Clustered DNA Damage Patterns after Proton Therapy Beam Irradiation Using Plasmid DNA.

Modeling ionizing radiation interaction with biological matter is a major scientific challenge, especially for protons that are nowadays widely used in cancer treatment. That presupposes a sound understanding of the mechanisms that take place from the early events of the induction of DNA damage. Herein, we present results of irradiation-induced complex DNA damage measurements using plasmid pBR322 along a typical Proton Treatment Plan at the MedAustron proton and carbon beam therapy facility (energy 137-198 MeV and Linear Energy Transfer (LET) range 1-9 keV/µm), by means of Agarose Gel Electrophoresis and DNA fragmentation using Atomic Force Microscopy (AFM). The induction rate Mbp-1 Gy-1 for each type of damage, single strand breaks (SSBs), double-strand breaks (DSBs), base lesions and non-DSB clusters was measured after irradiations in solutions with varying scavenging capacity containing 2-amino-2-(hydroxymethyl)propane-1,3-diol (Tris) and coumarin-3-carboxylic acid (C3CA) as scavengers. Our combined results reveal the determining role of LET and Reactive Oxygen Species (ROS) in DNA fragmentation. Furthermore, AFM used to measure apparent DNA lengths provided us with insights into the role of increasing LET in the induction of highly complex DNA damage.

Voxel model of individual cells and its implementation in microdosimetric calculations using GEANT4.

Accurate dosimetric calculations at cellular and sub-cellular levels are crucial to obtain an increased understanding of the interactions of ionizing radiation with a cell and its nucleus and cytoplasm. Ion microbeams provide a superior opportunity to irradiate small biological samples, e.g., DNA, cells, and to compare their response to computer simulations. However, the phantoms used to simulate small biological samples at cellular levels are often simplified as simple volumes filled with water. As a first step to improve the situation in comparing measurements of cell response to ionizing radiation with model calculations, a realistic voxel model of a KB cell was constructed and used together with an already constructed geometry and tracking 4 (GEANT4) model of the horizontal microbeam line of the Centre d'Etudes Nucléaires de Bordeaux-Gradignan (CENBG) 3.5 MV Van de Graaf accelerator at the CENBG, France. The microbeam model was then implemented into GEANT4 for simulations of the average number of particles hitting an irradiated cell when a specified number of particles are produced in the beam line. The result shows that when irradiating the developed voxel model of a KB cell with 200 α particles, with a nominal energy of 3 MeV in the beam line and 2.34 MeV at the cell entrance, 100 particles hit the cell on average. The mean specific energy is 0.209 ± 0.019 Gy in the nucleus and 0.044 ± 0.001 Gy in the cytoplasm. These results are in agreement with previously published data, which indicates that this model could act as a reference model for dosimetric calculations of radiobiological experiments, and that the proposed method could be applied to build a cell model database.

Clustered DNA damage on subcellular level: effect of scavengers.

Clustered DNA damages are induced by ionizing radiation, particularly of high linear energy transfer (LET). Compared to isolated DNA damage sites, their biological effects can be more severe. We investigated a clustered DNA damage induced by high LET radiation (C 290 MeV u(-1) and Fe 500 MeV u(-1)) in pBR322 plasmid DNA. The plasmid is dissolved in pure water or in aqueous solution of one of the three scavengers (coumarin-3-carboxylic acid, dimethylsulfoxide, and glycylglycine). The yield of double strand breaks (DSB) induced in the DNA plasmid-scavenger system by heavy ion radiation was found to decrease with increasing scavenging capacity due to reaction with hydroxyl radical, linearly with high correlation coefficients. The yield of non-DSB clusters was found to occur twice as much as the DSB. Their decrease with increasing scavenging capacity had lower linear correlation coefficients. This indicates that the yield of non-DSB clusters depends on more factors, which are likely connected to the chemical properties of individual scavengers.

Radium deposition in human brain tissue: A Geant4-DNA Monte Carlo toolkit study.

NASA has encouraged studies on 226Ra deposition in the human brain to investigate the effects of exposure to alpha particles with high linear energy transfer, which could mimic some of the exposure astronauts face during space travel. However, this approach was criticized, noting that radium is a bone-seeker and accumulates in the skull, which means that the radiation dose from alpha particles emitted by 226Ra would be heavily concentrated in areas close to cranial bones rather than uniformly distributed throughout the brain. In the high background radiation areas of Ramsar, Iran, extremely high levels of 226Ra in soil contribute to a large proportion of the inhabitants' radiation exposure. A prospective study on Ramsar residents with a calcium-rich diet was conducted to improve the dose uniformity due to 226Ra throughout the cerebral and cerebellar parenchyma. The study found that exposure of the human brain to alpha particles did not significantly affect working memory but was significantly associated with increased reaction times. This finding is crucial because astronauts on deep space missions may face similar cognitive impairments due to exposure to high charge and energy particles. The current study was aimed to evaluate the validity of the terrestrial model using the Geant4 Monte Carlo toolkit to simulate the interactions of alpha particles and representative cosmic ray particles, acknowledging that these radiation types are only a subset of the complete space radiation environment.

Digital Screen Time and the Risk of Female Breast Cancer: A Retrospective Matched Case-Control Study.

Background: As the use of electronic devices such as mobile phones, tablets, and computers continues to rise globally, concerns have been raised about their potential impact on human health. Exposure to high energy visible (HEV) blue light, emitted from digital screens, particularly the so-called artificial light at night (ALAN), has been associated with adverse health effects, ranging from disruption of circadian rhythms to cancer. Breast cancer incidence rates are also increasing worldwide. Objective: This study aimed at finding a correlation between breast cancer and exposure to blue light from mobile phone. Material and Methods: In this retrospective matched case-control study, we aimed to investigate whether exposure to blue light from mobile phone screens is associated with an increased risk of female breast cancer. We interviewed 301 breast cancer patients (cases) and 294 controls using a standard questionnaire and performed multivariate analysis, chi-square, and Fisher's exact tests for data analysis. Results: Although heavy users in the case group of our study had a statistically significant higher mean 10-year cumulative exposure to digital screens compared to the control group (7089±14985 vs 4052±12515 hours, respectively, P=0.038), our study did not find a strong relationship between exposure to HEV and development of breast cancer. Conclusion: Our findings suggest that heavy exposure to HEV blue light emitted from mobile phone screens at night might constitute a risk factor for promoting the development of breast cancer, but further large-scale cohort studies are warranted.

Probiotic Bacteria Cannot Mitigate the Adverse Effects of Radioactive Iodine-131 Treatment.

Thyroid carcinoma is the most common cancer of the endocrine system, accounting for 12% of all cancer cases in adolescents in the United States. Radioiodine therapy plays a key role in differentiated thyroid cancer (DTC) treatment. This double-blind, randomized, placebo-controlled clinical trial was aimed at evaluating the effect of probiotics supplementation in reducing the acute side-effects of radioiodine therapy in PTC patients. Fifty-six patients were randomly divided into four groups: one placebo and three intervention groups. The probiotics product used in this study was LactoCare (ZistTakhmir Co., Tehran, Iran), a multi-strain commercially available symbiotic containing 12 strains of probiotic species including Lactobacillus strains, Bifidobacteria strains, and Streptococcus thermophilus, plus Fructo-oligosaccharides as the prebiotic. Group 0 was our placebo group (no probiotics), while the other three groups received probiotics capsules for 2/4 days, starting only 2 days prior to radioiodine therapy, only 4 days after radioiodine therapy or 2 days prior and 4 days after radioiodine therapy. Six patients were withdrawn during the study because of poor compliance or at their own request. The symptoms reported by patients including data about the incidence and duration of each complication were recorded. The probiotics' effectiveness was confirmed for dry mouth and taste loss or change when it was administered prior to the radioiodine treatment. The benefit was not confirmed for other radiation-induced complications such as pain and swelling in the neck, nausea and vomiting, salivary gland swelling, and diarrhea. Further large-scale clinical trials are warranted to improve our knowledge in this quickly evolving field.

How the adaptation of the human microbiome to harsh space environment can determine the chances of success for a space mission to Mars and beyond.

The ability of human cells to adapt to space radiation is essential for the well-being of astronauts during long-distance space expeditions, such as voyages to Mars or other deep space destinations. However, the adaptation of the microbiomes should not be overlooked. Microorganisms inside an astronaut's body, or inside the space station or other spacecraft, will also be exposed to radiation, which may induce resistance to antibiotics, UV, heat, desiccation, and other life-threatening factors. Therefore, it is essential to consider the potential effects of radiation not only on humans but also on their microbiomes to develop effective risk reduction strategies for space missions. Studying the human microbiome in space missions can have several potential benefits, including but not limited to a better understanding of the major effects space travel has on human health, developing new technologies for monitoring health and developing new radiation therapies and treatments. While radioadaptive response in astronauts' cells can lead to resistance against high levels of space radiation, radioadaptive response in their microbiome can lead to resistance against UV, heat, desiccation, antibiotics, and radiation. As astronauts and their microbiomes compete to adapt to the space environment. The microorganisms may emerge as the winners, leading to life-threatening situations due to lethal infections. Therefore, understanding the magnitude of the adaptation of microorganisms before launching a space mission is crucial to be able to develop effective strategies to mitigate the risks associated with radiation exposure. Ensuring the safety and well-being of astronauts during long-duration space missions and minimizing the risks linked with radiation exposure can be achieved by adopting this approach.

Monte Carlo simulation of semiconductor-based detector in mixed radiation field in the atmosphere.

Calculation of radiation protection quantities in tissue equivalent material from measurements using semiconductor detectors requires correction factors for conversion of the measured values in the semiconductor material to the tissue equivalent material. This approach has been used many times in aircraft and for space dosimetry. In this paper, we present the results of Monte Carlo simulations which reveal the need to take into account both the radiation field and the detector material when performing the conversion of measured values to radiation protection quantities. It is shown that for low Z target material, most of the dose equivalent at aviation altitudes comes from neutrons originating from nuclear reactions, while in high Z targets most of the dose equivalent comes from photons, originating from electromagnetic reactions.

SPACEDOS: AN OPEN-SOURCE PIN DIODE DOSEMETER FOR APPLICATIONS IN SPACE.

A new Open-Source dosemeter, SPACEDOS, has been developed for measurements of cosmic radiation on board spacecraft and small satellites. Its main advantages are that it is small and lightweight with low power consumption. It can be adjusted for specific applications, e.g. used in pressurized cabins of spacecraft or in vacuum environments in CubeSats or larger satellites. The open-source design enables better portability and reproduction of the results than other similar detectors. The detector has already successfully performed measurements on board the International Space Station. The obtained results are discussed and compared with those measured with thermoluminescent detectors located in the same position as SPACEDOS.

Dose estimation for astronauts using dose conversion coefficients calculated with the PHITS code and the ICRP/ICRU adult reference computational phantoms.

Absorbed-dose and dose-equivalent rates for astronauts were estimated by multiplying fluence-to-dose conversion coefficients in the units of Gy.cm(2) and Sv.cm(2), respectively, and cosmic-ray fluxes around spacecrafts in the unit of cm(-2) s(-1). The dose conversion coefficients employed in the calculation were evaluated using the general-purpose particle and heavy ion transport code system PHITS coupled to the male and female adult reference computational phantoms, which were released as a common ICRP/ICRU publication. The cosmic-ray fluxes inside and near to spacecrafts were also calculated by PHITS, using simplified geometries. The accuracy of the obtained absorbed-dose and dose-equivalent rates was verified by various experimental data measured both inside and outside spacecrafts. The calculations quantitatively show that the effective doses for astronauts are significantly greater than their corresponding effective dose equivalents, because of the numerical incompatibility between the radiation quality factors and the radiation weighting factors. These results demonstrate the usefulness of dose conversion coefficients in space dosimetry.

Biological Protection in Deep Space Missions.

During deep space missions, astronauts are exposed to highly ionizing radiation, incl. neutrons, protons and heavy ions from galactic cosmic rays (GCR), solar wind (SW) and solar energetic particles (SEP). This increase the risks for cancerogenisis, damages in central nervous system (CNS), cardiovascular diseases, etc. Large SEP events can even cause acute radiation syndrome (ARS). Long term manned deep space missions will therefor require unique radiation protection strategies. Since it has been shown that physical shielding alone is not sufficient, this paper propose pre-flight screening of the aspirants for evaluation of their level of adaptive responses. Methods for boosting their immune system, should also be further investigated, and the possibility of using radiation effect modulators are discussed. In this paper, especially, the use of vitamin C as a promising non-toxic, cost-effective, easily available radiation mitigator (which can be used hours after irradiation), is described. Although it has previously been shown that vitamin C can decrease radiation-induced chromosomal damage in rodents, it must be further investigated before any conclusions about its radiation mitigating properties in humans can be concluded.

Requirements for Designing an Effective Metallic Nanoparticle (NP)-Boosted Radiation Therapy (RT).

Many different tumor-targeted strategies are under development worldwide to limit the side effects and improve the effectiveness of cancer therapies. One promising method is to enhance the radiosensitization of the cancer cells while reducing or maintaining the normal tissue complication probability during radiation therapy using metallic nanoparticles (NPs). Radiotherapy with MV photons is more commonly available and applied in cancer clinics than high LET particle radiotherapy, so the addition of high-Z NPs has the potential to further increase the efficacy of photon radiotherapy in terms of NP radiosensitization. Generally, when using X-rays, mainly the inner electron shells are ionized, which creates cascades of both low and high energy Auger electrons. When using high LET particles, mainly the outer shells are ionized, which give electrons with lower energies than when using X-rays. The amount of the produced low energy electrons is higher when exposing NPs to heavy charged particles than when exposing them to X-rays. Since ions traverse the material along tracks, and therefore give rise to a much more inhomogeneous dose distributions than X-rays, there might be a need to introduce a higher number of NPs when using ions compared to when using X-rays to create enough primary and secondary electrons to get the desired dose escalations. This raises the questions of toxicity. This paper provides a review of the fundamental processes controlling the outcome of metallic NP-boosted photon beam and ion beam radiation therapy and presents some experimental procedures to study the biological effects of NPs' radiosensitization. The overview shows the need for more systematic studies of the behavior of NPs when exposed to different kinds of ionizing radiation before applying metallic-based NPs in clinical practice to improve the effect of IR therapy.

Biological dose estimation for charged-particle therapy using an improved PHITS code coupled with a microdosimetric kinetic model.

Microdosimetric quantities such as lineal energy, y, are better indexes for expressing the RBE of HZE particles in comparison to LET. However, the use of microdosimetric quantities in computational dosimetry is severely limited because of the difficulty in calculating their probability densities in macroscopic matter. We therefore improved the particle transport simulation code PHITS, providing it with the capability of estimating the microdosimetric probability densities in a macroscopic framework by incorporating a mathematical function that can instantaneously calculate the probability densities around the trajectory of HZE particles with a precision equivalent to that of a microscopic track-structure simulation. A new method for estimating biological dose, the product of physical dose and RBE, from charged-particle therapy was established using the improved PHITS coupled with a microdosimetric kinetic model. The accuracy of the biological dose estimated by this method was tested by comparing the calculated physical doses and RBE values with the corresponding data measured in a slab phantom irradiated with several kinds of HZE particles. The simulation technique established in this study will help to optimize the treatment planning of charged-particle therapy, thereby maximizing the therapeutic effect on tumors while minimizing unintended harmful effects on surrounding normal tissues.

HOW DETECTION OF PLASMID DNA FRAGMENTATION AFFECTS RADIATION STRAND BREAK YIELDS.

A compromised detection of radiation-induced plasmid DNA fragments results in underestimation of calculated damage yields. Electrophoretic methods are easy and cheap, but they can only detect a part of the fragments, neglecting the shortest ones. These can be detected with atomic force microscopy, but at the expense of time and price. Both methods were used to investigate their capabilities to detect the DNA fragments induced by high-energetic heavy ions. The results were taken into account in calculations of radiation-induced yields of single and double strand breaks. It was estimated that the double strand break yield is twice as high when the fragments are at least partially detected with the agarose electrophoresis, compared to when they were completely omitted. Further increase by 13% was observed when the measured fragments were corrected for the fraction of the shortest fragments up to 300 base pairs, as detected with the atomic force microscopy. The effect of fragment detection on the single strand break yield was diminished.

Development of PARMA: PHITS-based analytical radiation model in the atmosphere.

Estimation of cosmic-ray spectra in the atmosphere has been essential for the evaluation of aviation doses. We therefore calculated these spectra by performing Monte Carlo simulation of cosmic-ray propagation in the atmosphere using the PHITS code. The accuracy of the simulation was well verified by experimental data taken under various conditions, even near sea level. Based on a comprehensive analysis of the simulation results, we proposed an analytical model for estimating the cosmic-ray spectra of neutrons, protons, helium ions, muons, electrons, positrons and photons applicable to any location in the atmosphere at altitudes below 20 km. Our model, named PARMA, enables us to calculate the cosmic radiation doses rapidly with a precision equivalent to that of the Monte Carlo simulation, which requires much more computational time. With these properties, PARMA is capable of improving the accuracy and efficiency of the cosmic-ray exposure dose estimations not only for aircrews but also for the public on the ground.

Transport calculations and accelerator experiments needed for radiation risk assessment in space.

The major uncertainties on space radiation risk estimates in humans are associated to the poor knowledge of the biological effects of low and high LET radiation, with a smaller contribution coming from the characterization of space radiation field and its primary interactions with the shielding and the human body. However, to decrease the uncertainties on the biological effects and increase the accuracy of the risk coefficients for charged particles radiation, the initial charged-particle spectra from the Galactic Cosmic Rays (GCRs) and the Solar Particle Events (SPEs), and the radiation transport through the shielding material of the space vehicle and the human body, must be better estimated Since it is practically impossible to measure all primary and secondary particles from all possible position-projectile-target-energy combinations needed for a correct risk assessment in space, accurate particle and heavy ion transport codes must be used. These codes are also needed when estimating the risk for radiation induced failures in advanced microelectronics, such as single-event effects, etc., and the efficiency of different shielding materials. It is therefore important that the models and transport codes will be carefully benchmarked and validated to make sure they fulfill preset accuracy criteria, e.g. to be able to predict particle fluence, dose and energy distributions within a certain accuracy. When validating the accuracy of the transport codes, both space and ground based accelerator experiments are needed The efficiency of passive shielding and protection of electronic devices should also be tested in accelerator experiments and compared to simulations using different transport codes. In this paper different multipurpose particle and heavy ion transport codes will be presented, different concepts of shielding and protection discussed, as well as future accelerator experiments needed for testing and validating codes and shielding materials.

Monte-Carlo calculations of particle fluences and neutron effective dose rates in the atmosphere.

Monitoring of radiation exposure of aircrew is a legal requirement for many airlines in the EU and a challenging task in dosimetry. Monte-Carlo simulations of cosmic particles in the atmosphere can contribute to the understanding of the corresponding radiation field. Calculations of secondary neutron fluences in the atmosphere produced by galactic cosmic rays together with the resulting neutron-effective dose rates are shown in this paper and compared with results from the AIR project. The PLANETOCOSMICS package based on GEANT4 and two models for the local interstellar spectra of galactic cosmic rays have been used for the calculations. Furthermore, secondary muon fluences have been computed and are compared with CAPRICE measurements.

Benchmarking of PHITS for Carbon Ion Therapy.

PURPOSE: Up to now, carbon ions have shown the most favorable physical and radiobiological properties for radiation therapy of, for example, deep-seated radioresistant tumors. However, when carbon ions penetrate matter, they undergo inelastic nuclear reactions that give rise to secondary fragments contributing to the dose in the healthy tissue. This can cause damage to radiosensitive organs at risk when they are located in the vicinity of the tumor. Therefore, predictions of the yields and angular distributions of the secondary fragments are needed to be able to estimate the resulting biological effects in both the tumor region and the healthy tissues. This study presents the accuracy of simulations of therapeutic carbon ion beams with water, with the 3D MC (Monte Carlo) general purpose particle and ion transport code PHITS. MATERIALS AND METHODS: Simulations with PHITS of depth-dose distributions, beam attenuation, fragment yields, and fragment angular distributions from interactions of therapeutic carbon ion beams with water are compared to published measurements performed at Gesellschaft für Schwerionen Forschung (GSI). RESULTS: The results presented in this study demonstrate that PHITS simulations of therapeutic carbon ion beams in water show overall a good agreement with measurements performed at GSI; for example, for light ions like H and He, simulations agree within about 10%. However, there is still a need to further improve the calculations of fragment yields, especially for underproduction of Li of up to 50%, by improving the nucleus-nucleus cross-section models. CONCLUSION: The simulated data are clinically acceptable but there is still a need to further improve the models in the transport code PHITS. More reliable experimental data are therefore needed.

Length computation of irradiated plasmid DNA molecules.

Compromised detection of short DNA fragments can result in underestimation of radiation-induced clustered DNA damage. The fragments can be detected with atomic force microscopy (AFM), followed by image analysis to compute the length of plasmid molecules. Plasmid molecules imaged with AFM are represented by open or closed curves, possibly with crossings. For the analysis of such objects, a dedicated algorithm was developed, and its usability was demonstrated on the AFM images of plasmid pBR322 irradiated with 60Co gamma rays. The analysis of the set of the acquired AFM images revealed the presence of DNA fragments with lengths shorter than 300 base pairs that would have been neglected by a conventional detection method.