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

In this paper we present the main outcomes of a wide collaborative effort (carried out, within the INFN project, "EPICA" and in part within the European projects "RISC-RAD" and "NOTE" and the ASI project MoMa-COUNT), both experimental and theoretical, devoted to the characterization and quantification of the induction of DNA-targeted and non-DNA-targeted molecular and cellular biological endpoints, following irradiation of human cells with different Charged particles The work was mainly aimed at reaching a better understanding of the mechanisms governing the physical and biophysical pathways leading from the initial energy deposition by radiation in matter to the induction of observable radiobiological damage, with particular focus on the role played by radiation quality. More, specifically we characterized the induction of DNA DSB within different fragment-size ranges outlining the effectiveness of high-LET radiation at inducing small fragments and thus clustered DNA breaks, which can evolve in terms of endpoints like chromosome aberrations (CAs). This was confirmed by the development and application of a model of CA induction based oil the assumption that only DNA breaks can lead to aberrations. Concerning non-DNA-targeted damage, we quantified the time-dependent induction of medium-mediated DNA damage in bystander cells and we characterized the time and dose dependence of cytokine concentration in the medium of sham-irradiated and irradiated cells, since medium-mediated bystander damage is thought to arise from molecular signalling between irradiated and unirradiated cells. The mechanisms governing such Signalling were investigated developing a model and a MC code simulating cytokine release, diffusion mid internalization, showing good agreement with experimental data. Non-DNA-targeted effects were further characterized by MRS investigation of the radiation effects on lipids and oxidative metabolism, which are particularly relevant also considering that, they may differently expressed in different tumors and ill normal tissues.