The chemical stage of the Monte Carlo track-structure (MCTS) code Geant4-DNA was extended for its use in DNA strand break (SB) simulations and compared against published experimental data. Geant4-DNA simulations were performed using pUC19 plasmids (2686 base pairs) in a buffered solution of DMSO irradiated by60Co or137Csγ-rays. A comprehensive evaluation of SSB yields was performed considering DMSO, DNA concentration, dose and plasmid supercoiling. The latter was measured using the super helix density value used in a Brownian dynamics plasmid generation algorithm. The Geant4-DNA implementation of the independent reaction times method (IRT), developed to simulate the reaction kinetics of radiochemical species, allowed to score the fraction of supercoiled, relaxed and linearized plasmid fractions as a function of the absorbed dose. The percentage of the number of SB after •OH + DNA and H• + DNA reactions, referred as SSB efficiency, obtained using MCTS were 13.77% and 0.74% respectively. This is in reasonable agreement with published values of 12% and 0.8%. The SSB yields as a function of DMSO concentration, DNA concentration and super helix density recreated the expected published experimental behaviors within 5%, one standard deviation. The dose response of SSB and DSB yields agreed with published measurements within 5%, one standard deviation. We demonstrated that the developed extension of IRT in Geant4-DNA, facilitated the reproduction of experimental conditions. Furthermore, its calculations were strongly in agreement with experimental data. These two facts will facilitate the use of this extension in future radiobiological applications, aiding the study of DNA damage mechanisms with a high level of detail.

• Klíčová slova
• DNA damage, geant4-DNA, plasmid, radiation chemistry, simulation, track-structure,
• MeSH
• dimethylsulfoxid * MeSH
• DNA chemie   MeSH
• konformace nukleové kyseliny MeSH
• metoda Monte Carlo MeSH
• plazmidy MeSH
• počítačová simulace MeSH
• poškození DNA * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• dimethylsulfoxid * MeSH
• DNA MeSH

PURPOSE: The simulation of individual particle tracks and the chemical stage following water radiolysis in biological tissue is an effective means of improving our knowledge of the physico-chemical contribution to the biological effect of ionizing radiation. However, the step-by-step simulation of the reaction kinetics of radiolytic species is the most time-consuming task in Monte Carlo track-structure simulations, with long simulation times that are an impediment to research. In this work, we present the implementation of the independent reaction times (IRT) method in Geant4-DNA Monte Carlo toolkit to improve the computational efficiency of calculating G-values, defined as the number of chemical species created or lost per 100 eV of deposited energy. METHODS: The computational efficiency of IRT, as implemented, is compared to that from available Geant4-DNA step-by-step simulations for electrons, protons and alpha particles covering a wide range of linear energy transfer (LET). The accuracy of both methods is verified using published measured data from fast electron irradiations for • OH and e aq - for time-dependent G-values. For IRT, simulations in the presence of scavengers irradiated by cobalt-60 γ-ray and 2 MeV protons are compared with measured data for different scavenging capacities. In addition, a qualitative assessment comparing measured LET-dependent G-values with Geant4-DNA calculations in pure liquid water is presented. RESULTS: The IRT improved the computational efficiency by three orders of magnitude relative to the step-by-step method while differences in G-values by 3.9% at 1 μs were found. At 7 ps, • OH and e aq - yields calculated with IRT differed from recent published measured data by 5% ± 4% and 2% ± 4%, respectively. At 1 μs, differences were 9% ± 5% and 6% ± 7% for • OH and e aq - , respectively. Uncertainties are one standard deviation. Finally, G-values at different scavenging capacities and LET-dependent G-values reproduced the behavior of measurements for all radiation qualities. CONCLUSION: The comprehensive validation of the Geant4-DNA capabilities to accurately simulate the chemistry following water radiolysis is an ongoing work. The implementation presented in this work is a necessary step to facilitate performing such a task.

• Klíčová slova
• Geant4-DNA, LET, Monte Carlo, independent reaction times, radiolysis, track-structure,
• MeSH
• chemické modely * MeSH
• DNA MeSH
• lineární přenos energie * MeSH
• metoda Monte Carlo MeSH
• počítačová simulace MeSH
• reakční čas MeSH
• voda MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA MeSH
• voda MeSH

Understanding the fundamental mechanisms involved in the induction of biological damage by ionizing radiation remains a major challenge of today's 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.

• Klíčová slova
• Geant4-DNA, Ionizing radiation, Monte Carlo, Radiobiology, Radiolysis,
• MeSH
• chemické jevy MeSH
• DNA chemie   MeSH
• lidé MeSH
• metoda Monte Carlo * MeSH
• molekulární modely * MeSH
• voda chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• DNA MeSH
• voda MeSH

PURPOSE: Geant4-DNA is used to calculate S-values for different subcellular distributions of low-energy electron sources in various cell geometries. METHOD: Calculations of cellular S-values for monoenergetic electron sources with energy from 1 to 100 keV and the Auger-electron emitting radionuclides Tc-99m, In-111, and I-125 have been made using the Geant4 Monte Carlo toolkit. The Geant4-DNA low-energy extension is employed for simulating collision-by-collision the complete slowing-down of electron tracks (down to 8 eV) in liquid water, used as a surrogate of human cells. The effect of cell geometry on S-values is examined by simulating electron tracks within different cell geometries, namely, a spherical, two ellipsoidal, and an irregular shape, all having equal cellular and nuclear volumes. Algorithms for randomly sampling the volume of the nucleus, cytoplasm, surface, and whole cell for each cell phantom are presented. RESULTS: Differences between Geant4-DNA and MIRD database up to 50% were found, although, for the present radionuclides, they mostly remain below 10%. For most source-target combinations the S-values for the spherical cell geometry were found to be within 20% of those for the ellipsoidal cell geometries, with a maximum deviation of 32%. Differences between the spherical and irregular geometries are generally larger reaching 100-300%. Most sensitive to the cell geometry is the absorbed dose to the nucleus when the source is localized on the cell surface. Interestingly, two published AAPM spectra for I-125 yield noticeable differences (up to 19%) in cellular S-values. CONCLUSION: Monte Carlo simulations of cellular S-values with Geant4-DNA reveal that, for the examined radionuclides, the widely used approximation of spherical cells is reasonably accurate (within 20-30%) even for ellipsoidal geometries. For irregular cell geometries the spherical approximation should be used with caution because, as in the present example, it may lead to erroneous results for the nuclear dose for the commonly encountered situation where the source is localized to the cell surface.

• Klíčová slova
• Cellular dosimetry, Geant4-DNA, Monte Carlo, Radionuclide dosimetry, S-values,
• MeSH
• absorpce radiace * MeSH
• biologické modely * MeSH
• dávka záření MeSH
• elektrony MeSH
• lidé MeSH
• metoda Monte Carlo MeSH
• počítačová simulace MeSH
• radiometrie metody   MeSH
• statistické modely * MeSH
• velikost buňky * MeSH
• viabilita buněk účinky léků   fyziologie   MeSH
• vztah dávky záření a odpovědi MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

PURPOSE: Simulation of indirect damage originating from the attack of free radical species produced by ionizing radiation on biological molecules based on the independent pair approximation is investigated in this work. In addition, a new approach, relying on the independent pair approximation that is at the origin of the independent reaction time (IRT) method, is proposed in the chemical stage of Geant4-DNA. METHODS: This new approach has been designed to respect the current Geant4-DNA chemistry framework while proposing a variant IRT method. Based on the synchronous algorithm, this implementation allows us to access the information concerning the position of radicals and may make it more convenient for biological damage simulations. Estimates of the evolution of free species as well as biological hits in a segment of DNA chromatin fiber in Geant4-DNA were compared for the dynamic time step approach of the step-by-step (SBS) method, currently used in Geant4-DNA, and this newly implemented IRT. RESULTS: Results show a gain in computation time of a factor of 30 for high LET particle tracks with a better than 10% agreement on the number of DNA hits between the value obtained with the IRT method as implemented in this work and the SBS method currently available in Geant4-DNA. CONCLUSION: Offering in Geant4-DNA more efficient methods for the chemical step based on the IRT method is a task in progress. For the calculation of biological damage, information on the position of chemical species is a crucial point. This can be achieved using the method presented in this paper.

• Klíčová slova
• DNA damage, Geant4-DNA, IRT, diffusion-controlled reaction,
• MeSH
• chromatin genetika   MeSH
• DNA * genetika   MeSH
• metoda Monte Carlo MeSH
• poškození DNA * MeSH
• reakční čas MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chromatin MeSH
• DNA * MeSH

NASA has encouraged studies on 226Ra deposition in the human brain to investigate the effects of exposure to alpha particles with high linear energy transfer, which could mimic some of the exposure astronauts face during space travel. However, this approach was criticized, noting that radium is a bone-seeker and accumulates in the skull, which means that the radiation dose from alpha particles emitted by 226Ra would be heavily concentrated in areas close to cranial bones rather than uniformly distributed throughout the brain. In the high background radiation areas of Ramsar, Iran, extremely high levels of 226Ra in soil contribute to a large proportion of the inhabitants' radiation exposure. A prospective study on Ramsar residents with a calcium-rich diet was conducted to improve the dose uniformity due to 226Ra throughout the cerebral and cerebellar parenchyma. The study found that exposure of the human brain to alpha particles did not significantly affect working memory but was significantly associated with increased reaction times. This finding is crucial because astronauts on deep space missions may face similar cognitive impairments due to exposure to high charge and energy particles. The current study was aimed to evaluate the validity of the terrestrial model using the Geant4 Monte Carlo toolkit to simulate the interactions of alpha particles and representative cosmic ray particles, acknowledging that these radiation types are only a subset of the complete space radiation environment.

• Klíčová slova
• Alpha particles, Monte Carlo simulation, Radiation, Radium, Space exploration,
• MeSH
• DNA MeSH
• lidé MeSH
• lineární přenos energie MeSH
• metoda Monte Carlo MeSH
• mozek MeSH
• prospektivní studie MeSH
• radium * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA MeSH
• radium * MeSH

The chemical stage of the Monte Carlo track-structure simulation code Geant4-DNA has been revised and validated. The root-mean-square (RMS) empirical parameter that dictates the displacement of water molecules after an ionization and excitation event in Geant4-DNA has been shortened to better fit experimental data. The pre-defined dissociation channels and branching ratios were not modified, but the reaction rate coefficients for simulating the chemical stage of water radiolysis were updated. The evaluation of Geant4-DNA was accomplished with TOPAS-nBio. For that, we compared predicted time-dependentGvalues in pure liquid water for·OH, e-aq, and H2with published experimental data. For H2O2and H·, simulation of added scavengers at different concentrations resulted in better agreement with measurements. In addition, DNA geometry information was integrated with chemistry simulation in TOPAS-nBio to realize reactions between radiolytic chemical species and DNA. This was used in the estimation of the yield of single-strand breaks (SSB) induced by137Csγ-ray radiolysis of supercoiled pUC18 plasmids dissolved in aerated solutions containing DMSO. The efficiency of SSB induction by reaction between radiolytic species and DNA used in the simulation was chosen to provide the best agreement with published measurements. An RMS displacement of 1.24 nm provided agreement with measured data within experimental uncertainties for time-dependentGvalues and under the presence of scavengers. SSB efficiencies of 24% and 0.5% for·OH and H·, respectively, led to an overall agreement of TOPAS-nBio results within experimental uncertainties. The efficiencies obtained agreed with values obtained with published non-homogeneous kinetic model and step-by-step Monte Carlo simulations but disagreed by 12% with published direct measurements. Improvement of the spatial resolution of the DNA damage model might mitigate such disagreement. In conclusion, with these improvements, Geant4-DNA/TOPAS-nBio provides a fast, accurate, and user-friendly tool for simulating DNA damage under low linear energy transfer irradiation.

• Klíčová slova
• DNA damage, Geant4-DNA, TOPAS-nBio, plasmid DNA, radiation chemistry, track structure, validation,
• MeSH
• lineární přenos energie MeSH
• metoda Monte Carlo MeSH
• počítačová simulace MeSH
• poškození DNA * MeSH
• voda * MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• validační studie MeSH
• Názvy látek
• voda * MeSH

Protons are the dominant particles both in galactic cosmic rays and in solar particle events and, furthermore, proton irradiation becomes increasingly used in tumour treatment. It is believed that complex DNA damage is the determining factor for the consequent cellular response to radiation. DNA plasmid pBR322 was irradiated at U120-M cyclotron with 30 MeV protons and treated with two Escherichia coli base excision repair enzymes. The yields of SSBs and DSBs were analysed using agarose gel electrophoresis. DNA has been irradiated in the presence of hydroxyl radical scavenger (coumarin-3-carboxylic acid) in order to distinguish between direct and indirect damage of the biological target. Pure scavenger solution was used as a probe for measurement of induced OH· radical yields. Experimental OH· radical yield kinetics was compared with predictions computed by two theoretical models-RADAMOL and Geant4-DNA. Both approaches use Geant4-DNA for description of physical stages of radiation action, and then each of them applies a distinct model for description of the pre-chemical and chemical stage.

• MeSH
• DNA chemie   účinky záření   MeSH
• hydroxylový radikál chemie   MeSH
• kinetika MeSH
• kumariny chemie   MeSH
• oprava DNA genetika   MeSH
• plazmidy chemie   genetika   MeSH
• poškození DNA účinky záření   MeSH
• proteiny z Escherichia coli metabolismus   MeSH
• protony * MeSH
• vztah dávky záření a odpovědi MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• coumarin-3-carboxylic acid MeSH Prohlížeč
• DNA MeSH
• hydroxylový radikál MeSH
• kumariny MeSH
• proteiny z Escherichia coli MeSH
• protony * MeSH

Experimental radiobiological studies in which the effects of ionizing radiation on a biological model are examined often highlight the biological aspects while missing detailed descriptions of the geometry, sample and dosimetric methods used. Such omissions can hinder the reproducibility and comparability of the experimental data. An application based on the Geant4 simulation toolkit was developed to design experiments using a biological solution placed in a microtube. The application was used to demonstrate the influence of the type of microtube, sample volume and energy of a proton source on the dose distribution across the sample, and on the mean dose in the whole sample. The results shown here are for samples represented by liquid water in the 0.4-, 1.5- and 2.0-ml microtubes irradiated with 20, 30 and 100 MeV proton beams. The results of this work demonstrate that the mean dose and homogeneity of the dose distribution within the sample strongly depend on all three parameters. Furthermore, this work shows how the dose uncertainty propagates into the scored primary DNA damages in plasmid DNA studies using agarose gel electrophoresis. This application is provided freely to assist users in verifying their experimental setup prior to the experiment.

• MeSH
• biologické modely MeSH
• dávka záření * MeSH
• elektroforéza v agarovém gelu MeSH
• ionizující záření MeSH
• nejistota MeSH
• plazmidy MeSH
• poškození DNA MeSH
• protony MeSH
• radiometrie metody   MeSH
• reprodukovatelnost výsledků MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• protony MeSH

PURPOSE: The complex relationship between linear energy transfer (LET) and cellular response to radiation is not yet fully elucidated. To better characterize DNA damage after irradiations with therapeutic protons, we monitored formation and disappearance of DNA double-strand breaks (DNA DSB) as a function of LET and time. Comparisons with conventional γ-rays and high LET carbon ions were also performed. MATERIALS AND METHODS: In the present work, we performed immunofluorescence-based assay to determine the amount of DNA DSB induced by different LET values along the 62 MeV therapeutic proton Spread out Bragg peak (SOBP) in three cancer cell lines, i.e. HTB140 melanoma, MCF-7 breast adenocarcinoma and HTB177 non-small lung cancer cells. Time dependence of foci formation was followed as well. To determine irradiation positions, corresponding to the desired LET values, numerical simulations were carried out using Geant4 toolkit. We compared γ-H2AX foci persistence after irradiations with protons to that of γ-rays and carbon ions. RESULTS: With the rise of LET values along the therapeutic proton SOBP, the increase of γ-H2AX foci number is detected in the three cell lines up to the distal end of the SOBP, while there is a decrease on its distal fall-off part. With the prolonged incubation time, the number of foci gradually drops tending to attain the residual level. For the maximum number of DNA DSB, irradiation with protons attain higher level than that of γ-rays. Carbon ions produce more DNA DSB than protons but not substantially. The number of residual foci produced by γ-rays is significantly lower than that of protons and particularly carbon ions. Carbon ions do not produce considerably higher number of foci than protons, as it could be expected due to their physical properties. CONCLUSIONS: In situ visualization of γ-H2AX foci reveal creation of more lesions in the three cell lines by clinically relevant proton SOBP than γ-rays. The lack of significant differences in the number of γ-H2AX foci between the proton and carbon ion-irradiated samples suggests an increased complexity of DNA lesions and slower repair kinetics after carbon ions compared to protons. For all three irradiation types, there is no major difference between the three cell lines shortly after irradiations, while later on, the formation of residual foci starts to express the inherent nature of tested cells, therefore increasing discrepancy between them.

• Klíčová slova
• DNA double-strand breaks, Human malignant cells, carbon ions, protons, γ-rays,
• MeSH
• časové faktory MeSH
• dvouřetězcové zlomy DNA * účinky záření   MeSH
• histony * metabolismus   MeSH
• lidé MeSH
• lineární přenos energie * MeSH
• MFC-7 buňky MeSH
• nádorové buněčné linie MeSH
• protonová terapie MeSH
• protony * MeSH
• vztah dávky záření a odpovědi MeSH
• záření gama MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• H2AX protein, human MeSH Prohlížeč
• histony * MeSH
• protony * MeSH