Charged particle effects: Experimental and theoretical studies on the mechanisms underlying the induction of molecular and cellular damage and the modulation of intercellular signalling

both experimental and theoretical, devoted to the characterization and quantifica-tion ofthe induction of DNA-targeted andnon-DNA-targeted molecular andcellularbiological endpoints, following irradiation of human cells with different charged par-ticles. The work was mainly aimed at reaching a better understanding of the mech-anisms governing the physical and biophysical pathways leading from the initial en-ergy deposition by radiation in matter to the induction of observable radiobiologicaldamage, with particular focus on the role played by radiation quality. More specif-ically, we characterized the induction of DNA DSB within different fragment-sizeranges outlining the effectiveness of high-LET radiation at inducing small fragmentsand thus clustered DNA breaks, which can evolve in terms of endpoints like chromo-some aberrations (CAs). This was confirmed by the development and application ofa model of CA induction based on the assumption that only clustered DNA breakscan lead to aberrations. Concerning non-DNA-targeted damage, we quantified thetime-dependent induction of medium-mediated DNA damage in bystander cells andwe characterized the time and dose dependence of cytokine concentration in theculture medium of sham-irradiated and irradiated cells, since medium-mediated by-stander damage is thought to arise from molecular signalling between irradiatedand unirradiated cells. The mechanisms governing such signalling were investigateddeveloping a model and a MC code simulating cytokine release, diffusion and in-ternalization, showing good agreement with experimental data. Non-DNA-targetedeffects were further characterized by MRS investigation of the radiation effects onlipids and oxidative metabolism, which are particularly relevant also consideringthat they may be differently expressed in different tumors and in normal tissues.PACS 87.53.-j – Effects of ionizing radiation on biological systems.