Dans cette thèse, nous présentons une modélisation numérique du comportement élastoplastique d'une pâte de ciment soumise à la dégradation chimique. Une courte synthèse bibliographique est d'abord présentée sur la composition minéralogique, la chimie, le comportement mécanique de base, les mécanismes de dégradation chimique et le couplage chimie-mécanique des matériaux cimentaires en général et de la pâte de ciment en particulier. En se basant sur cette synthèse et des données expérimentales, un modèle de comportement élastoplastique est ensuite formulé dans le chapitre 2, pour des pâtes de ciment soumises essentiellement à des contraintes de compression. Deux mécanismes de déformations plastiques sont identifiés, liés respectivement au cisaillement déviatorique et à la compaction des pores. En définissant la dégradation chimique par une variable d'endommagement chimique, les propriétés élastiques et plastiques sont affectées par cet endommagement. Les essais mécaniques effectués sur des échantillons sains et chimiquement dégradés sont simulés par le modèle proposé. La détermination de la cinétique de l'endommagement chimique est abordée dans le chapitre 3. En se basant sur un modèle phénoménologique de la lixiviation chimique, la cinétique de l'endommagement chimique est contrôlée par le processus de diffusion des ions calcium dans la solution interstitielle. La concentration en calcium de la solution interstitielle est alors considérée comme la variable d'état chimique. La variation de la teneur en calcium dans la matrice solide et celle de la porosité sont reliées à la concentration en calcium en fluide par la courbe d'équilibre thermodynamique. La méthode des éléments finis est utilisée par la résolution numérique de l'équation de diffusion généralisée. Le modèle proposé est enfin étendu pour inclure l'endommagement mécanique par microfissuration afin de décrire le comportement fragile des matériaux cimentaires. Un exemple d'application du modèle à une structure soumise à la dégradation chimique est présenté. / Thesis presents elastoplastic modelling of cement-based materials coupledwith chemical degradation and mechanical damage. The emphasis is put on cementpaste subjected to compressive stresses. A short literature review is first presented on the mineralogical composition, chemical degradation mechanisms, basic mechanical behaviour and chemical-mechanical coupling. Based on this analyses and a series of experimental data obtained from uncoupled and coupled tests, an elastoplastic constitutive model coupled with chemical damage is first formulated. Two plastic mechanisms are taken into account; respectivelyrelated to deviatoric shearing and pore collapse. The chemical damage is identified as relative variation of porosity. Elastic and plastic properties are affected by chemical damage. Numerical simulations are compared with experimental data and good agreements have been obtained. The evolution of the chemical damage has been described by the generalized diffusion equation which is based on the mass balance equation and a phenomenological chemistry model. We have used finite element method to solve the generalized diffusion equation. Coupled chemical-mechanical tests have been simulated by the proposed model and we have also obtained satisfactory concordance. An extension of the model is finally proposed by including mechanical damage due to microcracks in order to describe brittle responses of material under tensile stresses and low confining pressures. An example of application to structural analysis with chemical degradation is presented. It has been shown that the proposed model describes correctly the main features of the mechanical behaviours of cement-based materials at different stress conditions with chemical degradation.

Increasing demands for hyperthermia (HT) as an adjuvant therapy is caused from the contributions of thermal therapy to the traditional treatments. Latest improvements in hyperthermia make it popular among thermal therapies to cure cancer in any organ or body parts. HT takes advantage of EM radiation inside the tumor that provides temperature and blood perfusion increment that helps radiation therapy and chemotherapy to be more efficient. Therefore, some advantages makes HT preferred when compared to similar treatments. Being noninvasive and painless with an efficient cooling system, and helping to shorten the application period and session number of conventional treatments are most important advantages of HT. However, existing HT systems require high input power per elements on the applicators and long application time. Designing conformal and patient specific applicators with mild application can solve this issue. Moreover, mild HT application can make cancer treatment cheaper and more accessible. The main goal in this study is to design conformal HT applicators through optimization for liver and provide a patient specific and cost-effective local hyperthermia treatment that can be widely used in local clinical cancer treatment centers without expensive applicators.

The present work aims at studying the coupling between hydrodynamic fingering instabilities and chemical reactions at the interface between two miscible solutions. Hydrodynamic deformations of interfaces between two reactive fluids as well as flows induced by chemical reactions at the front between two initially steady fluids are encountered frequently in combustion, petroleum, chemical and pharmaceutical engineering. Most of the time, concrete applications imply a very large number of variables so that an understanding of the fundamental processes of chemo-hydrodynamic coupling is out of reach. Our goal is here to analyze a much simpler model system in which only one mechanism of hydrodynamic instability is at play and for which the chemical reactions can be modeled by a one or two-variable model. Buoyantly unstable, autocatalytic chemical fronts, are one such model system, which can be used as prototype to study the effects of the coupling between chemical reactions and hydrodynamic fingering instabilities. Fingering processes occur whenever a fluid of high mobility displaces a less mobile one in a porous medium. The initially planar interface looses then stability and a cellular fingering deformation of the interface is observed. Such an instability has been observed, for instance, in the iodate-arsenous acid and chlorite-tetrathionate reactions, autocatalytic redox reactions known to produce a change of density across a traveling front. Fingering happens there when the heavier solution lies on top of the lighter one in the gravity field. Our theoretical contribution to the analysis of fingering of chemical fronts focuses on different points which we detail in this thesis along the following outline. In chapter 2, we introduce fingering phenomena occurring in porous media and distinguish the situation of viscous and density fingering of pure non reactive fluids. Chapter 3 reviews the literature on coupling between fingering and chemical reactions before studying the linear stability conditions as well as nonlinear dynamics of density fingering of isothermal iodate-arsenous acid fronts. This prototype nonlinear redox reaction is the first one on which experimental results on fingering in spatially extended set-ups have been obtained. We next analyze in chapter 4 the density fingering of another front producing autocatalytic system i.e. the chlorite-tetrathionate reaction in order to address the influence of the chemical kinetics on the dynamics observed. The influence of the exothermicity of the reaction is then presented in chapter 5. Eventually, chapter 6 analyzes what happens if the kinetics is now bistable and further compares the situation of both viscous and density fingering of bistable fronts. We then conclude and present suggestions for future work in this subject at the frontier between nonlinear chemistry, hydrodynamics and engineering.

Yes / The DNA damage response (DDR) is now known to play an important role in both cancer development and its treatment. Targeting proteins such as ATR (Ataxia telangiectasia mutated and Rad3-related) kinase, a major regulator of DDR, has demonstrated significant therapeutic potential in cancer treatment, with ATR inhibitors having shown anti-tumour activity not just monotherapies, but also in potentiating the effects of conventional chemotherapy, radiotherapy, and immunotherapy. This review focuses on the biology of ATR, its functional role in cancer development and treatment, and the rationale behind inhibition of this target as a therapeutic approach, including evaluation of the progress and current status of development of potent and specific ATR inhibitors that have emerged in recent decades. The current applications of these inhibitors both in preclinical and clinical studies either as single agents or in combinations with chemotherapy, radiotherapy and immunotherapy are also extensively discussed. This review concludes with some insights into the various concerns raised or observed with ATR inhibition in both the preclinical and clinical settings, with some suggested solutions.

Assessment of diffuse brain disorders, where the brain may appear normal, has proven difficult to translate into personalized treatments. Previous methods based on brain magnetic resonance imaging (MRI) resting state blood oxygen level dependent (rs-BOLD) signal routinely rely on group analysis where large data sets are assessed using region-of interest (ROI) or probabilistic independent component analysis (PICA) to identify temporal synchrony or desynchrony among regions of the brain. Brain connectivity occurs in a complex, multilevel and multi-temporal manner, driving the fluctuations observed in local oxygen demand. These fluctuations have previously been characterized as fractal, as they auto-correlate at different time scales. In this study we propose a model-free complexity analysis based on the fractal dimension of the rs-BOLD signal, acquired with MRI. The fractal dimension can be interpreted as a measure of signal complexity and connectivity. Previous studies have suggested that reduction in signal complexity can be associated with disease. Therefore, we hypothesized that a detectable differences in rs-BOLD signal complexity could be observed between patients with diffuse or heterogeneous brain disorders and healthy controls. In this study, we obtained anatomical and functional data from patients with brain disorders where traditional methods have been insufficient to fully assess the condition. More specifically, we tested our method on mild traumatic brain injury, autism spectrum disorder, chemotherapy-induced cognitive impairment and chronic fatigue syndrome patients. Three major databases from the Neuroimaging Informatics Tools and Resources Clearinghouse (NITRC) project were used to acquire large numbers of age matched healthy controls. Healthy control data was downloaded from the the Autism Brain Imaging Data Exchange (ABIDE), the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Human Connectome Project specifically matching our experimental design. In all of our studies, the voxel-wise rs-BOLD signal fractal dimension was calculated following a procedure described by Eke and Herman et al. 2000. This method was previously used to assess brain rs-BOLD signal in small mammals and humans. The method consists of estimating the Hurst exponent in the frequency domain using a power spectral density approach and refining the estimation in the time domain with de-trended fluctuation analysis and signal summation conversion methods. Voxel-wise fractal dimension (FD) was then calculated for every subject in the control and patient groups to create ROI-based Z-scores for each individual patient. Voxel-wise validation of FD normality across controls was studied and non-Gaussian voxels, determined using kurtosis and skewness calculations, were eliminated from subsequent analysis. To maintain a 95 % confidence level, only regions where Z-score values were at least 2 standard deviations away from the mean were included in the analysis. In the case of chronic fatigue patients and chemotherapy induced cognitive impairment, DTI analysis was added to also determine whether white matter abnormalities were also relevent. Similar Z-score analysis on DTI metrics was also performed. Brain microscopic networks, modeled as complex systems, become affected in diffuse brain disorders. Z-scoring of the fractal rs-BOLD frequency domain delineated patient-specific regional brain anomalies which correlated with patient-specific symptoms. This technique can be used alone, or in combination with DTI Z-scoring, to characterize a single patient without any need for group analysis, making it ideal for personalized diagnostics. / Thesis / Doctor of Philosophy (PhD)

Plumes are formed when a continuous buoyant forcing is supplied at a localized source. Buoyancy can be created by either a heat flux, a compositional difference between the fluid coming from the source and its surroundings, or a combination of both. In this thesis, two types of laminar plumes with different forcing mechanisms were investigated: forced plumes and autocatalytic plumes. The forced plumes were compositionally buoyant and were injected with inertial forcing into a fluid filled tank. The autocatalytic plumes were produced without mechanical forcing by buoyancy that was entirely the consequence of a nonlinear chemical reaction -- the iodate-arsenous acid (IAA) reaction. This reaction propagates as a reacting front and produces buoyancy by its exothermicity, and by the compositional difference between the reactant and product. Both the forced and autocatalytic plumes were examined in starting and steady states. The starting, or transient, state of the plume occurs when it initially rises through a fluid and develops a plume head on top of a trailing conduit. The steady state emerges after the plume head has risen to the top of a fluid filled tank leaving only a persistent conduit. Plume behaviour was studied through experimentation, simulation, and by using simple theoretical analysis. We performed the first ever study of plumes as they crossed over the transition between buoyancy-driven to momentum-driven flow. Regardless of the driving mechanism, forced plumes were found to exhibit a single power law relationship that explains their ascent velocity. However, the morphology of the plume heads was found to depend on the dominating driving mechanism. Confined heads were produced by buoyancy-driven plumes, and dispersed heads by momentum-driven plumes. Autocatalytic plumes were found to have rich dynamics that are a consequence of the interplay between fluid flow and chemical reaction. These plumes produced accelerating heads that detached from the conduit, forming free vortex rings. A second-generation head would then develop at the point of detachment. The detachment process for plumes was sensitively dependent on small fluctuations in their initial formation. In some cases, head detachment could occur multiple times for a single experimental run, thereby producing several generations of autocatalytic vortex rings. Head detachment was reproduced and studied using autocatalytic plume simulations. Autocatalytic flame balls, a phenomenon closely related to autocatalytic plumes, were also simulated. Flame balls were found to have three dynamical regimes. Below a critical radius, the smallest flame balls experienced front death. Above this radius, they formed elongating, reacting tails. The largest flame balls formed filamentary tails unable to sustain a reaction.

Plumes are formed when a continuous buoyant forcing is supplied at a localized source. Buoyancy can be created by either a heat flux, a compositional difference between the fluid coming from the source and its surroundings, or a combination of both. In this thesis, two types of laminar plumes with different forcing mechanisms were investigated: forced plumes and autocatalytic plumes. The forced plumes were compositionally buoyant and were injected with inertial forcing into a fluid filled tank. The autocatalytic plumes were produced without mechanical forcing by buoyancy that was entirely the consequence of a nonlinear chemical reaction -- the iodate-arsenous acid (IAA) reaction. This reaction propagates as a reacting front and produces buoyancy by its exothermicity, and by the compositional difference between the reactant and product. Both the forced and autocatalytic plumes were examined in starting and steady states. The starting, or transient, state of the plume occurs when it initially rises through a fluid and develops a plume head on top of a trailing conduit. The steady state emerges after the plume head has risen to the top of a fluid filled tank leaving only a persistent conduit. Plume behaviour was studied through experimentation, simulation, and by using simple theoretical analysis. We performed the first ever study of plumes as they crossed over the transition between buoyancy-driven to momentum-driven flow. Regardless of the driving mechanism, forced plumes were found to exhibit a single power law relationship that explains their ascent velocity. However, the morphology of the plume heads was found to depend on the dominating driving mechanism. Confined heads were produced by buoyancy-driven plumes, and dispersed heads by momentum-driven plumes. Autocatalytic plumes were found to have rich dynamics that are a consequence of the interplay between fluid flow and chemical reaction. These plumes produced accelerating heads that detached from the conduit, forming free vortex rings. A second-generation head would then develop at the point of detachment. The detachment process for plumes was sensitively dependent on small fluctuations in their initial formation. In some cases, head detachment could occur multiple times for a single experimental run, thereby producing several generations of autocatalytic vortex rings. Head detachment was reproduced and studied using autocatalytic plume simulations. Autocatalytic flame balls, a phenomenon closely related to autocatalytic plumes, were also simulated. Flame balls were found to have three dynamical regimes. Below a critical radius, the smallest flame balls experienced front death. Above this radius, they formed elongating, reacting tails. The largest flame balls formed filamentary tails unable to sustain a reaction.

No description available.

Several scientific and technological advancements in radiation oncology have resulted in dramatic improvements in dose conformity and delivery to the target volumes using external beam radiation therapy (EBRT). However, radiation therapy acts as a double-edged sword leading to drastic side-effects, one of them being secondary malignant neoplasms in cancer survivors. The latency time for the occurrence of second cancers is around $10$-$20$ years. Therefore, it is very important to evaluate the risks associated with various types of clinically relevant radiation treatment protocols, to minimize the second cancer risks to critical structures without impairing treatment to the primary tumor volume. A widely used biologically motivated model (known as the initiation-inactivation-proliferation model) with heterogeneous dose volume distributions of Hodgkin's lymphoma survivors is used to evaluate the excess relative risks (ERR). There has been a paradigm shift in radiation therapy from purely photon therapy to other particle therapies in cancer treatments. The extension of the model to include the dependence of linear energy transfer (LET) on the radio-biological parameters and mutation rate for charged particle therapy is discussed. Due to the increase in the use of combined modality regimens to treat several cancers, it is extremely important to evaluate the second cancer risks associated with these anti-cancer therapies. The extension of the model to include chemotherapy induced effects is also discussed. There have been several clinical studies on early and late relapses of cancerous tumors. A tumor control probability (TCP) model with recurrence dynamics in conjunction with the second cancer model is developed in order to enable design of efficient radiation regimens to increase the tumor control probability and relapse time, and at the same time decrease secondary cancer risks. Evolutionary dynamics has played an important role in modeling cancer progression of primary cancers. Spatial models of evolutionary dynamics are considered to be more appropriate to understand cancer progression for obvious reasons. In this context, a spatial evolutionary framework on lattices and unstructured meshes is developed to investigate the effect of cellular motility on the fixation probability. In the later part of this work, this model is extended to incorporate random fitness distributions into the lattices to explore the dynamics of invasion probability in the presence and absence of migration.

Platelet-derived growth factor D-chain (PDGF-D) is the newest member of the PDGF family of mitogens and chemo-attractants; it is expressed in a wide variety of cell types, including vascular smooth muscle cells (SMCs). The molecular mechanisms regulating PDGF-D transcription are unknown. Here I investigated the effects of angiotensin II (ATIl) and IL-1 beta on the transcription of PDGF-D and changes in vascular SMCs phenotype. Primer extension analysis mapped a single transcriptional start site to the ccAG CGC motif of PDGF-D promoter. Several potential transcription factor binding sites such as SpI, Ets-1, NF-??B, IRF-1, p53, Smad4 and AP1 were located in the proximal 1168bp of the PDGF-D promoter. ATII-inducible Ets-1 and PDGF-D gene expression is mediated via H202. IL-I beta supresses PDGF-D promoter activity, mRNA and protein expression in SMCs through NF-??B p65, IRF-1 and HDAC1, which form complex in the PDGF-D promoter. This study provides the first direct link between NF-KB and the PDGF-D promoter, IRF-1 with any member of the PDGF family and a new example of HDAC mediated inhibition of gene expression. In summary, this study investigates for the first time the mechanisms mediating the transcriptional regulation of PDGF-D in vascular SMCs. This provides valuable insights into the molecular control of vascular phenotype, and opens up potential opportunities for therapeutic intervention.