Implementation of new physics models for low energy electrons in liquid water in Geant4-DNA

A new alternative set of elastic and inelastic cross sections has been added to the very low energy extension of the Geant4 Monte Carlo simulation toolkit, Geant4-DNA, for the simulation of electron interactions in liquid water. These cross sections have been obtained from the CPA100 Monte Carlo track structure code, which has been a reference in the microdosimetry community for many years. They are compared to the default Geant4-DNA cross sections and show better agreement with published data.In order to verify the correct implementation of the CPA100 cross section models in Geant4-DNA, simulations of the number of interactions and ranges were performed using Geant4-DNA with this new set of models, and the results were compared with corresponding results from the original CPA100 code. Good agreement is observed between the implementations, with relative differences lower than 1% regardless of the incident electron energy.Useful quantities related to the deposited energy at the scale of the cell or the organ of interest for internal dosimetry, like dose point kernels, are also calculated using these new physics models. They are compared with results obtained using the well-known Penelope Monte Carlo code.     

A proposal for optical diagnostics through the enhancement of diffraction patterns using thin-film interference filters

Coarse clumping of solid materials within diseased biological cells can have a marked influence on the light scattering pattern. Perturbations in refractive index lead to distinct variations in the cytometric signature, especially apparent over wide scattering angles. The large dynamic range of scattering intensities restricts collection of data to narrow angular intervals believed to have the highest potential for medical diagnosis. We propose the use of an interference filter to reduce the dynamic range. Selective attenuation of scattering intensity levels is expected to allow simultaneous data collection over a wide angular interval. The calculated angular transmittance of a commercial shortwave-pass filter of cut-off wavelength 580 nm indicates significant attenuation of scattering peaks below ∼10°, and reasonable peak equalization at higher angles. For the three-dimensional calculation of laser light scattered by cells we use a spectral method code that models cells as spatially varying dielectrics, stationary in time. However, we perform preliminary experimental testing with the interference filter on polystyrene microspheres instead of biological cells. A microfluidic toolkit is used for the manipulation of the microspheres. The paper intends to illustrate the principle of a light scattering detection system incorporating an interference filter for selective attenuation of scattering peaks.     

The TOPAS tool for particle simulation,a Monte Carlo simulation tool for physics,biology and clinical research

PurposeThis paper covers recent developments and applications of the TOPAS TOol for PArticle Simulation and presents the approaches used to disseminate TOPAS.Materials and methodsFundamental understanding of radiotherapy and imaging is greatly facilitated through accurate and detailed simulation of the passage of ionizing radiation through apparatus and into a patient using Monte Carlo (MC). TOPAS brings Geant4, a reliable, experimentally validated MC tool mainly developed for high energy physics, within easy reach of medical physicists, radiobiologists and clinicians. Requiring no programming knowledge, TOPAS provides all of the flexibility of Geant4.ResultsAfter 5 years of development followed by its initial release, TOPAS was subsequently expanded from its focus on proton therapy physics to incorporate radiobiology modeling. Next, in 2018, the developers expanded their user support and code maintenance as well as the scope of TOPAS towards supporting X-ray and electron therapy and medical imaging. Improvements have been achieved in user enhancement through software engineering and a graphical user interface, calculational efficiency, validation through experimental benchmarks and QA measurements, and either newly available or recently published applications. A large and rapidly increasing user base demonstrates success in our approach to dissemination of this uniquely accessible and flexible MC research tool.ConclusionsThe TOPAS developers continue to make strides in addressing the needs of the medical community in applications of ionizing radiation to medicine, creating the only fully integrated platform for four-dimensional simulation of all forms of radiotherapy and imaging with ionizing radiation, with a design that promotes inter-institutional collaboration.     

The optimal balance between quality and efficiency in proton radiography imaging technique at various proton beam energies: A Monte Carlo study

Proton radiography is a novel imaging modality that allows direct measurement of the proton energy loss in various tissues. Currently, due to the conversion of so-called Hounsfield units from X-ray Computed Tomography (CT) into relative proton stopping powers (RPSP), the uncertainties of RPSP are 3–5% or higher, which need to be minimized down to 1% to make the proton treatment plans more accurate.In this work, we simulated a proton radiography system, with position-sensitive detectors (PSDs) and a residual energy detector (RED). The simulations were built using Geant4, a Monte Carlo simulation toolkit. A phantom, consisting of several materials was placed between the PSDs of various Water Equivalent Thicknesses (WET), corresponding to an ideal detector, a gaseous detector, silicon and plastic scintillator detectors. The energy loss radiograph and the scattering angle distributions of the protons were studied for proton beam energies of 150 MeV, 190 MeV and 230 MeV. To improve the image quality deteriorated by the multiple Coulomb scattering (MCS), protons with small angles were selected. Two ways of calculating a scattering angle were considered using the proton’s direction and position.A scattering angle cut of 8.7 mrad was applied giving an optimal balance between quality and efficiency of the radiographic image. For the three proton beam energies, the number of protons used in image reconstruction with the direction method was half the number of protons kept using the position method.     

Design of spread-out Bragg peaks in hadron therapy with oxygen ions

Aim

Design of a numerical method for creating spread-out Bragg peak (SOBP) and evaluation of the best parameter in Bortfeld Model to this aim in oxygen ion therapy.

Self Crowding of Globular Proteins Studied by Small-Angle X-Ray Scattering

Small-angle x-ray scattering (SAXS) was used to study the behavior of equine metmyoglobin (Mb) and bovine pancreatic trypsin inhibitor (BPTI) at concentrations up to 0.4 and 0.15 g/mL, respectively, in solutions also containing 50% D₂O and 1 M urea. For both proteins, significant effects because of interference between x-rays scattered by different molecules (interparticle interference) were observed, indicating nonideal behavior at high concentrations. The experimental data were analyzed by comparison of the observed scattering profiles with those predicted by crystal structures of the proteins and a hard-sphere fluid model used to represent steric exclusion effects. The Mb scattering data were well fit by the hard-sphere model using a sphere radius of 18 Å, only slightly smaller than that estimated from the three-dimensional structure (20 Å). In contrast, the scattering profiles for BPTI in phosphate buffer displayed substantially less pronounced interparticle interference than predicted by the hard-sphere model and the radius estimated from the known structure of the protein (15 Å). Replacing the phosphate buffer with 3-(N-morpolino)propane sulfonic acid (MOPS) led to increased interparticle interference, consistent with a larger effective radius and suggesting that phosphate ions may mediate attractive intermolecular interactions, as observed in some BPTI crystal structures, without the formation of stable oligomers. The scattering data were also used to estimate second virial coefficients for the two proteins: 2.0 ×10^-4 cm³mol/g² for Mb in phosphate buffer, 1.6 ×10^-4 cm³mol/g² for BPTI in phosphate buffer and 9.2 ×10^-4 cm³mol/g² for BPTI in MOPS. The results indicate that the behavior of Mb, which is nearly isoelectric under the conditions used, is well described by the hard-sphere model, but that of BPTI is considerably more complex and is likely influenced by both repulsive and attractive electrostatic interactions. The hard-sphere model may be a generally useful tool for the analysis of small-angle scattering data from concentrated macromolecular solutions.     

The role of 3-D collagen organization in stromal elasticity: a model based on X-ray diffraction data and second harmonic-generated images

Examining the cross-section of the human cornea with second harmonic-generated (SHG) imaging shows that many lamellae do not lie parallel to the cornea’s anterior surface but have inclined trajectories that take them through the corneal thickness with a depth-dependent distribution. A continuum mechanics-based model of stromal elasticity is developed based on orientation information extracted and synthesized from both X-ray scattering studies and SHG imaging. The model describes the effects of inclined lamella orientation by introducing a probability function that varies with depth through the stroma, which characterizes the range and distribution of lamellae at inclined angles. When combined with the preferred lamellar orientations found from X-ray scattering experiments, a fully 3-D representation of lamella orientation is achieved. Stromal elasticity is calculated by a weighted average of individual lamella properties based on the spatially varying 3-D orientation distribution. The model is calibrated with in vitro torsional shear experiments and in vivo indentation data and then validated with an in vitro inflation study. A quantitative explanation of the experimentally measured depth dependence of mechanical properties emerges from the model. The significance of the 3-D lamella orientation in the mechanics of the human cornea is demonstrated by investigating and contrasting the effects of previous modeling assumptions made on lamella orientation.     

Structure of tumour necrosis factor by X-ray solution scattering and preliminary studies by single crystal X-ray diffraction

The structure of tumour necrosis factor has been investigated by X-ray small-angle scattering and X-ray diffraction using synchrotron radiation. The overall radius of gyration is 25.5 A. A plausible model accounting for the scattering curves consists of an elongated trimer with an axial ratio of 3 to 4 and a maximal chord with a lower limit of 80 A. Tumour necrosis factor has been crystallized in a trigonal space group. Our results are in favour of a single trimer in the asymmetric unit. The diffraction extends to 3.5 A.     

Response of SOI microdosimeter in fast neutron beams: experiment and Monte Carlo simulations

In this study, Monte Carlo codes, Geant4 and MCNP6, were used to characterize the fast neutron therapeutic beam produced at iThemba LABS in South Africa. Experimental and simulation results were compared using the latest generation of Silicon on Insulator (SOI) microdosimeters from the Centre for Medical Radiation Physics (CMRP). Geant4 and MCNP6 were able to successfully model the neutron gantry and simulate the expected neutron energy spectrum produced from the reaction by protons bombarding a ⁹Be target. The neutron beam was simulated in a water phantom and its characteristics recorded by the silicon microdosimeters; bare and covered by a ¹⁰B enriched boron carbide converter, at different positions. The microdosimetric quantities calculated using Geant4 and MCNP6 are in agreement with experimental measurements. The thermal neutron sensitivity and production of ¹⁰B capture products in the p+ boron-implanted dopant regions of the Bridge microdosimeter is investigated. The obtained results are useful for the future development of dedicated SOI microdosimeters for Boron Neutron Capture Therapy (BNCT). This paper provides a benchmark comparison of Geant4 and MCNP6 capabilities in the context of further applications of these codes for neutron microdosimetry.     

Assessment of ideal neutron beams for neutron capture therapy.

The discrete-ordinates transport computer code DORT has been used to develop a two-dimensional cylindrical phantom model for use as a tool to assess beam design and dose distributions for boron neutron capture therapy. The model uses an S8 approximation for angular fluxes and a P3 Legendre approximation for scattering cross sections. A one-dimensional discrete-ordinates model utilizing the computer code ANISN was used to validate the energy-group structure used in the two-dimensional calculations. In the two-dimensional model the effects of varying basic parameters such as aperture width, neutron source energy, and tissue composition have been studied. Identical results were obtained when comparing narrow beam calculations to fine-mesh higher-order Sn treatments (up to S32), and with P5 cross sections. It is shown that, when the correct assessment volume is used, narrow beams will give little or no advantage for therapy even with an optimum-energy ideal neutron beam.     

A molecular ruler for measuring quantitative distance distributions

We report a novel molecular ruler for measurement of distances and distance distributions with accurate external calibration. Using solution X-ray scattering we determine the scattering interference between two gold nanocrystal probes attached site-specifically to a macromolecule of interest. Fourier transformation of the interference pattern provides a model-independent probability distribution for the distances between the probe centers-of-mass. To test the approach, we measure end-to-end distances for a variety of DNA structures. We demonstrate that measurements with independently prepared samples and using different X-ray sources are highly reproducible, we demonstrate the quantitative accuracy of the first and second moments of the distance distributions, and we demonstrate that the technique recovers complex distribution shapes. Distances measured with the solution scattering-interference ruler match the corresponding crystallographic values, but differ from distances measured previously with alternate ruler techniques. The X-ray scattering interference ruler should be a powerful tool for relating crystal structures to solution structures and for studying molecular fluctuations.     

A GATE/Geant4 beam model for the MedAustron non-isocentric proton treatment plans quality assurance

PurposeTo present a reference Monte Carlo (MC) beam model developed in GATE/Geant4 for the MedAustron fixed beam line. The proposed model includes an absolute dose calibration in Dose-Area-Product (DAP) and it has been validated within clinical tolerances for non-isocentric treatments as routinely performed at MedAustron.Material and MethodsThe proton beam model was parametrized at the nozzle entrance considering optic and energy properties of the pencil beam. The calibration in terms of absorbed dose to water was performed exploiting the relationship between number of particles and DAP by mean of a recent formalism. Typical longitudinal dose distribution parameters (range, distal penumbra and modulation) and transverse dose distribution parameters (spot sizes, field sizes and lateral penumbra) were evaluated. The model was validated in water, considering regular-shaped dose distribution as well as clinical plans delivered in non-isocentric conditions.ResultsSimulated parameters agree with measurements within the clinical requirements at different air gaps. The agreement of distal and longitudinal dose distribution parameters is mostly better than 1 mm. The dose difference in reference conditions and for 3D dose delivery in water is within 0.5% and 1.2%, respectively. Clinical plans were reproduced within 3%.ConclusionA full nozzle beam model for active scanning proton pencil beam is described using GATE/Geant4. Absolute dose calibration based on DAP formalism was implemented. The beam model is fully validated in water over a wide range of clinical scenarios and will be inserted as a reference tool for research and for independent dose calculation in the clinical routine.     

Self Crowding of Globular Proteins Studied by Small-Angle X-Ray Scattering

Small-angle x-ray scattering (SAXS) was used to study the behavior of equine metmyoglobin (Mb) and bovine pancreatic trypsin inhibitor (BPTI) at concentrations up to 0.4 and 0.15 g/mL, respectively, in solutions also containing 50% D₂O and 1 M urea. For both proteins, significant effects because of interference between x-rays scattered by different molecules (interparticle interference) were observed, indicating nonideal behavior at high concentrations. The experimental data were analyzed by comparison of the observed scattering profiles with those predicted by crystal structures of the proteins and a hard-sphere fluid model used to represent steric exclusion effects. The Mb scattering data were well fit by the hard-sphere model using a sphere radius of 18 Å, only slightly smaller than that estimated from the three-dimensional structure (20 Å). In contrast, the scattering profiles for BPTI in phosphate buffer displayed substantially less pronounced interparticle interference than predicted by the hard-sphere model and the radius estimated from the known structure of the protein (15 Å). Replacing the phosphate buffer with 3-(N-morpolino)propane sulfonic acid (MOPS) led to increased interparticle interference, consistent with a larger effective radius and suggesting that phosphate ions may mediate attractive intermolecular interactions, as observed in some BPTI crystal structures, without the formation of stable oligomers. The scattering data were also used to estimate second virial coefficients for the two proteins: 2.0 ×10^-4 cm³mol/g² for Mb in phosphate buffer, 1.6 ×10^-4 cm³mol/g² for BPTI in phosphate buffer and 9.2 ×10^-4 cm³mol/g² for BPTI in MOPS. The results indicate that the behavior of Mb, which is nearly isoelectric under the conditions used, is well described by the hard-sphere model, but that of BPTI is considerably more complex and is likely influenced by both repulsive and attractive electrostatic interactions. The hard-sphere model may be a generally useful tool for the analysis of small-angle scattering data from concentrated macromolecular solutions.     

Minibeam radiation therapy at a conventional irradiator: Dose-calculation engine and first tumor-bearing animals irradiation

Purpose: Minibeam radiation therapy (MBRT) is a novel therapeutic strategy, whose exploration was hindered due to its restriction to large synchrotrons. Our recent implementation of MBRT in a wide-spread small animal irradiator offers the possibility of performing systematic radiobiological studies. The aim of this research was to develop a set of dosimetric tools to reliably guide biological experiments in the irradiator.Methods: A Monte Carlo (Geant4)-based dose calculation engine was developed. It was then benchmarked against a series of dosimetric measurements performed with gafchromic films. Two voxelized rat phantoms (ROBY, computer tomography) were used to evaluate the treatment plan of F98 tumor-bearing rats. The response of a group of 7 animals receiving a unilateral irradiation of 58 Gy was compared to a group of non-irradiated controls.Results: The good agreement between calculations and the experimental data allowed the validation of the dose-calculation engine. The latter was first used to compare the dose distributions in computer tomography images of a rat’s head and in a digital model of a rat’s head (ROBY), obtaining a good general agreement. Finally, with respect to the in vivo experiment, the increase of mean survival time of the treated group with respect to the controls was modest but statistically significant.Conclusions: The developed dosimetric tools were used to reliably guide the first MBRT treatments of intracranial glioma-bearing rats outside synchrotrons. The significant tumor response obtained with respect to the non-irradiated controls, despite the heterogenous dose coverage of the target, might indicate the participation of non-targeted effects.     

An open‐source code for Mie extinction extended multiplicative signal correction for infrared microscopy spectra of cells and tissues

Infrared spectroscopy of single cells and tissue is affected by Mie scattering. During recent years, several methods have been proposed for retrieving pure absorbance spectra from such measurements, while currently no user‐friendly version of the state‐of‐the‐art algorithm is available. In this work, an open‐source code for correcting highly scatter‐distorted absorbance spectra of cells and tissues is presented, as well as several improvements of the latest version of the Mie correction algorithm based on extended multiplicative signal correction (EMSC) published by Konevskikh et al. In order to test the stability of the code, a set of apparent absorbance spectra was simulated. To this purpose, pure absorbance spectra based on a Matrigel spectrum are simulated. Scattering contributions where obtained by mimicking the scattering features observed in a set of experimentally obtained spectra . It can be concluded that the algorithm is not depending strongly on the reference spectrum used for initializing the algorithm and retrieves well the underlying pure absorbance spectrum. The calculation time of the algorithm is considerably improved with respect to the resonant Mie scattering EMSC algorithm used by the community today.      

X-ray lithography and small-angle X-ray scattering: a combination of techniques merging biology and materials science

The advent of micro/nanotechnology has blurred the border between biology and materials science. Miniaturization of chemical and biological assays, performed by use of micro/nanofluidics, requires both careful selection of the methods of fabrication and the development of materials designed for specific applications. This, in turn, increases the need for interdisciplinary combination of suitable microfabrication and characterisation techniques. In this review, the advantages of combining X-ray lithography, as fabrication technique, with small-angle X-ray scattering measurements will be discussed. X-ray lithography enables the limitations of small-angle X-ray scattering, specifically time resolution and sample environment, to be overcome. Small-angle X-ray scattering, on the other hand, enables investigation and, consequently, adjustment of the nanostructural morphology of microstructures and materials fabricated by X-ray lithography. Moreover, the effect of X-ray irradiation on novel materials can be determined by use of small-angle X-ray scattering. The combination of top-down and bottom-up methods to develop new functional materials and structures with potential in biology will be reported.     

In silico investigation of factors affecting the MV imaging performance of a novel water-equivalent EPID

PurposeA Geant4 model of a novel, water-equivalent electronic portal imaging device (EPID) prototype for radiotherapy imaging and dosimetry utilising an array of plastic scintillating fibres (PSFs) has been developed. Monte Carlo (MC) simulations were performed to quantify the PSF-EPID imaging performance and to investigate design aspects affecting performance for optimisation.MethodsUsing the Geant4 model, the PSF-EPID’s imaging performance for 6 MV photon beams was quantified in terms of its modulation transfer function (MTF), noise power spectrum (NPS) and detective quantum efficiency (DQE). Model parameters, including fibre dimensions, optical cladding reflectivity and scintillation yield, were varied to investigate impact on imaging performance.ResultsThe MC-calculated DQE(0) for the reference PSF-EPID geometry employing 30 mm fibres was approximately nine times greater than values reported for commercial EPIDs. When using 10 mm long fibres, the PSF-EPID DQE(0) was still approximately three times greater than that of a commercial EPID. Increased fibre length, cladding reflectivity and scintillation yield produced the greatest decreases in NPS and increases in DQE.ConclusionsThe potential to develop an optimised next-generation water-equivalent EPID with MV imaging performance at least comparable to commercial EPIDs has been demonstrated. Factors most important for optimising prototype design include fibre length, cladding reflectivity and scintillation yield.