In this thesis, a model of tissue oxygenation is presented, that takes into account the heterogeneous nature of tumor vasculature. Even though the model is rather simple, the resulting oxygen distributions agree very well with clinically observed oxygen distributions for most tumors and healthy normal tissues. The model shows that the vascular density may not describe the oxygenation of a tissue sufficiently well, unless the heterogeneity of the vascular system is taken into account. Based on the oxygen distributions from the tissue model, the associated radiation response at low and high doses can be determined. The radiation response of heterogeneous tumors should preferably be described by two clonogen compartments, one resistant and one sensitive, dominating the response at high and low radiation doses, respectively. Furthermore, each compartment should be characterized by the effective radiation resistance and the effective clonogen number. The resistant-sensitive model of radiation response has been analyzed in great detail. It accurately describes the response of severely heterogeneous tumors, both at low and high doses and LET values. The effective response parameters are given as integrals, averaged over the whole spectrum of radiation resistance. The parameters can also be determined from clinically established dose-response relations. The main properties of the dose-response relation for a generally heterogeneous tumor is described in some detail. The normalized dose-response gradient has been generalized to take heterogeneities in both dose delivery and radiation response into account. This quantity is important for accurate treatment plan optimization using intensity modulated radiation therapy for individual patients.

The International Organization for Standardization (ISO) provides no vibration-based sound power measurement standard that provides Precision (Grade 1) results. Current standards that provide Precision (Grade 1) results require known acoustic environments or complex setups. This thesis details the Vibration Based Radiation Mode (VBRM) method as one approach that could potentially be used to develop a Precision (Grade 1) standard. The VBRM method uses measured surface velocities of a structure and combines them with the radiation resistance matrix to calculate sound power. In this thesis the VBRM method is used to measure the sound power of a single-plate and multiple plate system. The results are compared to sound power measurements using ISO 3741 and good alignment between the 200 Hz and 4 kHz one-third octave band is shown. It also shows that in the case of two plates separated by a distance and driven with uncorrelated sources, the contribution to sound power of each individual plate can be calculated while they are simultaneously excited. The VBRM method is then extended to account for acoustically radiating cylindrical geometries. The mathematical formulations of the radiation resistance matrix and the accompanying acoustic radiation modes of a baffled cylinder are developed. Numberical sound power calculations using the VBRM method and a boundary element method (BEM) are compared and show good alignment. Experimental surface velocity measurements of a cylinder are taken using a scanning laser Doppler vibrometer (SLDV) and the VBRM method is used to calculate the sound power of a cylinder experimentally. The results are compared to sound power measurements taken using ISO 3741.

In search of new biomarkers suitable for the diagnosis and treatment of prostate cancer, genome-wide transcriptome sequencing was carried out with tissue specimens from 40 prostate cancer (PCa) and 8 benign prostate hyperplasia patients. We identified two intergenic long non-coding transcripts, located in close genomic proximity, which are highly expressed in PCa. Microarray studies on a larger cohort comprising 155 patients showed a profound diagnostic potential of these transcripts (AUC~0.94), which we designated as tumor associated prostate cancer increased lncRNA (TAPIR-1 and -2). To test their therapeutic potential, knockdown experiments with siRNA were carried out. The knockdown caused an increase in the p53/TP53 tumor suppressor protein level followed by downregulation of a large number of cell cycle- and DNA-damage repair key regulators. Furthermore, in radiation therapy resistant tumor cells, the knockdown leads to a renewed sensitization of these cells to radiation treatment. Accordingly, in a preclinical PCa xenograft model in mice, the systemic application of nanoparticles loaded with siRNA targeting TAPIR-1 significantly reduced tumor growth. These findings point to a crucial role of TAPIR-1 and -2 in PCa.

<p>Recent studies have implicated that a small sub population of cells within a tumour, termed cancer stem cells (CSCs), have an enhanced capacity for tumour formation in multiple cancers and may be responsible for recurrence of the disease after treatment. Further work has suggest that CSCs are radioresistant relative to other cell types composing tumours, in several solid cancers. The genetic and phenotypic heterogeneity of malignant CSCs, as well as the difficulty associated with culturing these cells in vitro, limits the capacity to study the response of CSCs to ionizing radiation. Further, the absence of normal known counterparts for many CSCs has made it difficult to compare the radiation responses of CSCs with the normal stem cells required for post radiotherapy tissue regeneration. Here we have shown that transformed human embryonic stem cells (t-hESCs), showing features of neoplastic progression, produce tumours resistant to radiation relative to their normal counterpart. We further show that t-hESCs have a reduced capacity for radiation induced cell death via apoptosis and exhibit altered cell cycle arrest in vitro, relative to hESCs. We found that decreased levels of p53ser15, following DNA double strand break induction, is associated with this radiation resistance.</p> / Master of Science (MSc)

Ce travail de thèse s’inscrit dans la caractérisation des cellules radiorésistantes des cancers du sein, à l’origine des rechutes après traitement par radiothérapie. La théorie des « Cellules Souches Cancéreuses » (CSC) place une sous-population cellulaire présentant une capacité accrue à induire des tumeurs et à proliférer au centre de la résistance à l’irradiation. Au cours de ce travail, nous avons montré que seul le marqueur de CSC CD24-/low permettait de définir une sous population radiorésistante, capable de transmettre une « mémoire » de l’irradiation se traduisant par une instabilité génétique persistante dans la descendance des cellules irradiées. En outre, nous avons montré que CD24 n’est pas uniquement un marqueur, mais bien un acteur de la réponse à l’irradiation. Ainsi, CD24 contrôle la prolifération cellulaire in vitro et in vivo, ainsi que les niveaux de ROS avant et après irradiation. L’ensemble de ces propriétés aboutit à une sensibilité réduite des cellules CD24-/low à l’irradiation γ, ainsi qu’à une baisse de l’instabilité génétique. Ces résultats permettent pour la première fois d’attribuer un rôle aux CSC CD24-/low dans la transmission de l’instabilité chromosomique. De plus, en apportant des informations pour évaluer la radiorésistance intrinsèque des tumeurs mammaires, le marquage CD24 pourrait contribuer à l’amélioration des protocoles de radiothérapie. / This work focuses on the characterization of radiation-resistant breast cancer cells, responsible for relapse after radiotherapy. The “Cancer Stem Cells” (CSC) theory describes a radiation-resistant cellular sub-population, with enhanced capacity to induce tumors and proliferate. In this work, we show that only the CSC marker CD24-/low defines a radiation resistant cell population, able to transmit the “memory” of irradiation, expressed as long term genomic instability in the progeny of irradiated cells. We show that CD24 is not only a marker, but is an actor of radiation-response. So, CD24 expression controls cell proliferation in vitro and in vivo, and ROS level before and after irradiation. As a result, CD24-/low cells display enhanced radiation-resistance and genomic stability. For the first time, our results attribute a role to CD24-/low CSCs in the transmission of genomic instability. Moreover, by providing informations on tumor intrinsic radiation-sensitivity, CD24- marker could help to design new radiotherapy protocols.

This thesis focuses on identifying acoustic noise generating components in piezoelectric blowers through transverse velocity measurements and the development of a numerical fluid model. Piezoelectric ceramics have proven useful for many industries and areas of research involving: high precision actuators, noise control, ultrasonic devices, and many other areas. As of late, a unique adaptation of piezoelectric ceramics is surfacing in the area of pumping and cooling. Air pumps that use these ceramics replace the traditional electric motor, resulting in lower power consumption, less moving parts, constant pressure gradients, lower overall weight, and a low profile. The current drawback of this application is the acoustic radiation produced by the blowers. Since these blowers are new to market, little research or development has been done to characterize the noise emissions. This thesis studies the acoustic emissions from the front face of a Murata piezoelectric blower. Jet noise and structural vibrations are two acoustic sources of interest that are studied in this research. A Direct Numerical Simulation (DNS) of the fluid flow through a Murata blower is developed to better identify noise generating mechanisms. The model solutions predict trends in sound pressure levels (SPL) of the jet noise and volumetric flow rates. Both the SPL and flow rate are shown to be functions of critical geometrical dimensions within the flow path of a Murata blower. Important dimensional components are identified as well as non-influential ones. Design guidelines are given to reduce noise emission from the front side of a blower and increase the volumetric flow rate. The results of this research have a direct impact on the piezoelectric blower industry and future blower designs.