Lorenzo Manti

Abstract Protontherapy is hadrontherapy’s fastest-growing modality and a pillar in the battle against cancer. Hadrontherapy’s superiority lies in its inverted depth-dose profile, hence tumour-confined irradiation. Protons, however, lack distinct radiobiological advantages over photons or electrons. Higher LET (Linear Energy Transfer) 12 C-ions can overcome cancer radioresistance: DNA lesion complexity increases with LET, resulting in efficient cell killing, i.e. higher Relative Biological Effectiveness (RBE). However, economic and radiobiological issues hamper 12 C-ion clinical amenability. Thus, enhancing proton RBE is desirable. To this end, we exploited the p + 11 B → 3α reaction to generate high-LET alpha particles with a clinical proton beam. To maximize the reaction rate, we used sodium borocaptate (BSH) with natural boron content. Boron-Neutron Capture Therapy (BNCT) uses 10 B-enriched BSH for neutron irradiation-triggered alpha particles. We recorded significantly increased cellular lethality and chromosome aberration complexity. A strategy combining protontherapy’s ballistic precision with the higher RBE promised by BNCT and 12 C-ion therapy is thus demonstrated.

mRNA splicing and export plays a key role in the regulation of gene expression, with recent evidence suggesting an additional layer of regulation of gene expression and cellular function through the selective splicing and export of genes within specific pathways. Here we describe a role for the RNA processing factors THRAP3 and BCLAF1 in the regulation of the cellular DNA damage response (DDR) pathway, a key pathway involved in the maintenance of genomic stability and the prevention of oncogenic transformation. We show that loss of THRAP3 and/or BCLAF1 leads to sensitivity to DNA damaging agents, defective DNA repair and genomic instability. Additionally, we demonstrate that this phenotype can be at least partially explained by the role of THRAP3 and BCLAF1 in the selective mRNA splicing and export of transcripts encoding key DDR proteins, including the ATM kinase. Moreover, we show that cancer associated mutations within THRAP3 result in deregulated processing of THRAP3/BCLAF1-regulated transcripts and consequently defective DNA repair. Taken together, these results suggest that THRAP3 and BCLAF1 mutant tumors may be promising targets for DNA damaging chemotherapy.

Evidence has accumulated that radiation induces a transmissible persistent destabilization of the genome, which may result in effects arising in the progeny of irradiated but surviving cells. An enhanced death rate among the progeny of cells surviving irradiation persists for many generations in the form of a reduced plating efficiency. Such delayed reproductive death is correlated with an increased occurrence of micronuclei. Since it has been suggested that radiation-induced chromosomal instability might depend on the radiation quality, we investigated the effects of alpha particles of different LET by looking at the frequency of delayed micronuclei in Chinese hamster V79 cells after cytochalasin-induced block of cell division. A dose-dependent increase in the frequency of micronuclei was found in cells assayed 1 week postirradiation or later. Also, there was a persistent increase in the frequency of dicentrics in surviving irradiated cells. Moreover, we found an increased micronucleus frequency in all of the 30 clones isolated from individual cells which had been irradiated with doses equivalent to either one, two or three alpha-particle traversals per cell nucleus. We conclude that the target for genomic instability in Chinese hamster cells must be larger than the cell nucleus.

The main direction proposed by the community of experts in the field of laser-driven ion acceleration is to improve particle beam features (maximum energy, charge, emittance, divergence, monochromaticity, shot-to-shot stability) in order to demonstrate reliable and compact approaches to be used for multidisciplinary applications, thus, in principle, reducing the overall cost of a laser-based facility compared to a conventional accelerator one and, at the same time, demonstrating innovative and more effective sample irradiation geometries. The mission of the laser-driven ion target area at ELI-Beamlines (Extreme Light Infrastructure) in Dolní Břežany, Czech Republic, called ELI Multidisciplinary Applications of laser-Ion Acceleration (ELIMAIA) , is to provide stable, fully characterized and tuneable beams of particles accelerated by Petawatt-class lasers and to offer them to the user community for multidisciplinary applications. The ELIMAIA beamline has been designed and developed at the Institute of Physics of the Academy of Science of the Czech Republic (IoP-ASCR) in Prague and at the National Laboratories of Southern Italy of the National Institute for Nuclear Physics (LNS-INFN) in Catania (Italy). An international scientific network particularly interested in future applications of laser driven ions for hadrontherapy, ELI MEDical applications (ELIMED), has been established around the implementation of the ELIMAIA experimental system. The basic technology used for ELIMAIA research and development, along with envisioned parameters of such user beamline will be described and discussed.