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2.
Phys Med ; 112: 102613, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37356419

ABSTRACT

PURPOSE: This study aimed to develop a computational environment for the accurate simulation of human cancer cell irradiation using Geant4-DNA. New cell geometrical models were developed and irradiated by alpha particle beams to induce DNA damage. The proposed approach may help further investigation of the benefits of external alpha irradiation therapy. METHODS: The Geant4-DNA Monte Carlo (MC) toolkit allows the simulation of cancer cell geometries that can be combined with accurate modelling of physical, physicochemical and chemical stages of liquid water irradiation, including radiolytic processes. Geant4-DNA is used to calculate direct and non-direct DNA damage yields, such as single and double strand breaks, produced by the deposition of energy or by the interaction of DNA with free radicals. RESULTS: In this study, the "molecularDNA" example application of Geant4-DNA was used to quantify early DNA damage in human cancer cells upon irradiation with alpha particle beams, as a function of linear energy transfer (LET). The MC simulation results are compared to experimental data, as well as previously published simulation data. The simulation results agree well with the experimental data on DSB yields in the lower LET range, while the experimental data on DSB yields are lower than the results obtained with the "molecularDNA" example in the higher LET range. CONCLUSION: This study explored and demonstrated the possibilities of the Geant4-DNA toolkit together with the "molecularDNA" example to simulate the helium beam irradiation of cancer cell lines, to quantify the early DNA damage, or even the following DNA damage response.


Subject(s)
Helium , Neoplasms , Humans , Computer Simulation , Linear Energy Transfer , DNA , Monte Carlo Method , DNA Damage , Neoplasms/radiotherapy
3.
Phys Med ; 105: 102508, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36549067

ABSTRACT

PURPOSE: Track structure Monte Carlo (MC) codes have achieved successful outcomes in the quantitative investigation of radiation-induced initial DNA damage. The aim of the present study is to extend a Geant4-DNA radiobiological application by incorporating a feature allowing for the prediction of DNA rejoining kinetics and corresponding cell surviving fraction along time after irradiation, for a Chinese hamster V79 cell line, which is one of the most popular and widely investigated cell lines in radiobiology. METHODS: We implemented the Two-Lesion Kinetics (TLK) model, originally proposed by Stewart, which allows for simulations to calculate residual DNA damage and surviving fraction along time via the number of initial DNA damage and its complexity as inputs. RESULTS: By optimizing the model parameters of the TLK model in accordance to the experimental data on V79, we were able to predict both DNA rejoining kinetics at low linear energy transfers (LET) and cell surviving fraction. CONCLUSION: This is the first study to demonstrate the implementation of both the cell surviving fraction and the DNA rejoining kinetics with the estimated initial DNA damage, in a realistic cell geometrical model simulated by full track structure MC simulations at DNA level and for various LET. These simulation and model make the link between mechanistic physical/chemical damage processes and these two specific biological endpoints.


Subject(s)
DNA Damage , Protons , Cricetinae , Animals , Cell Survival , Kinetics , DNA/chemistry , Monte Carlo Method
4.
Cancers (Basel) ; 13(19)2021 Sep 30.
Article in English | MEDLINE | ID: mdl-34638425

ABSTRACT

Accurately modeling the radiobiological mechanisms responsible for the induction of DNA damage remains a major scientific challenge, particularly for understanding the effects of low doses of ionizing radiation on living beings, such as the induction of carcinogenesis. A computational approach based on the Monte Carlo technique to simulate track structures in a biological medium is currently the most reliable method for calculating the early effects induced by ionizing radiation on DNA, the primary cellular target of such effects. The Geant4-DNA Monte Carlo toolkit can simulate not only the physical, but also the physico-chemical and chemical stages of water radiolysis. These stages can be combined with simplified geometric models of biological targets, such as DNA, to assess direct and indirect early DNA damage. In this study, DNA damage induced in a human fibroblast cell was evaluated using Geant4-DNA as a function of incident particle type (gammas, protons, and alphas) and energy. The resulting double-strand break yields as a function of linear energy transfer closely reproduced recent experimental data. Other quantities, such as fragment length distribution, scavengeable damage fraction, and time evolution of damage within an analytical repair model also supported the plausibility of predicting DNA damage using Geant4-DNA.The complete simulation chain application "molecularDNA", an example for users of Geant4-DNA, will soon be distributed through Geant4.

5.
Radiat Res ; 195(3): 221-229, 2021 03 01.
Article in English | MEDLINE | ID: mdl-33411888

ABSTRACT

Immunization with an inactivated virus is one of the strategies currently being tested towards developing a SARS-CoV-2 vaccine. One of the methods used to inactivate viruses is exposure to high doses of ionizing radiation to damage their nucleic acids. While gamma (γ) rays effectively induce lesions in the RNA, envelope proteins are also highly damaged in the process. This in turn may alter their antigenic properties, affecting their capacity to induce an adaptive immune response able to confer effective protection. Here, we modeled the effect of sparsely and densely ionizing radiation on SARS-CoV-2 using the Monte Carlo toolkit Geant4-DNA. With a realistic 3D target virus model, we calculated the expected number of lesions in the spike and membrane proteins, as well as in the viral RNA. Our findings showed that γ rays produced significant spike protein damage, but densely ionizing charged particles induced less membrane damage for the same level of RNA lesions, because a single ion traversal through the nuclear envelope was sufficient to inactivate the virus. We propose that accelerated charged particles produce inactivated viruses with little structural damage to envelope proteins, thereby representing a new and effective tool for developing vaccines against SARS-CoV-2 and other enveloped viruses.


Subject(s)
COVID-19 Vaccines/immunology , Monte Carlo Method , SARS-CoV-2/immunology , SARS-CoV-2/radiation effects , Humans , Linear Energy Transfer , RNA, Viral/radiation effects , Spike Glycoprotein, Coronavirus/radiation effects , Vaccines, Inactivated/immunology
6.
Cancers (Basel) ; 14(1)2021 Dec 22.
Article in English | MEDLINE | ID: mdl-35008196

ABSTRACT

The Geant4-DNA low energy extension of the Geant4 Monte Carlo (MC) toolkit is a continuously evolving MC simulation code permitting mechanistic studies of cellular radiobiological effects. Geant4-DNA considers the physical, chemical, and biological stages of the action of ionizing radiation (in the form of x- and γ-ray photons, electrons and ß±-rays, hadrons, α-particles, and a set of heavier ions) in living cells towards a variety of applications ranging from predicting radiotherapy outcomes to radiation protection both on earth and in space. In this work, we provide a brief, yet concise, overview of the progress that has been achieved so far concerning the different physical, physicochemical, chemical, and biological models implemented into Geant4-DNA, highlighting the latest developments. Specifically, the "dnadamage1" and "molecularDNA" applications which enable, for the first time within an open-source platform, quantitative predictions of early DNA damage in terms of single-strand-breaks (SSBs), double-strand-breaks (DSBs), and more complex clustered lesions for different DNA structures ranging from the nucleotide level to the entire genome. These developments are critically presented and discussed along with key benchmarking results. The Geant4-DNA toolkit, through its different set of models and functionalities, offers unique capabilities for elucidating the problem of radiation quality or the relative biological effectiveness (RBE) of different ionizing radiations which underlines nearly the whole spectrum of radiotherapeutic modalities, from external high-energy hadron beams to internal low-energy gamma and beta emitters that are used in brachytherapy sources and radiopharmaceuticals, respectively.

7.
Sci Rep ; 10(1): 20788, 2020 11 27.
Article in English | MEDLINE | ID: mdl-33247225

ABSTRACT

Ionising radiation induced DNA damage and subsequent biological responses to it 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. 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. We had previously developed an application allowing simulations of radiation induced early DNA damage on a naked cell nucleus model. In the new version presented in this work, we have developed three additional important features: (1) modeling of a realistic cell geometry, (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 Single Strand Break (SSB) yields for plasmid and Double Strand Break (DSB) yields for plasmid/human cell. In addition, the yields of indirect DSBs are compatible with the experimental scavengeable damage fraction. The simulation application also demonstrates agreement with experimental data of [Formula: see text]-H2AX yields for gamma ray irradiation. Using this application, it is now possible to predict biological response along time through track-structure MC simulations.


Subject(s)
DNA Damage , DNA Repair , Models, Biological , Computer Simulation , DNA/radiation effects , DNA Breaks, Double-Stranded , Gamma Rays/adverse effects , Histones/radiation effects , Humans , Monte Carlo Method , Software
8.
Sci Rep ; 9(1): 14891, 2019 10 17.
Article in English | MEDLINE | ID: mdl-31624294

ABSTRACT

Over millennia, life has been exposed to ionizing radiation from cosmic rays and natural radioisotopes. Biological experiments in underground laboratories have recently demonstrated that the contemporary terrestrial radiation background impacts the physiology of living organisms, yet the evolutionary consequences of this biological stress have not been investigated. Explaining the mechanisms that give rise to the results of underground biological experiments remains difficult, and it has been speculated that hereditary mechanisms may be involved. Here, we have used evolution experiments in standard and very low-radiation backgrounds to demonstrate that environmental ionizing radiation does not significantly impact the evolutionary trajectories of E. coli bacterial populations in a 500 generations evolution experiment.


Subject(s)
Background Radiation/adverse effects , Escherichia coli/genetics , Escherichia coli/radiation effects , Evolution, Molecular , Cosmic Radiation/adverse effects , Dose-Response Relationship, Radiation , Escherichia coli/growth & development , Genetic Fitness/radiation effects , Mutation
9.
Phys Med ; 62: 152-157, 2019 Jun.
Article in English | MEDLINE | ID: mdl-31109825

ABSTRACT

The advancement of multidisciplinary research fields dealing with ionising radiation induced biological damage - radiobiology, radiation physics, radiation protection and, in particular, medical physics - requires a clear mechanistic understanding of how cellular damage is induced by ionising radiation. Monte Carlo (MC) simulations provide a promising approach for the mechanistic simulation of radiation transport and radiation chemistry, towards the in silico simulation of early biological damage. We have recently developed a fully integrated MC simulation that calculates early single strand breaks (SSBs) and double strand breaks (DSBs) in a fractal chromatin based human cell nucleus model. The results of this simulation are almost equivalent to past MC simulations when considering direct/indirect strand break fraction, DSB yields and fragment distribution. The simulation results agree with experimental data on DSB yields within 13.6% on average and fragment distributions agree within an average of 34.8%.


Subject(s)
Cell Nucleus/genetics , Cell Nucleus/radiation effects , DNA Damage , Fractals , Models, Biological , Monte Carlo Method , Animals , DNA Breaks, Double-Stranded/radiation effects , DNA Breaks, Single-Stranded/radiation effects , Time Factors
10.
Cancer Nanotechnol ; 9(1): 9, 2018.
Article in English | MEDLINE | ID: mdl-30524511

ABSTRACT

A novel treatment planning framework, the Relative Biological Effective Dose (RBED), for high Z nanoparticle (NP)-enhanced photon radiotherapy is developed and tested in silico for the medical exemplar of neoadjuvant (preoperative) breast cancer MV photon radiotherapy. Two different treatment scenarios, conventional and high Z NP enhanced, were explored with a custom Geant4 application that was developed to emulate the administration of a single 2 Gy fraction as part of a 50 Gy radiotherapy treatment plan. It was illustrated that there was less than a 1% difference in the dose deposition throughout the standard and high Z NP-doped adult female phantom. Application of the RBED framework found that the extent of possible biological response with high Z NP doping was great than expected via the dose deposition alone. It is anticipated that this framework will assist the scientific community in future high Z NP-enhanced in-silico, pre-clinical and clinical trials.

11.
Phys Med ; 48: 135-145, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29628360

ABSTRACT

Mechanistic modelling of DNA damage in Monte Carlo simulations is highly sensitive to the parameters that define DNA damage. In this work, we use a simple testing geometry to investigate how different choices of physics models and damage model parameters can change the estimation of DNA damage in a mechanistic DNA damage simulation built in Geant4-DNA. The choice of physics model can lead to variations by up to a factor of two in the yield of physically induced strand breaks, and the parameters that determine scavenging, and physical and chemical single strand break induction can have even larger consequences. Using low energy electrons as primary particles, a variety of parameters are tested in this geometry in order to arrive at a parameter set consistent with past simulation studies. We find that the modelling of scavenging can play an important role in determining results, and speculate that high-scavenging regimes, where only chemical radicals within 1 nm of DNA are simulated, could provide a good means of testing mechanistic DNA simulations.


Subject(s)
DNA Damage , Monte Carlo Method , DNA/chemistry , DNA/genetics , Electrons/adverse effects , Models, Molecular , Nucleic Acid Conformation
12.
J Vis Exp ; (132)2018 02 03.
Article in English | MEDLINE | ID: mdl-29443063

ABSTRACT

Micro-analytical techniques based on chemical element imaging enable the localization and quantification of chemical composition at the cellular level. They offer new possibilities for the characterization of living systems and are particularly appropriate for detecting, localizing and quantifying the presence of metal oxide nanoparticles both in biological specimens and the environment. Indeed, these techniques all meet relevant requirements in terms of (i) sensitivity (from 1 up to 10 µg.g-1 of dry mass), (ii) micrometer range spatial resolution, and (iii) multi-element detection. Given these characteristics, microbeam chemical element imaging can powerfully complement routine imaging techniques such as optical and fluorescence microscopy. This protocol describes how to perform a nuclear microprobe analysis on cultured cells (U2OS) exposed to titanium dioxide nanoparticles. Cells must grow on and be exposed directly in a specially designed sample holder used on the optical microscope and in the nuclear microprobe analysis stages. Plunge-freeze cryogenic fixation of the samples preserves both the cellular organization and the chemical element distribution. Simultaneous nuclear microprobe analysis (scanning transmission ion microscopy, Rutherford backscattering spectrometry and particle induced X-ray emission) performed on the sample provides information about the cellular density, the local distribution of the chemical elements, as well as the cellular content of nanoparticles. There is a growing need for such analytical tools within biology, especially in the emerging context of Nanotoxicology and Nanomedicine for which our comprehension of the interactions between nanoparticles and biological samples must be deepened. In particular, as nuclear microprobe analysis does not require nanoparticles to be labelled, nanoparticle abundances are quantifiable down to the individual cell level in a cell population, independently of their surface state.


Subject(s)
Electron Probe Microanalysis/methods , Metal Nanoparticles/chemistry , Oxides/chemistry , Cells, Cultured , Humans
13.
Med Phys ; 45(5): 2230-2242, 2018 May.
Article in English | MEDLINE | ID: mdl-29480947

ABSTRACT

PURPOSE: Gold nanoparticles (GNPs) are known to enhance the absorbed dose in their vicinity following photon-based irradiation. To investigate the therapeutic effectiveness of GNPs, previous Monte Carlo simulation studies have explored GNP dose enhancement using mostly condensed-history models. However, in general, such models are suitable for macroscopic volumes and for electron energies above a few hundred electron volts. We have recently developed, for the Geant4-DNA extension of the Geant4 Monte Carlo simulation toolkit, discrete physics models for electron transport in gold which include the description of the full atomic de-excitation cascade. These models allow event-by-event simulation of electron tracks in gold down to 10 eV. The present work describes how such specialized physics models impact simulation-based studies on GNP-radioenhancement in a context of x-ray radiotherapy. METHODS: The new discrete physics models are compared to the Geant4 Penelope and Livermore condensed-history models, which are being widely used for simulation-based NP radioenhancement studies. An ad hoc Geant4 simulation application has been developed to calculate the absorbed dose in liquid water around a GNP and its radioenhancement, caused by secondary particles emitted from the GNP itself, when irradiated with a monoenergetic electron beam. The effect of the new physics models is also quantified in the calculation of secondary particle spectra, when originating in the GNP and when exiting from it. RESULTS: The new physics models show similar backscattering coefficients with the existing Geant4 Livermore and Penelope models in large volumes for 100 keV incident electrons. However, in submicron sized volumes, only the discrete models describe the high backscattering that should still be present around GNPs at these length scales. Sizeable differences (mostly above a factor of 2) are also found in the radial distribution of absorbed dose and secondary particles between the new and the existing Geant4 models. The degree to which these differences are due to intrinsic limitations of the condensed-history models or to differences in the underling scattering cross sections requires further investigation. CONCLUSIONS: Improved physics models for gold are necessary to better model the impact of GNPs in radiotherapy via Monte Carlo simulations. We implemented discrete electron transport models for gold in Geant4 that is applicable down to 10 eV including the modeling of the full de-excitation cascade. It is demonstrated that the new model has a significant positive impact on particle transport simulations in gold volumes with submicron dimensions compared to the existing Livermore and Penelope condensed-history models of Geant4.


Subject(s)
Electrons , Gold/chemistry , Metal Nanoparticles , Monte Carlo Method , Particle Size , Radiation Dosage
14.
Phys Med ; 48: 146-155, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29371062

ABSTRACT

We extended a generic Geant4 application for mechanistic DNA damage simulations to an Escherichia coli cell geometry, finding electron damage yields and proton damage yields largely in line with experimental results. Depending on the simulation of radical scavenging, electrons double strand breaks (DSBs) yields range from 0.004 to 0.010 DSB Gy-1 Mbp-1, while protons have yields ranging from 0.004 DSB Gy-1 Mbp-1 at low LETs and with strict assumptions concerning scavenging, up to 0.020 DSB Gy-1 Mbp-1 at high LETs and when scavenging is weakest. Mechanistic DNA damage simulations can provide important limits on the extent to which physical processes can impact biology in low background experiments. We demonstrate the utility of these studies for low dose radiation biology calculating that in E. coli, the median rate at which the radiation background induces double strand breaks is 2.8 × 10-8 DSB day-1, significantly less than the mutation rate per generation measured in E. coli, which is on the order of 10-3.


Subject(s)
DNA Damage , Electrons/adverse effects , Escherichia coli/genetics , Escherichia coli/radiation effects , Monte Carlo Method , Protons/adverse effects , DNA, Bacterial/chemistry , DNA, Bacterial/genetics , Escherichia coli/cytology , Models, Molecular , Nucleic Acid Conformation
15.
Evol Appl ; 10(7): 658-666, 2017 08.
Article in English | MEDLINE | ID: mdl-28717386

ABSTRACT

Biological experiments conducted in underground laboratories over the last decade have shown that life can respond to relatively small changes in the radiation background in unconventional ways. Rapid changes in cell growth, indicative of hormetic behaviour and long-term inheritable changes in antioxidant regulation have been observed in response to changes in the radiation background that should be almost undetectable to cells. Here, we summarize the recent body of underground experiments conducted to date, and outline potential mechanisms (such as cell signalling, DNA repair and antioxidant regulation) that could mediate the response of cells to low radiation backgrounds. We highlight how multigenerational studies drawing on methods well established in studying evolutionary biology are well suited for elucidating these mechanisms, especially given these changes may be mediated by epigenetic pathways. Controlled evolution experiments with model organisms, conducted in underground laboratories, can highlight the short- and long-term differences in how extremely low-dose radiation environments affect living systems, shining light on the extent to which epimutations caused by the radiation background propagate through the population. Such studies can provide a baseline for understanding the evolutionary responses of microorganisms to ionizing radiation, and provide clues for understanding the higher radiation environments around uranium mines and nuclear disaster zones, as well as those inside nuclear reactors.

16.
PLoS One ; 11(11): e0166364, 2016.
Article in English | MEDLINE | ID: mdl-27851794

ABSTRACT

At very low radiation dose rates, the effects of energy depositions in cells by ionizing radiation is best understood stochastically, as ionizing particles deposit energy along tracks separated by distances often much larger than the size of cells. We present a thorough analysis of the stochastic impact of the natural radiative background on cells, focusing our attention on E. coli grown as part of a long term evolution experiment in both underground and surface laboratories. The chance per day that a particle track interacts with a cell in the surface laboratory was found to be 6 × 10-5 day-1, 100 times less than the expected daily mutation rate for E. coli under our experimental conditions. In order for the chance cells are hit to approach the mutation rate, a gamma background dose rate of 20 µGy hr-1 is predicted to be required.


Subject(s)
Background Radiation , Computer Simulation , Escherichia coli/radiation effects , Radiation, Ionizing , Dose-Response Relationship, Radiation , Electrons , Likelihood Functions
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