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.

Multimodal treatment adding immunotherapy and photodynamic treatment (PDT) to standard therapy might improve the devastating therapeutic outcome of glioblastoma multiforme patients. As a first step, we provide investigations to optimize dendritic cell (DC) vaccination by using PDT and ionizing radiation (IR) to achieve maximal synergistic effects. In vitro experiments were conducted on murine glioblastoma GL261 cells, primary DCs differentiated from bone marrow and T cells, isolated from the spleen. Induction of cell death, reactive oxygen species, and inhibition of proliferation by tetrahydroporphyrin-tetratosylat (THPTS)-PDT and IR were confirmed by WST-1, LDH, ROS, and BrdU assay. Tumor cargo (lysate or cells) for DC load was treated with different combinations of THPTS-PDT, freeze/thaw cycles, and IR and immunogenicity analyzed by induction of T-cell activation. Cellular markers (CD11c, 83, 86, 40, 44, 69, 3, 4, 8, PD-L1) were quantified by flow cytometry. Cytotoxic T-cell response was evaluated by calcein AM assay. Immunogenicity of THPTS-PDT-treated GL261 cells lysate was superior to IR-treated lysate, or treated whole cells proven by increased DC phagocytosis, T-cell adhesion, proliferation, cytolytic activity, and cytokine release. These data strongly support the application of PDT together with IR for optimal immunogenic cell death induction in tumor cell lysate used to pulse DC vaccines.

Stressful experiences in early life can have profound and lasting impacts on phenotypic development. In anthropogenic environments, organisms are increasingly exposed to evolutionarily novel stressors that may play a major role in shaping the phenotypic variation upon which natural selection acts. For instance, ionizing radiation persists in areas affected by nuclear reactor accidents, nuclear weapons testing, and the nuclear power production process. This thesis explored the dose-response effects of early life ionizing radiation exposure on life- history traits in the cricket (Acheta domesticus L.). Specifically, this work had two goals: (1) to examine the effects of early life radiation stress on the potential tradeoff between growth and self-maintenance, and (2) to explore the dose-dependent effects of juvenile radiation exposure on adult trait expression (particularly fecundity, offspring investment, and offspring fitness). It was found that exposure to moderate doses of radiation in early development resulted in a slower juvenile growth rate but increased survival in early adulthood, suggesting that self- maintenance was prioritized over growth. Despite the strong inhibitory effects of early life radiation on adult female body mass, age-specific fecundity was negatively impacted only at relatively high radiation doses. Crickets exposed to moderate radiation doses in early development laid larger eggs in adulthood relative to controls and these eggs had a greater hatching success, suggesting that radiation exposure had transgenerational effects on offspring performance. No noticeable effects of early life radiation exposure were detected on total and non-enzymatic antioxidant capacity or hydrogen peroxide levels in adult females. Together, this research indicates that a single, acute exposure to ionizing radiation in early life can affect phenotypic development in a complex, dose-dependent manner and that rather than being purely negative, phenotypic responses can be sustained or even enhanced. / Thesis / Master of Science (MSc) / Stressful experiences in early life can have lasting impacts on organismal development, but the extent to which early life stress is harmful is unclear. In human-dominated environments, pollutants such as ionizing radiation can be a significant form of developmental stress. This thesis explores the fitness-related effects of early life ionizing radiation exposure in the cricket, Acheta domesticus. Impacts on growth, longevity, fecundity, and offspring fitness are explored. This research indicates that early life stress can affect phenotypic development in a complex, dose-dependent manner and that rather than being purely negative, responses can be sustained or even enhanced.

Prostate cancer is one of the most frequently diagnosed cancers and failure to manage localized disease contributes to the majority of deaths. Radiation therapy (RT) is a common treatment for localized prostate cancer and uses ionizing radiation (IR) to damage DNA. Although RT is potentially curative, tumors often recur and progress to terminal disease. The cellular response to RT is multidimensional. For example, cells respond to a single dose of IR by activating the DNA damage response (DDR) to repair the DNA. Targeting proteins involved in the DDR is an effective clinical strategy to sensitize cancer cells to RT. However, multiple radiation treatments, as in fractionated ionizing radiation (FIR), can promote neuroendocrine differentiation (NED). FIR-induced NED is an emerging resistance mechanism to RT and tumors that undergo NED are highly aggressive and remain incurable.<br><br> Currently, the only clinical approach that improves RT for prostate cancer treatment is androgen deprivation therapy (ADT). ADT blocks androgen receptor (AR) signaling which inhibits the repair of DNA damage. In 2017, my lab reported that targeting Protein arginine methyltransferase 5 (PRMT5) blocks AR protein expression. Therefore, targeting PRMT5 may also sensitize prostate cancer cells to RT via a novel mechanism of action.<br><br> This dissertation focuses on the role of PRMT5 in the cellular response to IR and the goal of my work is to validate PRMT5 as a therapeutic target to enhance RT for prostate cancer treatment. I demonstrate that PRMT5 has several roles in the cellular response to IR. Upon a single dose of IR, PRMT5 cooperates with pICln to function as a master epigenetic activator of DDR genes and efficiently repair IR-induced DNA damage. There is an assumption in the field that the methyltransferase activity and epigenetic function of PRMT5 is dependent on the cofactor MEP50. I demonstrate that PRMT5 can function independently of MEP50 and identify pICln as a novel epigenetic cofactor of PRMT5. During FIR, PRMT5, along with both cofactors MEP50 and pICln, are essential for initiation of NED, maintenance of NED, and cell survival. Targeting PRMT5 also sensitizes prostate cancer xenograft tumors in mice to RT, significantly reduces and delays tumor recurrence, and prolongs overall survival. Incredibly, while 100% of control mice died due to tumor burden, targeting PRMT5 effectively cured ~85% of mice from their xenograft tumor. Overall, this work provides strong evidence for PRMT5 as a therapeutic target and suggests that targeting PRMT5 during RT should be assessed clinically.<br>

Indiana University-Purdue University Indianapolis (IUPUI) / Translation Initiation in protein synthesis is a crucial step controlling gene expression that enhanced by eukaryotic translation initiation factors (eIFs). eIF3a, the largest subunit of eIF3 complexes, has been shown to regulate protein synthesis and cellular response to cisplatin treatment. Its expression has also been shown to negatively associate with prognosis. In this study, we tested a hypothesis that eIF3a regulates synthesis of proteins important for repair of double strand DNA breaks induced by ionizing radiation (IR). We found that eIF3a up-regulation sensitizes cellular response to IR while its knockdown causes resistance to IR. We also found that eIF3a over-expression increases IR-induced DNA damage and decreases Non-Homologous End Joining (NHEJ) activity by suppressing expression level of NHEJ repair proteins such as DNA-PKcs and vice versa. Together, we conclude that eIF3a plays an important role in cellular response to DNA-damaging treatments by regulating synthesis of DNA repair proteins and, thus, eIIF3a likely plays an important role in the outcome of cancer patients treated with DNA-damaging strategies including ionizing radiation.

BRCA1 est un suppresseur de tumeur majeur jouant un rôle dans la transcription, la réparation de l’ADN et le maintien de la stabilité génomique. En effet, des mutations dans le gène BRCA1 augmentent considerablement le risque de cancers du sein et de l’ovaire. BRCA1 a été en majorité caractérisé pour son rôle dans la réparation de l’ADN par la voie de recombinaison homologue (HR) en présence de bris double brins, par example, induits par l’irradiation gamma (IR). Cependant, la fonction de BRCA1 dans d’autres voies de réparation de l’ADN, comme la réparation par excision de nucléotides (NER) ou par excision de base (BER), demeurent toutefois obscures. Il est donc important de comprendre la régulation de BRCA1 en présence d’agents génotoxiques comme le méthyle méthanesulfonate (MMS) ou l’UV, qui promouvoient le BER et le NER respectivement. Nos observations suggèrent que BRCA1 est dégradée par le protéasome après traitement avec le MMS ou les UV, et non avec l’IR. Par ailleurs, cette dégradation semble compromettre le recrutement de Rad51, suggérant que la voie de HR est inhibée. Nos résultats suggèrent que la HR est inhibée afin d’éviter l’activation simultanée de multiples voies de réparation. Nous avons aussi observé que la dégradation BRCA1 est réversible et que la restauration des niveaux de BRCA1 coïncide avec le recrutement de Rad51 aux sites de dommages. Cela suggère que la HR est réactivée tardivement par les bris double brins générés suite à l’effondrement des fourches de réplication. Ayant observé que BRCA1 est hautement régulé par l’ubiquitination et est ciblé par le protéasome pour dégradation, nous avons émis une hypothèse que BRCA1 est régulé par des déubiquitinases. Cela amène à caractériser plus en profondeur par un criblage en déplétant les déubiquitinases individuellement par RNAi et en observant leur effet sur le recrutement de BRCA1 et des protéines reliées à cette voie. Un criblage préliminaire nous a permi d’identifié candidats potentiels tel que BAP1, CXORF53, DUB3, OTUB1 et USP36. / BRCA1 is a tumour suppressor involved in transcription, DNA repair and maintenance of genomic stability. Indeed, BRCA1 mutation carriers have an exceptionally higher risk of breast and ovarian cancers. BRCA1 is mainly known for its role in homologous recombination repair (HR) by recruiting HR proteins to chromatin upon double strand break (DSBs) formation, e.g., following treatment with ionizing irradiation (IR). However, the function of BRCA1 in other DNA repair pathways such as nucleotide excision repair (NER) or base excision repair (BER) is still obscure. It is thus of fundamental and clinical importance to investigate BRCA1 function following exposure to diverse genotoxic agents. Using human cultured cell, we observed that BRCA1 is downregulated by the proteasome upon treatment with MMS or UV, but not with IR. Moreover, this downregulation prevents Rad51 recruitment to chromatin following exposure to MMS. Given that DNA damage induced by UV and MMS trigger NER and BER pathways respectively, this implies that HR could be inhibited in order to prevent competition between independent DNA repair pathways. We also found that BRCA1 downregulation is reversible and the recovery of BRCA1 levels correlates with the reappearance of BRCA1 and Rad51 on chromatin. This implies that the HR has been reactivated at the late stage of DNA damage for the repair of double strand breaks generated by replication fork collapse. Since BRCA1 stability is highly regulated by ubiquitination and is downregulated following MMS treatment, one would expect that a deubiquitinase is responsible for relieving this downregulation to promote the reactivation of the HR pathway. To characterize this aspect further, we conducted DUB RNAi screens in which a particular DUB is depleted and the localization of BRCA1 and other related proteins were observed. According to a preliminary screen, a few DUBs (BAP1, CXORF53, DUB3, OTUB1, and USP36) were identified as potential regulators of the stability and localization of BRCA1 and proteins involved in homologous recombination.