Simulation of 125I-based radioprobing experiments to study DNA quadruplex structure and topology

Purpose: Certain guanine-rich DNA sequences have the capacity to fold into four-stranded structures stabilized by the stacking of square planar arrangements of four hydrogen-bonded guanine bases. However both the overall topology of folding and the more detailed three dimensional structure of these quadruplexes is difficult to determine or predict, and they can be polymorphic, altering radically depending on environmental conditions. Radioprobing experiments, in which Auger electrons emitted during the decay of a ¹²⁵I-containing base induce strand cleavage in a distance- and structure-dependent manner, have provided possible means of determining these details. Here we have used a combination of computer simulation methods to study the information obtained by one such experiment, reported in 2004.

Method: Models were constructed of three quadruplex topologies considered in the experiment, and one other topology proposed more recently. Molecular Dynamics simulations were used to equilibrate these structures and monitor how they evolved over several nanoseconds in solution. Snapshots from the trajectories were then subjected to Monte Carlo track structure prediction, from which theoretical cleavage patterns have been extracted.

Results: The four topologies were found to yield quite different cleavage patterns, which allow the presence of particular conformations in an experiment to be predicted.

Conclusion: Radioprobing, which is usable in biologically relevant environments, is sensitive enough to distinguish with some confidence between alternative folding topologies in a DNA structure. Monte Carlo track structure simulation can reinforce or question conclusions drawn from experiment, and Molecular Dynamics used with various restraints provides a practical means of guiding a model towards one that yields cleavage patterns closer to those found experimentally.     

Monte Carlo simulations of therapeutic proton beams for relative biological effectiveness of double-strand break

Abstract

Purpose: The relative biological effectiveness (RBE) values relative to ⁶⁰Co for the induction of double-strand breaks (DSB) were calculated for therapeutic proton beams. RBE-weighted absorbed doses were determined at different depths in a water phantom for proton beams.

Materials and methods: The depth-dose distributions and the fluence spectra for primary protons and secondary particles were calculated using the FLUKA (FLUktuierende KAskade) MC (Monte Carlo) transport code. These spectra were combined with the MCDS (Monte Carlo damage simulation) code to simulate the spectrum-averaged yields of clustered DNA lesions. RBE for the induction of DSB were then determined at different depths in a water phantom for the unmodulated and modulated proton beams.

Results: The maximum RBE for the induction of DSB at 1 Gy absorbed dose was found about 1.5 at 0.5 cm distal to the Bragg peak maximum for an unmodulated 160 MeV proton beam. The RBE-weighted absorbed dose extended the biologically effective range of the proton beam by 1.9 mm. The corresponding maximum RBE value was inversely proportional to the proton beam energy, reaching a value of about 1.9 for 70 MeV proton beam. For a modulated 160 MeV proton beam, the RBE weightings were more pronounced near the spread-out Bragg peak (SOBP) distal edge.

Conclusions: It was demonstrated that a fast MCDS code could be used to simulate the DNA damage yield for therapeutic proton beams. Simulated RBE for the induction of DSB were comparable to RBE measured in vitro and in vivo. Depth dependent RBE values in the SOBP region might have to be considered in certain treatment situations.     

Monte Carlo single-cell dosimetry of I-131, I-125 and I-123 for targeted radioimmunotherapy of B-cell lymphoma

Abstract

Purpose: To study the dosimetric characteristics of a non-internalizing and an internalizing monoclonal antibody (MAb) labeled with ¹³¹I, ¹²⁵I or ¹²³I, which targets a typical lymphoma B-cell. Materials and methods: Using our hybrid Monte Carlo (MC) code which combines detailed- and condensed-history electron track simulation we carry out transport calculations of Auger and beta electrons for different intracellular distributions of radioactivity. Results: Assuming permanent retention of the MAb in cells, ¹²⁵I gave the highest absorbed dose and ¹²³I the highest absorbed dose rate. Under the more realistic scenario of biologic excretion from the cells, ¹²³I resulted in the highest absorbed dose and absorbed dose rate. Conclusion: The present dosimetric analysis shows that biological half-life, subcellular localization, and the proper account of low-energy electrons is critical in assessing the energy deposition inside the targeted cells from the three iodide radioisotopes examined. From a dosimetric point of view and under the present approximations ¹²³I might be superior to the other two radioiodides in the treatment of microscopic disease in B-cell lymphoma patients.     

Dosimetric influence of seed spacers and end-weld thickness for permanent prostate brachytherapy

PurposeThe aim of this study was to analyze the dosimetric influence of conventional spacers and a cobalt chloride complex contrast (C4) agent, a novel marker for MRI that can also serve as a seed spacer, adjacent to ¹⁰³Pd, ¹²⁵I, and ¹³¹Cs sources for permanent prostate brachytherapy.Methods and MaterialsMonte Carlo methods for radiation transport were used to estimate the dosimetric influence of brachytherapy end-weld thicknesses and spacers near the three sources. Single-source assessments and volumetric conditions simulating prior patient treatments were computed. Volume–dose distributions were imported to a treatment planning system for dose–volume histogram analyses.ResultsSingle-source assessment revealed that brachytherapy spacers primarily attenuated the dose distribution along the source long axis. The magnitude of the attenuation at 1 cm on the long axis ranged from −10% to −5% for conventional spacers and approximately −2% for C4 spacers, with the largest attenuation for ¹⁰³Pd. Spacer perturbation of dose distributions was less than manufacturing tolerances for brachytherapy sources as gleaned by an analysis of end-weld thicknesses. Volumetric Monte Carlo assessment demonstrated that TG-43 techniques overestimated calculated doses by approximately 2%. Specific dose–volume histogram metrics for prostate implants were not perturbed by inclusion of conventional or C4 spacers in clinical models.ConclusionsDosimetric perturbations of single-seed dose distributions by brachytherapy spacers exceeded 10% along the source long axes adjacent to the spacers. However, no dosimetric impact on volumetric parameters was noted for brachytherapy spacers adjacent to ¹⁰³Pd, ¹²⁵I, or ¹³¹Cs sources in the context of permanent prostate brachytherapy implants.     

Estimation of background spectrum in a shielded HPGe detector using Monte Carlo simulations

Monte Carlo simulations are powerful tools used to estimate the background γ-radiation detected by high-resolution gamma-ray spectrometry systems with a HPGe (high purity germanium) detector contained inside a lead shield. The purpose of this work was to examine the applicability of Monte Carlo simulations to predict the optimal lead thickness necessary to reduce the background effect in spectrometer measurements. GEANT4 code was applied to simulate the background radiation spectrum at different thicknesses of lead. The simulated results were compared with experimental measurements of background radiation taken at the same shielding thickness. The results show that the background radiation detected depends on the thickness, size and lining of the shield. Simulation showed that 12 cm lead thick is the optimal shielding thickness.     

Detection of fast neutrons from shielded nuclear materials using a semiconductor alpha detector

The response of a semiconductor alpha detector to fast (>1 MeV) neutrons was investigated by using measurements and simulations. A polyethylene converter was placed in front of the detector to register recoil protons generated by elastic collisions between neutrons and hydrogen nuclei of the converter. The developed prototype equipment was tested with shielded radiation sources. The low background of the detector and insensitivity to high-energy gamma rays above 1 MeV are advantages when the detection of neutron-emitting nuclear materials is of importance. In the case of a ²⁵²Cf neutron spectrum, the intrinsic efficiency of fast neutron detection was determined to be 2.5×10⁻⁴, whereas three-fold greater efficiency was obtained for a ²⁴¹AmBe neutron spectrum.     

Computational analysis of determinants of dopamine (DA) dysfunction in DA nerve terminals

Dopamine signaling is involved in a number of brain pathways, and its disruption has been suggested to be involved in the several disease states, including Parkinson's disease (PD), schizophrenia, and attention deficit hyperactivity disorder (ADHD). It has been hypothesized that altered storage, release, and reuptake of dopamine contributes to both the hypo‐ and hyperdopaminergic states that exist in various diseases. Here, we use our recently described mathematical model of dopamine metabolism, combined with a comprehensive Monte Carlo simulation analysis, to identify key determinants of dopamine metabolism associated with the dysregulation of dopamine homeostasis that may contribute to the pathogenesis of dopamine‐based disorders. Our model reveals that the dopamine transporter (DAT), the vesicular monoamine transporter (VMAT2), and the enzyme monoamine oxidase (MAO) are the most influential components controlling the synaptic level of dopamine and the formation of toxic intracellular metabolites. The results are consistent with experimental observations and point to metabolic processes and combinations of processes that may be biochemical drivers of dopamine neuron degeneration. Since many of the identified components can be targeted therapeutically, the model may aid in the design of combined therapeutic regimens aimed at restoring proper dopamine signaling with toxic intermediates under control. Synapse 63:1133–1142, 2009. © 2009 Wiley‐Liss, Inc.     

β源支架剂量分布的蒙特卡罗算法

目的 比较数值积分和蒙特卡罗方法计算的放射性支架的剂量率分布。方法 以3种有代表性的剂量点核函数为计算模型，计算支架的剂量率分布。结果 分别计算了中心面的径向，支架表面及离支架表面0.5mm处的轴向剂量分布，径向最大差异为1．5％，轴向的差异也有1．5％之内。结论 3种函数用数值积分和蒙特卡罗方法计算的剂量分布是一致的，蒙特卡罗方法可用来计算放射性支架的剂量分布。