Ionization Clusters Research Articles

Stochastic simulation of radium-223 dichloride therapy at the sub-cellular level

Radium-223 dichloride (223Ra) is an alpha particle emitter and a natural bone-seeking radionuclide that is currently used for treating osteoblastic bone metastases associated with prostate cancer. The stochastic nature of alpha emission, hits and energy deposition poses some challenges for estimating radiation damage. In this paper we investigate the distribution of hits to cells by multiple alpha particles corresponding to a typical clinically delivered dose using a Monte Carlo model to simulate the stochastic effects. The number of hits and dose deposition were recorded in the cytoplasm and nucleus of each cell. Alpha particle tracks were also visualized. We found that the stochastic variation in dose deposited in cell nuclei (40%) can be attributed in part to the variation in LET with pathlength. We also found that 18% of cell nuclei receive less than one sigma below the average dose per cell (15.4 Gy). One possible implication of this is that the efficacy of cell kill in alpha particle therapy need not rely solely on ionization clustering on DNA but possibly also on indirect DNA damage through the production of free radicals and ensuing intracellular signaling.

Use of cluster counting technique for particle identification in a drift chamber with the cathode strip readout

The possibility of using the clusters counting technique for particle identification in a drift chamber with the cathode strip readout is experimentally investigated. Results of counting of primary ionization clusters on a relativistic particle track, as well as results of computer simulation of pion, kaon, and proton identification in the momentum range of 1–8 GeV/c, are presented.

Experimental investigation of ionisation track structure of carbon ions at HIL Warsaw.

In view of the upcoming radiation therapy with carbon ions, the ionisation structure of the carbon ion track at the nanometre scale is of particular interest. Two different nanodosimeters capable of measuring track structure of ionising particles in a gas target equivalent to a nanometric site in condensed matter were involved in the presented experimental investigation, namely the NCBJ Jet Counter and the PTB Ion Counter. At the accelerator facility of the HIL in Warsaw, simulated nanometric volumes were irradiated with carbon ions of 45 and 76 MeV of kinetic energy, corresponding to a range in the tissue of ∼85 µm and ∼190 µm, respectively. The filling gas of both nanodosimeters' ionisation volume was molecular nitrogen N2, and the ionisation cluster size distributions, i.e. the statistical distribution of the number of ionizations produced by one single primary carbon ion in the filling gas, were measured for the two primary particle energies.

Characterisation of a track structure imaging detector.

The spatial distribution of radiation-induced ionisations in sub-cellular structures plays an important role in the initial formation of radiation damage to biological tissues. Using the nanodosimetry approach, physical characteristics of the track structure can be measured and correlated to DNA damage. In this work, a novel nanodosimeter is presented, which detects positive ions produced by radiation interacting with a gas-sensitive volume in order to obtain a high resolution image of the radiation track structure. The characterisation of the detector prototype was performed and different configurations of the device were tested by varying the detector cathode material and the working gas. Preliminary results show that the ionisation cluster size distribution can be obtained with this approach. Further work is planned to improve the detector efficiency in order to register the complete three-dimensional track structure of ionising radiation.

OC-0157: Initial DNA damage patterns with Monte Carlo tracks and ionization clusters

OC-0157: Initial DNA damage patterns with Monte Carlo tracks and ionization clusters

PD-0448: Influence of geometry and DNA target composition on the ionization cluster distributions using MC methods

PD-0448: Influence of geometry and DNA target composition on the ionization cluster distributions using MC methods

Study of the single cluster response of a helium-isobutane drift chamber prototype using 8 keV X-rays

The identification of single clusters in the electronic signals produced by ionizing particles within a drift chamber is expected to significantly improve the performances of this kind of detectors in terms of particle identification capabilities and space resolution. In order to develop refined cluster recognition algorithms, it is essential to measure the response of the chamber and its electronics to single ionization clusters. This can be done by irradiating the chamber with X-rays. We report here on the studies performed on a drift chamber prototype for the MEG-II experiment at the X-ray facility of the INFN Frascati's National Laboratories ``XLab Frascati''. The prototype is operated with a helium-isobutane mixture and instrumented with high bandwidth custom pre-amplifiers. The results of this study have been used to develop an innovative method for cluster recognition, based on the Wiener filter technique, which has been tested on data collected at the Frascati's Beam Test Facility. As a side measurement, we also performed a study of the gas gain in a configuration which is similar to that of the MEG-II experiment.

SU-E-T-565: RAdiation Resistance of Cancer CElls Using GEANT4 DNA: RACE

Purpose: The objective of the RACE project is to develop a comparison between Monte Carlo simulation using the Geant4-DNA toolkit and measurements of radiation damage on 3D melanoma and chondrosarcoma culture cells coupled with gadolinium nanoparticles. We currently expose the status of the developments regarding simulations. Methods: Monte Carlo studies are driven using the Geant4 toolkit and the Geant4-DNA extension. In order to model the geometry of a cell population, the opensource CPOP++ program is being developed for the geometrical representation of 3D cell populations including a specific cell mesh coupled with a multi-agent system. Each cell includes cytoplasm and nucleus. The correct modeling of the cell population has been validated with confocal microscopy images of spheroids. The Geant4 Livermore physics models are used to simulate the interactions of a 250 keV X-ray beam and the production of secondaries from gadolinium nanoparticles supposed to be fixed on the cell membranes. Geant4-DNA processes are used to simulate the interactions of charged particles with the cells. An atomistic description of the DNA molecule, from PDB (Protein Data Bank) files, is provided by the so-called PDB4DNA Geant4 user application we developed to score energy depositions in DNA base pairs and sugar-phosphate groups. Results: At the microscopic level, our simulations enable assessing microscopic energy distribution in each cell compartment of a realistic 3D cell population. Dose enhancement factors due to the presence of gadolinium nanoparticles can be estimated. At the nanometer scale, direct damages on nuclear DNA are also estimated. Conclusion: We successfully simulated the impact of direct radiations on a realistic 3D cell population model compatible with microdosimetry calculations using the Geant4-DNA toolkit. Upcoming validation and the future integration of the radiochemistry module of Geant4-DNA will propose to correlate clusters of ionizations with in vitro experiments. All those developments will be released publicly. This work was supported by grants from Plan Cancer 2009-2013 French national initiative managed by INSERM (Institut National de la Sante et de la Recherche Medicale)

A novel approach to study radiation track structure with nanometer-equivalent resolution

Clustered DNA damages are considered the critical lesions in the pathways leading from the initial energy deposition by radiation to radiobiological damage. The spatial distribution of the initial DNA damage is mainly determined by radiation track-structure at the nanometer level. In this work, a novel experimental approach to image the three-dimensional structure of micrometric radiation track segments is presented. The approach utilizes the detection of single ions created in low-pressure gas. Ions produced by radiation drift towards a GEM-like 2D hole-pattern detector. When entering individual holes, ions can induce ion-impact ionization of the working-gas starting a confined electron avalanche that generates the output signal. By registering positive ions rather than electrons, diffusion is reduced and a spatial resolution of the track image of the order of water-equivalent nanometers can be achieved. Measurements and simulations to characterize the performance of a few detector designs were performed. Different cathode materials were tested and ionization cluster size distributions of 241Am alpha particles were measured. The electric field configuration in the detector was calculated to optimize the ion focusing into the detector holes. The preliminary results obtained show the directions for further development of the detector.

Status report: Nanodosimetry of carbon ion beam at HIL

We present preliminary data for measured distributions of ionization cluster size produced by carbon ions in tissue equivalent media. The experiments were carried out with a beam of 92MeV carbon ions from the U200p cyclotron at the Heavy Ion Laboratory (HIL), University of Warsaw, and nitrogen targets using the so-called Jet Counter set-up.

Revealing the underlying mechanism of microbeam radiation therapy with low energy Monte Carlo simulations

Microbeam radiation therapy (MRT) is a new experimental oncological modality, intended for the treatment of inoperable brain tumours, particularly in difficult cases where conventional radiation therapy can cause irreversible damage. MRT consists of an array of highly collimated, quasi-parallel x-ray microbeams aimed at the tumour tissue, delivering high dose within the beam path and low doses in regions between the beams. For reasons still not fully understood, healthy tissue exposed to the microbeam array is able to regenerate while tumour volumes are significantly reduced. Low energy Monte Carlo radiative transport simulations provide new insight into understanding the underlying mechanisms of MRT. In particular, predicting the ionisation cluster distribution, which is a significant cause of lethal damage to cells, would provide insight into the biological responses. Geant4-DNA was used to model an x-ray microbeam of width 20 μm in liquid water. Secondary electrons, predominately responsible for ionisation clustering, were tracked to predict damage to cells within and adjacent to the beams. We find that higher energy beams (100 keV) produce less secondary electrons in the regions outside the beam than low energy beams (30-50 keV).

Comparison of measured and Monte Carlo simulated track structure parameters in nanometric volumes

The track structure of ionising particles in biological matter can only be assessed by simulations, since neither the type of interaction and its products nor the interaction positions in biological matter can be detected with nanometer resolution. Hence, there is a need to benchmark the deployed computer codes using suitable experimental data. For this purpose, the frequency distributions of ionisation clusters produced in the sensitive volume of the PTB ion counting nanodosemeter by monoenergetic protons and alpha particles (with energies between 0.1 and 20 MeV) were measured. C3H8 and N2 were alternately used as the working gas. The measured data were compared with the results of simulations obtained with the PTB Monte Carlo code PTra. Measured and simulated characteristics of the particle track structure are in good agreement for protons over the entire energy range investigated. For alpha particles with energies above the Bragg peak a good agreement can also be seen, whereas for energies below the Bragg peak differences of as much as 25 % occur.

Ionization cross section data of nitrogen, methane, and propane for light ions and electrons and their suitability for use in track structure simulations

Track structure Monte Carlo simulations are frequently applied in micro- and nanodosimetry to calculate the radiation transport in detail. The use of a well-validated set of cross section data in such simulation codes ensures accurate calculations of transport parameters, such as ionization yields. These cross section data are, however, scarce and often discrepant when measured by different groups. This work surveys literature data on ionization and charge-transfer cross sections of nitrogen, methane, and propane for electrons, protons, and helium particles, focusing on the energy range between 100 keV and 20 MeV. Based on the evaluated data, different models for the parametrization of the cross section data are implemented in the code ptra, developed for simulating proton and alpha particle transport in an ion-counting nanodosimeter. The suitability of the cross section data is investigated by comparing the calculated mean ionization cluster size and energy loss with experimental results in either nitrogen or propane. For protons, generally good agreement between measured and simulated data is found when the Rudd model is used in ptra. For alpha particles, however, a considerable influence of different parametrizations of cross sections for ionization and charge transfer is observed. The ptra code using the charge-transfer data is, nevertheless, successfully benchmarked by the experimental data for the calculation of nanodosimetric quantities, but remaining discrepancies still have to be further investigated (up to 13% lower energy loss and 19% lower mean ionization cluster size than in the experiment). A continuation of this work should investigate data for the energy loss per interaction as well as differential cross section data of nitrogen and propane. Interpolation models for ionization and charge-transfer data are proposed. The Barkas model, frequently used for a determination of the effective charge in the ionization cross section, significantly underestimates both the energy loss (by up to 19%) and the mean ionization cluster size (up to 65%) for alpha particles. It is, therefore, not recommended for particle-track simulations.

Analytical calculation of the charge spectrum generated by ionizing particles in Resistive Plate Chambers at low gas gain

In this article it is shown analytically that the charge spectrum generated by ionizing particles in Resistive Plate Chambers under Townsend avalanche conditions, that is, for sufficiently small avalanches not affected by space-charge and considering single-electron ionization clusters follows closely the statistical gamma distribution. This distribution describes well comparable simulation data taken from the literature, but seems to describe as well experimental data measured beyond these assumptions, rising some interpretation issues.

Nanoscale characterization of ion tracks: MC simulations versus analytical approach

The goal of this work was to investigate the agreement of physical parameters related to the particle track structure on the nanometer scale, obtained by means of a detailed track structure simulation (PTra) as well as by a rapid analytical approach. Parameters describing the tracks of secondary electrons produced by 0.3 MeV/u C6+-ions were of particular interest as those particles are densely ionizing. For this purpose, the target volume in form of a nanometric water cylinder was positioned at different radial distances from the ion trajectory and track structure parameters were determined as function of the radial distance. While the fluence of electrons through the target surface and the mean ionization cluster size obtained by both approaches were in good agreement, the probabilities of specific cluster sizes (one, two and three) turned out to be rather different in the two approaches.

Reduced Contribution of Thermally-Labile Sugar Lesions to DNA Double-Strand Break Formation after Exposure to Neutrons

In cells exposed to ionizing radiation, double-strand breaks (DSBs) form within clustered damage sites from lesions disrupting the DNA sugar-phosphate backbone. It is commonly assumed that DSBs form promptly and are immediately detected and processed by the cellular DNA damage response apparatus. However, DSBs also form by delayed chemical conversion of thermally-labile sugar lesions (TLSL) to breaks. We recently reported that conversion of thermally-labile sugar lesions to breaks occurs in cells maintained at physiological temperatures. Here, we investigate the influence of radiation quality on the formation of thermally-labile sugar lesions dependent DSBs. We show that, although the yields of total DSBs are very similar after exposure to neutrons and X rays, the yields of thermally-labile sugar lesions dependent DSBs from neutrons are decreased in comparison to that from X rays. Thus, the yields of prompt DSBs for neutrons are greater than for X rays. Notably, after neutron irradiation the decreased yield of thermally-labile sugar lesion dependent DSBs is strongly cell line dependent, likely reflecting subtle differences in DNA organization. We propose that the higher ionization density of neutrons generates with higher probability prompt DSBs within ionization clusters and renders the ensuing chemical evolution of thermally-labile sugar lesions inconsequential to DNA integrity. Modification of thermally-labile sugar lesion evolution may define novel radiation protection strategies aiming at decreasing DSB formation by chemically preserving thermally-labile sugar lesions until other DSB contributing lesions within the clustered damage site are removed by non-DSB repair pathways.

Nanodosimetry of 125I Auger electrons

Purpose: The nanodosimetric description of the radiation action of Auger electrons on nitrogen targets of nanometric size is presented.Materials and methods: Experimental microdosimetry at nanometer scale for Auger electrons has been accomplished with the set-up called Jet Counter. This consists of a pulse-operated valve which injects an expanding nitrogen jet into an interaction chamber where a gaseous sensitive volume of cylindrical shape is created. The ionization cluster size distributions (ICSD) created by Auger electrons emitted by 125I while crossing a nanometer-sized volume have been measured.Results: The ICSD for the sensitive volumes corresponding to 3 and 12 nm in diameter (in unit density 1 g/cm3) irradiated by electrons emitted by a 125I source were collected and compared with the corresponding Monte Carlo (MC) simulation. The preliminary results of the experiments with Auger electrons of 125I interacting with a nitrogen jet having nanometric size comparable to a deoxyribonucleic acid (DNA) and nucleosome, showing the discrete spectrum of ICSD with extended cluster size, are described.Conclusions: The presented paper describes for the first time the nanodosimetric experiments with Auger electrons emitted by 125I. A set of the new descriptors of the radiation quality describing the radiation effect at nanometer level is proposed. The ICSD were determined for the first time for an Auger emitter of 125I.

Comparison of nanodosimetric parameters of track structure calculated by the Monte Carlo codes Geant4-DNA and PTra

The concept of nanodosimetry is based on the assumption that initial damage to cells is related to the number of ionizations (the ionization cluster size) directly produced by single particles within, or in the close vicinity of, short segments of DNA. The ionization cluster-size distribution and other nanodosimetric quantities, however, are not directly measurable in biological targets and our current knowledge is mostly based on numerical simulations of particle tracks in water, calculating track structure parameters for nanometric target volumes. The assessment of nanodosimetric quantities derived from particle-track calculations using different Monte Carlo codes plays, therefore, an important role for a more accurate evaluation of the initial damage to cells and, as a consequence, of the biological effectiveness of ionizing radiation. The aim of this work is to assess the differences in the calculated nanodosimetric quantities obtained with Geant4-DNA as compared to those of the ad hoc particle-track Monte Carlo code ‘PTra’ developed at Physikalisch-Technische Bundesanstalt (PTB), Germany. The comparison of the two codes was made for incident electrons of energy in the range between 50 eV and 10 keV, for protons of energy between 300 keV and 10 MeV, and for alpha particles of energy between 1 and 10 MeV as these were the energy ranges available in both codes at the time this investigation was carried out. Good agreement was found for nanodosimetric characteristics of track structure calculated in the high-energy range of each particle type. For lower energies, significant differences were observed, most notably in the estimates of the biological effectiveness. The largest relative differences obtained were over 50%; however, generally the order of magnitude was between 10% and 20%.

A comparison of X-ray and proton beam low energy secondary electron track structures using the low energy models of Geant4

Purpose: Lethal cell damage by ionising radiation is generally initiated by the formation of complex strand breaks, resulting from ionisation clusters in the DNA molecule. A better understanding of the effect of the distribution of ionisation clusters within the cell and particularly in regard to DNA segments could be beneficial to radiation therapy treatment planning. Low energy X-rays generate an abundance of low energy electrons similar to that associated with MeV protons. The study and comparison of the track structure of photon and proton beams could permit the substitution of photon microbeams for single cell ion irradiations at proton facilities used to predict the relative biological effectiveness (RBE) of charged particle fields. Materials and methods: The track structure of X-ray photons is compared with proton pencil beams in voxels of approximate DNA strand size (2 × 2 × 5 nm). The Very Low Energy extension models of the Monte Carlo simulation toolkit GEometry ANd Tracking 4 (Geant4) is used. Simulations were performed in a water phantom for an X-ray and proton beam of energies 100 keV and 20 MeV, respectively. Results: The track structure of the photon and proton beams are evaluated using the ionisation cluster size distribution as well as the radial dose deposition of the beam. Conclusions: A comparative analysis of the ionisation cluster distribution and radial dose deposition obtained is presented, which suggest that low energy X-rays could produce similar ionisation cluster distributions to MeV protons on the DNA scale of size at depths greater than ∼10 μm and at distances greater than ∼1 μm from the beam centre. Here the ionisation cluster size for each beam is less than ∼100. The radial dose deposition is also approximately equal at large depths and at distances greater than 10 μm from the beam centre.

Simulation of ionisation clusters formed in nanometric volumes of the deoxyribose-substitute tetrahydrofuran

Purpose: To investigate the implications of using interaction cross sections of liquid water for the target volume when studying radiation action at the DNA level by particle track structure simulations.Materials and methods: Absolute interaction cross sections for low energy electrons between 20 eV and 1 keV were measured for tetrahydrofuran (THF), which is a substitute for deoxyribose. From these data a complete interaction cross section data set was derived and integrated in our PTB Track structure Monte Carlo code ‘PTra’. Simulations of electron track structure in THF and water were performed and ionisation cluster size distributions in nanometric target volumes were determined. From these a nanodosimetric estimate for the probability to produce a double strand break was derived.Results: The probability distribution of ionisation cluster sizes was found to be shifted towards smaller values for a THF-filled target as compared to a water-filled one. For all electron energies investigated, the nanodosimetric estimates for double-strand break probability in the THF-filled target have lower values than for a target of liquid water.Conclusion: The preliminary results indicate that simulations based on cross sections of water would overestimate the initial direct radiation damage to the DNA.