Biomedical subjects

H Nikjoo

Publications and source records attributed to H Nikjoo.

At least 19 recordsLinked to original sources

PubMed2002

Modelling the effect of incorporated halogenated pyrimidine on radiation-induced DNA strand breaks.

PURPOSE: To estimate the enhancement of DNA strand breaks induced by low linear energy transfer (LET) radiation in the presence of halogenated pyrimidines and to examine complexity and clustering properties of damage that could provide a correlation between DNA damage and lethality. MATERIALS AND METHODS: Monte Carlo track structure methods were used to model and estimate the induction of strand breakage by X-ray photons with and without the incorporated Br/I deoxyuridine in cell-mimetic conditions. The increase of DNA strand break induction was modelled by taking into account the direct energy deposition and the reactions of radicals. The yield and spectrum of strand breaks were calculated at various degrees of Br/IdU incorporation. The excess strand breaks due to Br/IdU incorporation was assumed to be induced by highly reactive uracilyl radicals. Four mechanisms were considered for the production of uracilyl radicals classified into three groups, by hydrated electrons, by direct energy deposition, and by both hydrated electrons and direct energy depositions. In total, nine different models were considered to test the excess strand breaks by incorporated Br/IdU assuming different pathways. RESULTS: Model calculations show the following: the yield of strand breaks is enhanced by both the e(aq)(-) reaction and the direct energy deposition on base moiety; there is a significant contribution to the enhancement of yield of strand breaks due to energy transfer about four bases along the DNA to Br/IdU and DNA strand break complexity increases with degree of Br/IdU incorporation. Enhancement ratios of 1.8 and 2.5 for 40% Br/IdU substitution were obtained for single- and double-strand breaks, respectively. CONCLUSIONS: The increase in the yield of strand breaks due to Br/IdU incorporation could be explained by the mechanism of uracilyl radical production by e(aq)(-) and direct energy deposition. The importance of energy transfer along the DNA is demonstrated. It is shown that the incorporation of Br/IdU causes a spectral shift towards a greater complexity of clustered DNA damage.

Base Sequence↗

PubMed2002

Track structure for low energy ions including charge exchange processes.

The model and development is described of a new generation of Monte Carlo track structure codes. The code LEPHIST simulates full slowing down of low-energy proton history tracks in the range 1 keV-1 MeV and the code LEAHIST simulates low-energy alpha particle history tracks in the range 1 keV-8 MeV in water. All primary ion interactions are followed down to 1 keV and all electrons to 1 eV. Tracks of secondary electrons ejected by ions were traced using the electron code KURBUC. Microdosimetric parameters derived by analysis of generated tracks are presented.

Alpha Particles↗

PubMed2002

Modelling of DNA damage induced by energetic electrons (100 eV to 100 keV).

Modelling and calculations are presented for the spectrum of initial DNA damage produced by 100 eV to 100 keV energetic electrons. Analysis of the initial spectrum of damage, based upon the source (direct energy deposition and reactions with diffusing OH radicals) and complexity of damage, indicates that the majority of the interactions cause no damage to DNA and any damage that does occur is most likely to be a simple single strand break (SSB). The fraction of complex damage for energetic electrons is lower than that induced by low energy electrons and ultrasoft X rays but still represents an appreciable fraction (20-30%) of the total double strand breaks (DSBs). Relative yields of strand breaks are investigated for dependence on the assumed energy deposition threshold and on the probability of the hydroxyl radicals to produce a single strand break. The ratio of direct to indirect damage does not change significantly across the electron energy range investigated and the values lie well within the experimental data. The direct energy deposition in DNA represents a larger proportion of the damage although the contribution from the hydroxyl radicals is also substantial, both in terms of the absolute yield of the breaks and the complexity of the damage.

Computer Simulation↗

PubMed2002

Computational model of the modulation of gene expression following DNA damage.

High linear energy transfer (LET) radiation, such as heavy ions or neutrons, has an increased biological effectiveness compared to X rays for gene mutation, genomic instability, and carcinogenesis. In the traditional paradigm, mutations or chromosomal aberrations are causative of late effects. However, in recent years experimental evidence has demonstrated the important role of the description of the modification of gene expression by radiation in understanding the mechanisms of radiation action. In this report, approaches are discussed to the mathematical description of mRNA and protein expression kinetics following DNA damage. Several hypotheses for models of radiation modulation of protein expression are discussed including possible non-linear processes that evolve from the linear dose responses that follow the initial DNA damage produced by radiation.

Cell Division↗

PubMed2002

Quantitative analysis of the energetics of DNA damage.

Application of Monte Carlo track structure has been very successful in the modelling and quantification of DNA damage, clustered-damage and spectrum of DNA damage for energetic electrons and ions. However, there are paradoxical axioms in quantitative assessment of the energetics of DNA damage at very low electron energy and in the vacuum UV region. This paper, after a brief review of the parameters used in modelling of DNA damage, presents an analysis of experimental data of strand breaks in aqueous solution in the vacuum UV, the region to which little attention has been paid in spite of its fundamental importance in providing reaction parameters for radiation actions.

Biophysics↗

PubMed2001

Development of a Monte Carlo track structure code for low-energy protons in water.

PURPOSE: The development of a new generation of Monte Carlo track structure code is described, which simulates full slowing down of low-energy proton history tracks (lephist) in the range 1 keV-1 MeV in water. MATERIAL AND METHODS: All primary protons are followed down to 1 keV and all electrons to 1 eV. All primary interactions, including elastic scattering, ionization, excitation and charge exchange processes by protons and neutral hydrogen were taken into account. Cross-sections for proton and hydrogen impact were obtained from experimental data for water. Where data were lacking, the existing experimental data were fitted and extrapolated. The tracks of secondary electrons were generated using the electron track code kurbuc. The cross-sections and the energy transfer data were individually evaluated for the principal interactions induced by protons and hydrogen atoms in water. The analysis starts with the published cross-section data for water using a semi-empirical model including contributions from the neutral hydrogen atoms. For excitation cross-sections, the original Miller-Green analytical formula was used. For ionization by neutral hydrogen atoms, the same energy spectrum was assumed for secondary electrons as for protons. The total cross-sections were taken from the experiment of Blorizadeh and Rudd (1986b, c). For the stripping of charge by neutral hydrogen the data of Toburen et al. (1968) were used. RESULTS: Data are presented on total and differential elastic cross-sections as a function of energy and scattering angle respectively; single and double differential cross-sections for secondary electrons ejected by various energy proton impact; total cross-sections due to proton and hydrogen impact on water; stopping power cross-sections; and fraction of stopping power for water for protons as a functions of proton energy. CONCLUSIONS: Tracks were analysed to provide confirmation on the reliability of the code and information on physical quantities, such as range, W, restricted stopping power, radial dose profiles and some microdosimetric parameters. Model calculations show good agreement with the experimental and calculated data.

Algorithms↗

PubMed2001

Yields of SSB and DSB induced in DNA by Al(K) ultrasoft X-rays and alpha-particles: comparison of experimental and simulated yields.

PURPOSE: To compare experimental yields of single strand breaks (SSB) and double strand breaks (DSB) induced in plasmid DNA in aqueous solution by alpha-particles and Al(K) ultrasoft X-rays (USX) with the corresponding yields, generated via computer simulations, for a range of mean diffusion distances of the hydroxyl radical (*OH). MATERIALS AND METHODS: Aerobic, aqueous solutions of plasmid DNA were irradiated at 277K with 238Pu alpha-particles or USX in the presence of 10(-4) to 0.33 mol dm(-3) Tris and the yields of SSB and DSB determined by gel electrophoresis. Computer simulations, using Monte Carlo track-structure codes for 1.5keV electrons (CPA100) and 3.2MeV alpha-particle track segments (PITS), were used to obtain yields of DNA SSB and DSB at different *OH scavenger conditions. RESULTS: The experimental yield of SSB and DSB induced by AlK USX and SSB induced by alpha-particles and the dependences on the mean diffusion distance of the *OH are in reasonable agreement with the corresponding simulated yields and their corresponding dependences. However, for DSB induced by alpha-particles, a significant systematic difference exists between the simulated and experimental yields over the full *OH scavenging range, with the simulated yields being a factor of two to three greater than the experimental values. CONCLUSION: That the simulated yields of strand breaks are generally in reasonable agreement with those determined experimentally over a wide range of *OH scavenging capacities, increases confidence in the use of these simulations as a valuable source of quantitative, mechanistic information on DNA damage induced at very low radiation doses.

Alpha Particles↗

PubMed2001

Preface.

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Aerospace Medicine↗

PubMed2001

Computational approach for determining the spectrum of DNA damage induced by ionizing radiation.

To study the characteristics of molecular damage induced by ionizing radiation at the DNA level, Monte Carlo track simulation of energetic electrons and ions in liquid water, a canonical model of B-DNA, and a comprehensive classification of DNA damage in terms of the origin and complexity of damage were used to calculate the frequencies of simple and complex strand breaks. A threshold energy of 17.5 eV was used to model the damage by direct energy deposition, and a probability of 0.13 was applied to model the induction of a single-strand break produced in DNA by OH radical reactions. For preliminary estimates, base damage was assumed to be induced by the same direct energy threshold deposition or by the reaction of an OH radical with the base, with a probability of 0.8. Computational data are given on the complexity of damage, including base damage by electrons with energies of 100-4500 eV and ions with energies of 0.3-4.0 MeV/nucleon (59-9 keV microm(-1) protons and 170-55 keV microm(-1) alpha particles). Computational data are presented on the frequencies of single- and double-strand breaks induced as a function of the LET of the particles, and on the relative frequencies of complex single- and double-strand breaks for electrons. The modeling and calculations of strand breaks show that: (1) The yield of strand breaks per unit absorbed dose is nearly constant over a wide range of LET. (2) The majority of DNA damage is of a simple type, but the majority of the simple single-strand breaks are accompanied by at least one base damage. (3) For low-energy electrons, nearly 20-30% of the double-strand breaks are of a complex type by virtue of additional breaks. The proportion of this locally clustered damage increases with LET, reaching about 70% for the highest-LET alpha particles modeled, with the complexity of damage increasing further, to about 90%, when base damage is considered. (4) The extent of damage in the local hit region of the DNA duplex is mostly limited to a length of a few base pairs. (5) The frequency of base damage when no strand breaks are present in the hit segment of DNA varies between 20-40% as a function of LET for protons and alpha particles.

Alpha Particles↗

PubMed2001

Monte Carlo track structure for radiation biology and space applications.

Over the past two decades event by event Monte Carlo track structure codes have increasingly been used for biophysical modelling and radiotherapy. Advent of these codes has helped to shed light on many aspects of microdosimetry and mechanism of damage by ionising radiation in the cell. These codes have continuously been modified to include new improved cross sections and computational techniques. This paper provides a summary of input data for ionizations, excitations and elastic scattering cross sections for event by event Monte Carlo track structure simulations for electrons and ions in the form of parametric equations, which makes it easy to reproduce the data. Stopping power and radial distribution of dose are presented for ions and compared with experimental data. A model is described for simulation of full slowing down of proton tracks in water in the range 1 keV to 1 MeV. Modelling and calculations are presented for the response of a TEPC proportional counter irradiated with 5 MeV alpha-particles. Distributions are presented for the wall and wall-less counters. Data shows contribution of indirect effects to the lineal energy distribution for the wall counters responses even at such a low ion energy.

Algorithms↗

PubMed2000

Distribution of strand breaks produced by Auger electrons in decay of 125I in triplex DNA.

In this study we investigate the possibility of using Auger electrons as a probing agent for the study of structures of nucleic acids. To this end, we present the distribution of breaks produced in strands of a DNA duplex and a triplex-forming oligonucleotide (TFO) carrying Auger emitting radionuclide 125I. The method of calculation includes use of a molecular model of plasmid DNA duplex with bound TFO carrying a labelled 125I at position C5 of a single deoxycytosine residue, a source of Auger spectra, Monte Carlo electron track structure and the ensuing chemistry codes, to simulate the distribution of breaks produced in both strands of a plasmid DNA. Frequencies of fragment length distributions were obtained for the TFO, the purine and the pyrimidine strands. The frequency of breaks in the purine strand showed good correlation with the published experimental results, while that for the pyrimidine strand is lower by a factor of 3. It is concluded that the true structure of triplex DNA may not be purely of B-form.

DNA↗

PubMed2000

Kinetics of DSB rejoining and formation of simple chromosome exchange aberrations.

PURPOSE: To investigate the role of kinetics in the processing of DNA double strand breaks (DSB), and the formation of simple chromosome exchange aberrations following X-ray exposures to mammalian cells based on an enzymatic approach. METHODS: Using computer simulations based on a biochemical approach, rate-equations that describe the processing of DSB through the formation of a DNA-enzyme complex were formulated. A second model that allows for competition between two processing pathways was also formulated. The formation of simple exchange aberrations was modelled as misrepair during the recombination of single DSB with undamaged DNA. Non-linear coupled differential equations corresponding to biochemical pathways were solved numerically by fitting to experimental data. RESULTS: When mediated by a DSB repair enzyme complex, the processing of single DSB showed a complex behaviour that gives the appearance of fast and slow components of rejoining. This is due to the time-delay caused by the action time of enzymes in biomolecular reactions. It is shown that the kinetic- and dose-responses of simple chromosome exchange aberrations are well described by a recombination model of DSB interacting with undamaged DNA when aberration formation increases with linear dose-dependence. Competition between two or more recombination processes is shown to lead to the formation of simple exchange aberrations with a dose-dependence similar to that of a linear quadratic model. CONCLUSIONS: Using a minimal number of assumptions, the kinetics and dose response observed experimentally for DSB rejoining and the formation of simple chromosome exchange aberrations are shown to be consistent with kinetic models based on enzymatic reaction approaches. A non-linear dose response for simple exchange aberrations is possible in a model of recombination of DNA containing a DSB with undamaged DNA when two or more pathways compete for DSB repair.

Animals↗

PubMed2000

A method for radioprobing DNA structures using Auger electrons.

PURPOSE: To present a new method for radioprobing a DNA triple helix structure by Auger electrons emitted in the decay of 125I using theoretical/computational approaches. MATERIALS AND METHODS: A Monte Carlo track structure method was used to simulate the damage to a triplex resulting from Auger electrons emitted in the decay of an incorporated 125I atom in plasmid DNA. Comparison of the theoretical frequency distributions of single-strand breaks induced on the Pu and Py strands with the experimental data and a knowledge of the distances from the strand breaks to the iodine provide information on the structures otherwise difficult to obtain with X-ray crystallography. RESULTS: In comparing theoretical frequency distributions of single-strand breaks with the experimental data it is found that the results are very sensitive to the conformation of the triplex model used. It is found that the best fit to the experimental data results from using a hybrid triplex model, in which the base-step geometry is A-like, while the sugar puckers adopt the B-like C2'-endo conformation. CONCLUSIONS: The approach and technique presented here represent a valuable new addition to the methods available for DNA structure determination since they provide information on medium-range structure otherwize difficult to obtain in the absence of X-ray crystallography. It is concluded that currently accepted models for triplex structure are not optimal, and a modified structure is proposed that fits the radioprobing results better, while maintaining agreement with the fibre diffraction and NMR data. Although the method has proved to be very useful for scoring alternative trial solutions, further studies combining experimental data from multiple iodine positions with track structure modelling are required for directing structural optimization.

Base Sequence↗

PubMed2000

Model for radial dependence of frequency distributions for energy imparted in nanometer volumes from HZE particles.

This paper develops a deterministic model of frequency distributions for energy imparted (total energy deposition) in small volumes similar to DNA molecules from high-energy ions of interest for space radiation protection and cancer therapy. Frequency distributions for energy imparted are useful for considering radiation quality and for modeling biological damage produced by ionizing radiation. For high-energy ions, secondary electron (delta-ray) tracks originating from a primary ion track make dominant contributions to energy deposition events in small volumes. Our method uses the distribution of electrons produced about an ion's path and incorporates results from Monte Carlo simulation of electron tracks to predict frequency distributions for ions, including their dependence on radial distance. The contribution from primary ion events is treated using an impact parameter formalism of spatially restricted linear energy transfer (LET) and energy-transfer straggling. We validate our model by comparing it directly to results from Monte Carlo simulations for proton and alpha-particle tracks. We show for the first time frequency distributions of energy imparted in DNA structures by several high-energy ions such as cosmic-ray iron ions. Our comparison with results from Monte Carlo simulations at low energies indicates the accuracy of the method.

Alpha Particles↗

PubMed2000

Electron and photon spectra for three gadolinium-based cancer therapy approaches.

Some recent neutron capture therapy research has focused on using compounds containing the element gadolinium, which produces internal conversion and Auger cascade electrons. The low-energy, short-range Auger electrons are absorbed locally and increase cell killing dramatically as the gadolinium compounds are introduced into the cell nucleus and bind to the DNA. Detailed electron and photon spectra are needed for biophysical modeling and Monte Carlo calculations of damage to DNA. This paper presents calculated electron and photon spectra for three cases: thermal neutron absorption by (157)Gd, the beta-particle decay of (159)Gd, and the K-shell photoelectric event in gadolinium. The Monte Carlo sampling of atomic and nuclear transitions for each of the three cases was used to calculate a large number of representative decays. The sampled decays were used to determine average emissions and energy deposited in small spheres of tissue. The kinetic energy nuclear recoil from gamma-ray and electron emissions was calculated and found to be more than 10 eV for 26% of all (157)Gd neutron capture reactions.

Adult↗

PubMed1999

Quantitative modelling of DNA damage using Monte Carlo track structure method.

This paper presents data on modelling of DNA damage induced by electrons, protons and alpha-particles to provide an insight into factors which determine the biological effectiveness of radiations of high and low linear energy transfer (LET). These data include the yield of single- and double-strand breaks (ssb, dsb) and base damage in a cellular environment. We obtain a ratio of 4-15 for ssb:dsb for solid and cellular DNA and a preliminary ratio of about 2 for base damage to strand breakage. Data are also given on specific characteristics of damage at the DNA level in the form of clustered damage of varying complexity, that challenge the repair processes and if not processed adequately could lead to the observed biological effects. It is shown that nearly 30% of dsb are of complex form for low-LET radiation, solely by virtue of additional breaks, rising to about 70% for high-LET radiation. Inclusion of base damage increases the complex proportion to about 60% and 90% for low- and high-LET radiation, respectively. The data show a twofold increase in frequencies of complex dsb from low-LET radiation when base damage is taken into account. It is shown that most ssb induced by high-LET radiation have associated base damages, and also a substantial proportion is induced by low-energy electrons.

DNA↗

PubMed1999

Applications of amorphous track models in radiation biology.

The average or amorphous track model uses the response of a system to gamma-rays and the radial distribution of dose about an ion's path to describe survival and other cellular endpoints from proton, heavy ion, and neutron irradiation. This model has been used for over 30 years to successfully fit many radiobiology data sets. We review several extensions of this approach that address objections to the original model, and consider applications of interest in radiobiology and space radiation risk assessment. In the light of present views of important cellular targets, the role of target size as manifested through the relative contributions from ion-kill (intra-track) and gamma-kill (inter-track) remains a critical question in understanding the success of the amorphous track model. Several variations of the amorphous model are discussed, including ones that consider the radial distribution of event-sizes rather than average electron dose, damage clusters rather than multiple targets, and a role for repair or damage processing.

Animals↗

PubMed1999

A Monte Carlo code for positive ion track simulation.

An ion interaction model has been described for simulating positive ion tracks in a variety of media with the capability of interfacing with several secondary electron transport codes. Data are presented for single-and double-differential cross-sections, binding energies, probability density distribution for delocalisation parameters for conductors and tissue, branching ratios and ionisation efficiencies for water vapour and liquid water.

Computer Simulation↗