Le mélanome est une tumeur réputée radiorésistante. Ceci est conforté par ses caractéristiques radiobiologiques observées notamment in vitro. Le mélanocyte dont la transformation maligne engendre cette tumeur est le siège d’un métabolisme unique, la mélanogenèse. Celle-ci produit des pigments bien connus dans leur rôle de photoprotecteurs, mais leur éventuelle participation à une modulation de la sensibilité de ces cellules aux radiations ionisantes bien que suggérée dans la littérature, ne révèle que quelques résultats publiés criticables voire contradictoires. Notre travail s’est intéressé à préciser les rôles des pigments et du stress oxydant généré par les radiations ionisantes dans la modulation de la radiosensibilité du mélanocyte malin et d’en évaluer l’impact aussi bien sur la survie cellulaire, les lésions à l'ADN qu' aux processus de mort cellulaire. Nos résultats montrent que la nature du pigment, les eumélanines (pigment brun ou noir) en particulier ainsi que leur quantité influencent directement la radiosensibilité des cellules en terme de survie. Ceci a été démontré aussi bien en comparant des lignées cellulaires de pigmentation différentes qu’en stimulant cette dernière par son précurseur naturel, la tyrosine. D’autre part et d’une manière inattendue, l’altération de la barrière chimique cellulaire la plus importante que représentent les radioprotecteurs :Glutathion et son précurseur, Cystéine, semble favoriser la survie des mélanocytes malins au lieu d’en augmenter la radiosensibilité. Or, ces deux molécules sont aussi impliquées dans la mélanogenèse et entrent même dans la composition d’un type de pigments riches en soufre que sont les phaeomélanines. La mesure de la balance des deux types de pigments dans ces conditions nous a fourni un élément de réponse :en absence de GSH et surtout de Cys, l’eumélanogenèse a été favorisée en rejoignant ainsi nos premiers résultats concernant la manipulation des pigments. Nous avons également examiné les lésions immédiates à l’ADN occasionnées par l’irradiation dans les mêmes conditions que pour la survie cellulaire. Nos résultats montrent une protection significative de l’ADN lorsque la pigmentation est stimulée soit par la tyrosine, soit par déplétion de cystéine. Aussi une corrélation a pu être établie entre ces effets, l’aboutissement de l’apoptose radioinduite et la survie cellulaire. Enfin, nous nous sommes intéressés à la stimulation directe de la mélanogenèse par les radiations ionisantes. Nous avons observé un effet activateur dose-dépendant sur la tyrosinase, l’enzyme-clé de la pigmentation. Les mécanismes par lesquels les pigments, spécialement les eumélanines, agissent, pourraient être liés aux propriétés protectrices connues pour ces pigments comme pièges des radicaux libres. Cependant, une interaction directe des radiations avec le polymère solide, lui-même contenant des métaux lourds, n’est pas à écarter. En conclusion, les mélanines semblent fortement impliquées dans la modulation de la radiosensibilité du mélanocyte malin et peuvent compenser la perte des deux radioprotecteurs cellulaires les plus importants, le Glutathion et surtout la Cystéine. Est-ce qu’une stratégie consistant en l’inhibition de la formation de pigments trouverait sa place en radiothérapie du mélanome ?est une question ouverte par ce travail. / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished

Amifostine (WR-2721, delivered as Ethyol) is a radioprotector agent that reduces the likelihood of early and/or late biological effects by eliminating free radical particles during ionizing radiation fraction (radiotherapy). It activates in under normal tissues conditions to reduce mutation and fraction in DNA. Among 4000 prodrug compounds, amifostine is the only agent has been approved from the US Food and Drug Administration in clinical purposes. The main effective mechanisms of amifostine are based on scavenging for free radical, improving for DNA repair step and indication of cellular hypoxia. In the same time, this drug is not widely used around the world for different reasons mainly its high cost and toxicity level (lethal dose). Conjugating a monoclonal antibody with amifostine by a suitable linker is a process of Antibody Drug Conjugate producing immuno-radioprotector molecule hypothesis. Administrated molecule is an approach of targeted delivery therapy that increases the dosage uptake into particular area of treatment to minimize the dose distribution in non-targeted area in the body. In the present work, we proposed a three-compartment system model to simulate the two-pore theory pathway of an immuno-radioprotector molecule when it is crossing the physiological barriers. The model investigated its distribution and elimination in porous media (with both large and small pores) within a pharmacokinetics compartmented model approach.

<p> The purpose of this paper is to examine how lay perceptions of risk influence individual behaviour. The study focuses on health care practitioners who are daily exposed to low levels of ionizing radiation. By using qualitative research methods, the goal was to understand how individuals attach meaning to the environment they work in, when there is a risk involved. It points out that people must go through a risk assessing procedure, in order· to be able to deal with the daily risks to their health. People will develop different mechanism to cope with this daily risk. A model of risk perception was developed from this qualitative data. It is hoped that this model will contribute to the existing literature on risk perception models. </p> / Thesis / Bachelor of Arts (BA)

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Medical radiation is vital in acquiring a patient diagnosis, but some clinicians are concerned with the perceived risks associated with ionizing radiation. This risk is heightened when incorporating in utero exposures due to the risk to the developing foetus. Although other organ systems have been studied, there is a paucity of data on the effects to the respiratory system from in utero exposures. The aim of this thesis was to understand the long-term effects on the respiratory system from in utero exposures, but as a first step, it was important to determine what levels patients receive whilst admitted to hospital. Two polar populations were chosen based on their predicted exposure levels during hospitalisation; one with high levels, intensive care unit (ICU) patients, and one with low levels, pregnant patients. Most patients cumulatively received < 1mSv with median exposures of 0.99 mSv (ICU patients) and 0.02 mSv (pregnant patients). However, both cohorts had patients that surpassed 10 mSv. To assess the effects from in utero exposures on the respiratory system, two animal models were conducted both exposed during late gestation, one healthy model and one acute lung injury model. In the health animal model, cardiovascular outcomes were also measured, however, ionizing radiation (50, 300, 1000 mGy) did not appear to influence these two organ systems from the outcomes measured. In the acute lung injury model, lipopolysaccharide (3mg/Kg) stimulated an acute lung inflammatory response, however, there was also no overt effect of radiation from the outcomes measured (10, 100, 1000 mGy). In both models, ionizing radiation did cause growth restriction up to 16 weeks of age, but this was only observed from doses above 100 mGy. Overall, the levels of ionizing radiation patients receive is low and from diagnostic exposures during pregnancy, there does not appear to be any strong effects on the developing foetus. / Thesis / Doctor of Philosophy (PhD) / Radiation is necessary in medicine to observe the internal structures of the body, but it can sometimes cause unwanted biological changes within the body. This risk is heightened when considering exposure to developing baby because of the dynamic changing it is naturally going through and possible lifetime left to experience effects. This thesis aimed to understand what levels of radiation patients receive in hospital, observing one population predicted to receive high levels (Intensive care patients) and one predicted to receive low levels (pregnant patients). Overall, the majority of patients in the two cohorts received less than the recommended yearly public limit of 1 millisievert (mSv). The second aim was to observe the effects on the growth, lungs and hearts of the babies in an animal model when they are exposed during pregnancy. Radiation had no overall effect on the lungs or heart but can reduce body weight at moderate (100 milligrays (mGy) and high (1000 mGy) exposures.

In the thesis I focus on evaluation of the effect of familiar occurrence of cancer on presence and number of micro-nuclei in blood preparations with particular groups of persons. One of the biodosimetry methods, test for presence, number and kind of micro-nuclei, was used. I was not investigating the dosages as such and connection of the number of micro-nuclei with the dose, however, I followed up the effect of potentially influencing side factor on presence and number of micro-nuclei, which is the familiar occurrence of tumour. As a lot of information about ionizing radiation, its sources, radioactivity, radio-biologically important quantities, mechanisms of effects, molecular and cellular changes and biodosimetric methods as such falls under the topic, the theoretical part of diploma project is dedicated to such information. In the practical part, evaluation of the number and kind of micro-nuclei with set groups of persons is carried out. These groups of persons are particularly exposed to ? radiation. They are employees of spa Lázně Jáchymov, former miners from already closed uranium mines in Příbram and current miners from uranium mines GEAM o. z. Dolní Rožínka. These selected persons are divided according to their workplaces into two groups, i.e. a group of persons without cancer occurrence in the family and a group of persons with occurrence of cancer in their families. The numbers of bi-nuclei cells without micro-nuclei and with micro-nuclei and the kinds of micro-nuclei were determined with all these persons using fluorescence microscope. Expression and comparison of percentages of bi-nuclei cells with micro-nuclei to total number of all bi-nuclei followed and then expression and comparison of proportion of micro-nuclei without centromeres to the number of micro-nuclei of both kinds (with centromeres and without centromeres) with all persons and groups were carried out. Based on the results gained from statistical assessment, it was found that differences between percentages of the two main compared groups of persons did not show higher genomic instability (statistically significant difference) in persons with familiar occurrence of cancer than in persons without cancer in the family. But by comparing the shares of micronuclei without centromeres was proved statistically significant difference between these main groups.