Cette thèse présente le développement d'un système de contrôle en temps réel basé sur un détecteur en diamant pour la nouvelle source de rayons gamma en cours de construction à Magurele, en Roumanie, pour le projet Extreme Light Infrastructure (ELI). La machine comprend un accélérateur linéaire d'électrons qui se sépare en deux lignes, une à basse énergie entre 80 et 320 MeV et l'autre à plus haute énergie pouvant atteindre 720 MeV. Sur les deux lignes, un recirculateur optique guide un laser haute puissance pour entrer en collision avec 32 paquets d'électrons afin de produire des rayons gamma par interaction Compton inverse. Cette machine est construite par le consortium européen EuroGammaS, dont le Laboratoire de l'Accélérateur Linéaire fait partie et qui a pour mission de développer la plupart des composants optiques. C'est aussi là où j'ai préparé le travail présenté dans ce manuscrit. Les paquets d'électrons séparés de 16 ns collisionneront avec une impulsion laser à une fréquence de 100 Hz. Pour s'assurer de la qualité et de la stabilité de ces interactions, le système du détecteur diamant a été mis en place. Cela a impliqué du travail de simulation sous GEANT4 ainsi que des expériences pour tester l'équipement à HiGS aux Etats-Unis et à newSubaru au Japon, deux établissements scientifiques qui proposent aussi des sources de rayons gamma produits par interaction Compton inverse. Les résultats obtenus démontrent l'efficacité de ce système en analysant l'efficacité de détection, la charge collectée ou encore la forme de faisceau. Ceci est encourageant en vue de l'installation et du commissioning qui sont attendus pour 2019. / This thesis discusses the development of a real-time monitoring system based on a diamond detector for the new gamma source being built in Magurele, Romania as part of the Extreme Light Infrastructure (ELI) project. The machine consists of an electron linear accelerator that branches into two lines, one at low energy between 80 and 320 MeV and one at higher energy going up to 720 MeV. On both lines, an optical recirculator leads a high power laser to collide with 32 electrons bunches to produce gamma rays by inverse Compton interaction. This machine is built by a European consortium named EuroGammaS, of which the "Laboratoire de l'Accélérateur Linéaire" is a member and tasked with developing most of the optical components. This is where I prepared the work presented in this manuscript. The electron bunches separated by 16 ns will collide with a circulating laser pulse at a rate of 100 Hz. To monitor the quality and stability of these interactions, the diamond detector system has been set-up. This involved simulation work on GEANT4 as well as two experiments to test the equipment at HiGS in the USA and newSubaru in Japan, two facilities that also offer gamma ray beams produced by inverse Compton scattering. The results obtained demonstrate the effectiveness of the system by analysing detection efficiency, charge collected or beam shape. This is promising in anticipation of the installation and commissioning expected for 2019.

L'analyse isotopique des actinides est nécessaire pour le pilotage du cycle du combustible, le contrôle du traité de non-prolifération ou pour la surveillance environnementale. La précision de ces analyses peut être limitée par la performance du détecteur utilisé mais aussi par les incertitudes associées aux intensités d’émission disponibles dans les tables de données nucléaires. La désintégration des actinides est généralement suivie par d’intenses émissions de photons X et gamma dans la gamme d’énergie inférieure à 100 keV. Leur détection peut être intéressante pour l'analyse des actinides. Cependant, les techniques conventionnelles de mesure ne permettent pas de séparer correctement les raies des émissions concernées. Cette thèse a été consacrée à la mesure des intensités à l’aide d’un détecteur cryogénique. Ce dernier est basé sur un calorimètre métallique magnétique (MMC) qui permet de mesurer le dépôt d’énergie sous forme d’une élévation de température. Le MMC, appelé SMX3, comporte quatre pixels ; il est spécifiquement conçu pour la spectrométrie X et gamma de haute résolution dans la gamme d'énergie inférieure à 100 keV en vue de la mesure des intensités d’émission des actinides. Outre la haute résolution fournie par SMX3, due à son principe de fonctionnement, ce détecteur possède un rendement de détection constant et quasiment égal à 100% dans la gamme d'énergie inférieure à 25 keV, où les rayons XL des actinides sont émis. La courbe de rendement de SMX3 a été étalonnée par une méthode qui consiste en une mesure d’une seule source étalon d’Am-241 combinée à des simulations Monte Carlo. Les trois actinides Pu-238, Pu-239, et Cm-244 ont été mesurés afin de fournir des intensités absolues et relatives des émissions Li-Yj (avec Y=L,M,N,O,P i=1,2,3 et j=1..7). Grâce à la très haute résolution en énergie du MMC, les raies XL individuelles des actinides peuvent être séparées. Les raies satellites sont aussi détectées, leurs intensités relatives aux raies diagrammes dépendent de l’isotope en fonction des paramètres fondamentaux atomiques. Les intensités des raies XL individuelles ont pu être déterminées pour la première fois, notamment pour les transitions L₁-L₃. De plus, les intensités des régions XLi (i=1,2,3) ont été établies. Les intensités des groupes XL et XL globale sont comparées avec les calculs et les données expérimentales disponibles dans la littérature. / Isotopic analysis of actinides is necessary for fuel cycle management, non-proliferation treaty control or environmental monitoring. The accuracy of these analyses may be limited by the performance of the detector used but also by the uncertainties associated with the emission intensities available in the nuclear data tables. The disintegration of actinides is generally followed by intense X-ray and gamma photon emissions in the energy range below 100 keV. Their detection may be of particular interest for actinide analysis. However, conventional measurement techniques do not allow to properly separate the lines of the considered emissions. This thesis was devoted to the measurement of intensities using a cryogenic detector. The latter is based on a magnetic metallic calorimeter (MMC) that measures energy deposition as a temperature rise. The MMC, called SMX3, has four pixels and is specifically designed for high resolution X-ray and gamma spectrometry in the energy range below 100 keV to measure actinide emission intensities. In addition to the high resolution provided by SMX3 through its operating principle, this detector has a constant detection efficiency and almost equal to 100% over the energy range below 25 keV, where actinides' XL rays are emitted.The SMX3 yield curve was calibrated by a method that consists of a single standard source measurement of Am-241 combined with Monte Carlo simulations. The three actinides Pu-238, Pu-239, and Cm-244 were measured to provide absolute and relative intensities of Li-Yj emissions (with Y=L,M,N,O,P i=1,2,3 and j=1..7). Thanks to the very high energy resolution of the MMC, the individual XL lines of actinides can be separated. Satellite lines are also detected, their intensities relative to the diagram lines depend on the isotope according to the fundamental atomic parameters. The intensities of the individual XL lines could be determined for the first time, especially for the transitions L₁-L₃. In addition, the intensities of the XLi regions (i=1,2,3) were established. The intensities of the overall XL and XL groups are compared with the calculations and experimental data available in the literature.

La radiothérapie basée sur l'utilisation des photons de haute énergie (rayons X) est l'approche la plus courante dans le traitement du cancer. Toutefois, elle est limitée par la tolérance des tissus sains. Par conséquent, il est d'un intérêt majeur de développer de nouvelles techniques et protocoles pour améliorer le ciblage dans les tumeurs. Dans cette perspective, la hadronthérapie (irradiation de la tumeur par des protons ou des ions carbone) est considérée comme l'une des techniques les plus prometteuses car le dépôt d'énergie est maximum en fin de parcours, ce qui permet de cibler la tumeur. Pourtant, l’utilisation de cette modalité reste limitée du fait de la dose reçue par les tissus sains situés à l'entrée du faisceau.Pour améliorer les performances des thérapies par radiation, une nouvelle stratégie basée sur la combinaison de nanoparticules métalliques (nano-médecine) avec des rayonnements ionisants a été développée par le groupe. En effet, les nanoparticules ont une chimie de surface remarquable qui permet de les fonctionnaliser avec des ligands qui les rendent plus futiles et moins reconnus des macrophages afin de les concentrer dans les tumeurs.Le but de mon travail a été de développer des nanoparticules à base de platine (NPs de platine pelylée et des nanoparticules bimétalliques) visant à améliorer l’effet des rayonnements ionisants (photons et ions carbone) dans les cellules.Une méthode originale de synthèse en une seule étape combinant la radiolyse et la PEGylation in situ a été optimisée. Cette méthode a permis d’obtenir des NPs stables, de taille homogène (cœur métallique proche de 3 nm).L'impact biologique de ces nouvelles NPs a été évalué sur deux lignées de cellules cancéreuses humaines. Il a été observé que les NPs, non-toxiques, ont un mode d’internalisation qui dépend de la lignée cellulaire. Celles-ci sont, dans tous les cas, localisées exclusivement dans le cytoplasme. Les NPs de platine développées dans ce travail permettent d’amplifier significativement la destruction des cellules cancéreuses, en particulier lorsqu’un faisceau médical d’ions carbone est utilisé comme rayonnement. Les mécanismes moléculaires à l’origine de cet effet ont été étudiés grâce à l’utilisation d’une nanosonde biologique. Ces expériences ont montré que les NPs sont responsables de l’augmentation de dommages nanométriques, qui peuvent être létaux pour les cellules. Cet effet est attribué à des processus électroniques d’activation et de reneutralisation de la NP qui engendre une forte perturbation dans le volume nanométrique qui l’entoure tel que la production groupée de radicaux fortement réactifs et toxiques.En conclusion, ce travail à l’interface de la physique, chimie et biologie montre les capacités des NPs à base de platine à améliorer l’éradication par radiation des cellules cancéreuses. / Radiotherapy based on the use of high energy photons (X-rays) is the most common approach in cancer treatment. However, its implementation is limited by the tolerance of healthy tissue. Therefore, it is of major interest the development of new techniques and protocols to improve the selectivity of radiation effects within the tumor. In this perspective, the hadrontherapy (tumor irradiation by protons or carbon ions) is considered as one of the most promising techniques due to the energy deposition of ions in depth which is maximum at the end of the track. However, the use of this modality remains restricted by the lower but significant damage induced to the normal tissue located at the entrance of the ion beam.To improve the performance of radiation therapies, a new strategy based on the combination of metallic nanoparticles (nanomedicine) with ionizing radiations was studied. These treatments have been developed by the group. Indeed, the nanoparticles present a remarkable surface chemistry that allows their functionalization with ligands which make them less recognized by macrophages allowing an important accumulation of these nano-agents selectively into the tumors.The goal of my work was thus to develop platinum based nanoparticles (mono- and bimetallic Pt NPs) to enhance the effect of radiations (photons and carbon ions) into the cells.A novel one-step method of synthesis combining radiolysis and in situ PEGylation has been optimized. This method enabled to obtain stable NPs with a uniform size (metallic core diameter close to 3 nm) and shape. The biological impact of these new Pt NPs was evaluated in two human cancer cell lines.It has been observed that non-toxic Pt NPs have an internalization pathway that strongly depends on the cell line. These are, in all cases, exclusively localized in the cytoplasm. The Pt NPs developed in this work significantly enhanced cancer cell killing, particularly when medical carbon ions are used to irradiate.The molecular mechanisms underlying this effect were investigated through the use of a bio-nanoprobe. These experiments showed that NPs are responsible for the increase of nanometric damage, lesions that can be lethal to cells. This effect is attributed to an electronic activation processes and to the reneutralisation of NPs, which generates a strong perturbation in the surrounding nanometer volume producing highly reactive and toxic free radical clusters.In conclusion, this work at the interface of physics, chemistry and biology shows the potential of platinum NPs to improve the eradication of cancer cells by radiation.

Blazars are active galactic nuclei characterized by ultra-luminous broad-band, non-thermal radio to gamma-ray continuum radiation, and by irregular, rapid flux variability across wavebands. They are divided into two subclasses: BL Lac objects and flat spectrum radio quasars (FSRQs). A primary method employed to probe our understanding of these objects is to study their spectral energy distributions (SEDs). Until recently, however, studies of blazar SEDs have been hindered by an insufficient number of simultaneous observations across the spectrum, a critical deficiency with such variable objects. In this thesis, I discuss the data accumulated by an international, long-term, 35-blazar monitoring program led by the Boston University blazar group. By systematically processing these data, I produce SEDs using measurements obtained on average within nine hours per epoch. Sufficient measurements exist within the data set to study the sources in differing states of activity. I propose a definition of quiescent and active states, and extract measurements for epochs during which the sources were either quiescent or active in the gamma-ray regime. For these epochs, I measure the spectral slopes and statistically analyze the relationships between slopes at the different frequency regimes. While the subclasses exhibit some distinct characteristics in the optical and gamma-ray indices when quiescent, these distinctions are significantly less pronounced when the objects are active. The spectral indices for the FSRQs steepen when active in the optical, flatten in the gamma-ray, and remain flat and stable in the X-ray. Generally, BL Lacs exhibit less pronounced changes between states than do the FSRQs.

In this project, different fission models in the nuclear reaction code TALYS have been compared to GEF version 2020/1.2. The data included in the comparison are mass yield distributions, average prompt neutron energies per fragment mass, and average multiplicities of both neutrons and γ-rays per fragment mass. The reaction studied in the first part of the project is 1 keV neutron-induced fission of 235U. In the second part of the study, a variety of different nuclei and different incident energies were included in comparisons, but a limitation was set to only include neutron-induced fission. The results from the comparison suggested that TALYS fymodel 2 and 3 were less consistent with GEF than fymodel 4. For the comparisons with experimental data, fymodel 4 also performed better overall. TALYS fymodel 2 and 3 make use of implemented partial versions of GEF to produce fission fragment distributions, while fymodel 4 takes fission fragment distribution data from separate yieldfiles. A database of these yieldfiles with 737 different nuclei and 10 energy levels was produced, to be implemented in future versions of TALYS. The energy levels were chosen to get a range of energies that can be accurately interpolated between. This method of using TALYS fymodel 4 with a yieldfile from GEF consistently showed a strong agreement with GEF version 2020/1.2 for the mass yield distributions and the neutron multiplicities. The γ-ray multiplicities and the neutron energies show a slightly weaker agreement, and TALYS gives consistently smaller values than GEF for these quantities.

The quasar 3C 279 was the target of an extensive multiwavelength monitoring campaign from 2006 January through April. An optical-IR-radio monitoring campaign by the Whole Earth Blazar Telescope (WEBT) collaboration was organized around target-of-opportunity X-ray and soft γ-ray observations with Chandra and INTEGRAL in 2006 mid-January, with additional X-ray coverage by RXTE and Swift XRT. In this paper we focus on the results of the WEBT campaign. The source exhibited substantial variability of optical flux and spectral shape, with a characteristic timescale of a few days. The variability patterns throughout the optical BVRI bands were very closely correlated with each other, while there was no obvious correlation between the optical and radio variability. After the ToO trigger, the optical flux underwent a remarkably clean quasi-exponential decay by about 1 mag, with a decay timescale of T d ∼ 12.8 days. In intriguing contrast to other (in particular, BL Lac type) blazars, we find a lag of shorter wavelength behind longer wavelength variability throughout the RVB wavelength ranges, with a time delay increasing with increasing frequency. Spectral hardening during flares appears delayed with respect to a rising optical flux. This, in combination with the very steep IR-optical continuum spectral index of α0 ∼ 1.5-2.0, may indicate a highly oblique magnetic field configuration near the base of the jet, leading to inefficient particle acceleration and a very steep electron injection spectrum. An alternative explanation through a slow (timescale of several days) acceleration mechanism would require an unusually low magnetic field of B ≲ 0.2 G, about an order of magnitude lower than inferred from previous analyses of simultaneous SEDs of 3C 279 and other flat-spectrum radio quasars with similar properties.

No description available.

<p>This thesis describes the development of a method to measure <em>in vivo</em> gadolinium (Gd) content by prompt gamma neutron activation analysis (PGNAA). PGNAA is a quantitative measurement technique that is completely non-invasive. Gadolinium has the highest thermal neutron capture cross section of all the stable elements. Gadolinium-based contrast agents are widely used in magnetic resonance imaging (MRI). The primary intention of this work is to quantify <em>in vivo</em> Gd retention to investigate the potential toxicity of these agents. This study involves the optimization of the McMaster University ²³⁸Pu/Be PGNAA facility for Gd measurements. Monte Carlo simulations were performed in parallel with the experimental work using MCNP version 5. Excellent agreement has been demonstrated between the Monte Carlo model of the system and the experimental measurements (both sensitivity and dosimetry). The initial study on the sensitivity of Gd demonstrated the feasibility of the measurement system. The Monte Carlo dosimetry simulations and experimental survey measurements demonstrated consistently that the radiation exposures for a single measurement were quite low, with an effective dose rate of 1.1 µSv/hr for a leg muscle measurement, 74 µSv/hr for a kidney measurement, and 48 µSv/hr for a liver measurement. The initial studies confirmed the Gd measurement feasibility which ultimately led to an <em>in vivo</em> pilot study on 10 healthy volunteers. The pilot study was successful with 9 out of 10 volunteers having measureable Gd in muscle above the <em>in vivo</em> detection limit of 0.58 ppm within 1 hour of administration, and the remaining participant had detectable Gd 196 minutes post administration. The concentrations measured ranged from 6.9 to 56 uncertainties different from zero. The system has been validated in humans and can now be used in future studies of short or long-term retention of Gd after contrast administration in at risk populations, such as those with reduced kidney function, patients with multiple exposures over the treatment period, and patients who are prescribed higher dosages. In addition, experiments and simulations were extended to another high neutron absorbing element, samarium (Sm).</p> / Doctor of Philosophy (PhD)

<p> It has been suggested that combination treatment of high dose rate (HDR) intraluminal brachytherapy and PDT (Photodynamic therapy) in non-small cell lung cancer (NSCLC) may improve the efficacy of treatment, reduce the toxicity and improve quality of life for patients. To provide a cellular basis for this approach we have examined the in vitro sensitivity of normal lung fibroblasts (MRC5) and four NSCLC cell lines (SKMES-1, A549, NCIH460 and NCIH23) following, UVC treatment, HDR radiation, HDR radiation with Photofrin alone, PDT and combined HDR radiation and PDT. Cell sensitivity was measured using clonogenic survival. HDR radiation was cobalt-60 gamma rays (1.5-1.9 Gy/min). For PDT treatment, cells were exposed to 2.5 J.lg/ml Photofrin for 18-24 h followed by light exposure (20mW/cm2). D37 values calculated from the survival curves indicated a 2-fold difference in sensitivity to UVC, 6-fold difference in HDR radiation sensitivity and an 8-fold difference in PDT sensitivity. All cell lines showed a similar Photofrin uptake per cell when measured by flow cytometry using 488nm excitation and 620-675 nm emission wavelengths. Photofrin alone at concentrations up to 10 J.lg/ml had no significant effect on the survival of the NSCLC cell lines, whereas 10 J.lg/ml ofPhotofrin alone reduced survival significantly in MRC5 cells. A radiosensitizing effect of Photofrin was detected in MRC5 and NCIH460 cells, but not in A549, SKMES-1 and NCI-H23 cells. For combined treatment cells were exposed to Photofrin and then either exposed to light and 15-30 minutes later exposed to HDR radiation or exposed to HDR radiation and 15-30 minutes later exposed to light. Results showed that although light followed by gamma rays resulted in a somewhat greater tumor cell kill compared to gamma rays followed by light this difference was not significant for any of the cell lines tested. However, this difference was significant when data for all NSCLC cell lines were pooled. The combined treatment with high dose rate HDR radiation and PDT was not significantly different from an additive effect of the individual treatment modalities for in vitro survival of 4 NSCLC cells. In contrast the combined treatment was less than additive for the MRCS cells suggesting that the combined treatment would have the potential advantage of doing less damage to the normal lung cells and suggests that equivalent tumour cell kill in vivo may be possible at reduced systemic effects to patients. In preliminary experiments we have started to examine the effects of Photofrin-mediated PDT on the extra cellular signal-activated protein kinase (ERK) signaling pathway in NSCLC cells. The use of multiple NSCLC cell lines allows for the possible identification of cell line specific changes involved in resistance to PDT and HDR radiation and this will be explored in future work. </p> / Thesis / Master of Science (MSc)

Photodynamic therapy (PDT) is a new form of cancer treatment that uses the localized delivery of light and a photosensitizing drug, which is selectively retained in tumor tissue, to cause photochemically induced cell death. Although PDT mediated by the sensitizer Photofrin (Ph-PDT) is currently in Phase III trials for a number of human cancers, the exact mechanism(s) involved in PDT induced cytotoxicity is not fully understood. Also, Photofrin has a number of drawbacks including extended cutaneous photosensitization and low absorption in the red region of the spectrum. This has lead to the search for improved sensitizers. In vitro, tumor cells resistant to PDT have been developed from PDT sensitive cell lines to examine the mechanism(s) of PDT action. In this work, the sensitivity of RIF-1 murine fibrosarcoma cells and RIF-1 derived Ph-PDT resistant RIF-8A cells was examined following several damaging agents including PDT mediated by the novel Ruthenium phthalocyanine photosensitizer JM2929 (JM2929-PDT), UV, gamma-radiation, and hyperthermia. Gamma-radiation sensitivity of two other RIF-1 derived Ph-PDT resistant variants, CPR-C1 and RIF-P16CL8, was also examined. RIF-8A cells showed cross resistance to UV but increased sensitivity to gamma-rays compared to RIF-1 cells. RIF-1 and RIF-8A cells showed similar sensitivity to JM2929-PDT and hyperthermia. It is possible that Ph-PDT induces a "UV -like" component of damage and/or there is some overlap in the pathways for the repair of UV and Ph-PDT induced damage, but not JM2929-PDT, hyperthermia, and ionizing radiation damage in RIF-1 and RIF-8A cells. A cross resistance to gamma-rays was observed for CPR-C1 but not RIF-P16CL8 cells. Since Ph-PDT resistant CPR-C1 cells, but not RIF-8A cells or RIF-P16CL8 cells, show a cross resistance to gamma radiation, these results suggest that the cellular changes required for RIF-8A, RIF-P16CL8, and CPR-C1 cells to become resistant to Ph-PDT are different. Survival of RIF-1 and RIF-8A cells following gamma-rays in the presence of either Photofrin or JM2929 was also examined. Results suggest sensitization of RIF-1 cells, but not RIF-8A cells, to gamma-radiation in the presence of Photofrin. Gamma-radiation in the presence of JM2929 had no sensitizing effects on the survival of RIF-1 and RIF-8A cells. DNA repair of a UV-damaged reporter gene was also examined in untreated as well as Ph-PDT, JM2929-PDT, UV, cisplatin, and hyperthermia pretreated RIF-1 and RIF-8A cells. Results suggest an increased repair of UV damaged DNA in untreated RIF-1 cells compared to untreated RIF-8A cells. Ph-PDT, JM2929-PDT, and UV pretreatments resulted in an increased reactivation of a UV damaged reporter gene in RIF-1 cells compared to RIF-8A cells. Enhanced reactivation of a UV damaged reporter gene was not observed in either RIF-1 or RIF-8A cells following cisplatin or hyperthermia pretreatment. Enhanced expression of an undamaged reporter gene was greater in RIF-8A cells compared to RIF-1 cells following Ph-PDT pretreatment, but similar to RIF-1 cells following pretreatment with all other agents. These results suggest that the relation between survival, DNA repair of an actively transcribed gene, and transcriptional enhancement of an actively transcribed gene, varies in RIF-1 and RIF-8A cells depending on the damaging agent used. However, decreased reactivation of a UV damaged reporter gene in RIF-8A cells may be related to Ph-PDT and UV resistance seen in RIF-8A cells. / Thesis / Master of Science (MSc)