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1. Introduction Ionising radiation induced DNA damage and subsequent biological responses depend on the radiation’s track structure and its energy loss distribution pattern. To investigate the underlying biological mechanisms involved in such complex system, there is need of predicting biological response by integrated Monte Carlo (MC) simulations across physics, chemistry and biology. Typically, modeling of survival fraction and/or kinetics of repair proteins attracts interests of researchers in the fields of radiobiology including medical physics. Hence, in this work, we have developed an application using the open source Geant4‐DNA toolkit to propose a realistic “fully integrated” MC simulation to calculate both early DNA damage and subsequent biological responses with time. 2. Materials and Methods We had previously developed an application allowing simulations of radiation induced early DNA damage on a naked cell nucleus model and its sub-components model (shown in top panels of Fig.1) [1]. In the new version presented in this work [2], we have developed three additional important features: (1) modeling of a realistic cell geometry including cytoplasm and the materials surrounding irradiated cells (shown in bottom panels of Fig.1), (2) inclusion of a biological repair model, (3) refinement of DNA damage parameters for direct damage and indirect damage scoring. The simulation results are validated with experimental data in terms of Double Strand Break (DSB) yields for human fibroblast cell as well as yield of accumulated γ-H2AX. In addition, the yields of indirect DSBs are compatible with the experimental scavengeable damage fraction. 3. Results and Discussion The simulated quantities are showing good agreements with the reference experimental quantities. For instance, as shown in Fig.2, the simulation application also demonstrates agreement with experimental data of γ-H2AX yields for gamma ray irradiation. 4. Conclusion As a new important step for radiobiological simulation using Geant4-DNA, the first fully integrated simulation chain has been developed across the physical, chemical and biological stages of cellular radiation action in a single application. The application is validated with the reference experimental results., 第121回 日本医学物理学会学術大会

The objective of this work was to study the differences in terms of early biological effects that might exist between different X-rays energies by using a mechanistic approach. To this end, radiobiological experiments exposing cell monolayers to three X-ray energies were performed in order to assess the yields of early DNA damage, in particular of double-strand breaks (DSBs). The simulation of these irradiations was set in order to understand the differences in the obtained experimental results. Hence, simulated results in terms of microdosimetric spectra and early DSB induction were analyzed and compared to the experimental data. Human umbilical vein endothelial cells (HUVECs) were irradiated with 40, 220 kVp, and 4 MV X-rays. The Geant4 Monte Carlo simulation toolkit and its extension Geant4-DNA were used for the simulations. Microdosimetric calculations aiming to determine possible differences in the variability of the energy absorbed by the irradiated cell population for those photon spectra were performed on 10,000 endothelial cell nuclei representing a cell monolayer. Nanodosimetric simulations were also carried out using a computation chain that allowed the simulation of physical, physico-chemical, and chemical stages on a single realistic endothelial cell nucleus model including both heterochromatin and euchromatin. DNA damage was scored in terms of yields of prompt DSBs per Gray (Gy) and per giga (109) base pair (Gbp) and DSB complexity was derived in order to be compared to experimental data expressed as numbers of histone variant H2AX (&gamma, H2AX) foci per cell. The calculated microdosimetric spread in the irradiated cell population was similar when comparing between 40 and 220 kVp X-rays and higher when comparing with 4 MV X-rays. Simulated yields of induced DSB/Gy/Gbp were found to be equivalent to those for 40 and 220 kVp but larger than those for 4 MV, resulting in a relative biological effectiveness (RBE) of 1.3. Additionally, DSB complexity was similar between the considered photon spectra. Simulated results were in good agreement with experimental data obtained by IRSN (Institut de radioprotection et de s&ucirc, ret&eacute, nucl&eacute, aire) radiobiologists. Despite differences in photon energy, few differences were observed when comparing between 40 and 220 kVp X-rays in microdosimetric and nanodosimetric calculations. Nevertheless, variations were observed when comparing between 40/220 kVp and 4 MV X-rays. Thanks to the simulation results, these variations were able to be explained by the differences in the production of secondary electrons with energies below 10 keV.

Understanding the fundamental mechanisms involved in the induction of biological damage by ionizing radiation remains a major challenge of todays radiobiology research. The Monte Carlo simulation of physical, physicochemical and chemical processes involved may provide a powerful tool for the simulation of early damage induction. The Geant4-DNA extension of the general purpose Monte Carlo Geant4 simulation toolkit aims to provide the scientific community with an open source access platform for the mechanistic simulation of such early damage. This paper presents the most recent review of the Geant4-DNA extension, as available to Geant4 users since June 2015 (release 10.2 Beta). In particular, the review includes the description of new physical models for the description of electron elastic and inelastic interactions in liquid water, as well as new examples dedicated to the simulation of physicochemical and chemical stages of water radiolysis. Several implementations of geometrical models of biological targets are presented as well, and the list of Geant4-DNA examples is described.

International audience; An accurate modeling of radial energy deposition around ion tracks is a key requirement of radiation transport software used for simulations in radiobiology at the sub-cellular scale. The work presented in this paper is part of the on-going benchmarking of the "Geant4-DNA" physics processes and models, which are available in the Geant4 Monte Carlo simulation toolkit for the low energy transport of particles in liquid water. We present for the first time radial dose distributions of incident ion tracks simulated with "Geant4-DNA". Simulation results are compared to other results available in the literature, obtained from analytical calculations, step-by-step Monte Carlo simulations and measurements. They show a reasonable agreement with reference data. © 2014 Elsevier B.V. All rights reserved.

Agradecimentos: The Geant4-DNA project received funding from the French Agence Nationale de la Recherche contract number ANR-09-BLAN-0135-01 and from the European Space Agency BioRad Project under contract number AO6041-22712/09/NL/AT. It was also supported in part by the RFBR 09-02-91065 grant and the CNRS PICS-4865 grant. The Region Aquitaine, France, funded the computing farm used in this work through the RESEARCH project. M. Bernal thanks the FAEPEX fund, UNICAMP, and the FAPESP foundation (FAPESP 2011/51594-2), both in Brazil, for financing his research activities. This work has been developed as a part of the activities planned in the Programme de Cooperation ECOS-Sud A09E04 Abstract: In the perspective of building an open source simulation platform dedicated to the modelling of early biological molecular damages due to ionising radiation at the DNA scale, the general-purpose Geant4 Monte Carlo simulation toolkit has been recently extended with specific very low energy electromagnetic physics processes for liquid water medium. These processes - also called "Geant4-DNA" processes - simulate the physical interactions induced by electrons, hydrogen and helium atoms of different charge states. The present work reports on the energy deposit distributions obtained for incident electrons, protons and alpha particles in nanometre-size volumes comparable to those present in the genetic material of mammalian cells. The frequency distributions of the energy deposition obtained for three typical geometries of nanometre-size cylindrical targets placed in a spherical phantom are found to be in reasonable agreement with prior works. Furthermore, we present a combination of the Geant4-DNA processes with a simplified geometrical model of a cellular nucleus allowing the evaluation of energy deposits in volumes of biological interest FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP Fechado

Purpose: Indirect biological damage due to reactive species produced in water radiolysis reactions is responsible for the majority of biological effect for low linear energy transfer (LET) radiation. Modeling water radiolysis and the subsequent interactions of reactive species, as well as track structures, is essential to model radiobiology on the microscale. Recently, chemistry models have been developed for Geant4-DNA to be used in combination with the comprehensive existing physics models. In the current work, the first detailed, independent, in silico validation of all species yields with published experimental observations and comparison with other radiobiological simulations is presented. Additionally,the effect of LET of protons and heavier ions on reactive species yield in the model was examined, as well as the completeness of the chemical reactions following the radiolysis within the time after physical interactions simulated in the model. Methods: Yields over time of reactive species were simulated for water radiolysis by incident electrons,protons, alpha particles, and ions with various LETs using Geant4 and RITRACKS simulation tools. Water dissociation and recombination was simulated using Geant4 to determine the completeness of chemical reactions at the end of the simulation. Yield validation was performed by comparing yields simulated using Geant4 with experimental observations and other simulations. Validation was performed for all species for low LET radiation and the solvated electron and hydroxyl radical for high LET ions. Results: It was found that the Geant4-DNA chemistry yields were generally in good agreement with experimental observations and other simulations. However, the Geant4-DNA yields for the hydroxyl radical and hydrogen peroxide at the end of the chemistry stage were found to be respectively considerably higher and lower than the experimentally observed yields. Increasing the LET of incident hadrons increased the yield of secondary species and decreased the yield of primary species. The effect of LET on the yield of the hydroxyl radical at 100 ns simulated with Geant4 was in good agreement with experimental measurements. Additionally, by the end of the simulation only 40% of dissociated water molecules had been recombined and the rate of recombination was slowing. Conclusions: The yields simulated using Geant4 are within reasonable agreement with experimental observations. Higher LET radiation corresponds with increased yields of secondary species and decreased yields of primary species. These trends combined with the LET having similar effects on the 100 ns hydroxyl radical yield for Geant4 and experimental measurements indicate that Geant4accurately models the effect of LET on radiolysis yields. The limited recombination within the modeled chemistry stage and the slowing rate of recombination at the end of the stage indicate potential long-range indirect biological damage. Refereed/Peer-reviewed