The TOPAS Monte Carlo (MC) system is used in radiation therapy and medical imaging research, having played a significant role in making Monte Carlo simulations widely available for proton therapy related research. While TOPAS provides detailed simulations of patient scale properties, the fundamental unit of the biological response to radiation is a cell. Thus, our goal was to develop TOPAS-nBio, an extension of TOPAS dedicated to advance understanding of radiobiological effects at the (sub-)cellular, (i.e., the cellular and sub-cellular) scale. TOPAS-nBio was designed as a set of open source classes that extends TOPAS to model radiobiological experiments. TOPAS-nBio is based on and extends Geant4-DNA, which extends the Geant4 toolkit, the basis of TOPAS, to include very low-energy interactions of particles down to vibrational energies, explicitly simulates every particle interaction (i.e., without using condensed histories) and propagates radiolysis products. To further facilitate the use of TOPAS-nBio, a graphical user interface was developed. TOPAS-nBio offers full track-structure Monte Carlo simulations, integration of chemical reactions within the first millisecond, an extensive catalogue of specialized cell geometries as well as sub-cellular structures such as DNA and mitochondria, and interfaces to mechanistic models of DNA repair kinetics. We compared TOPAS-nBio simulations to measured and published data of energy deposition patterns and chemical reaction rates (G values). Our simulations agreed well within the experimental uncertainties. Additionally, we expanded the chemical reactions and species provided in Geant4-DNA and developed a new method based on independent reaction times (IRT), including a total of 72 reactions classified into 6 types between neutral and charged species. Chemical stage simulations using IRT were a factor of 145 faster than with step-by-step tracking. Finally, we applied the geometric/chemical modeling to obtain initial yields of double-strand breaks (DSBs) in DNA fibers for proton irradiations of 3 and 50 MeV and compared the effect of including chemical reactions on the number and complexity of DSB induction. Over half of the DSBs were found to include chemical reactions with approximately 5% of DSBs caused only by chemical reactions. In conclusion, the TOPAS-nBio extension to the TOPAS MC application offers access to accurate and detailed multiscale simulations, from a macroscopic description of the radiation field to microscopic description of biological outcome for selected cells. TOPAS-nBio offers detailed physics and chemistry simulations of radiobiological experiments on cells simulating the initially induced damage and links to models of DNA repair kinetics.

This study confirmed the dosimetric feasibility of real-time MRI-guided proton therapy and delivering a clinically acceptable dose to patients with various tumor locations within magnetic fields of up to 1.5 T. This work could serve as a guide and encouragement for further efforts toward clinical implementation of hybrid MRI-proton gantry systems.

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Super-Kamiokande atmospheric neutrino data were fit with an un-binned maximum likelihood method to search for the appearance of tau leptons resulting from the interactions of oscillation-generated tau neutrinos in the detector. Relative to the expectation of unity, the tau normalization is found to be 1. 42 ± 0.35 (stat) +0.14 −0.12 (sys) excluding the no-tau-appearance hypothesis, for which the normalization would be zero, at the 3.8σ level. We estimate that 180.1 ± 44.3 (stat) +17.8 −15.2 (sys) tau leptons were produced in the 22.5 kton fiducial volume of the detector by tau neutrinos during the 2806 day running period. In future analyses, this large sample of selected tau events will allow the study of charged current tau neutrino interaction physics with oscillation produced tau neutrinos. RENO [16] experiments reported the first precision measurements of the θ 13 mixing angle which drives three-flavor oscillation.Definitive proof of flavor oscillation requires unambiguous appearance of the charged current interaction of a neutrino not in the original source. In the dominant oscillation for ν µ at GeV energies, ν µ → ν τ oscillations, observing the resulting τ lepton is quite difficult. This is because producing a tau lepton requires a neutrino of energy greater than a threshold of 3.5 GeV. Long-baseline experiments tuned to the neutrino oscillation maximum for their distances tend to have the bulk of their neutrinos below this energy. Furthermore, the tau lepton immediately decays to final states with an electron, muon or mesons plus a tau neutrino so the tau lepton itself cannot be easily seen. Nevertheless, the OPERA collaboration was recently able to show evidence for a single reconstructed event in their emulsion consistent with tau appearance [17]. The Super-K collaboration first published a search for tau appearance in atmospheric neutrinos in 2006 [18]. Since the atmospheric neutrino flux extends to energies well above 10 GeV, and spans a wide range of baselines, we expect to see tau leptons produced in the Super-K detector. However, these events must be distinguished from other high-energy atmospheric neutrino interactions. Further comparisons of these techniques can be found in [19] and prospects for future detectors can be found in [20].This letter reports a result from a new search utilizing the Super-Kamiokande experiment. This analysis addresses the question of whether the atmospheric data is consistent with lack of oscillation-generated ν τ , or whether they are necessary to explain the observations. Super-Kamiokande (Super-K) is a 50,000 ton water Cherenkov detector[21] with 22.5 ktons of fiducial volume. It consists of two concentric detectors: a inner-detector with 11,129 inward-looking 20 inch photodetectors, and an outer-detector with 1885 outward-facing 8 inch photo-detectors which acts as a veto. Its large target mass makes it well suited to look for the rare appearance of tau neutrinos from oscillations. The typical energy of atmospheric neutrinos is about 1 GeV. Due to the previ...

Extremely high-dose-rate irradiation, referred to as FLASH, has been shown to be less damaging to normal tissues than the same dose administrated at conventional dose rates. These results, typically seen at dose rates exceeding 40 Gy/s (or 2,400 Gy/min), have been widely reported in studies utilizing photon or electron radiation as well as in some proton radiation studies. Here, we report the development of a proton irradiation platform in a clinical proton facility and the dosimetry methods developed. The target is placed in the entry plateau region of a proton beam with a specifically designed double-scattering system. The energy after the double-scattering system is 227.5 MeV for protons that pass through only the first scatterer, and 225.5 MeV for those that also pass through the second scatterer. The double-scattering system was optimized to deliver a homogeneous dose distribution to a field size as large as possible while keeping the dose rate .100 Gy/s and not exceeding a cyclotron current of 300 nA. We were able to obtain a collimated pencil beam (1.6 3 1.2 cm 2 ellipse) at a dose rate of ;120 Gy/s. This beam was used for dose-response studies of partial abdominal irradiation of mice. First results indicate a potential tissuesparing effect of FLASH.

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Computational simulations offer a powerful tool for quantitatively investigating radiation interactions with biological tissue and can help bridge the gap between physics, chemistry and biology. The TOPAS collaboration is tackling this challenge by extending the current Monte Carlo tool to allow for sub-cellular in silico simulations in a new extension, TOPAS-nBio. TOPAS wraps and extends the Geant4 Monte Carlo simulation toolkit and the new extension allows the modeling of particles down to vibrational energies (~ 2 eV) within realistic biological geometries. Here we present a validation of biological geometries available in TOPAS-nBio, by comparing our results to two previously published studies. We compare the prediction of strand breaks in a simple linear DNA strand from TOPAS-nBio to a published Monte Carlo track structure simulation study. While TOPAS-nBio confirms the trend in strand break generation, it predicts a higher frequency of events below an energy of 17.5 eV compared to the alternative Monte Carlo track structure study. This is due to differences in the physics models used by each code. We also compare the experimental measurement of strand breaks from incident protons in DNA plasmids to TOPAS-nBio simulations. Our results show good agreement of single and double strand breaks predicting a similar increase in the strand break yield with increasing LET.

We present the results of searches for nucleon decay via n →νπ 0 and p →νπ + using data from a combined 172.8 kton · years exposure of Super-Kamiokande-I, -II, and -III. We set lower limits on the partial lifetime for each of these modes: τ n→νπ 0 > 1.1×10 33 years and τ p→νπ + > 3.9×10 32 years at 90% confidence level.