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

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<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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Most breast cancer patients undergo radiation diagnostics and are also treated with radiotherapy. In addition to being an important treatment modality, ionizing radiation (IR) is a potent tumour-causing agent that has been linked to breast cancer development. However, the exact molecular etiology of IR-induced mammary gland carcinogenesis remains unknown. We set out to analyze the role of DNA methylation in mammary gland responses to low dose IR using a well-established rat model. We also studied low dose IR effects on global gene expression and microRNAome. We found that exposure to low, mammography-like dose of IR led to a significant loss of global DNA methylation in rat mammary gland tissue. Furthermore, low dose IR significantly affected rat mammary gland transcriptome and microRNAome. The datasets generated within the scope of this thesis may be used to identify novel predictive biomarkers for assessment of the magnitude of IR effects on mammary gland tissue. / xi, 120 leaves ; 29 cm

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.

Ph.D. / Molecular and Medical Genetics / The objective of this study is to examine, in light of the expression of multiple p53 family member isoforms, the specific role of p73 in malignant conversion, cellular response to DNA damage, and direct or indirect cooperation with other p53 family members in a clonal model of epidermal carcinogenesis. We first focused on the role of p73 in malignant conversion. Whether sporadic or siRNA induced, loss of p73 in initiated p53+/+ keratinocytes lead to conversion to squamous cell carcinoma (SCC) in vivo which was reversible upon reconstitution of TAp73α but not ΔNp73α. Second, we investigated the cellular response to ionizing radiation (IR) in the presence and absence of p73, showing that loss of p73 at malignant conversion was associated with resistance to IR in vitro. The loss of radiation sensitivity and malignant conversion was characterized by reduced steady state DNA binding levels of transcriptionally active p63 isoforms to the p21 promoter, failure to induce specific p53 family transcriptional targets, and failure to arrest in G1. Reconstitution of TAp73α, but not ΔNp73α, increased steady state DNA binding capabilities of TAp63β, TAp63γ, and ΔNp63γ, and steady state levels of p53 family target mRNA, but did not restore cellular sensitivity to IR. We thus uncovered a functional cooperation between TA isoforms of p73 and p63 and showed that p73-mediated DNA damage response was uncoupled from its tumor suppressive role. We observed preferential DNA binding of the inhibitory ΔNp63α isoform both in vitro and invivo in SCC suggesting that in the absence of TAp73α a balance is tipped toward DNA binding of the inhibitory isoforms. Third, we studied the role of the p53 family inkeratinocyte response to UVB. Tumorigenic cells lacking p73 that were resistant to IR remained sensitive to UVB, accompanied by DNA binding of the TAp63γ isoform, suggesting that keratinocyte response to UVB is not dependent upon p73 and suggesting a hierarchy of p53 family member responses to DNA damage. Finally, we examined TAp73α interaction with the p53 family inhibitor Mdm2. Mdm2 was in complex with DNA-bound p53 family members in malignant cells, but reconstitution of cells withTAp73α correlated with removal of Mdm2 from the complex, making them more like primary keratinocytes or initiated cells. Like the initiated cells, cells expressing TAp73α were refractory to treatment with the Mdm2-p53 inhibitor Nutlin-3 while cells lacking p73 expression or expressing ΔNp73α were sensitive. Thus, we suggest that p73 may be acting as a molecular shield to keep p53 family member inhibitors, such as ΔNp63α andMdm2, at bay. Further understanding of p53 family interplay in tumor development and DNA damage response could lead to new therapies or optimization of current therapeutic strategies in solid tumors of epithelium, particularly where deregulation or loss of p63 and p73 expression is associated with increased tumor invasiveness, treatment resistance, and poor patient prognosis.