Development of DynamicMC for PHITS Monte Carlo package.

Previously, we have developed DynamicMC for modeling relative movement of Oak Ridge National Laboratory phantom in a radiation field for the Monte Carlo N-Particle package (Health Physics. 2023,124(4):301-309). Using this software, three-dimensional dose distributions in a phantom irradiated by a certain mono-energetic (Mono E) source can be deduced through its graphical user interface. In this study, we extended DynamicMC to be used in combination with the Particle and Heavy Ion Transport code System (PHITS) by providing it with a higher flexibility for dynamic movement for an anthropomorphic phantom. For this purpose, we implemented four new functions into the software, which are (1) to generate not only Mono E sources but also those having an energy spectrum of an arbitrary radioisotope (2) to calculate the absorbed doses for several radiologically important organs (3) to automatically average the calculated absorbed doses along the path of the phantom and (4) to generate user-defined slab shielding materials. The first and third items utilize the PHITS-specific modalities named radioisotope-source and sumtally functions, respectively. The computational cost and complexity can be dramatically reduced with these features. We anticipate that the present work and the developed open-source tools will be in the interest of nuclear radiation physics community for research and teaching purposes.

Low-dose ionizing radiation promotes motor recovery and brain rewiring by resolving inflammatory response after brain injury and stroke.

Traumatic brain injury (TBI) and stroke share a common pathophysiology that worsens over time due to secondary tissue injury caused by sustained inflammatory response. However, studies on pharmacological interventions targeting the complex secondary injury cascade have failed to show efficacy. Here, we demonstrated that low-dose ionizing radiation (LDIR) reduced lesion size and reversed motor deficits after TBI and photothrombotic stroke. Magnetic resonance imaging demonstrated significant reduction of infarct volume in LDIR-treated mice after stroke. Systems-level transcriptomic analysis showed that genes upregulated in LDIR-treated stoke mice were enriched in pathways associated with inflammatory and immune response involving microglia. LDIR induced upregulation of anti-inflammatory- and phagocytosis-related genes, and downregulation of key pro-inflammatory cytokine production. These findings were validated by live-cell assays, in which microglia exhibited higher chemotactic and phagocytic capacities after LDIR. We observed substantial microglial clustering at the injury site, glial scar clearance and reversal of motor deficits after stroke. Cortical microglia/macrophages depletion completely abolished the beneficial effect of LDIR on motor function recovery in stroke mice. LDIR promoted axonal projections (brain rewiring) in motor cortex and recovery of brain activity detected by electroencephalography recordings months after stroke. LDIR treatment delayed by 8 h post-injury still maintained full therapeutic effects on motor recovery, indicating that LDIR is a promising therapeutic strategy for TBI and stroke.

Genome-wide study reveals novel roles for formin-2 in axon regeneration as a microtubule dynamics regulator and therapeutic target for nerve repair.

Peripheral nerves regenerate successfully; however, clinical outcome after injury is poor. We demonstrated that low-dose ionizing radiation (LDIR) promoted axon regeneration and function recovery after peripheral nerve injury (PNI). Genome-wide CpG methylation profiling identified LDIR-induced hypermethylation of the Fmn2 promoter, exhibiting injury-induced Fmn2 downregulation in dorsal root ganglia (DRGs). Constitutive knockout or neuronal Fmn2 knockdown accelerated nerve repair and function recovery. Mechanistically, increased microtubule dynamics at growth cones was observed in time-lapse imaging of Fmn2-deficient DRG neurons. Increased HDAC5 phosphorylation and rapid tubulin deacetylation were found in regenerating axons of neuronal Fmn2-knockdown mice after injury. Growth-promoting effect of neuronal Fmn2 knockdown was eliminated by pharmaceutical blockade of HDAC5 or neuronal Hdac5 knockdown, suggesting that Fmn2deletion promotes axon regeneration via microtubule post-translational modification. In silico screening of FDA-approved drugs identified metaxalone, administered either immediately or 24-h post-injury, accelerating function recovery. This work uncovers a novel axon regeneration function of Fmn2 and a small-molecule strategy for PNI.

DynamicMC: An Open-source GUI Program Coupled with MCNP for Modeling Relative Dynamic Movement of Radioactive Source and ORNL Phantom in a 3-dimensional Radiation Field.

ABSTRACT: The present work introduces an open-source graphical user interface (GUI) computer program called DynamicMC. The present program has the ability to generate ORNL phantom input script for the Monte Carlo N-Particle (MCNP) package. The relative dynamic movement of the radiation source with respect to the ORNL phantom can be modeled, which essentially resembles the dynamic movement of source-to-target (i.e., human phantom) distance in a 3-dimensional radiation field. The present program makes the organ-based dosimetry of the human body much easier, as users are not required to write lengthy scripts or deal with any programming that many may find tedious, time consuming, and error prone. In this paper, we have demonstrated that the present program can successfully model simple and complex relative dynamic movements (i.e., those involving rotation of source and human phantom in a 3-dimensional field). The present program would be useful for organ-based dosimetry and could also be used as a tool for teaching nuclear radiation physics and its interaction with the human body.

Radiation-Induced Rescue Effect: Insights from Microbeam Experiments.

The present paper reviews a non-targeted effect in radiobiology known as the Radiation-Induced Rescue Effect (RIRE) and insights gained from previous microbeam experiments on RIRE. RIRE describes the mitigation of radiobiological effects in targeted irradiated cells after they receive feedback signals from co-cultured non-irradiated bystander cells, or from the medium previously conditioning those co-cultured non-irradiated bystander cells. RIRE has established or has the potential of establishing relationships with other non-traditional new developments in the fields of radiobiology, including Radiation-Induced Bystander Effect (RIBE), Radiation-Induced Field Size Effect (RIFSE) and ultra-high dose rate (FLASH) effect, which are explained. The paper first introduces RIRE, summarizes previous findings, and surveys the mechanisms proposed for observations. Unique opportunities offered by microbeam irradiations for RIRE research and some previous microbeam studies on RIRE are then described. Some thoughts on future priorities and directions of research on RIRE exploiting unique features of microbeam radiations are presented in the last section.

Golgi Phosphoprotein 3 Mediates Radiation-Induced Bystander Effect via ERK/EGR1/TNF-α Signal Axis.

The radiation-induced bystander effect (RIBE), an important non-targeted effect of radiation, has been proposed to be associated with irradiation-caused secondary cancers and reproductive damage beyond the irradiation-treated area after radiotherapy. However, the mechanisms for RIBE signal(s) regulation and transduction are not well understood. In the present work, we found that a Golgi protein, GOLPH3, was involved in RIBE transduction. Knocking down GOLPH3 in irradiated cells blocked the generation of the RIBE, whereas re-expression of GOLPH3 in knockdown cells rescued the RIBE. Furthermore, TNF-α was identified as an important intercellular signal molecule in the GOLPH3-mediated RIBE. A novel signal axis, GOLPH3/ERK/EGR1, was discovered to modulate the transcription of TNF-α and determine the level of released TNF-α. Our findings provide new insights into the molecular mechanism of the RIBE and a potential target for RIBE modulation.

Ambient PM2.5 exposure causes cellular senescence via DNA damage, micronuclei formation, and cGAS activation.

Ambient PM2.5 is one of the environmental risk factors and was correlated with senescence-related diseases based on the epidemiologic investigation. However, little is known about senescence induced by PM2.5 as well as the underlying mechanisms. In this study, we demonstrated that PM2.5 exposure aggravated cellular senescence in vivo and in vitro, and disrupted micronuclei (MN) played a vital role in this process. Our results suggested that the nuclear envelope (NE) of PM2.5-induced MN was ruptured. Subsequently, cGAS was found to localize to approximately 80% of the disrupted MN but few for intact MN. Upon examination of cGAMP and SA-ß-Gal, the cGAS-STING pathway was found activated and related to cellular senescence induced by PM2.5. Taken together, we reported a novel finding that PM2.5 exposure causes cellular senescence via DNA damage, MN formation, and cGAS activation. These results revealed the potential toxicity of PM2.5 and its related mechanisms in cellular senescence.

On the effectiveness of proton boron fusion therapy (PBFT) at cellular level.

The present work introduced a framework to investigate the effectiveness of proton boron fusion therapy (PBFT) at the cellular level. The framework consisted of a cell array generator program coupled with PHITS Monte Carlo package with a dedicated terminal-based code editor that was developed in this work. The framework enabled users to model large cell arrays with normal, all boron, and random boron filled cytoplasm, to investigate the underlying mechanism of PBFT. It was found that alpha particles and neutrons could be produced in absence of boron mainly because of nuclear reaction induced by proton interaction with 16O, 12C and 14N nuclei. The effectiveness of PBFT is highly dependent on the incident proton energy, source size, cell array size, buffer medium thickness layer, concentration and distribution of boron in the cell array. To quantitatively assess the effectiveness of PBFT, of the total energy deposition by alpha particle for different cases were determined. The number of alpha particle hits in cell cytoplasm and nucleus for normal and 100 ppm boron were determined. The obtained results and the developed tools would be useful for future development of PBFT to objectively determine the effectiveness of this treatment modality.

Corrigendum: Low-Dose Radiation Can Cause Epigenetic Alterations Associated With Impairments in Both Male and Female Reproductive Cell.

[This corrects the article DOI: 10.3389/fgene.2021.710143.].

RadStat: An open-source statistical analysis tool for counts obtained by a GM counter.

The interaction of ionizing radiation with matter is a stochastic process and statistical analysis of such a process would be a crucial step in understanding radioactivity. Geiger-Müller (GM) counter is a widely used radiation detector used in nuclear radiation surveying, which produces counts upon exposure to a radioactive source. There are a variety of multi-purpose software that can be used to perform statistical analysis of measured counts from a GM counter. However, statistical analysis is a lengthy, error prone and time-consuming process, which gets more tedious when the number of measurements increases. In the present work, we have developed an open-source and easy-to-use graphical user interface (GUI) computer program named RadStat for statistical analysis of counts measured by a GM counter. RadStat has its own scripting syntaxes and bundled with gnuplot for quick visualization of output results. We believe the present open-source GUI program would be a useful tool for research and teaching of nuclear radiation physics.

Development of PHITS graphical user interface for simulation of positron emitting radioisotopes production in common biological materials during proton therapy.

The Monte Carlo (MC) method is a powerful tool for modeling nuclear radiation interaction with matter. A variety of MC software packages has been developed, especially for applications in radiation therapy. Most widely used MC packages require users to write their own input scripts for their systems, which can be a time consuming and error prone process and requires extensive user experience. In the present work, we have developed a graphical user interface (GUI) bundled with a custom-made 3D OpenGL visualizer for PHITS MC package. The current version focuses on modeling proton induced positron emitting radioisotopes, which in turn can be used for verification of proton ranges in proton therapy. The developed GUI program does not require extensive user experience. The present open-source program is distributed under GPLv3 license that allows users to freely download, modify, recompile and redistribute the program.

MCHP (Monte Carlo + Human Phantom): Platform to facilitate teaching nuclear radiation physics.

Some concepts in nuclear radiation physics are abstract and intellectually demanding. In the present paper, an "MCHP platform" (MCHP was an acronym for Monte Carlo simulations + Human Phantoms) was proposed to provide assistance to the students through visualization. The platform involved Monte Carlo simulations of interactions between ionizing radiations and the Oak Ridge National Laboratory (ORNL) adult male human phantom. As an example to demonstrate the benefits of the proposed MCHP platform, the present paper investigated the variation of the absorbed photon dose per photon from a 137Cs source in three selected organs, namely, brain, spine and thyroid of an adult male for concrete and lead shields with varying thicknesses. The results were interesting but not readily comprehensible without direct visualization. Graphical visualization snapshots as well as video clips of real time interactions between the photons and the human phantom were presented for the involved cases, and the results were explained with the help of such snapshots and video clips. It is envisaged that, if the platform is found useful and effective by the readers, the readers can also propose examples to be gradually added onto this platform in future, with the ultimate goal of enhancing students' understanding and learning the concepts in an undergraduate nuclear radiation physics course or a related course.

Review on Toxic Effects of Di(2-ethylhexyl) Phthalate on Zebrafish Embryos.

Di(2-ethylhexyl) phthalate (DEHP) is widely used as a plasticizer in consumer products. People are continuously exposed to DEHP through ingestion, inhalation and dermal absorption. From epidemiological studies, DEHP has been shown to associate with various adverse health effects, such as reproductive abnormalities and metabolic diseases. Health concerns have been raised regarding DEHP exposures; therefore, relevant risk assessment has become necessary through toxicological testing of DEHP. In the past 10 years, an increasing number of DEHP toxicity studies have been using zebrafish embryos as an in vivo model due to their high fecundity, rapid embryonic development as well as optical transparency, which have now been established as an alternative of the more conventional rodent model. The aim of the present paper is to review the effects of acute (from embryo stage to ≤1 week) and chronic (from embryo stage to >1 week) DEHP exposures on zebrafish, which start from the embryonic stage, and to analyze acute and potential long-term effects induced by acute exposure and effects induced by chronic exposure of DEHP upon subjecting to exposures, starting from the embryonic stage to different developmental stages, with a view to facilitate risk assessments on DEHP exposures.

Low-Dose Radiation Can Cause Epigenetic Alterations Associated With Impairments in Both Male and Female Reproductive Cells.

Humans are regularly and continuously exposed to ionizing radiation from both natural and artificial sources. Cumulating evidence shows adverse effects of ionizing radiation on both male and female reproductive systems, including reduction of testis weight and sperm count and reduction of female germ cells and premature ovarian failure. While most of the observed effects were caused by DNA damage and disturbance of DNA repairment, ionizing radiation may also alter DNA methylation, histone, and chromatin modification, leading to epigenetic changes and transgenerational effects. However, the molecular mechanisms underlying the epigenetic changes and transgenerational reproductive impairment induced by low-dose radiation remain largely unknown. In this study, two different types of human ovarian cells and two different types of testicular cells were exposed to low dose of ionizing radiation, followed by bioinformatics analysis (including gene ontology functional analysis and Ingenuity Pathway Analysis), to unravel and compare epigenetic effects and pathway changes in male and female reproductive cells induced by ionizing radiation. Our findings showed that the radiation could alter the expression of gene cluster related to DNA damage responses through the control of MYC. Furthermore, ionizing radiation could lead to gender-specific reproductive impairment through deregulation of different gene networks. More importantly, the observed epigenetic modifications induced by ionizing radiation are mediated through the alteration of chromatin remodeling and telomere function. This study, for the first time, demonstrated that ionizing radiation may alter the epigenome of germ cells, leading to transgenerational reproductive impairments, and correspondingly call for research in this new emerging area which remains almost unknown.

A comparative study on dispersed doses during photon and proton radiation therapy in pediatric applications.

The Monte Carlo method was employed to simulate realistic treatment situations for photon and proton radiation therapy for a set of Oak Ridge National Laboratory (ORNL) pediatric phantoms for 15, 10, 5 and 1-year olds as well as newborns. Complete radiotherapy situations were simulated using the previously developed NRUrad input code for Monte Carlo N-Particle (MCNP) code package. Each pediatric phantom was irradiated at five different positions, namely, the testes, colon, liver, left lung and brain, and the doses in targeted organs (Dt) were determined using the track length estimate of energy. The dispersed photon and proton doses in non-targeted organs (Dd), namely, the skeleton, skin, brain, spine, left and right lungs were computed. The conversion coefficients (F = Dd/Dt) of the dispersed doses were used to study the dose dispersion in different non-targeted organs for phantoms for 15, 10, 5 and 1-year olds as well as newborns. In general, the F values were larger for younger patients. The F values for non-targeted organs for phantoms for 1-year olds and newborns were significantly larger compared to those for other phantoms. The dispersed doses from proton radiation therapy were also found to be significantly lower than those from conventional photon radiation therapy. For example, the largest F values for the brain were 65.6% and 0.206% of the dose delivered to the left lung (P4) for newborns during photon and proton radiation therapy, respectively. The present results demonstrated that dispersion of photons and generated electrons significantly affected the absorbed doses in non-targeted organs during pediatric photon therapy, and illustrated that proton therapy could in general bring benefits for treatment of pediatric cancer patients.

Updates to TRACK_TEST and TRACK_VISION Computer Programs.

The computer programs TRACK_TEST and TRACK_VISION were previously developed to model profiles and optical appearances of tracks developed in solid-state nuclear track detectors. The programs were based on a track development model that involved the bulk etch rate Vb and the track etch rate Vt or the V function (i.e., Vt/Vb). The present work reported our work to update and modify these two programs. In the revised TRACK_TEST, two new V functions were added and enabled. Sample results for the CR-39 detector obtained using the three original and the two new V functions were compared. Discrepancies were within ~10% and <14% for incident alpha-particle energies of 1 MeV and >1 MeV, respectively. Another major revision of TRACK_TEST was to enable calculations for the Makrofol detector. In the revised TRACK_VISION, the two new V functions, as well as the option for the Makrofol detector, were also added. The experimental results on the Makrofol detectors were obtained (irradiated with 3.6-MeV alpha particles under normal incidence and then etched to achieve a removed detector thickness of 30 µm) for comparisons with the modeled results using the revised TRACK_VISION. The track diameters obtained from the experiment and model were 24.7 and 23.2 µm, respectively. Moreover, a bright area in the central parts, together with an outer dark ring, were present in both the simulated and experimental tracks. The track-opening diameters and the general optical appearances of the tracks were in good agreement.

Role of PARP1 regulation in radiation-induced rescue effect.

Radiation-induced rescue effect (RIRE) in cells refers to the phenomenon where irradiated cells (IRCs) receive help from feedback signals produced by partnered bystander unirradiated cells (UIRCs) or from the conditioned medium (CM) that has previously conditioned the UIRCs. In the present work, we explored the role of poly (ADP-ribose) polymerase 1 (PARP1) regulation in RIRE and the positive feedback loop between PARP1 and nuclear factor-kappa-light-chain-enhancer of activated B cell (NF-κB) in RIRE using various cell lines, including HeLa, MCF7, CNE-2 and HCT116 cells. We first found that when the IRCs (irradiated with 2 Gy X-ray) were treated with CM, the relative mRNA expression levels of both tumor suppressor p53-binding protein 1 (53BP1) and PARP1, the co-localization factor between 53BP1 and γH2AX as well as the fluorescent intensity of PARP1 were reduced. We also found that IRCs treated with the PARP1 inhibitor, Olaparib (AZD2281) had a higher 53BP1 expression. These results illustrated that PARP1 was involved in RIRE transcriptionally and translationally. We further revealed that treatment of IRCs with CM together with Olaparib led to significantly lower mRNA expression levels and fluorescent intensities of NF-κB, while treatment of IRCs with CM together the NF-κB inhibitor BAY-11-7082 led to significantly lower mRNA expression levels as well as fluorescent intensities of PARP1. These results illustrated that PARP1 and NF-κB were involved in the positive feedback loop transcriptionally and translationally. Thus, the results supported the occurrence of a PARP1-NF-κB positive feedback loop in RIRE. The present work provided insights into potential exploitation of inhibition of PARP1 and/or the PARP1-NF-κB positive feedback loop in designing adjuncts to cancer radiotherapeutics.

Cold atmospheric plasma induces GSDME-dependent pyroptotic signaling pathway via ROS generation in tumor cells.

Cold atmospheric plasma (CAP) has been proposed as a novel promising anti-cancer treatment modality. Apoptosis and necrosis have been revealed in CAP-induced cell death, but whether CAP induces pyroptosis, another kind of programmed cell death is still unknown. In the present study, we first reported that CAP effectively induced pyroptosis in a dose-dependent manner in Gasdermin E (GSDME) high-expressed tumor cell lines. Interestingly, the basal level of GSDME protein was positively correlated with the sensitivity to CAP in three selected cancer cell lines, implying GSDME might be a potential biomarker of prognosis in the forthcoming cancer CAP treatment. Moreover, our study revealed that CAP-induced pyroptosis depended on the activation of mitochondrial pathways (JNK/cytochrome c/caspase-9/caspase-3) and the cleavage of GSDME but not Gasdermin D (GSDMD). ROS generation induced by CAP was identified to initiate the pyroptotic signaling. These results complemented our knowledge on CAP-induced cell death and provide a strategy to optimize the effect of CAP cancer treatment.

Medium-thickness-dependent proton dosimetry for radiobiological experiments.

A calibration method was proposed in the present work to determine the medium-thickness-dependent proton doses absorbed in cellular components (i.e., cellular cytoplasm and nucleus) in radiobiological experiments. Consideration of the dependency on medium thickness was crucial as the linear energy transfer (LET) of protons could rise to a sharp peak (known as the Bragg peak) towards the end of their ranges. Relationships between the calibration coefficient R vs medium-layer thickness were obtained for incident proton energies of 10, 15, 20, 25, 30 and 35 MeV, and for various medium thicknesses up to 5000 µm, where R was defined as the ratio DA/DE, DA was the absorbed proton dose in cellular components, and DE was the absorbed proton dose in a separate radiation detector. In the present work, DA and DE were determined using the MCNPX (Monte Carlo N-Particle eXtended) code version 2.4.0. For lower incident proton energies (i.e., 10, 15 and 20 MeV), formation of Bragg-peak-like features were noticed in their R-vs-medium-layer-thickness relationships, and large R values of >7 and >6 were obtained for cytoplasm and nucleus of cells, respectively, which highlighted the importance of careful consideration of the medium thickness in radiobiological experiments.