RESUMO
"FLASH radiotherapy" is a new method of radiation treatment by which large doses of radiation are delivered at high dose rates to tumors almost instantaneously (a few milliseconds), paradoxically sparing healthy tissue while preserving anti-tumor activity. To date, no definitive mechanism has been proposed to explain the different responses of the tumor and normal tissue to radiation. As a first step, and given that living cells and tissues consist mainly of water, we studied the effects of high dose rates on the transient yields (G values) of the radical and molecular species formed in the radiolysis of deaerated/aerated water by irradiating protons, using Monte Carlo simulations. Our simulation model consisted of two steps: 1. The random irradiation of a right circular cylindrical volume of water, embedded in nonirradiated bulk water, with single and instantaneous pulses of N 300-MeV incident protons ("linear energy transfer" or LET â¼ 0.3 keV/µm) traveling along the axis of the cylinder; and 2. The development of these N proton tracks, which were initially contained in the irradiated cylinder, throughout the solution over time. The effect of dose rate was studied by varying N, which was calibrated in terms of dose rate. For this, experimental data on the yield G(Fe3+) of the super-Fricke dosimeter as a function of dose rate up to â¼1010 Gy/s were used. Confirming previous experimental and theoretical studies, significant changes in product yields were found to occur with increasing dose rate, with lower radical and higher molecular yields, which result from an increase in the radical density in the bulk of the solution. Using the kinetics of the decay of hydrated electrons, a critical time (τc), which corresponds to the "onset" of dose-rate effects, was determined for each value of N. For the cylindrical irradiation model, τc was inversely proportional to the dose rate. Moreover, the comparison with experiments with pulsed electrons underlined the importance of the geometry of the irradiation volume for the estimation of τc. Finally, in the case of aerated water radiolysis, we calculated the yield of oxygen consumption and estimated the corresponding concentration of consumed (depleted) oxygen as a function of time and dose rate. It was shown that this concentration increases substantially with increasing dose rate in the time window â¼1 ns-10 µs, with a very pronounced maximum around 0.2 µs. For high-dose-rate irradiations (>109 Gy/s), a large part of the available oxygen (â¼0.25 mM for an air-saturated solution) was found to be consumed. This result, which was obtained on a purely water radiation chemistry basis, strongly supports the hypothesis that the normal tissue-sparing effect of FLASH stems from temporary hypoxia due to oxygen depletion induced by high-dose-rate irradiation.
Assuntos
Neoplasias/radioterapia , Radioterapia (Especialidade)/métodos , Radioterapia/métodos , Simulação por Computador , Elétrons , Humanos , Cinética , Transferência Linear de Energia/efeitos da radiação , Método de Monte Carlo , Oxigênio/metabolismo , Consumo de Oxigênio/efeitos da radiação , Prótons , Doses de Radiação , Radioquímica , Água/químicaRESUMO
The cellular response to ionizing radiation continues to be of significant research interest in cancer radiotherapy, and DNA is recognized as the critical target for most of the biologic effects of radiation. Incident particles can cause initial DNA damages through physical and chemical interactions within a short time scale. Initial DNA damages can undergo repair via different pathways available at different stages of the cell cycle. The misrepair of DNA damage results in genomic rearrangement and causes mutations and chromosome aberrations, which are drivers of cell death. This work presents an integrated study of simulating cell response after proton irradiation with energies of 0.5-500 MeV (LET of 60-0.2 keV/µm). A model of a whole nucleus with fractal DNA geometry was implemented in TOPAS-nBio for initial DNA damage simulations. The default physics and chemistry models in TOPAS-nBio were used to describe interactions of primary particles, secondary particles, and radiolysis products within the nucleus. The initial DNA double-strand break (DSB) yield was found to increase from 6.5 DSB/Gy/Gbp at low-linear energy transfer (LET) of 0.2 keV/µm to 21.2 DSB/Gy/Gbp at high LET of 60 keV/µm. A mechanistic repair model was applied to predict the characteristics of DNA damage repair and dose response of chromosome aberrations. It was found that more than 95% of the DSBs are repaired within the first 24 h and the misrepaired DSB fraction increases rapidly with LET and reaches 15.8% at 60 keV/µm with an estimated chromosome aberration detection threshold of 3 Mbp. The dicentric and acentric fragment yields and the dose response of micronuclei formation after proton irradiation were calculated and compared with experimental results.
Assuntos
Modelos Biológicos , Método de Monte Carlo , Prótons , Aberrações Cromossômicas/efeitos da radiação , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Humanos , Transferência Linear de Energia/efeitos da radiaçãoRESUMO
DNA damage induced by ionizing radiation exposure is enhanced in the presence of oxygen (the "oxygen effect"). Despite its practical importance in radiotherapy, the oxygen effect has largely been excluded from models that predict DNA damage from radiation tracks. A Monte Carlo-based algorithm was developed in MATLAB software to predict DNA damage from physical and chemical tracks through a cell nucleus simulated in Geant4-DNA, taking into account the effects of cellular oxygenation (pO2) on DNA radical chemistry processes. An initial spatial distribution of DNA base and sugar radicals was determined by spatially clustering direct events (that deposited at least 10.79 eV) and hydroxyl radical (â¢OH) interactions. The oxygen effect was modeled by increasing the efficiency with which sugar radicals from direct-type effects were converted to strand breaks from 0.6 to 1, the efficiency with which sugar radicals from the indirect effect were converted to strand breaks from 0.28 to 1 and the efficiency of base-to-sugar radical transfer from â¢OH-mediated base radicals from 0 to 0.03 with increasing pO2 from 0 to 760 mmHg. The DNA damage induction algorithm was applied to tracks from electrons, protons and alphas with LET values from 0.2 to 150 keV/µm under different pO2 conditions. The oxygen enhancement ratio for double-strand break induction was 3.0 for low-LET radiation up to approximately 15 keV/µm, after which it gradually decreased to a value of 1.3 at 150 keV/µm. These values were consistent with a range of experimental data published in the literature. The DNA damage yields were verified using experimental data in the literature and results from other theoretical models. The spatial clustering approach developed in this work has low memory requirements and may be suitable for particle tracking simulations with a large number of cells.
Assuntos
Simulação por Computador , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Dano ao DNA/efeitos da radiação , DNA/efeitos da radiação , Algoritmos , Humanos , Radical Hidroxila/química , Transferência Linear de Energia/efeitos da radiação , Método de Monte Carlo , Oxigênio/química , Prótons , Radiação IonizanteRESUMO
Radiation damage to the central nervous system (CNS) has been an on-going challenge for the last decades primarily due to the issues of brain radiotherapy and radiation protection for astronauts during space travel. Although recent findings revealed a number of molecular mechanisms associated with radiation-induced impairments in behaviour and cognition, some uncertainties exist in the initial neuronal cell injury leading to the further development of CNS malfunction. The present study is focused on the investigation of early biological damage induced by ionizing radiations in a sample neural network by means of modelling physico-chemical processes occurring in the medium after exposure. For this purpose, the stochastic simulation of incident particle tracks and water radiation chemistry was performed in realistic neuron phantoms constructed using experimental data on cell morphology. The applied simulation technique is based on using Monte-Carlo processes of the Geant4-DNA toolkit. The calculations were made for proton, 12C, and 56Fe particles of different energy within a relatively wide range of linear energy transfer values from a few to hundreds of keV/µm. The results indicate that the neuron morphology is an important factor determining the accumulation of microscopic radiation dose and water radiolysis products in neurons. The estimation of the radiolytic yields in neuronal cells suggests that the observed enhancement in the levels of reactive oxygen species may potentially lead to oxidative damage to neuronal components disrupting the normal communication between cells of the neural network.
Assuntos
Modelos Biológicos , Rede Nervosa/citologia , Neurônios/metabolismo , Neurônios/efeitos da radiação , Água/metabolismo , Animais , Neoplasias Encefálicas/radioterapia , Carbono/efeitos adversos , Ferro/efeitos adversos , Transferência Linear de Energia/efeitos da radiação , Masculino , Método de Monte Carlo , Rede Nervosa/efeitos da radiação , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
PURPOSE: The motivation of this study was to find and eliminate the cause of errors in dose-averaged linear energy transfer (LET) calculations from therapeutic protons in small targets, such as biological cell layers, calculated using the geant 4 Monte Carlo code. Furthermore, the purpose was also to provide a recommendation to select an appropriate LET quantity from geant 4 simulations to correlate with biological effectiveness of therapeutic protons. METHODS: The authors developed a particle tracking step based strategy to calculate the average LET quantities (track-averaged LET, LETt and dose-averaged LET, LETd) using geant 4 for different tracking step size limits. A step size limit refers to the maximally allowable tracking step length. The authors investigated how the tracking step size limit influenced the calculated LETt and LETd of protons with six different step limits ranging from 1 to 500 µm in a water phantom irradiated by a 79.7-MeV clinical proton beam. In addition, the authors analyzed the detailed stochastic energy deposition information including fluence spectra and dose spectra of the energy-deposition-per-step of protons. As a reference, the authors also calculated the averaged LET and analyzed the LET spectra combining the Monte Carlo method and the deterministic method. Relative biological effectiveness (RBE) calculations were performed to illustrate the impact of different LET calculation methods on the RBE-weighted dose. RESULTS: Simulation results showed that the step limit effect was small for LETt but significant for LETd. This resulted from differences in the energy-deposition-per-step between the fluence spectra and dose spectra at different depths in the phantom. Using the Monte Carlo particle tracking method in geant 4 can result in incorrect LETd calculation results in the dose plateau region for small step limits. The erroneous LETd results can be attributed to the algorithm to determine fluctuations in energy deposition along the tracking step in geant 4. The incorrect LETd values lead to substantial differences in the calculated RBE. CONCLUSIONS: When the geant 4 particle tracking method is used to calculate the average LET values within targets with a small step limit, such as smaller than 500 µm, the authors recommend the use of LETt in the dose plateau region and LETd around the Bragg peak. For a large step limit, i.e., 500 µm, LETd is recommended along the whole Bragg curve. The transition point depends on beam parameters and can be found by determining the location where the gradient of the ratio of LETd and LETt becomes positive.
Assuntos
Transferência Linear de Energia/fisiologia , Modelos Estatísticos , Método de Monte Carlo , Terapia com Prótons/métodos , Planejamento da Radioterapia Assistida por Computador/métodos , Software , Simulação por Computador , Relação Dose-Resposta à Radiação , Humanos , Transferência Linear de Energia/efeitos da radiação , Modelos Biológicos , Dosagem RadioterapêuticaRESUMO
The authors describe a numerical algorithm to optimise the entrance spectra of a composition of pristine carbon ion beams which delivers a pre-assumed dose-depth profile over a given depth range within the spread-out Bragg peak. The physical beam transport model is based on tabularised data generated using the SHIELD-HIT10A Monte-Carlo code. Depth-dose profile optimisation is achieved by minimising the deviation from the pre-assumed profile evaluated on a regular grid of points over a given depth range. This multi-dimensional minimisation problem is solved using the L-BFGS-B algorithm, with parallel processing support. Another multi-dimensional interpolation algorithm is used to calculate at given beam depths the cumulative energy-fluence spectra for primary and secondary ions in the optimised beam composition. Knowledge of such energy-fluence spectra for each ion is required by the mixed-field calculation of Katz's cellular Track Structure Theory (TST) that predicts the resulting depth-survival profile. The optimisation algorithm and the TST mixed-field calculation are essential tools in the development of a one-dimensional kernel of a carbon ion therapy planning system. All codes used in the work are generally accessible within the libamtrack open source platform.
Assuntos
Sobrevivência Celular/efeitos da radiação , Radioterapia com Íons Pesados/normas , Transferência Linear de Energia/efeitos da radiação , Modelos Teóricos , Planejamento da Radioterapia Assistida por Computador/métodos , Planejamento da Radioterapia Assistida por Computador/normas , Algoritmos , Animais , Células CHO , Simulação por Computador , Cricetinae , Cricetulus , Método de Monte Carlo , Radiometria/métodos , Dosagem RadioterapêuticaRESUMO
In a recent paper, the authors reported that the dose mean lineal energy, [Formula: see text] in a volume of about 10-15 nm is approximately proportional to the α-parameter in the linear-quadratic relation used in fractionated radiotherapy in both low- and high-LET beams. This was concluded after analyses of reported radiation weighting factors, WisoE (clinical RBE values), and [Formula: see text] values in a large range of volumes. Usually, microdosimetry measurements in the nanometer range are difficult; therefore, model calculations become necessary. In this paper, the authors discuss the calculation method. A combination of condensed history Monte Carlo and track structure techniques for calculation of mean lineal energy values turned out to be quite useful. Briefly, the method consists in weighting the relative dose fractions of the primary and secondary charged particles with their respective energy-dependent dose mean lineal energies. The latter were obtained using a large database of Monte Carlo track structure calculations.
Assuntos
Transferência Linear de Energia/efeitos da radiação , Nanotecnologia/métodos , Neoplasias/radioterapia , Aceleradores de Partículas/instrumentação , Radiometria/instrumentação , Eficiência Biológica Relativa , Simulação por Computador , Humanos , Modelos Biológicos , Método de Monte Carlo , Radiometria/métodos , Dosagem RadioterapêuticaRESUMO
Microbeam experiments approximating high-LET tracks by bunches of lower-LET particles focussed to submicrometre scales (Schmid et al. 2012, Phys. Med. Biol. 57, 5889) provide an unprecedented benchmark for models of biological effects of radiation. PARTRAC track structure-based Monte Carlo simulations have verified that focussed 20 MeV proton bunches resemble the radial dose distributions of single 55 MeV carbon ions as used in the experiments. However, the predicted yields of double-strand break and short (<1 kbp) DNA fragments by focussed protons correspond to homogeneous proton irradiation and are much smaller than for carbon tracks. The calculated yields of dicentrics overestimate the effect of focussing but reproduce the fourfold difference between carbon ions and homogeneously distributed protons. The extent to which focussed low-LET particles approximate high-LET radiation is limited by the achievable focussing: submicrometre focussing of proton bunches cannot reproduce local nanometre clustering, i.e. DNA damage complexity characteristic of high-LET radiation.
Assuntos
Dano ao DNA/efeitos da radiação , DNA/química , DNA/efeitos da radiação , Transferência Linear de Energia/efeitos da radiação , Modelos Químicos , Prótons , Quebras de DNA de Cadeia Dupla , Método de Monte Carlo , Radiação IonizanteRESUMO
A simulation approach for the calculation of the LET-dependent yield of double-strand breaks (DSB) is presented. The model considers DSB formed as two close-lying single-strand breaks (SSB), whose formation is mediated by both intra-track processes (single electrons) or at local doses larger than about 1000 Gy in particle tracks also by electron inter-track processes (two independent electron tracks). A Monte Carlo algorithm and an analytical formula for the DSB yield are presented. The approach predicts that the DSB yield is enhanced after charged particle irradiation of high LET compared with X-ray or gamma radiation. It is used as an inherent part of the local effect model, which is applied to estimate the relative biological effectiveness of high LET radiation.
Assuntos
Simulação por Computador , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Elétrons , Transferência Linear de Energia/efeitos da radiação , Método de Monte Carlo , Raios gama , Eficiência Biológica Relativa , Raios XRESUMO
In the recent version of the local effect model (LEM), the biological effects of ionising radiation can be well described trough the consideration of DNA double-strand breaks (DSB) clustering at the micrometre scale. Assuming a giant-loop organisation for the chromatin higher-order structure, two classes of DSB are defined, namely isolated (iDSB) and clustered DSB (cDSB), according to whether exactly one or more than one DSB are induced in a loop, respectively. Here, a DSB kinetic rejoining model based on the LEM is applied to the description of two specific aspects of DSB rejoining, namely the dose dependence of the rejoining capacity after photon radiation and the residual damage observed at late times after ion irradiation. Based on the hypothesis that iDSB and cDSB can be associated to the fast and slow components of rejoining, the model is able to reproduce the experimental data, therefore supporting the relevance of micrometre scale clustering of damage for photon radiation as well as for high-LET radiation.
Assuntos
Simulação por Computador , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Reparo do DNA/efeitos da radiação , Transferência Linear de Energia/efeitos da radiação , Método de Monte Carlo , Fótons , Derme/efeitos da radiação , Relação Dose-Resposta à Radiação , Elétrons , Fibroblastos/efeitos da radiação , Humanos , Modelos Teóricos , Radiação Ionizante , Eficiência Biológica RelativaRESUMO
The role played by DNA cluster damage and chromosome aberrations in radiation-induced cell killing was investigated, assuming that certain chromosome aberrations (dicentrics, rings and large deletions, or 'lethal aberrations') lead to clonogenic inactivation and that chromosome aberrations are due to micrometre-scale rejoining of chromosome fragments derived from DNA cluster lesions (CLs). The CL yield and the threshold distance governing fragment rejoining were left as model parameters. The model, implemented as a Monte Carlo code called BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations), provided simulated survival curves that were compared with survival data on AG1522 and V79 cells exposed to different radiation types, including heavy ions. The agreement between simulation outcomes and experimental data suggests that lethal aberrations are likely to play an important role in cell killing not only for AG1522 cells exposed to X rays, as already reported by others, but also for other radiation types and other cells. Furthermore, the results are consistent with the hypothesis that the critical DNA lesions leading to cell death and chromosome aberrations are double-strand break clusters (possibly involving the â¼1000-10 000 bp scale) and that the effects of such clusters are modulated by micrometre-scale proximity effects during DNA damage processing.
Assuntos
Sobrevivência Celular/efeitos da radiação , Aberrações Cromossômicas/efeitos da radiação , Simulação por Computador , Dano ao DNA/efeitos da radiação , Fibroblastos/efeitos da radiação , Pulmão/efeitos da radiação , Modelos Teóricos , Animais , Células Cultivadas , Cricetinae , Cricetulus , Fibroblastos/citologia , Humanos , Transferência Linear de Energia/efeitos da radiação , Pulmão/citologia , Método de Monte Carlo , Doses de Radiação , Raios XRESUMO
In view of the emerging interest of carbon ions in radiotherapy and of the strong correlation between the track structure and the radiobiological effectiveness of ionising radiations, the track-structure properties of (12)C-ions were studied at particle energies close to the Bragg peak. To perform the investigations, ionisation-cluster-size distributions for nanometre-sized target volumes were measured with the track-nanodosimeter installed at the TANDEM-ALPI accelerator complex at LNL, and calculated using a dedicated Monte Carlo simulation code. The resulting cluster-size distributions are used to derive particular descriptors of particle track structure. Here, the main emphasis is laid on the mean ionisation-cluster size M1 and the cumulative probability Fk of measuring cluster sizes ν ≥ k. From the radiobiological point of view, Fk is of particular interest because an increasing k corresponds to an increase of damages of higher complexity. In addition, Fk saturates with increasing radiation quality like radiobiological cross sections as a function of linear energy transfer. Results will be presented and discussed for (12)C-ions at 96 and 240 MeV.
Assuntos
Radioisótopos de Carbono/efeitos adversos , Transferência Linear de Energia/efeitos da radiação , Nanotecnologia/métodos , Radiometria/métodos , Simulação por Computador , Humanos , Método de Monte Carlo , Doses de RadiaçãoRESUMO
Physical aspects of particle track structure are important in determining the induction of clustered damage in relevant subcellular structures like the DNA and higher-order genomic structures. The direct measurement of track-structure properties of ionising radiation is feasible today by counting the number of ionisations produced inside a small gas volume. In particular, the so-called track-nanodosimeter, installed at the TANDEM-ALPI accelerator complex of LNL, measures ionisation cluster-size distributions in a simulated subcellular structure of dimensions 20 nm, corresponding approximately to the diameter of the chromatin fibre. The target volume is irradiated by pencil beams of primary particles passing at specified impact parameter. To directly relate these measured track-structure data to radiobiological measurements performed in broad homogeneous particle beams, these data can be integrated over the impact parameter. This procedure was successfully applied to 240 MeV carbon ions and compared with Monte Carlo simulations for extended fields.
Assuntos
Partículas Elementares/efeitos adversos , Transferência Linear de Energia/efeitos da radiação , Nanotecnologia/métodos , Aceleradores de Partículas/instrumentação , Radiometria/métodos , Simulação por Computador , Humanos , Método de Monte Carlo , Doses de RadiaçãoRESUMO
An algorithm was developed of a treatment planning system (TPS) kernel for carbon radiotherapy in which Katz's Track Structure Theory of cellular survival (TST) is applied as its radiobiology component. The physical beam model is based on available tabularised data, prepared by Monte Carlo simulations of a set of pristine carbon beams of different input energies. An optimisation tool developed for this purpose is used to find the composition of pristine carbon beams of input energies and fluences which delivers a pre-selected depth-dose distribution profile over the spread-out Bragg peak (SOBP) region. Using an extrapolation algorithm, energy-fluence spectra of the primary carbon ions and of all their secondary fragments are obtained over regular steps of beam depths. To obtain survival vs. depth distributions, the TST calculation is applied to the energy-fluence spectra of the mixed field of primary ions and of their secondary products at the given beam depths. Katz's TST offers a unique analytical and quantitative prediction of cell survival in such mixed ion fields. By optimising the pristine beam composition to a published depth-dose profile over the SOBP region of a carbon beam and using TST model parameters representing the survival of CHO (Chinese Hamster Ovary) cells in vitro, it was possible to satisfactorily reproduce a published data set of CHO cell survival vs. depth measurements after carbon ion irradiation. The authors also show by a TST calculation that 'biological dose' is neither linear nor additive.
Assuntos
Sobrevivência Celular/efeitos da radiação , Radioterapia com Íons Pesados , Transferência Linear de Energia/efeitos da radiação , Modelos Teóricos , Planejamento da Radioterapia Assistida por Computador/métodos , Algoritmos , Animais , Células CHO , Simulação por Computador , Cricetinae , Cricetulus , Método de Monte Carlo , Radiobiologia , Radiometria/métodos , Dosagem RadioterapêuticaRESUMO
The number of small radiation-induced DNA fragments can be heavily underestimated when determined from measurements of DNA mass fractions by gel electrophoresis, leading to a consequent underestimation of the initial DNA damage induction. In this study we reanalyzed the experimental results for DNA fragmentation and DNA double-strand break (DSB) yields in human fibroblasts irradiated with γ rays and nitrogen ion beams with linear energy transfer (LET) equal to 80, 125, 175 and 225 keV/µm, originally measured by Höglund et al. (Radiat Res 155, 818-825, 2001 and Int J Radiat Biol 76, 539-547, 2000). In that study the authors converted the measured distributions of fragment masses into DNA fragment distributions using mid-range values of the measured fragment length intervals, in particular they assumed fragments with lengths in the interval of 0-48 kbp had the mid-range value of 24 kbp. However, our recent detailed simulations with the Monte Carlo code PARTRAC, while reasonably in agreement with the mass distributions, indicate significantly increased yields of very short fragments by high-LET radiation, so that the actual average fragment lengths, in the interval 0-48 kbp, 2.4 kbp for 225 keV/µm nitrogen ions were much shorter than the assumed mid-range value of 24 kbp. When the measured distributions of fragment masses are converted into fragment distributions using the average fragment lengths calculated by PARTRAC, significantly higher yields of DSB related to short fragments were obtained and resulted in a constant relative biological effectiveness (RBE) for DSB induction yield of 2.3 for nitrogen ions at 125-225 keV/µm LET. The previously reported downward trend of the RBE values over this LET range for DSB induction appears to be an artifact of an inadequate average fragment length in the smallest interval.
Assuntos
Quebras de DNA de Cadeia Dupla/efeitos da radiação , Transferência Linear de Energia/efeitos da radiação , Método de Monte Carlo , Nitrogênio/efeitos adversos , Fragmentação do DNA/efeitos da radiação , Humanos , Eficiência Biológica RelativaRESUMO
Radiation quality and cellular oxygen concentration have a substantial impact on DNA damage, reproductive cell death and, ultimately, the potential efficacy of radiation therapy for the treatment of cancer. To better understand and quantify the effects of radiation quality and oxygen on the induction of clustered DNA lesions, we have now extended the Monte Carlo Damage Simulation (MCDS) to account for reductions in the initial lesion yield arising from enhanced chemical repair of DNA radicals under hypoxic conditions. The kinetic energy range and types of particles considered in the MCDS have also been expanded to include charged particles up to and including (56)Fe ions. The induction of individual and clustered DNA lesions for arbitrary mixtures of different types of radiation can now be directly simulated. For low-linear energy transfer (LET) radiations, cells irradiated under normoxic conditions sustain about 2.9 times as many double-strand breaks (DSBs) as cells irradiated under anoxic conditions. New experiments performed by us demonstrate similar trends in the yields of non-DSB (Fpg and Endo III) clusters in HeLa cells irradiated by γ rays under aerobic and hypoxic conditions. The good agreement among measured and predicted DSBs, Fpg and Endo III cluster yields suggests that, for the first time, it may be possible to determine nucleotide-level maps of the multitude of different types of clustered DNA lesions formed in cells under reduced oxygen conditions. As particle LET increases, the MCDS predicts that the ratio of DSBs formed under normoxic to hypoxic conditions by the same type of radiation decreases monotonically toward unity. However, the relative biological effectiveness (RBE) of higher-LET radiations compared to (60)Co γ rays (0.24 keV/µm) tends to increase with decreasing oxygen concentration. The predicted RBE of a 1 MeV proton (26.9 keV/µm) relative to (60)Co γ rays for DSB induction increases from 1.9 to 2.3 as oxygen concentration decreases from 100% to 0%. For a 12 MeV (12)C ion (681 keV/µm), the 'predicted RBE for DSB induction increases from 3.4 (100% O(2)) to 9.8 (0% O(2)). Estimates of linear-quadratic (LQ) cell survival model parameters (α and ß) are closely correlated to the Monte Carlo-predicted trends in DSB induction for a wide range of particle types, energies and oxygen concentrations. The analysis suggests α is, as a first approximation, proportional to the initial number of DSBs per cell, and ß is proportional to the square of the initial number of DSBs per cell. Although the reported studies provide some evidence supporting the hypothesis that DSBs are a biologically critical form of clustered DNA lesion, the induction of Fpg and Endo III clusters in HeLa cells irradiated by γ rays exhibits similar trends with oxygen concentration. Other types of non-DSB cluster may still play an important role in reproductive cell death. The MCDS captures many of the essential trends in the formation of clustered DNA lesions by ionizing radiation and provides useful information to probe the multiscale effects and interactions of ionizing radiation in cells and tissues. Information from Monte Carlo simulations of cluster induction may also prove useful for efforts to better exploit radiation quality and reduce the impact of tumor hypoxia in proton and carbon-ion radiation therapy.
Assuntos
Dano ao DNA , Método de Monte Carlo , Oxigênio/metabolismo , Morte Celular/efeitos da radiação , Hipóxia Celular/efeitos da radiação , Linhagem Celular , Sobrevivência Celular/efeitos da radiação , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Humanos , Ferro/efeitos adversos , Cinética , Transferência Linear de Energia/efeitos da radiação , Prótons/efeitos adversos , Eficiência Biológica RelativaRESUMO
PURPOSE: To resolve the difficulty in counting merged DNA damage foci in high-LET (linear energy transfer) ion-induced patterns. MATERIALS AND METHODS: The analysis of patterns of RIF (radiation-induced foci) produced by high-LET Fe and Ti ions were conducted by using a Monte Carlo model that combines the heavy ion track structure with characteristics of the human genome on the level of chromosomes. The foci patterns were also simulated in the maximum projection plane for flat nuclei. RESULTS: The model predicts the spatial and genomic distributions of DNA DSB (double-strand breaks) in a cell nucleus for a particular dose of radiation. We used the model to do analyses for three irradiation scenarios: (i) The ions were oriented perpendicular to the flattened nuclei in a cell culture monolayer; (ii) the ions were parallel to that plane; and (iii) round nucleus. In the parallel scenario we found that the foci appeared to be merged due to their high density, while, in the perpendicular scenario, the foci appeared as one bright spot per hit. The statistics and spatial distribution of regions of densely arranged foci, termed DNA foci chains, were predicted numerically using this model. Another analysis was done to evaluate the number of ion hits per nucleus, which were visible from streaks of closely located foci. CONCLUSIONS: We showed that DSB clustering needs to be taken into account to determine the true DNA damage foci yield, which helps to determine the DSB yield. Using the model analysis, a researcher can refine the DSB yield per nucleus per particle. We showed that purely geometric artifacts, present in the experimental images, can be analytically resolved with the model, and that the quantisation of track hits and DSB yields can be provided to the experimentalists who use enumeration of radiation-induced foci in immunofluorescence experiment using proteins that detect DNA damage.
Assuntos
Quebras de DNA de Cadeia Dupla/efeitos da radiação , Íons Pesados/efeitos adversos , Método de Monte Carlo , Núcleo Celular/metabolismo , Núcleo Celular/efeitos da radiação , Fibroblastos/citologia , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Humanos , Transferência Linear de Energia/efeitos da radiação , Processos EstocásticosRESUMO
This study includes the design and testing of a program that creates quadric-based geometric models of the trabecular region, designed specifically for use with the 2005 version of the Monte Carlo radiation transport code PENELOPE. Our model was tested, by comparison with published data, in two aspects: the distributions of path lengths throughout the geometry and absorbed fraction values from the monoenergetic emission of electrons from within our geometry. In both comparisons, our results show a close agreement with published methods.
Assuntos
Osso e Ossos/fisiologia , Transferência Linear de Energia/fisiologia , Modelos Biológicos , Método de Monte Carlo , Radiometria/métodos , Software , Animais , Carga Corporal (Radioterapia) , Simulação por Computador , Humanos , Transferência Linear de Energia/efeitos da radiação , Doses de Radiação , Eficiência Biológica Relativa , Espalhamento de RadiaçãoRESUMO
During the last decade, computational fluid dynamics techniques proved to be a powerful tool in the modelling of biological processes and the design of biomedical devices. In this work, a computational fluid dynamics method was applied to model the transport of inhaled air and radioactive particles within the human respiratory tract. A finite volume numerical approach was used to compute the flow field characteristics and particle trajectories in the lumen of the first five airway generations of the human tracheobronchial tree, leading to the right upper lobe. The computations were performed for breathing and exposure conditions characteristic of uranium mines and homes. Primary radon daughter deposition patterns and energy distributions were computed, exhibiting highly inhomogeneous particle and energy deposition patterns. The results of the present modelling effort can serve as input data in lung cancer risk analysis.
Assuntos
Neoplasias Pulmonares/fisiopatologia , Pulmão/fisiopatologia , Pulmão/efeitos da radiação , Modelos Biológicos , Lesões por Radiação/fisiopatologia , Radiometria/métodos , Produtos de Decaimento de Radônio/efeitos adversos , Administração por Inalação , Aerossóis/efeitos adversos , Poluentes Radioativos do Ar/efeitos adversos , Sobrevivência Celular/efeitos da radiação , Simulação por Computador , Relação Dose-Resposta à Radiação , Humanos , Transferência Linear de Energia/efeitos da radiação , Neoplasias Pulmonares/etiologia , Doses de Radiação , Lesões por Radiação/etiologia , Produtos de Decaimento de Radônio/administração & dosagem , Reologia/métodosRESUMO
For diamond film the one-hit model that is used to interpret low-energy X-ray thermoluminescence (TL) will require some modifications. After the films were irradiated with a superficial X-ray machine with different peak voltages, a two-compartment model with three parameters, the target size, the microscopic saturation factor and the high-LET saturation factor, was used to more precisely describe the TL response to X-ray with energies down to 10 kV. The microdosimetric distribution was calculated using single-event Monte Carlo code developed by authors together with EEDL cross-section data library. Some mechanistic insight into the physical aspect of radiation interaction with solid detectors can be obtained. The sensitive size in diamond was found to be about 15 nm. The saturation of one group of sublevels combined with the activation of another group of sublevels caused the relative efficiency to have a local minimum near 20 keV. The relative efficiency becomes higher below 10 keV, which is similar to the increasing relative biological effectiveness when the linear energy transfer passing through a biological system increases. The similarity made this material to be a molecular-scale dosimeter in the future.