O objetivo deste trabalho foi propor, caracterizar e avaliar, por meio de simulações computacionais, um sistema de detecção de um tomógrafo PET (Positron Emission Tomography) dedicado para pequenas regiões. Os principais fatores considerados para a modelagem do sistema foram: resolução energética, resolução espacial, sensibilidade de detecção e custo do sistema. O pacote GATE (Geant4 Application for Tomographic Emission), baseado no código de transporte de radiação Geant4, foi escolhido para as simulações. Como forma de acompanhar os avanços da tecnologia PET, o tomógrafo Q-PEM/DoPET, da Universidade de Pisa - Itália, foi simulado e um modelo óptico analítico foi proposto para comparação entre os resultados simulados e experimentais. Assim, a utilidade do modelo óptico foi demonstrada, pois o mesmo evita o tempo de computação excessivamente longo de uma simulação com os processos ópticos do GATE ativados. Foi feita a caracterização de um bloco detector que consiste de um cristal cintilador monolítico acoplado a uma matriz de fotodetectores, baseados na tecnologia das fotomultiplicadoras de silício. A posição da interação do fóton gama dentro do cristal foi determinada usando um método baseado na estimativa de parâmetros de um modelo que descreve a distribuição da intensidade dos sinais dos fótons ópticos coletados pela matriz de fotodetectores, de acordo com o local da interação. O método possui a capacidade de determinação da profundidade da interação dentro do cristal, o que diminui consideravelmente os erros de paralaxe. O bloco detector proposto também pode ter aplicação em outras áreas da física e afins que fazem uso da instrumentação nuclear e que necessitam de detectores sensíveis à posição. Foi proposto um sistema de detecção para um tomógrafo PET com aplicação na Mamografia por Emissão de Pósitrons - PEM (Positron Emission Mammography). O conceito proposto tem o potencial para aperfeiçoar a capacidade da tecnologia PET de visualizar, quantificar e caracterizar tumores de mama. O tomógrafo foi avaliado, onde os parâmetros de desempenho para uma fonte pontual de 22Na no centro do campo de visão e distância entre planos detectores de 10 cm foram: resolução energética em 511 keV de 12,1(3)%, resolução espacial 3D de 1;34(1) x 1;26(1) x 2;04(2)mm3 e sensibilidade de detecção de 8(1)%. Os resultados mostram que o conceito proposto possui desempenho compatível aos tomógrafos já existentes, além de ter um custo menor, por ser baseado em cristais cintiladores monolíticos. / The aim of this work was to propose, to characterize and to evaluate, by means of computational simulations, a detection system of a dedicated PET (Positron Emission Tomography) tomograph. The main factors considered for the system modeling were: energetic resolution, spatial resolution, detection sensitivity and system cost. The package GATE (Geant4 Application for Tomographic Emission), based on Geant4 radiation transport code, was chosen for the simulations. To follow the advances on PET technology, the Q-PEM/DoPET tomograph, from University of Pisa - Italy, was simulated and an analytical optical model was proposed for comparison between simulated and experimental results. Thus, the usefulness of the optical model was demonstrated, since it avoids the excessively long computation time when activating the optical processes in GATE. A block detector made of a monolithic scintillator crystal coupled to a photodetector array based on silicon photomultiplier technology was characterized. The interaction position of gamma radiation inside the crystal was determined using a method based on estimating parameters of a model which describes the signal distribution of the optical photons collected by the photodectetor array. The method has the ability of determining the depth of interaction inside the crystal, which decreases considerably parallax errors. The proposed block detector also can be used in other applications of nuclear instrumentation that require sensitive position detectors. A detection system of a PET tomograph was proposed to be applied in Positron Emission Mammography - PEM. The proposed design has the potential to improve the PET ability to visualize, quantify and characterize breast tumors. The tomograph performance was evaluated and the following parameters were obtained from an acquisition of a 22Na point source in the center of the field view and for a distance of 10 cm between the detector planes: energy resolution at 511 keV of 12,1(3)%, 3D spatial resolution of 1;34(1) x 1;26(1) x 2;04(2)mm3 and detection sensitivity of 8(1)%. The results show that the performance of the proposed design is similar to existing tomographs, in addition to have a lower cost due to the employment of monolithic crystals.

Les glioblastomes (GBMs) sont des tumeurs cérébrales au pronostic défavorable. La résistance aux thérapies actuelles et la rechute des GBMs pourraient être due à l'existence de cellules aux propriétés souches. L'objectif de ma thèse a été la caractérisation des cellules souches de GBMs (CSGs) isolées à partir de tumeurs. L'analyse du profil souche et de pluripotence des CSGs a montré qu'elles sont maintenues dans un état souche par SOX2 et que COL1A1 et IFITM1 peuvent être des cibles thérapeutiques potentielles. L'étude de la radiosensibilité des CSGs à travers l'analyse des courbes de clonogénicité a mis en évidence deux groupes dont un «atypique» pouvant être composé de sous-populations de cellules aux radiosensibilités différentes qu'il conviendra de caractériser. L'étude de la réparation a mis en évidence deux autres groupes dont un ayant un fort potentiel de réparation qui exprime plus fortement le gène RAD51 après irradiations. Le traitement par un inhibiteur spécifique de RAD51 ralentirait la capacité de réparation de ces cellules. Malgré cette hétérogénéité, l'inhibition de la voie Hedgehog (HH) par un vecteur glucuronylé de la cyclopamine, activé par le microenvironnement tumoral, inhibe la prolifération et l'auto-renouvellement des CSGs in vitro et ralentit la croissance tumorale in vivo. La voie HH semble être une cible thérapeutique intéressante commune à toutes les CSGs. Néanmoins, il est nécessaire de prendre en compte l'hétérogénéité dans les populations tumorales pour le développement de la médecine personnalisée. / Glioblastomas (GBMs) are brain tumors with a poor prognosis. Their resistance to current therapies and the occurrence of tumor relapse may be related to the existence of cells bearing stem cell characteristics. The aim of this PhD research was to characterize glioblastoma stem cells (GSCs) having been isolated from tumors. Analysis of the stemness and pluripotency profiles of GSCs indicated that their stemness states are maintained by SOX2 and that COL1A1 and IFITM1 may be potential therapeutic targets. Clonogenic studies of GSC radiosensitivity underscored the presence of two groups, one of them composed of sub-populations of cells with different degrees of radiosensitivity that have yet to be fully characterized. Study of DNA repair capacity highlighted two additional groups including one with high repair potential overexpressing the RAD51 gene after 4Gy. However, treatment with RAD51 inhibitor is likely to slow down repair of GSC lesions. Notwithstanding GSC heterogeneity, in our study inhibition of the Hedgehog pathway (HH) by a cyclopamine glucuronid prodrug, activated by the tumor microenvironment, inhibited in vitro proliferation and self-renewal in all the GSCs tested and slowed down tumor growth in vivo. Hence, HH pathway appears to be conserved among GSCs and constitutes an interesting potential therapeutic target. With regard to the development of personalized medicine, it is nevertheless highly advisable to take into account the pronounded heterogeneity of tumor populations.

Taquizoítos de T. gondii esterilizados por radiação ionizante é uma vacina interessante para induzir uma imunidade semelhante à infecção, mas sem a formação de cistos. Neste estudo avaliamos as populações celulares do sangue e do baço induzidas pela imunização, a resposta imune humoral, celular e a proteção após desafio com parasitas viáveis. Camundongos foram imunizados com taquizoítos de T. gondii irradiados por v.o. ou i.p.. Os animais foram desafiados com 10 cistos da cepa ME-49 ou VEG por via oral e apresentaram altos níveis de proteção com baixa carga parasitária. Camundongos imunizados por i.p. e v.o. apresentaram anticorpos específicos no soro e o aumento das populações de células B, plasmócitos, células TCD4+ e TCD8+ tanto no sangue como no baço. As células esplênicas de camundongos imunizados por i.p. mostraram a produção de IL-10, IFN-γ e IL-4. Células TCD4+ e células B do baço de camundongos imunizados por i.p. proliferaram após a estimulação com antígeno. A imunização com esse modelo vacinal induziu uma resposta imune mediada com células B, TCD4+ e TCD8+, com aumento da resposta imune humoral e celular que são necessárias para proteção do hospedeiro após uma infecção. Essa resposta imune induzida é uma resposta semelhante a uma infecção natural, sendo assim o desenvolvimento de vacinas utilizando a radiação ionizante como uma ferramenta, pode ser um modelo atrativo e eficiente para testar novos imunógenos no futuro. / Tachyzoites of T. gondii sterilized by ionizing radiation is an interesting vaccine for inducing immunity to infection similarly but without the formation of cysts. In this study we evaluated the cell populations from blood and spleen induced by immunization, the humoral immune response, cellular and protection after challenge with viable parasites. Mice were immunized with irradiated tachyzoites of T. gondii by v.o. or i.p.. The animals were challenged with 10 cysts of the ME-49 or VEG strain orally and showed high levels of protection with low worm burden. Immunized mice by i.p. and v.o. present specific antibodies in the serum and increased populations of B cells, plasma cells, CD4+ and CD8+ T cells in blood and spleen. The spleen cells of immunized mice by i.p. showed the production of IL-10, IFN-γ and IL-4. CD4+ T cells and B cells in the spleen of immunized mice i.p. proliferated upon stimulation with antigen. The immunization with this vaccine model induced an immune response mediated by B cells, CD4+ and CD8+ with increased humoral and cellular immune response are necessary for host protection after infection. This induced immune response is a response similar to natural infection, therefore the development of vaccines using ionizing radiation as a tool, can be an attractive and efficient model for testing new immunogens in the future.

Les cassures double-brin de l’ADN (CDB) sont des événements clés dans la réponse aux rayonnements ionisants qui, avec le profil génétique et épigénétique individuel, peuvent conditionner le devenir des tissus sains d’un individu exposé. À la suite des cassures de la molécule d’ADN et de la déstabilisation de la chromatine, une série de modifications post-traductionnelles des histones se produit, notamment la phosphorylation de la serine 139 de l'histone H2A.X (gamma-H2A.X), conduisant à la formation de foyers radio-induits. La réparation des CDB, et donc la disparition de ces foyers, a lieu dans les heures suivant l’exposition. Toutefois, une certaine proportion de ces foyers gamma-H2A.X persiste 24 heures après l’irradiation. La nature et le rôle de ces foyers persistants sont encore peu clairs. L’objectif de ce travail est d'explorer les caractéristiques de ces foyers persistants et leurs conséquences sur le devenir des cellules. Pour étudier la dynamique des foyers radio-induits, nous avons exposé des HUVEC synchronisées en phase G0/G1 à des doses de 1 et 5 Gy de rayons X. Les foyers radio-induits ont été étudiés à partir de 10 minutes et jusqu'à 7 jours après l'exposition par l’analyse de gamma-H2A.X et de l’association temporelle de la protéine 53BP1 et des CN-PML (corps nucléaires PML). L’impact des foyers persistants sur la prolifération cellulaire a également été exploré. Nous avons analysé en microscopie à fluorescence une moyenne de 4 000 cellules pour chaque condition à l'aide d'une analyse d’image permettant la détection automatique des noyaux et des foyers. L'analyse d'un grand nombre d‘évènements nous a permis de discriminer des sous-populations de cellules ou de foyers sur la base de différentes caractéristiques, telles que leur aire ou la phase du cycle cellulaire, et de mesurer leur représentativité dans l'ensemble de la population de cellules exposées. Ainsi, nous avons déterminé que les foyers gamma-H2A.X persistant ont une aire supérieure à 0,72 ± 0,11 µm² et qu’ils sont toujours colocalisés avec 53BP1. Plus de 70% des cellules exposées à 5 Gy ont au moins un foyer persistant 24 heures après l'exposition. De plus, ces foyers persistants sont observables au moins jusqu'à 7 jours après l’irradiation. Une association spatiale significative entre les CN-PML et les foyers gamma-H2A.X a été observée à partir de 10 minutes après l'exposition et 24 heures après l’exposition, environ 90% des foyers persistants sont associés à un CN-PML. De plus, la présence de foyers persistants ne bloque pas définitivement la prolifération des cellules. Cependant, la fréquence des foyers persistants est plus faible dans les cellules filles que dans les cellules irradiées, probablement en raison d'une certaine proportion de distribution asymétrique des foyers persistants entre les cellules filles. Nous avons également mesuré une corrélation positive entre la présence d'un foyer persistant et la probabilité de mauvaise ségrégation de l'ADN par l'observation de phénomènes de catastrophes mitotiques. Il semble donc que la structure formée après le passage d'un foyer persistant à travers les phases S et G2 soit susceptible d’empêcher la séparation correcte des chromatides sœurs du chromosome affecté. Nous suggérons donc que la nature des foyers persistants n’est pas la même avant et après la première division cellulaire due à une résolution anormale de l'anaphase. Ces assemblages chromosomiques atypiques résultants d’anaphases anormales pourraient être létaux pour la cellule ou entraîner un déséquilibre du dosage génique et une instabilité génomique accrue pouvant conduire à une mosaïque de phénotypes cellulaires. / The DNA double-stranded breaks (DSB) are key events in the cell response to ionizing radiation that may affect, with the individual genetic and epigenetic profile, the fate of healthy tissues of people exposed. Following initial breaks and chromatin destabilization, a set of post-translational modifications of histones occurs, including the phosphorylation of serine 139 of histone H2AX (gamma-H2A.X), which leads to the formation of ionizing radiation-induced foci (IRIF). DSB repair results in the disappearance of most IRIF within hours after exposure. However, a proportion of IRIF remains 24 hours upon irradiation. The nature and role of these persistent IRIF are still unclear. The goal of this work is to explore the characteristics of these persistent IRIF and their consequences on the cell behavior. To investigate the dynamic of IRIF in our model, we exposed G0/G1-phase synchronized HUVECs to 1 or 5 Gy of X-rays. IRIF were studied from 10 minutes up to 7 days after exposure by monitoring gamma-H2A.X foci, their temporal association with 53BP1 protein and PML NBs (Promyelocytic leukemia nuclear bodies), and their impact on cell proliferation. We analyzed a mean of 4 000 cells for each condition using an automated detection of nuclei and foci. The analysis of a large number of cells and foci allowed us to screen subpopulations of cells or foci through different characteristics, such as size, shape or cell cycle phase among others, and to weight their representativeness in the whole population of exposed cells. We identified that persistent gamma-H2A.X foci after irradiation had a size superior to 0.72 ± 0.11 µm² and always collocated with 53BP1. More than 70% of cells exposed to 5 Gy had at least one persistent IRIF 24 hours after exposure and we observed these persistent IRIF up to 7 days post irradiation. A significant spatial association between PML NBs and IRIF was observed from 10 minutes after exposure; at 24h post irradiation, around 90% of persistent IRIF were associated with PML NBs. Moreover we demonstrated that persistent IRIF did not block cell proliferation definitively. The frequency of IRIF was lower in daughter cells, probably due to a certain amount of asymmetric distribution of IRIF between them. We report a positive association between the presence of an IRIF and the likelihood of DNA missegregation by observation of mitotic catastrophes. Hence, the structure formed after the passage of a persistent IRIF across the S and G2 phases may impede the correct segregation of sister chromatids of the chromosome affected. Consequently, the nature of IRIF in the nucleus of daughter cells might differ before and after the first cell division due to an abnormal resolution of anaphase. The resulting atypical chromosomal assembly may be lethal or result in a gene dosage imbalance and possible enhanced genomic instability, and could lead to a patchwork of cell phenotypes.

This master thesis discuss about ionizing radiation, interaction with matter and effects on her. In the work is discussed differend types of interactions of directly ionizing radiation and indirectly ionizing radiation. Below is an overview of methods of shielding from all of types of ionizing radiation. Second part of this thesis discuss about single event effects in semiconductors which are cause by ionizing radiation. At the end is described design of measuring instrument included FPGA chips. This design is discused both from point of wiew hardware and software too.

This master’s thesis deals with the problematics of influence of ionizing radiation on semiconductor devices and their properties. The aim of the thesis is to analyze the different types of radiation that can occur in the areas of application of these components. In the second part, the degradation processes are explored, with emphasis on the influence caused by the radiation dose. Also, the displacement damage and SEE effects are described, but just slightly, because they are not part of this work. The third part describes the device design process and harmful effects, that have to be considered during the design phase. In the forth and the fifth parts of this work were done modeling of radiation effects (influence of dose rate, Single-Event Upset and Total Ionizing Dose) in PSpice program and was carried out the possibility of designing a simple dosimeter with silicon diode. In conclusion, the results of the thesis are summarized and evaluated.

This master thesis discuss about ionizing radiation, interaction with matter and effects on her. In the work is discussed differend types of interactions of directly ionizing radiation and indirectly ionizing radiation. Below is an overview of methods of shielding from all of types of ionizing radiation. Second part of this thesis discuss about single event effects in semiconductors which are cause by ionizing radiation. At the end is described design of measuring instrument included FPGA chips. This design is discused both from point of wiew hardware and software too.

The task of this thesis is to familiarize readers with the basics of the problem of ionizing radiation from its types and resources, through mechanisms of action and its effects on the human organism, to the possibility of calculating various characteristics. Close attention is paid to the use of ionizing radiation in medical approaches. There is in detail described process of radiotherapy planning and a basic properties of planning systems. Part of the thesis is also program RT-Plan processed in Matlab. The program simulates the planning system for external ionizing radiation therapy used in treatment. There is supplemented a detailed help and series of tests for the plan. It is suitable for possible use in teaching.

Antalet datortomografiundersökningar (DT) ökar i Sverige och hela världen. En nackdel med denna undersökning är höga stråldoser som kan orsaka stokastiska skador (cancer) på patienter. Mest strålkänsliga patienter är barn. De har snabbare celldelning och längre livstid kvar vilket innebär att cancer har större möjlighet att utvecklas i framtiden. Syfte: Syfte med denna studie är att belysa hälsorisker som kan förekomma vid joniserande strålning inom DT med fokus på barn samt unga vuxna. Metod: En litteraturöversikt gjordes där artiklarna valdes från två databaser PubMed och CINAHL. 10 artiklar kvalitetsgranskades och resultaten av de utvalda artiklarna analyserades. Resultat:  Resultaten visade att DT-undersökning som genomförs under barndomen kan leda till ökad risk för malignitet och deterministiska skador. Det finns ett direkt samband mellan mängden av stråldos, ålder och kön vid exponering av joniserande strålning av DT och risken att drabbas av cancer. Ju högre dos och desto yngre patienten är, samt hos flickor överlag, finns större risk att drabbas av cancersjukdom. Slutsatser: På grund av hälsorisker som förekommer efter exponering med joniserande strålning krävs ett stort ansvar både hos radiologer och röntgensjuksköterskor, för att minimera skadorna hos barn. Därför är det även av stor vikt att alla undersökningar som utförs inom DT är berättigade och optimerade för att nyttan av att utföra undersökningen ska bli större än skadan. / The number of computed tomography (CT) examinations is increasing in Sweden and worldwide. A disadvantage of this method is high radiation doses that can cause stochastic effects (cancer) on patients. The most radiation-sensitive patients are children. They have faster cell division and longer life, which means that cancer has a greater chance of developing in the future. Aim: The aim of this study is to elucidate health risks that can occur in ionizing radiation in CT with focus on children and young adults. Method: A literature review was conducted where the articles were selected from the two databases PubMed and CINAHL. Ten articles were quality checked and the results of the selected articles were analyzed.Results: The results showed that CT examination conducted during childhood could lead to an increased risk of malignancy and deterministic injuries. There is a direct correlation between the amount of radiation dose, age and sex, when exposed to ionizing radiation from CT and the risk of cancer. The higher the dose and the younger the patient, and in girls overall, there is a greater risk of suffering from cancer. Conclusions: Due to health risks that occur after exposure to ionizing radiation, a great responsibility is required of both radiologists and X-ray nurses, to minimize the damage in children. Therefore, it is also of great importance that all investigations carried out within CT are justified and optimized so that the benefit of carrying out the investigation should be greater than the damage.

[pt] Esta dissertação aborda a aplicação da legislação às instalações de radioterapia visando à proteção no ambiente ocupacional. O estudo de caso foi realizado no INCA, na unidade HC 1, um hospital público vinculado ao SUS, situado no Rio de Janeiro. Ao menos 52% dos casos de câncer são tratados através de técnicas medicinais que envolvem a radiação ionizante. Estas técnicas são aplicadas através dos equipamentos de telecobaltoterapia, aceleradores lineares de partículas ou ainda, através de aplicações de radiofármacos diretamente nos pacientes. A radiação possui particularidades físicas que, apesar de suas vantagens como tratamentos, em doses elevadas, são nocivas e podem causar sérios danos ao organismo. A radiação ionizante recebida é cumulativa e, ao longo do tempo, os danos eventualmente provocados são severos. Durante os tratamentos na radioterapia é imprescindível manter condições seguras quanto às blindagens, inclusão de equipamentos de proteção, treinamentos e supervisão constante para que os profissionais que atuam nestas áreas não sofram exposição excessiva. Ao longo das últimas décadas foram elaboradas legislações e normas de segurança que visam proteger a saúde dos indivíduos ocupacionalmente expostos que operam diretamente com a radioatividade. Esta pesquisa teve como objetivo apresentar as principais legislações relacionadas à saúde e segurança no meio ambiente ocupacional que visam à radioproteção para os IOE no setor de radioterapia do INCA. Verificou-se que as medidas de segurança adotadas pela Instituição são as previstas na legislação tornando possível manter o atendimento aos pacientes e garantira segurança dos profissionais envolvidos, dos usuários e do meio ambiente de modo geral. / [en] The study addresses at relevant laws that guide and regulate the use of ionizing radiation in radiotherapy services inside a public hospital (INCA - National Cancer Institute, HC 1), situated in Rio de Janeiro, Brazil. Radioactivity is a phenomenon of natural origin easily found in the environment or artificially generated. It has beneficial applications being applied in agriculture, energy production, industry and medicine in health treatments. It brings harmful effects when used inappropriately, as it has physical peculiarities that, despite of advantages, in high-level doses can cause severe damage to the body (PERUZZO, 2012). During radiotherapy treatments, it is essential to maintain safe shielding conditions, including protective equipment and constant supervision so that professionals working in these areas do not suffer excessive exposure. Radiotherapy assists in the treatment of diseases using diagnostic and therapy techniques employing radioactive substances such as Cesium, Cobalt, Iodine, Technetium among others. These substances are present in radiopharmaceuticals, applied directly to patients through brachytherapy techniques or into the capsules installed in the pieces of equipment used in teletherapy. Currently, regulation of activities involving radioprotection and nuclear safety in Brazil is under the responsibility of the CNEN (National Nuclear Energy Commission), an autarchy of the Ministry of Science, Technology and Innovations. It is a government agency responsible for licensing and controlling all practices involving ionizing radiation.