that was 12.21±3.2µm thick. Under these conditions, the rates of penetration of doxorubicin, imatinib and gefitinib were respectively 42, 26 and 13 folds greater than when no CFF exists. Reversing the CFF so that it opposed the drug diffusion gradient significantly impairs drug penetration. In conclusion, a novel in vitro model for assessing the impact of CFF on drug delivery has been developed. This model could be used to evaluate strategies designed to increase drug delivery to solid tumours by modifying the CFF.

Dans ce manuscrit nous développons l'approche cinématique 2D du calcul à la rupture pour examinerles effondrements en extension (ou failles normales) de la croûte supérieure cassante qui résultent desurpressions de fluides. Les sujets d'intérêt liés à la déformation en extension sont (1) les roles de lapression des fluides, des processus de surface, et des propriétés des matériaux et des failles sur lastabilité des structures d'extension; (2) la formation de failles normales à faible pendage et de failleslistriques; (3) la distribution de la déformation au dessus d'un glissement à faible pendage; et (4)l'influence de l'adoucissement mécanique des failles et des processus de sédimentation sur cettedistribution.Cette approche mécanique est vérifiée par la théorie du prisme critique de Coulomb, et la généralise pour étudier la topographie complexe de la péninsule de Mejillones dans le Nord du Chili. Cetteapproche est aussi appliquée à l'instabilité gravitaire dans le delta du Niger en reliant les structurescompressives en bas de pente aux structure extensives en amont par un détachement profond. Nousprédisons des surpressions de fluides beaucoup plus élevée que celles obtenues par application duprisme de Coulomb. Enfin, cette méthodologie est appliquée à l'étude de la forme de failles normalesreliant un détachement profond à la surface. Dans le cas du delta du Niger, nous montrons que lesfailles à faible pendage et les failles listriques impliquent que la profondeur de rétention des fluides estfaible. La version séquentielle de l'analyse limite ouvre de nouvelles voies pour suivre l'évolutionstructurale dans le temps du jeu sur les failles normales. Les simulations montrent en particulier qu'unefaille normale tourne vers des pendage plus faibles au fur et à mesure de la dénudation du mur, formantune région qui passe du mur au toit de la faille active en rotation. La prédiction de cette région estillustrée par des expériences analogiques et des exemples de terrain. / This manuscript develops a 2D kinematic approach of Limit Analysis to examine the extensionalfailures in the brittle, upper crust resulting from fluid overpressures and normal faulting. There aremany interesting topics related to the extensional deformation such as (1) the roles of fluid pressure,topographic process, material and fault properties on the stability of extensional structures; (2) theformation of low-angle and listric normal fault; (3) the deformation pattern due to slip on a low-anglefault; and (4) the influence of fault softening and sedimentation processes on this deformation pattern.This mechanical approach applied to wedge prototypes is validated by the critical Coulomb wedge(CCW) theory, and it generalizes the CCW theory to investigate the complex topography on theMejillones peninsula, Northern Chile. Additionally, this approach is also applied to investigate gravityinstability of Niger Delta by linking down-slope compressional to up-slope extensional failures througha deep detachment. We predict much higher fluid overpressures than that of the CCW theory. Finally,this Limit Analysis methodology is applied to investigate the shape of normal fault linking a lowdetachment to the surface. The application to Niger Delta implies that the formation of very low-angleand strongly listric faults results from a shallow fluid-retention depth. The sequential version of LimitAnalysis opens new ways to envision the structural evolution through time resulting from normalfaulting. The simulations show that the normal fault rotates during extension, forming a region of Footto-Hanging Wall (FHW) where the material in the footwall is sheared upon entering the hanging wall.The creation of the FHW region is illustrated by sandbox experiments and field examples.

Both joint sets and fault-related fractures serve as important conduits for fluid flow. In the former case, they can strongly influence both permeability and permeability anisotropy, with implications for production of water, hydrocarbons and contaminant transport. The latter can affect issues of fluid flow, such as whether a given fault seals or leaks, and fault mechanics. These fractures are commonly interpreted as Natural Hydraulic Fractures (NHFs), i.e., mode 1 fractures produced when pore fluid pressure exceeds the tensile strength of the rock. Various mathematical models have been a rich source of hypotheses to explain the formation and propagation of NHFs, but have provided only limited information and nothing about processes of fracture initiation in originally intact rock. Recent laboratory experiments of French et al. (2012) have advanced our understanding of mechanical controls on fracture initiation and spacing. Here, detailed analysis of both through-going fracture surfaces, non-through-going fractures, in experimentally deformed samples provide a deeper understanding of NHF processes and resulting geometric features in porous siliciclastic sedimentary rocks. Observations indicate that both fracture planarity and microcrack damage (which has not previously been reported for opening mode fractures) vary significantly depending on the degree of mechanical heterogeneity and anisotropy of the host rock. Variations reflect mechanical controls on fracture initiation and propagation, suggesting that fracture spacing may in part reflect the distribution of mechanical heterogeneities. These data indicate that the more homogeneous the rock, the greater the microcrack damage surrounding a given NHF, increasing expected fracture-associated permeability for a given fracture aperture.

In vielen industriellen Anwendungen sind Dichtungen im Einsatz. Vergleicht man den Preis mit dem eines Gesamtsystems, in denen Dichtungen verwendet werden, so sind Dichtungen verhältnismäßig günstig. Jedoch führt ein Versagen von Dichtungen meist zu schwerwiegenden Konsequenzen. Dichtungen sind komplexe Subsysteme und ihre Auslegung erfordert umfangreiche Kenntnisse im Bereich Materialmodellierung, Belastung und Versagenskriterien. Die heutige Simulationstechnologie ermöglicht einen parametrischen Workflow für die Berechnung des Verhaltens von Dichtungen mit den auftretenden Effekten wie nichtlinearem Materialverhalten, wechselnden Kontaktbedingungen und Flüssigkeitsunterwanderung bei Druck. Als ein führendes Simulationswerkzeug für diese physikalische Fragestellung wird ANSYS Mechanical für die Auslegung herangezogen. Desweiteren kann das Verständnis für das Produkt erhöht werden, was zu einer Verbesserung der Funktionalität und der Zuverlässigkeit führt. Versuchsdaten können als Spannungs-Dehnungskurven in ANSYS importiert werden, welche das Materialverhalten des hyperelastischen Werkstoffs mit traditionellen Materialmodellen wie Mooney Rivlin, Ogden and Yeoh oder einer neueren Formulierung, der Antwortfunktionsmethode, widerspiegeln. Robuste Kontakttechnologien beschleunigen die Simulation und Entwicklungszeit-Berechnungszeiten und gewährleisten ein genaues Verhalten des Simulationsmodells. Insbesondere bei Dichtungen ist die druckbeaufschlagte Fläche in 2D und 3D Anwendungen von Bedeutung. ANSYS berechnet diese automatisch in Abhängigkeit des aktuellen Kontaktzustandes. Diese benutzerfreundliche Unterstützung führt zu einer höheren Genauigkeit des Simulationsergebnisses, da ein manuelles Schätzen der Druckflächen entfällt. Mit einem parametrischen und durchgängigen Ansatz innerhalb von ANSYS Workbench, beginnend bei der CAD-Geometrie, über die Vernetzung, Material- und Randbedingungsdefinition und Lösung. können eine Reihe von Varianten in kurzer Zeit berechnet werden. Neben einem besseren Verständnis für das Produkt hilft dies dem Ingenieur Änderungen vorzunehmen, was zu exakten und aussagekräftigen Ergebnissen führt. Desweiteren kann der Einfluss von Unsicherheiten berücksichtigt werden, sodass der Berechnungsingenieur fernab von idealen Bedingungen robuste und zuverlässige Dichtungen entwickeln kann.

Overpressure, or abnormally low effective pressures, is hazardous in drilling operations and construction of sea-bottom facilities in deepwater environments. Estimation of the locations of overpressure can improve safety in these operations and significantly reduce overall project costs. Propagation velocities of both seismic P and S wave are sensitive to bulk elastic parameters and density of the sediments, which can be related to porosity, pore fluid content, lithology, and effective pressures. Overpressured areas can be analyzed using 4C seismic reflection data, which includes P-P and P-SV reflections. In this thesis, the effects on compressional (P) and shear (S) wave velocities are investigated to estimate the magnitude and location of excess pore pressure utilizing Eaton’s approach for pressure prediction (Eaton, 1969). Eaton’s (1969) method relates changes in pore pressure to changes in seismic P-wave velocity. The underlying assumption of this method utilizes the ratio of observed P-wave velocity obtained from areas of both normal and abnormal pressure. This velocity ratio evaluated through an empirically determined exponent is then related to the ratio of effective stress under normal and abnormal pressure conditions. Effective stress in a normal pressured condition is greater than the effective stress value in abnormally overpressured conditions. Due to an increased sensitivity of variations in effective pressure to seismic interval velocity, Ebrom et al. (2003) employ a modified Eaton equation to incorporate the S-wave velocity in pore pressure prediction. The data preparation and subsequent observations of seismic P and S wave velocity estimates in this thesis represent a preliminary analysis for pore pressure prediction. Six 2D receiver gathers in the regional dip direction are extracted from six individual ocean-bottom 4C seismic recording nodes for P-P and P-SV velocity analysis. The receiver gathers employed have minimal pre-processing procedures applied. The main processing steps applied were: water bottom mute, 2D rotation of horizontal components to SV and SH orientation, deconvolution, and frequency filtering. Most the processing was performed in Matlab with a volume of scripts designed by research scientists from the University of Texas, Bureau of Economic Geology. In this thesis, fluid pressure prediction is estimated utilizing several 4C multicomponent ocean-bottom nodes in the Atlantis Field in deepwater Gulf of Mexico. Velocity analysis is performed through a ray tracing approach utilizing P-P and P-SV registration. A modified Eaton’s Algorithm is then used for pore pressure prediction using both P and S wave velocity values. I was able to successfully observe both compressional and shear wave velocities to sediment depths of approximately 800 m below the seafloor. Using Hamilton (1972, 1976) and Eberhart-Phillips et al. (1989) regressions as background depth dependent velocity values and well-log derived background effective pressure values from deepwater Gulf of Mexico, I am able to solve for predicted effective pressure for the study area. The results show that the Atlantis subsurface study area experiences a degree of overpressure. / text

Les acides gras polyinsaturés n-3 (acide docosahexaènoïque, DHA et acide eicosapentaènoïque, EPA) sensibilisent les tumeurs mammaires aux agents anticancéreux. Cette sensibilisation implique la régulation de la vascularisation tumorale. En effet, un régime nutritionnel EPA/DHA, associé à une chimiothérapie par le Docétaxel (Taxane) diminue la quantité de vascularisation (effet anti-angiogénique). Une amélioration de la qualité vasculaire est aussi observée par une diminution de la pression du liquide interstitiel, paramètre décrit comme un frein à la délivrance des drogues dans les tumeurs. Cette diminution est associée à une extravasation plus importante du bleu d’Evans, suggérant une meilleure distribution des agents anticancéreux au sein des tumeurs. L’effet antiangiogénique du DHA implique une diminution de la voie de signalisation VEGF/eNOS/NO. Ainsi, l’activation de la NO synthase endothéliale (eNOS) est diminuée dans des cellules endothéliales en culture et dans les tumeurs mammaires. Nos résultats suggèrent que l’apport d'acides gras EPA/DHA aux patients au cours de la chimiothérapie pourrait être une nouvelle approche thérapeutique pour normaliser la vascularisation tumorale et améliorer l’efficacité des traitements anticancéreux. / Polyunsaturated fatty acids n-3 (docosahexaenoic acid, DHA and eicosapentaenoic acid, EPA) sensitize mammary tumors to anticancer drugs. This sensitization involves the regulation of tumor vasculature. Indeed, a nutritional diet with EPA / DHA, in combination with taxane chemotherapy (docetaxel) decreases the vascular quantity (anti-angiogenic effect). An improvement of vascular quality is also observed by a decrease of interstitial fluid pressure, a parameter described as a barrier to drug delivery in tumors. This decrease improves extravasation of Evans blue, suggesting a better distribution of anticancer agents in tumors. The antiangiogenic effect of DHA involves a decrease of signaling pathway VEGF / eNOS / NO. Thus, activation of endothelial NO synthase (eNOS) is decreased in endothelial cells in culture and in mammary tumors. Our results suggest that intake of fatty acids EPA / DHA to patients during chemotherapy could be a new therapeutic approach to normalize tumor vasculature and improve the efficacy of cancer treatments.

La formation des gisements métallogéniques en général et uranifères en particulier, dans les bassins paléoprotérozoïques, dépend de la migration des fluides riches en divers éléments (U, Cu, Fe, etc.). L’objet de cette thèse a été de définir le contexte tectonique, sédimentologique et diagénétique associées aux gisements bitume--‐uranium du bassin de Franceville. L’étude tectonique réalisée met en évidence des failles de transfert N180--‐170, héritées de la tectonique archéenne et des failles normales longitudinales N110--‐120. Ces deux familles de failles compartimentent le bassin de Franceville en plusieurs sous--‐bassins de subsidence variable. Les failles longitudinales N110--‐120° contrôlent la mise en place d’anticlinaux de mur et des synclinaux de toit synsédimentaires (i.e. discordances progressives). Les gisements d’uranium du bassin de Franceville, se localisent au niveau des anticlinaux de mur des failles normales. L’étude sédimentologique du bassin caractérise la distribution spatiale des paléoenvironnements de dépôt. Quatre grands environnements de dépôts sont respectivement mis en évidence : fluviatile (formation FA inferieur), deltaïque (formation FA moyen), tidal (formation FA Supérieur) et marin profond (formation FB). La distribution des facies sédimentaires à la transition FA--‐FB est responsable de la mise en place de barrières de perméabilité. Les barrières de perméabilité sont responsables de l’augmentation de la pression fluide, qui favorise la mise en place des structures de surpression fluide (dykes, stylolites, veines de quartz), au voisinage des anticlinaux de mur contrôlés par les failles normales. Les différences de pression dans le bassin favorisent la migration des fluides uranifères et des hydrocarbures, des zones profondes du bassin vers les anticlinaux de mur. Les structures de fracturation hydraulique vont contrôler la mise en place des bitumes et des minéralisations d’uranium associées. / Metallogenic deposits within paleproterozoic basins depend on generation and migration of fluids. The aim of this study is to provide a better understanding of tectonic, sedimentological and diagenetic setting of the uranium deposits in the Franceville basin and to characterize hydraulic fracturing impact on fluid migration processes in sandstone reservoirs.Tectonic study define the N180-170° transfer faults, associated with Archean tectonic and the N110-120° longitudinal normal faults. These two fault directions split the Franceville basin into small sub-basins. The longitudinal normal faults are associated with footwall anticlines and hanging wall synclines. The uranium deposits of Franceville basin are located in footwall anticlines of longitudinal normal faults.Sedimentological analysis allows to describe four depositional environments: Fluvial (lower FA), deltaic (middle FA), tidal (upper FA), and open marine environments (FB). Facies distribution in the FA-FB transition promotes the establishment of permeability barriers. These latter are responsible of the increase in fluid pressure and of the formation of fluid pressure structures (dykes, stylolites, quartz veins), in footwall anticlines of longitudinal normal faults. Increase in fluid pressure allows the migration of uranium-fluids, and hydrocarbon from the deep basin to the footwall anticline. Hydraulic fracturing processes lead the precipitation of uranium mineralization, associated with bitumen, in microfractures.

Les structures de déformation pré-lithification s’enregistrent dans les sédiments meubles. Ces structures sont abondantes dans les domaines sous-glaciaires et marins profonds en raison du développement de surpressions de fluide. A partir de cas d’études choisis dans ces deux environnements, leurs implications sur les (1)reconstructions paléoenvironnementales, leurs impacts sur la (2) morphologie glaciaire, et sur les (3) propriétés pétrophysiques ont pu être définis.(1) L’analyse de ces structures de déformation a permis de mieux contraindre les paléoenvironnements sédimentaires. Ces structures de déformation ont été utilisées comme des «proxy » permettant d’estimer les variations de la vitesse d’écoulement, de l’épaisseur de glace, de la production d’eaux de fonte et de la position de la marge glaciaire.(2) Les séries sédimentaires des vallées tunnels ordoviciennes enregistrent la mise en place de nombreuses structures de déformation liées aux surpressions de fluides. L’analyse de ces structures a permis de proposer un nouveau modèle de creusement des vallées tunnels induits par des pressions de fluides élevées. Ce modèle de creusement, lié aux surpressions de fluide, est favorisé dans les zones d’inter ice-stream. A l’inverse, sous les ice-stream, l’écoulement des eaux de fonte se produit à l’interface glace-substrat et favorise d’autres modèles de formation des vallées tunnels.(3) Les processus de remobilisation sédimentaire ont un impact sur les propriétés pétrophysiques des réservoirs sableux. Les études pétrophysiques menées sur des grès déposés en environnements marins profonds et glaciaires ont permis de mettre en évidence l’impact des surpressions de fluides sur les propriétés réservoirs des sables. Les processus de fluidisation sont capable de créer de bons réservoirs, tandisque les processus d’élutriations ont tendance a réduire la porosité/perméabilité. / Soft-sediment deformation structures (SSDs) occur in unconsolidated sediments, during or shortly after deposition. SSDs are abundant in subglacial and deep-marine environments because of the development of fluid overpressure. Case studies of these two sedimentary environments were used (1) to reconstruct palaeoenvironments from SSDS, and (2) to define the impacts of SSDS on glacial morphologies and (3) petrophysical properties.(1) Analyses of strain regimes, deformation mechanisms, and chronologies in SSDs served to improve palaeoenvironmental reconstructions. These structures were used as proxys to estimate variations of ice flow velocities, ice thickness, meltwater production, and position of the ice margin.(2) The sedimentary series of ordovician tunnel valleys record numerous SSDs induced by fluid overpressure. A new model of tunnel valley formation controlled by the increase of porewater pressure in the bed is proposed. This model of formation occurs in inter-ice stream zones, where meltwater is transferred to the substratum. In ice-stream corridors, meltwater circulates at the ice-bed interface and promotes the formation of tunnel valleys controlled by meltwater processes.(3) Remobilisation processes triggered by the increase of fluid pressure have an impact on the granular framework and on the geometry of reservoirs. Petrophysical studies of subglacial and deep-marine sandstones demonstrated the impact of fluid overpressure on reservoir properties. Processes of fluidisation are responsible for the increase in porosity/permeability, while elutriation processes lead to a decrease in these petrophysical properties.