La mesure de temps de vol de photons et/ou de temps de propagation d’ondes RF et ultra large bande est devenue une technique essentielle et indispensable pour de nombreuses applications telles qu’en géolocalisation en intérieur, en détection LASER et en imagerie biomédicale, notamment en tomographie optique diffuse (TOD) avec des mesures dans le domaine temporel (DT). De telles mesures nécessitent des convertisseurs temps-numérique aptes à mesurer des intervalles de temps très courts avec grande précision, et ce, à des résolutions temporelles allant de quelques picosecondes à quelques dizaines de picosecondes. Les scanners TOD-DT ont généralement recours à des cartes électroniques de comptage de photons uniques intégrant essentiellement des convertisseurs temps-numérique hybrides (un mixte de circuits monolithiques et non-monolithiques). Dans le but de réduire le temps d’acquisition de ces appareils et d’augmenter leur précision, plusieurs mesures à différentes positions et longueurs d’ondes doivent pouvoir être effectuées en parallèle, ce qui exige plusieurs cartes de comptage de photons. L’implémentation de tels dispositifs en technologie CMOS apporte de multiples avantages particulièrement en termes de coût, d’intégration et de consommation de puissance. Cette thèse apporte une solution architecturale d’un convertisseur temps-numérique à 10-bits dédié aux applications de TOD-DT. Le convertisseur réalisé en technologie CMOS 0,13 μm d’IBM et occupant une surface en silicium de 1,83 x 2,23 mm[indice supérieur 2] incluant les plots de connexion, présente une résolution temporelle de 12 ps sur une fenêtre de 12 ns pour une consommation en courant de 4,8 mA. Les avantages de l’architecture proposée par rapport à d’autres réalisations rapportées dans la littérature résident dans son immunité face aux variations globales du procédé de fabrication, l’indépendance de la résolution temporelle vis-à-vis de la technologie ciblée et la faible gigue temporelle qu’il présente. Le circuit intégré réalisé trouvera plusieurs champs d’applications autres que la TOD notamment dans les tomographes d’émission par positrons, les boucles à verrouillage de phase numériques et dans les systèmes de télédétection et d’imagerie 3D.

Diffuse transfers of pesticides from agricultural land to ground and surface waters can lead to significant drinking water quality issues. This thesis describes the development and application of a parameter-efficient, numerical model to predict pesticide concentrations in raw water sources within an integrated hydrological framework. As such, it fills an unoccupied niche that exists in pesticide fate modelling for a computationally undemanding model that contains enough process complexity to be applicable in a wide range of catchments and hydrogeological settings in the UK and beyond. The model represents the key processes involved in pesticide fate (linear sorption and first-order degradation) and transport (surface runoff, lateral throughflow, drain flow, percolation to the unsaturated zone, calculated using a soil water balance) in the soil at a daily time step. Soil properties are derived from the national soil database for England and Wales and are used to define the boundary conditions at the interface between the subsoil and the unsaturated zone. This is the basis of the integrated hydrological framework which enables the application of the model to both surface water catchments and groundwater resources. The unsaturated zone model accounts for solute transport through two flow domains (accounting for fracture flow and intergranular matrix flow) in three hydrogeological settings (considering the presence and permeability of superficial deposits). The model was first applied to a small headwater sub-catchment in the upper Cherwell. Performance was good for drainflow predictions (Nash Sutcliffe Efficiency > 0.61) and performed better than the MACRO model and as well as the modified MACRO model. Surface water model performance was evaluated for eight pesticides in five different catchments. Performance was generally good for flow prediction (Nash Sutcliffe Efficiency > 0.59 and percentage bias below 10 %, in the validation period for all but two catchments). The 90th percentile measured concentration was captured by the model in 62 % of catchment-pesticide combinations. In theremaining cases predictions were within, at most, a factor of four of measured 90th percentile concentrations. The rank order of the frequency of pesticides detected over 0.1 μg L-1 was also predicted reasonably well (Spearman’s rank coefficient > 0.75; p < 0.05 in three catchments). Pesticide transport in the unsaturated zone model was explored at the point scale in three aquifers (chalk, limestone and sandstone). The results demonstrate that representing the unsaturated zone processes can have a major effect on the timing and magnitude of pesticide transfers to the water table. In comparison with the other catchment scale pesticide fate models that predict pesticide exposure at a daily time-step, the model developed stands out requiring only a small number of parameters for calibration and quick simulation times. The benefit of this is that the model can be used to predict pesticide exposure in multiple surface and groundwater resources relatively quickly which makes it a useful tool for water company risk assessment. The broad-scale approach to pesticide fate and transport modelling presented here can help to identify and prioritise pesticide monitoring strategies, to compare catchments in order to target catchment management and to highlight potential problems that could arise under different future scenarios.

Radio frequency (RF) lesioning and deep brain stimulation (DBS) are the two prevailing surgical treatments for movement disorders within the field of stereotactic and functional neurosurgery. For RF-lesioning, a small volume of brain tissue is coagulated and knowledge of the lesion size and growth is of great importance for the safety and outcome of the procedure. This thesis deals with adapting the laser Doppler perfusion monitoring (LDPM) technique for measurements in brain tissue during RF-lesioning. The relation between LDPM signal changes and developed lesion size was investigated. LDPM measurements were evaluated both in vitro (albumin protein solution) and in vivo in the porcine brain during RF-lesioning corresponding to a bilateral thalamotomy in man. The investigated signals from the LDPI measurements can be used for following the lesioning time course and to detect if a lesion was created, both in vitro and in the animal model. For the albumin model, both the total backscattered light intensity and the perfusion signal can be used as markers for estimating the final coagulation size, while in the animal model this conclusion was not statistical verified. Independent on surgical method, RF-lesioning or DBS, intracerebral guidance is an important aspect within stereotactic and functional neurosurgery. To increase the accuracy and precision of reaching the correct target, different methods for intracerebral guidance exist, such as microelectrode recording and impedance methods. In this thesis, the possibility of developing an optical intracerebral guidance method has been investigated. Diffuse reflectance spectroscopy served as technology and all measurements were performed stereotactically in both porcine and human brain. Measurements of white and gray matter showed large differences, with higher reflectivity for white brain matter, both in porcine and in human brain. For the human measurements during DBS-implants, large differences between white matter and functional targets were found. Additionally, differences between native and lesioned porcine brain matter were detected. Both studies support the idea of using diffuse reflectance spectroscopy for developing an intracerebral guidance method.

Assister les personnes âgées dans les situations d’urgence représente un facteur important qui pourrait augmenter le sentiment de sécurité chez cette population. Les risques et les situations d’urgence les plus fréquentes auxquelles les personnes âgées peuvent être confrontées sont la chute, l’errance et les crises de santé. Ces risques les affectent et augmentent chez eux la peur, ce qui les rend dépendantes. Face à ces risques, les personnes âgées ont besoin des outils d’assistance qui permettent de les protéger durant les activités quotidiennes. Aujourd’hui, le bénévolat joue un rôle important dans la chaîne des moyens d’assistance pour les personnes âgées. En plus, la technologie, et en particulier l'informatique diffuse et mobile, peut être utilisée pour réduire les impacts négatifs associés au vieillissement. Cette technologie peut également être utilisée pour faciliter le travail des bénévoles en le rendant plus efficace et moins contraignant. Le bénévolat dans sa forme actuelle exige une déclaration préalable de disponibilités des bénévoles (indication d’un lieu et d’horaires précis). Cette forme d’engagement exclut des bénévoles potentiels qui souhaiteraient s’investir dans des activités de bénévolat, mais qui ne connaissent pas leurs disponibilités à l’avance. Nous proposons dans ce mémoire un système pour aider les personnes âgées dans les situations d'urgence, que nous appelons Assist-Me. L’objectif du système Assist-Me est d'améliorer la qualité de vie et d’augmenter l'indépendance et l'autonomie des personnes âgées dans leurs activités quotidiennes, puisqu’il offre une assistance rapide dans les situations d'urgence via l'intervention offerte par des bénévoles, qui, par ailleurs, peuvent alléger l'intervention non nécessaire des centres d'urgence. Assist-Me est un système intelligent ayant deux applications sur les téléphones intelligents. Ces applications peuvent partager des informations indépendamment de l’emplacement physique: une application pour les personnes âgées qui demandent de l'assistance, et une deuxième pour les bénévoles qui reçoivent les demandes d’assistance. Un contrôle centralisé des informations est assuré via un système de gestion de la situation d'urgence. Ce système est muni d’un moteur de sélection basé sur la « logique floue » qui sélectionne automatiquement les bénévoles appropriées.

This thesis uses the results of analysis of data recorded at a solar monitoring station in West Texas and the knowledge from an existing solar radiation estimation model to develop a methodology to predict the energy output from a panel at a site using only partial radiation data - global horizontal radiation measurements. The prediction using partial data is validated against estimates acquired using the complete radiation data and constraints are defined for accurate prediction. The methodology presented in this thesis can be used to accurately predict the solar power/energy incident on a collector at any location possessing global horizontal radiation measurements. / text

Nous proposons un cadre générique, permettant l'incorporation des différentes lois de comportement de mécanique linéaires ou non-linéaires (i.e. elastoviscoplastique) dans les approches des champs de phases utilisées pour la modélisation et la simulation de la mobilité d'interfaces diffuses. Dans ce cadre, une formulation par éléments finis des modèles couplés champ de phases-élastoplasticité pour les alliages binaires est développée dans le formalisme général de la thermodynamique des milieux continus. Cette formulation est basée sur la théorie d'équilibre des microforces, proposée par Gurtin, où une équation supplémentaire, fonction du paramètre d'ordre et de son gradient, est introduite. La formulation est employée pour simuler les évolutions morphologiques complexes des microstructures hétérogènes et décrire l'interface diffuse entre deux phases en présence des contraintes induites par transformation de phase. En utilisant les principes de la thermodynamique des processus irréversibles, les lois de comportement et les équations d'évolution sont clairement exposées et séparées dans la formulation de sorte que des modèles non-linéaires et fortement couplés puissent être implantés plus facilement dans un code par éléments finis. Cette formulation peut être appliquée aux corps finis périodiques et non périodiques, aux microstructures hétérogènes. Les conditions initiales et les conditions aux limites en paramètre d'ordre et en concentration ainsi que leurs quantités duales sont clairement énoncées. Des techniques d'homogénéisation ont été utilisées pour décrire le comportement dans les interfaces diffuses. Les conséquences de ces choix de modélisation ont été déterminées en ce qui concerne les effets des contraintes mécaniques sur les équilibres de phases et la cinétique de transformation. L'ensemble des équations d'évolution couplées, à savoir l'équation d'équilibre statique local, l'équation de champ de phases et l'équation de conservation de la masse, est résolu en utilisant la méthode des éléments finis pour la discrétisation spatiale et un schéma implicite des différences finies pour la discrétisation temporelle. Afin d'illustrer l'intérêt de l'approche proposée, des calculs par éléments finis ont été effectués sur des situations élémentaires telles que le calcul des concentrations d'équilibre des phases en présence de contraintes et la croissance de précipités dans une matrice élastique ou élasto-plastique, situations pour lesquelles des solutions analytiques pour des interfaces parfaites sont disponibles.

La pollution diffuse provenant des milieux agricoles a une influence majeure sur la qualité de l’eau. Le transport de sédiments et de nutriments, tels que le phosphore et l’azote, est particulièrement préoccupant. Les changements climatiques anticipés modifieront le régime hydrologique des rivières, ce qui entraînera des conséquences difficiles à anticiper, notamment sur la qualité de l’eau. Le site à l’étude est le bassin versant de la rivière Tomifobia, situé au sud-ouest du Québec, qui possède une superficie de 436 km² et qui comporte une forte activité agricole. Il a un impact important sur la qualité de l’eau du lac Massawippi puisqu’il draine 70% de son bassin versant. Le modèle hydrologique spatialisé Soil and Water Assessment Tool (SWAT) a été utilisé pour effectuer l’évaluation quantitative et qualitative de l’apport en eau à la rivière. Les activités agricoles ont été représentées dans le modèle selon un calendrier typique pour chacune des différentes cultures. Le calage et la validation du modèle pour le débit de la rivière Tomifobia ont été effectués à l’aide de la reconstitution des apports au lac Massawippi. Pour la qualité de l’eau, les données provenant de l’Institut de recherche et de développement en agroenvironnement (IRDA), du Comité de gestion du bassin versant de la rivière Saint-François (COGESAF) et la campagne d’échantillonnage du Groupe de recherche sur l’eau de l’Université de Sherbrooke (GREAUS) ont été utilisées. Les éléments analysés par rapport à la qualité de l’eau sont les sédiments, le phosphore et les nitrates. Différentes projections climatiques ont été entrées dans le modèle dans le but de déterminer les tendances hydrologiques futures. L’impact des changements climatiques sur le régime hydrologique se traduit principalement par une augmentation des débits hivernaux et une diminution des débits printaniers. Aucune tendance statistiquement significative n’a été observée pour la période estivale et automnale. L’effet des changements climatiques sur les exportations de nitrates est similaire à celui sur le débit. Pour les exportations de sédiments et de phosphore, on note une hausse à l’hiver, une baisse au printemps et une hausse pour l’été et l’automne.

<p>Diffuse reflectance spectroscopy (DRS) is a simple, yet powerful technique that has the potential to offer practical, non-invasive, and cost effective information for op- tical diagnostics and therapeutics guidance. Any progress towards moving DRS systems from their current laboratory settings to clinical settings, field settings and ambitiously to home settings, is a significant contribution to society in terms of reducing ever growing healthcare expenditures of an aging society. Additionally, im- proving on the existing mathematical models used to analyze DRS signals; in terms of speed, robustness, accuracy, and capability in accounting for larger feature space dimensionality (i.e. extraction of more tissue-relevant information) is equally im- portant for real-time diagnosis in the desired settings and to enable use of DRS in as many biomedical applications (e.g. skin cancer diagnosis, diabetics care, tissue oxygenation monitoring) as possible. Improving the reflectance signal complexity and density through novel DRS instrumentation, would facilitate development of the desired models or put the existing ones built on simulations in practical use; which otherwise could not go beyond being a theoretical demonstration.</p><p>DRS studies tissue morphology and composition through quantification of one or more (ideally all of them) of the tissue- and wavelength-specific optical properties: absorption coefficient (μa), reduced scattering coefficient (μ1s), scattering anisotropy (g), tissue thickness, and scattering phase function details (e.g. higher order moments of the scattering phase function). DRS involves sampling of diffusely reflected photons which experience multiple scattering and absorption as they travel within the tissue, at the tissue surface. Spatially resolved diffuse reflectance spectroscopy (SRDRS) is a subset of general DRS technique, which involves sampling of diffuse reflectance signals at multiple distances to an illumination source. SRDRS provides additional spatial information about the photon path; yielding depth-resolved tissue information critical to layered tissue analysis and early cancer diagnostics. Exist- ing SRDRS systems use fiber optic probes, which are limited in accommodation of large number and high-density collection fibers (i.e. yielding more and dense spa- tially resolved diffuse reflectance (SRDR) measurement data) due to difficulty of fiber multiplexing. The circular shape of the fibers restricts the implementable probe ge- ometries and reduces the fill factor for a given source to detector (i.e. collection fiber) separation (SDS); resulting in reduced light collection efficiency. The finite fiber nu- merical aperture (NA) reduces the light collection efficiency well as; and prevents selective interrogation of superficial tissues where most cancers emerge. Addition- ally, SRDR systems using fiber optic probes for photon collection, require one or more photodetectors (i.e. a cooled CCD); which are often expensive components of the systems.</p><p>This thesis deals with development of an innovative silicon SRDRS probe, which partially addresses the challenge of realizing high measurement density, miniaturized, and inexpensive SRDRS systems. The probe is fabricated by conventional, flexible and inexpensive silicon fabrication technology, which demonstrates the feasibility of developing SRDRS probes in any desired geometry and complexity. Although this approach is simple and straightforward, it has been overlooked by the DRS community due to availability of the conventional fiber optic probe technology. This new probe accommodates large number and high density of detectors; and it is in the form of a concentric semi-annular photodiode (PD) array (CMPA) with a central illumination aperture. This is the first multiple source-detector spacing Si SRDRS probe reported to date, and the most densely packed SRDRS probe reported to date for all types of SRDRS systems. The closely spaced and densely packed detectors enable higher density SRDR measurements compared to fiber-based SRDR probes, and the higher PD NA compared to that of fibers results in a higher SNR increasing light collection efficiency. The higher NA of the PDs and the presence of PDs positioned at very short distances from the illumination aperture center enable superficial tissue analysis as well as depth analysis.</p> / Dissertation

<p>Worldwide, head and neck squamous cell cancers (HNSCC) account for over 375,000 deaths annually. The majority of these cancers arise in the outermost squamous cells which progress through a series of precancerous changes before developing into invasive HNSCC. It is widely accepted that prognosis is strongly correlated to the stage of diagnosis, with early detection more than doubling the patient’s chance of survival. Currently, however, 60% of HNSCCs are diagnosed when they have already progressed to stage 3 or stage 4 disease. The current diagnostic method of visual examination often fails to recognize early indicators of HNSCC, thereby missing an important prevention window.</p><p> </p><p>Determination of cancer from non-malignant tissues is dependent on pathological examination of lesion biopsies. Thus, all patients with any clinically suspicious lesions undergo surgical biopsies. Furthermore, these surgical biopsies carry risks. In addition to the risk of general anesthesia for patients undergoing panedoscopy, some patients have poor healing and develop ulcerations or infections as a result of surgical biopsy at any anatomical site. Additionally, studies have shown that approximately 50% of suspected biopsies are later pathologically confirmed normal. An enormous amount of labor, facility, and monetary resources are expended on non-malignant biopsies and patients who ultimately have no malignancy. It would be of immense overall benefit to clinicians and patients to have a non-invasive and portable technique that could rapidly identify those patients that would benefit from further surgical biopsy from those that only need follow-up clinical observations.</p><p> </p><p>Once carcinoma is confirmed in a patient, treatment currently involves modalities of surgery, radiation, and chemotherapy. Radiotherapy plays a significant role, particularly in the management of localized HNSCC, because it is a non-invasive and function-preserving modality. However, the effectiveness of radiotherapy is limited by hypoxia. Previous studies showed that tumors reoxygenated during radiotherapy treatment may have a better prognosis. Despite decades of work, there is still no reliable, cost-effective way for measuring tumor hypoxia over multiple time points to estimate the prognosis. </p><p>To address these unmet clinical needs, three aims were proposed. The first aim was to improve early detection by identifying biomarkers of early pre-cancer as well as developing an objective algorithm to detect early disease. Neovasculature is an important biomarker for early cancer diagnosis. Even before the development of a clinically detectable lesion, the tumor vasculature undergoes structural and morphological changes in response to oncogenic signaling pathways [8]. Without receiving a sufficient supply of oxygen and nutrients to proliferate, early tumor growth is limited to only 1-2 mm. High-resolution optical imaging is well suited to characterize the earliest neovascularization changes that accompany neoplasia owing to its sensitivity to hemoglobin absorption and resolution to visualize capillary level architecture. Dark field microscopy is a low-cost and robust method to image the neovasculature. We imaged neovascularization in vivo in a spontaneous hamster oral mucosa carcinogen model using a label-free, reflected-light spectral dark field microscope. Hamsters’ cheek pouches were painted with 7, 12-Dimethylbenz[a]anthracene (DMBA) to induce precancerous to cancerous changes, or mineral oil as control. Spectral dark field images were obtained during carcinogenesis and in control oral mucosa, and quantitative vascular features were computed. Vascular tortuosity increased significantly in oral mucosa diagnosed as hyperplasia, dysplasia and squamous cell carcinoma (SCC) compared to normal. Vascular diameter and area fraction decreased significantly in dysplasia and SCC compared to normal. The areas under the receiver operative characteristic (ROC) curves (AUC) computed using a Support Vector Machine (SVM) were 0.95 and 0.84 for identifying SCC or dysplasia, respectively, vs. normal and hyperplasia oral mucosa combined. To improve AUCs for identifying dysplasia, quantitative vascular features were computed again after the vessels were split into large and small vessels based on diameter. The large vessels preserved the same significant trends, while small vessels demonstrated the opposite trends. Significant increases in diameter and decreases in area fraction were observed in SCC and dysplasia. The AUCs were improved to 0.99 and 0.92 for identifying SCC and dysplasia. These results suggest that dark field vascular imaging is a promising tool for pre-cancer detection.</p><p>Optical imaging can also be applied to quantifying other important characteristics of solid tumors in head and neck cancer (HNC), such as hypoxia, abnormal vascularity and cell proliferation. Diffuse reflectance spectroscopy is a simple and robust method to measure tissue oxygenation, vascularity and cell density. It is particularly suitable for applications in the operation room because of its compact design and portability. In addition, a fiber probe-based system is ideal for obtaining measurements at suspicious lesions in the head and neck area during surgery. Thus, my second aim was to reduce the number of unnecessary HNSCC biopsies by developing a robust tool and rapid analysis method appropriate for clinical settings. We propose the use of morphological optical biomarkers for rapid detection of human HNSCC by leveraging the underlying tissue characteristics in the aerodigestive tracts Prior to biopsy, diffuse reflectance spectra were obtained from malignant and contra-lateral non-malignant tissues of 57 patients undergoing panendoscopy. Oxygen saturation (SO2), total hemoglobin concentration ([THb]), and the reduced scattering coefficient were extracted using an inverse Monte Carlo (MC) method previously developed by former student in our lab. Differences in malignant and non-malignant tissues were examined based on two different groupings: by anatomical site and by morphological tissue type. Measurements were acquired from 252 sites, 51 of which were pathologically classified as SCC. Optical biomarkers exhibited statistical differences between malignant and non-malignant samples. Contrast was enhanced when parsing tissues by morphological classification rather than by anatomical subtype for unpaired comparisons. Corresponding linear discriminant models using multiple optical biomarkers showed improved predictive ability when accounting for morphological classification, particularly in node-positive lesions. The false-positive rate was retrospectively found to decrease by 34.2% in morphologically- vs. anatomically-derived predictive models. In glottic tissue, the surgeon exhibited a false-positive rate of 45.7% while the device showed a lower false-positive rate of only 12.4%. Additionally, comparisons of optical parameters were made to further understand the physiology of tumor staging and potential causes of high surgeon false-positive rates. Optical spectroscopy is a user-friendly, non-invasive tool capable of providing quantitative information to discriminate malignant from non-malignant head and neck tissues. Predictive models demonstrated promising results for diagnostics. Furthermore, the strategy described appears to be well suited to reduce the clinical false-positive rate.</p><p>To further improve the speed for extracting the tissue oxygenation and [THb] to reduce the time when patients were under anesthesia, the third aim was to develop a rapid heuristic ratiometric analysis for estimating tissue [THb] and SO2 from measured tissue diffuse reflectance spectra. The analysis was validated in tissue-mimicking phantoms and applied to clinical measurements in head and neck, cervical and breast tissues. The analysis works in two steps. First, a linear equation that translates the ratio of the diffuse reflectance spectra at 584 nm to 545 nm to estimate the tissue [THb] using a Monte carlo (MC)-based lookup table was developed. This equation is independent of tissue scattering and oxygen saturation. Second, SO2 was estimated using non-linear logistic equations that translate the ratio of the diffuse reflectance spectra at 539 nm to 545 nm into the tissue SO2. Correlations coefficients of 0.89 (0.86), 0.77 (0.71) and 0.69 (0.43) were obtained for the tissue hemoglobin concentration (oxygen saturation) values extracted using the full spectral MC and the ratiometric analysis, for clinical measurements in head and neck, breast and cervical tissues, respectively. The ratiometric analysis was more than 4000 times faster than the inverse MC analysis for estimating tissue [THb] and SO2 in simulated phantom experiments. In addition, the discriminatory power of the two analyses was similar. These results show the potential of such empirical tools to rapidly estimate tissue hemoglobin and oxygenation for real-time applications.</p><p>In addition to its use as a diagnostic marker for various cancers, tissue oxygenation is believed to play a role in the success of cancer therapies, particularly radiotherapy. However, since little effort has been made to develop tools to exploit this relationship, the fourth aim was to estimate patient prognosis by measuring tumor hypoxia over multiple time points so physicians are able to develop more informed and effective clinical treatment plan. To test if oxygenation kinetics correlates with the likelihood for local tumor control following fractionated radiotherapy, we again used diffuse reflectance spectroscopy to noninvasively measure tumor vascular oxygenation and [THb] associated with radiotherapy of 5 daily fractions (7.5, 9 or 13.5 Gy/day) in FaDu xenografts. Spectroscopy measurements were obtained immediately before each daily radiation fraction and during the week after radiotherapy. SO2 and [THb] were computed using an inverse MC model. Oxygenation kinetics during and after radiotherapy, but before a change in tumor volume, was associated with local tumor control. Locally controlled tumors exhibited significantly faster increases in oxygenation after radiotherapy (days 12-15) compared with tumors that recurred locally. (2) Within the group of tumors that recurred, faster increases in oxygenation during radiotherapy (days 3-5) were correlated with earlier recurrence times. An AUC of 0.74 was achieved when classifying the local control tumors from all irradiated tumors using the oxygen kinetics with a logistic regression model. (3) The rate of increase in oxygenation was radiation dose dependent. Radiation doses ≤9.5 Gy/day did not initiate an increase in oxygenation whereas 13.5 Gy/day triggered significant increases in oxygenation during and after radiotherapy. Additional confirmation is required in other tumor models, but these results suggest that monitoring tumor oxygenation kinetics could aid in the prediction of local tumor control after radiotherapy.</p><p>Angiogenesis is a highly regulated process to support tissue growth. Neovasculature is designed by nature to grow toward areas lacking nutrition and oxygen. Cancer cells proliferate too quickly to have their nutritional and oxygen needs completely satisfied, which results in an imbalanced state of angiogenesis leading to tortuous blood vessels, hypoxic tissues and radioresistance. We characterized the tumor-induced vascular features with simple, robust and low-cost dark field microscopy and spectroscopy to enable early cancer diagnosis, improvement of surgical biopsy accuracy and better predict the prognosis of radiotherapy for HNC. Our results demonstrated that these noninvasively measured, label-free vascular features are able to detect pre-cancer, reduce unnecessary surgical biopsies and predict prognosis of radiotherapy.</p> / Dissertation

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma (NHL). The current standard of care is the combination of rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), but this only results in a 60% over-all 5-year survival rate, thus highlighting a need for new therapeutic approaches. Histone deacetylase inhibitors (HDACi) are novel therapeutics that is being clinically evaluated for combination therapy. Rational selection of companion therapeutics for HDACi is difficult due to their poorly understood, cell-type specific mechanisms of action. To understand these mechanisms better, we developed a pre-clinical model system of response to the HDACi belinostat. Using this model system, we identified two major responses. Resistance, consisting of a reversible G1 cell cycle arrest with little induction of apoptosis; or sensitivity, consisting of mitotic arrest and high levels of apoptosis. In this dissertation, we determine that the induction of G1 cell cycle arrest is due to the increased expression of cyclin dependent kinase inhibitors (CDKi) that bind to and inhibit the cyclin E/CDK2 complex thereby blocking the final repressive phosphorylation steps of Rb protein. Repression of transcriptional elongation blocked CDKi upregulation and prevented G1 cell cycle arrest in belinostat-resistant cells. Additionally, we identified that belinostat arrests sensitive cells prior to metaphase and belinostat-resistant cells slow-down in mitosis but complete the process prior to arresting in G1. The combination of belinostat with the microtubule-targeting agent, vincristine resulted in strong synergistic induction of apoptosis by targeting mitotic progression. Furthermore, this combination prevents polyploidy, a key mechanism of resistance to microtubule targeting agents. Finally, we utilized selective class one HDAC inhibitors to identify the individual contributions of HDACs in the eliciting the responses observed with belinostat treatment. HDAC1&2 inhibition recapitulated the belinostat-resistant phenotype of G1 cell cycle arrest with little apoptosis, in both belinostat-resistant and sensitive cell lines. HDAC3 inhibition resulted in the induction of DNA damage, increased S phase and the induction of apoptosis in belinostat-resistant cells. Belinostat-resistant cells did not have observable effects to HDAC3 inhibitor alone but when combined with vincristine had significantly increased G2/M population at early time points. This suggests that HDAC3 maintains roles in DNA replication and also in mitotic progression. HDAC3 inhibition combined with vincristine resulted in a significant increase in polyploidy, suggesting that HDAC3 might not regulate the expression of apoptotic regulating factors as belinostat does.