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This work aims to develop and validate a framework for the multiscale simulation of the biological response to ionizing radiation in a population of cells forming a tissue. We present TOPAS-Tissue, a framework to allow coupling two Monte Carlo (MC) codes: TOPAS with the TOPAS-nBio extension, capable of handling the track-structure simulation and subsequent chemistry, and CompuCell3D, an agent-based model simulator for biological and environmental behavior of a population of cells. We verified the implementation by simulating the experimental conditions for a clonogenic survival assay of a 2-D PC-3 cell culture model (10 cells in 10,000 µm2) irradiated by MV X-rays at several absorbed dose values from 0-8 Gy. The simulation considered cell growth and division, irradiation, DSB induction, DNA repair, and cellular response. The survival was obtained by counting the number of colonies, defined as a surviving primary (or seeded) cell with progeny, at 2.7 simulated days after irradiation. DNA repair was simulated with an MC implementation of the two-lesion kinetic model and the cell response with a p53 protein-pulse model. The simulated survival curve followed the theoretical linear-quadratic response with dose. The fitted coefficients α = 0.280 ± 0.025/Gy and β = 0.042 ± 0.006/Gy2 agreed with published experimental data within two standard deviations. TOPAS-Tissue extends previous works by simulating in an end-to-end way the effects of radiation in a cell population, from irradiation and DNA damage leading to the cell fate. In conclusion, TOPAS-Tissue offers an extensible all-in-one simulation framework that successfully couples Compucell3D and TOPAS for multiscale simulation of the biological response to radiation.

Background Physicians in certain specialities are routinely exposed to procedural ionizing radiation. Their risk of cancer is unknown, including by cancer sub-types. Aims To assess cancer risk among exposed physicians. Methods This population-based case–control study was completed in Ontario, Canada, where healthcare is universal, using linkage of physician billing claims to a province-wide cancer registry. Up to five cancer-free physician controls were matched to each cancer-affected physician, by sex, and both age at and year of, entry into practice. Cumulative exposure to procedural ionizing radiation was captured by physician billing claims. Conditional logistic regression generated an odds ratio (OR) of cancer per 1000 procedures performed and as a binary exposure comparing physicians above the upper 95th percentile cumulative number of procedures (≥200) to those below this cut point. Results Mean (standard deviation) age of the 1265 cases and 5772 non-cancer controls was 39.7 (10.7) and 37.7 (9.0) years, and 45% and 49% were female, respectively. After a median (interquartile ranges) of 13.0 (6.9–20.4) and 12.5 (6.5–20.1) years of lookback among cases and controls, the OR of cancer was 1.02 (95% confidence interval 0.99–1.05; P  = NS) per 1000 additional procedures performed. Modelling the cumulative exposure to procedures nonlinearly did not change the observed association (P  > 0.40 for each). Comparing physicians above versus below the upper 95th percentile cumulative number of procedures, the OR of cancer was 1.23 (95% confidence interval 0.75–2.01, P  = NS). Conclusions Physician exposure to procedural ionizing radiation was not associated with a higher risk of cancer. Measures that minimize radiation exposure should continue. [ABSTRACT FROM AUTHOR]

BACKGROUND: Many high-dose groups demonstrate increased leukaemia risks, with risk greatest following childhood exposure; risks at low/moderate doses are less clear. METHODS: We conducted a pooled analysis of the major radiation-associated leukaemias (acute myeloid leukaemia (AML) with/without the inclusion of myelodysplastic syndrome (MDS), chronic myeloid leukaemia (CML), acute lymphoblastic leukaemia (ALL)) in ten childhood-exposed groups, including Japanese atomic bomb survivors, four therapeutically irradiated and five diagnostically exposed cohorts, a mixture of incidence and mortality data. Relative/absolute risk Poisson regression models were fitted. RESULTS: Of 365 cases/deaths of leukaemias excluding chronic lymphocytic leukaemia, there were 272 AML/CML/ALL among 310,905 persons (7,641,362 person-years), with mean active bone marrow (ABM) dose of 0.11 Gy (range 0-5.95). We estimated significant (P

Introduction Exposure to high doses of ionizing radiation can result in hematopoietic acute radiation syndrome. Currently, there is no radiation medical countermeasure approved by the U.S. FDA which can be used before radiation exposure to protect exposed individuals. Here we aimed to evaluate the therapeutic potential of an aqueous suspension of synthetic genistein nanoparticles (BIO 300) as a radioprotectant in a pilot efficacy study using a nonhuman primate model of total body irradiation. Materials and Methods Eight rhesus macaques were divided into two groups; four received vehicle and four received BIO 300 Injectable Suspension 24 h before 5.8 Gy total-body irradiation. Survival, blood cell counts, blood chemistry, and clinical parameters were monitored over the 60 days of the study. Tissues were collected at necropsy 60 days post-irradiation or from animals that met unscheduled euthanasia criteria and subjected to histopathological analysis. Tissues analyzed included the duodenum, jejunum, ileum, sternum, lung, heart, liver, kidney, spleen, gut-associated lymphoid tissue, and urinary bladder. Results In this pilot study, all BIO 300 Injectable Suspension treated animals survived to day 60, while only 50% of the vehicle-treated animals survived. We found that BIO 300 Injectable Suspension did not mediate an improvement in blood cell counts (e.g. neutrophils, platelets, white blood cells). However, BIO 300 Injectable Suspension treated animals had a lower incidence of fever and febrile neutropenia, were able to better maintain their body weight post radiation exposure, and exhibited less anemia and faster recovery from anemia. Histopathological analysis revealed that BIO 300-treated animals had less irradiation-induced damage to the sternum and other tissues compared to vehicle controls. Conclusions BIO 300's mechanism of action is complex and protection against irradiation is attainable without much improvement in the complete blood count (CBC) profile. BIO 300's mechanism for radioprotection involves multiple biological pathways and systems. [ABSTRACT FROM AUTHOR]

Radon is a source of ionizing radiation that shows a carcinogenic potential. Thus, tracking radon exposure levels in the environment and managing exposure conditions is necessary for reducing the hazards such as lung cancer, which is known to be the second largest impact of radon on humans worldwide. A LR‐115 Type II strippable detector for monitoring radon radiation was installed in 30 mud and 26 block houses in the periurban (Duakor) areas in the Cape Coast Metropolis, Central Region, for 3 months to determine the exposure levels. The results showed that block houses (n = 26) had a radon ionization concentration in a range of 125–356 Bq m−3 and mean of 221 ± 61.4 Bq m−3, which was significantly higher than that of mud houses (n = 30), which ranged from 50.8 to 349 Bq m−3, with a mean of 186 ± 13.3 Bq m−3. About 80% and 10% of both types of houses showed levels that were above WHO's lower (100 Bq m−3) and upper (300 Bq m−3) limits of the annual residential guidelines. Moreover, over 70% of both building types showed annual effective doses of indoor radon levels that were within the action levels (3–10 mSv year−1). The data shows that the occupants have lived in their apartments for more than 10 years, while only about 3.0% have ever received some education on radon. Additional steps to manage indoor radon exposure in the community to avoid lung cancer are necessary. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both the upper and lower motor neurons, it has a heterogeneous clinical presentation, there are atypical variants that differ from the classic form of the disease. The criteria for diagnosis have evolved over time, with the support of electromyography (EMG), we present a patient series with these variants in which EMG was crucial to make the diagnosis. Clinical cases: Six cases are described with atypical presentation of motor neuron disease, for the isolated bulbar ALS phenotype, three cases are reported: two male patients (68 and 62 years old) and one woman (33 years old), with initial symptoms in the bulbar segment and late progression. to a second segment, corroborating characteristic findings by EMG. For the variant of Vulpian-Bernhardt syndrome (VBS), two male patients aged 82 and 72 years are reported, with initial symptoms in the thoracic segment with electromyographic support for the diagnosis; Finally, a case of amyotrophic diplegia of the legs (APD) is described in a 50-year-old female patient with symptoms isolated to the pelvic limbs, with a slow clinical evolution, corroborated by EMG with involvement of other spinal segments. Conclusions: ALS is part of the spectrum of motor neuron diseases, a neurodegenerative disease of the central nervous system, without curative treatment and with a fatal outcome. The diagnosis of ALS is complex and becomes more complicated for atypical phenotypes, as observed in the cases presented, EMG is an essential part of the approach and is part of the most recent diagnostic criteria. [ABSTRACT FROM AUTHOR]

The number of people living with dementia is rising globally as life expectancy increases. Dementia is a multifactorial disease. Due to the ubiquity of radiation exposure in medical and occupational settings, the potential association between radiation and dementia, and its subtypes (Alzheimer's and Parkinson's disease), is of particular importance. There has also been an increased interest in studying radiation induced dementia risks in connection with the long-term manned space travel proposed by The National Aeronautics and Space Administration (NASA). Our aim was to systematically review the literature on this topic, and use meta-analysis to generate a summary measure of association, assess publication bias and explore sources of heterogeneity across studies. We identified five types of exposed populations for this review: 1. survivors of atomic bombings in Japan; 2. patients treated with radiation therapy for cancer or other diseases; 3. occupationally exposed workers; 4. those exposed to environmental radiation; and 5. patients exposed to radiation from diagnostic radiation imaging procedures. We included studies that considered incident or mortality outcomes for dementia and its subtypes. Following PRISMA guidelines, we systematically searched the published literature indexed in PubMed between 2001 and 2022. We then abstracted the relevant articles, conducted a risk-of-bias assessment, and fit random effects models using the published risk estimates. After we applied our eligibility criteria, 18 studies were identified for review and retained for meta-analysis. For dementia (all subtypes), the summary relative risk was 1.11 (95% CI: 1.04, 1.18; P = 0.001) comparing individuals receiving 100 mSv of radiation to those with no exposure. The corresponding summary relative risk for Parkinson's disease incidence and mortality was 1.12 (95% CI 1.07, 1.17; P

Exposure to ionizing radiation is considered by NASA to be a major health hazard for deep space exploration missions. Ionizing radiation sensitivity is modulated by both genomic and environmental factors. Understanding their contributions is crucial for designing experiments in model organisms, evaluating the risk of deep space (i.e. high-linear energy transfer, or LET, particle) radiation exposure in astronauts, and also selecting therapeutic irradiation regimes for cancer patients. We identified single nucleotide polymorphisms in 15 strains of mice, including 10 collaborative cross model strains and 5 founder strains, associated with spontaneous and ionizing radiation-induced in vitro DNA damage quantified based on immunofluorescent tumor protein p53 binding protein (53BP1) positive nuclear foci. Statistical analysis suggested an association with pathways primarily related to cellular signaling, metabolism, tumorigenesis and nervous system damage. We observed different genomic associations in early (4 and 8 h) responses to different LET radiation, while later (24 hour) DNA damage responses showed a stronger overlap across all LETs. Furthermore, a subset of pathways was associated with spontaneous DNA damage, suggesting 53BP1 positive foci as a potential biomarker for DNA integrity in mouse models. Our results suggest several mouse strains as new models to further study the impact of ionizing radiation and validate the identified genetic loci. We also highlight the importance of future human in vitro studies to refine the association of genes and pathways with the DNA damage response to ionizing radiation and identify targets for space travel countermeasures.

Human exposure to low-to-moderate dose ionizing radiation (LMD-IR) is increasing via environmental, medical, occupational sources. Acute exposure to LMD-IR can cause subclinical damage to cells, resulting in altered gene expression and cellular function within the human brain. It has been difficult to identify diagnostic and predictive biomarkers of exposure using traditional research models due to factors including lack of 3D structure in monolayer cell cultures, limited ability of animal models to accurately predict human responses, and technical limitations of studying functional human brain tissue. To address this gap, we generated brain/cerebral organoids from human induced pluripotent stem cells to study the radiosensitivity of human brain cells, including neurons, astrocytes, and oligodendrocytes. While organoids have become popular models for studying brain physiology and pathology, there is little evidence to confirm that exposing brain organoids to LMD-IR will recapitulate previous in vitro and in vivo observations. We hypothesized that exposing brain organoids to proton radiation would (1) cause a time- and dose-dependent increase in DNA damage, (2) induce cell type-specific differences in radiosensitivity, and (3) increase expression of oxidative stress and DNA damage response genes. Organoids were exposed to 0.5 or 2 Gy of 250 MeV protons and samples were collected at 30 minute, 24 hour, and 48 hour timepoints. Using immunofluorescence and RNA sequencing, we found time- and dose-dependent increases in DNA damage in irradiated organoids; no changes in cell populations for neurons, oligodendrocytes, and astrocytes by 24 hours; decreased expression of genes related to oligodendrocyte lineage, astrocyte lineage, mitochondrial function, and cell cycle progression by 48 hours; increased expression of genes related to neuron lineage, oxidative stress, and DNA damage checkpoint regulation by 48 hours. Our findings demonstrate the possibility of using organoids to characterize cell-specific radiosensitivity and early radiation-induced gene expression changes within the human brain, providing new avenues for further study of the mechanisms underlying acute neural cell responses to IR exposure at low-to-moderate doses.

Exposure to ionizing radiation, especially during childhood, is a well-established risk factor for thyroid cancer. Following the 1986 Chernobyl nuclear power plant accident the total number of cases of thyroid cancer registered between 1991 and 2015 in males and females who were less than 18 years old exceeded 19,000 (in Belarus and Ukraine, and in the most contaminated oblasts of the Russian Federation). However, as indicated by the United Nations Scientific Committee on the Effects of Atomic Radiation the fraction of the incidence of thyroid cancer attributable to radiation exposure among the non-evacuated residents of the contaminated regions of Belarus, Ukraine and Russia is of the order of 0.25. Apparently, the increased registration of thyroid neoplasms in the parts of these countries is a classical 'screening effect', i.e., massive diagnostic examinations of the risk-aware populations performed with modern eqipment resulting in detection of many occult neoplasms (incidentalomas). Moreover, one type of thyroid cancer previously called 'encapsulated follicular variant of papillary thyroid carcinoma' is non-invasive and instead of 'carcinoma' should now be recognized as 'noninvasive follicular thyroid neoplasm with papillary-like nuclear features.' Other potential causes of overdiagnosing of thyroid tumors include increase of the spontaneous incidence rate of this disease with age, iodine deficiency among children from Belarus, Russia and Ukraine, and/or consumption by these children of drinking water containing high levels of nitrates that likely coincides with the carcinogenic effect of radiation on the thyroid gland. [ABSTRACT FROM AUTHOR]

Hair follicles (HFs) are stem-cell-rich mammalian mini-organs that can undergo cyclic regenerations over the life span of the organism. The cycle of a HF consists of three consecutive phases: anagen-the active proliferation phase, catagen-the degeneration phase, and telogen-the resting phase. While HFs undergo irreversible degeneration during catagen, recent experimental research on mice shows that when anagen HFs are subject to ionizing radiation (IR), they undergo a transient degeneration, followed by a nearly full regeneration that makes the HFs return to homeostatic state. The mechanisms underlying these IR-induced HF regenerative dynamics and the catagen degenerative dynamics, remain unknown. In this work, we develop an ODE type cell differentiation population model to study the control mechanisms of HF regeneration. The model is built based on current theoretical knowledge in biology and mathematically formulated using feedback mechanisms. Model parameters are calibrated to IR experimental data, and we then provide modeling results with both deterministic ODE simulations and corresponding stochastic simulations. We perform stability and bifurcation analyses on the ODE model, which reveal that for anagen HFs, a low spontaneous apoptosis rate secures the stability of the HF homeostatic steady state, allowing the HF to regenerate even when subject to strong IR. On the other hand, the irreversible degeneration during catagen results from both strong spontaneous apoptosis rate and strong apoptosis feedback. Lastly, we perform sensitivity analysis to identify key parameters in the model to validate these hypotheses.

Track structure Monte Carlo simulations are a useful tool to investigate the damage induced to DNA by ionizing radiation. These simulations usually rely on simplified geometrical representations of the DNA subcomponents. DNA damage is determined by the physical and physicochemical processes occurring within these volumes. In particular, damage to the DNA backbone is generally assumed to result in strand breaks. DNA damage can be categorized as direct (ionization of an atom part of the DNA molecule) or indirect (damage from reactive chemical species following water radiolysis). We also consider quasi-direct effects, i.e., damage originated by charge transfers after ionization of the hydration shell surrounding the DNA. DNA geometries are needed to account for the damage induced by ionizing radiation, and different geometry models can be used for speed or accuracy reasons. In this work, we use the Monte Carlo track structure tool TOPAS-nBio, built on top of Geant4-DNA, for simulation at the nanometer scale to evaluate differences among three DNA geometrical models in an entire cell nucleus, including a sphere/spheroid model specifically designed for this work. In addition to strand breaks, we explicitly consider the direct, quasi-direct, and indirect damage induced to DNA base moieties. We use results from the literature to determine the best values for the relevant parameters. For example, the proportion of hydroxyl radical reactions between base moieties was 80%, and between backbone, moieties was 20%, the proportion of radical attacks leading to a strand break was 11%, and the expected ratio of base damages and strand breaks was 2.5-3. Our results show that failure to update parameters for new geometric models can lead to significant differences in predicted damage yields.

Objectives: Fluoroscopy has significantly improved lead placement and decreased surgical time for implantable sacral neuromodulation (SNM). There is a paucity of data regarding radiation and safety of fluoroscopy during SNM procedures. Our study aims to characterize fluoroscopy time and dose used during SNM surgery across multiple institutions and assess for predictors of increased fluoroscopy time and radiation dose. Methods: Electronic medical records were queried for SNM procedures (Stage 1 and full implant) from 2016 to 2021 at four academic institutions. Demographic, clinical, and intraoperative data were collected, including fluoroscopy time and radiation dose in milligray (mGy). The data were entered into a centralized REDCap database. Univariate and multivariate analysis were performed to assess for predictive factors using STATA/BE 17.0. Results: A total of 664 procedures were performed across four institutions. Of these, 363 (54.6%) procedures had complete fluoroscopy details recorded. Mean surgical time was 58.8 min. Of all procedures, 79.6% were performed by Female Pelvic Medicine and Reconstructive Surgery specialists. There was significant variability in fluoroscopy time and dose based on surgical specialty and institution. Most surgeons (76.4%) were considered "low volume" implanters. In a multivariate analysis, bilateral finder needle testing, surgical indication, surgeon volume, and institution significantly predicted increased fluoroscopy time and radiation dose (p < 0.05). Conclusions: There is significant variability in fluoroscopy time and radiation dose utilized during SNM procedures, with differences across institutions, surgeons, and subspecialties. Increased radiation exposure can have harmful impacts on the surgical team and patient. These findings demonstrate the need for standardized fluoroscopy use during SNM procedures. [ABSTRACT FROM AUTHOR]

Radiation-induced liver disease (RILD), also known as radiation hepatitis, is subacute liver injury induced by radiation. As the focus of senescence-related studies, the deacetylase family Sirtuins (SIRTs) have the molecular functions including DNA repair and chromatin regulation, which makes SIRTs a hub for regulating genome and epigenome stability. Radiation-induced hepatic DNA damage and reaction is the primary physiological and pathological process of RILD, which is similar to the function of SIRTs. This article briefly introduces the structure and function of the SIRTs protein family, elaborates on the basic concepts and progress of the physical physiology of radiation therapy, discusses the internal relationship between SIRTs and RILD from the perspective of radiobiology, and points out the possibility of SIRTs as a target for the prevention and treatment of RILD. [ABSTRACT FROM AUTHOR]

Introduction: Cranial CT scans are associated with radiation exposure to the eye lens, which is a particularly radiosensitive organ. Children are more vulnerable to radiation than adults. Therefore, it is essential to use the available dose reduction techniques to minimize radiation exposure. According to the European Consensus on patient contact shielding by the IRCP from 2021, shielding is not recommended in most body areas anymore. This study aims to evaluate whether bismuth shielding as well as its combination with other dose-saving technologies could still be useful. Methods: Cranial CT scans of a pediatric anthropomorphic phantom were performed on two up-to-date MDCT scanners. Eye lens dose measurements were performed using thermoluminescent dosimeters. Furthermore, the impact of BS and of the additional placement of standoff foam between the patient and BS on image quality was also assessed. Results: Bismuth shielding showed a significant lens dose reduction in both CT scanners (GE: 41.50 ± 4.04%, p < 0.001; Siemens: 29.75 ± 6.55%, p = 0.00). When combined with AEC, the dose was lowered even more (GE: 60.75 ± 3.30%, p < 0.001; Siemens: 41.25 ± 8.02%, p = 0.00). The highest eye dose reduction was achieved using BS + AEC + OBTCM (GE: 71.25 ± 2.98%, p < 0.001; Siemens: 58.75 ± 5.85%, p < 0.001). BS caused increased image noise in the orbital region, which could be mitigated by foam placement. Eye shielding had no effect on the image noise in the cranium. Conclusions: The use of BS in cranial CT can lead to a significant dose reduction, which can be further enhanced by its combination with other modern dose reduction methods. BS causes increase in image noise in the orbital region but not in the cranium. The additional use of standoff foam reduces image noise in the orbital region. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Radon is carcinogenic, but more studies are needed to understand relationships with lung cancer and extrathoracic cancers at low exposures. There are few studies evaluating associations with cancer incidence or assessing the modifying effects of smoking. METHODS: We conducted a case-cohort study with 16 434 underground uranium miners in the Czech Republic with cancer incidence follow-up 1977-1996. Associations between radon exposure and lung cancer, and extrathoracic cancer, were estimated with linear excess relative rate (ERR) models. We examined potential modifying effects of smoking, time since exposure and exposure rate. RESULTS: Under a simple ERR model, assuming a 5-year exposure lag, the estimated ERR of lung cancer per 100 working level months (WLM) was 0.54 (95% CI 0.33 to 0.83) and the estimated ERR of extrathoracic cancer per 100 WLM was 0.07 (95% CI -0.17 to 0.72). Most lung cancer cases were observed among smokers (82%), and the estimated ERR of lung cancer per 100 WLM was larger among smokers (ERR/100 WLM=1.35; 95% CI 0.84 to 2.15) than among never smokers (ERR/100 WLM=0.12; 95% CI -0.05 to 0.49). Among smokers, the estimated ERR of lung cancer per 100 WLM decreased with time since exposure from 3.07 (95% CI -0.04 to 10.32) in the period 5-14 years after exposure to 1.05 (95% CI 0.49 to 1.87) in the period 25+ years after exposure. CONCLUSIONS: We observed positive associations between cumulative radon exposure and lung cancer, consistent with prior studies. We observed a positive association between cumulative radon exposure and extrathoracic cancers, although the estimates were small. There was evidence that the association between radon and lung cancer was modified by smoking in a multiplicative or super-multiplicative fashion.

There is limited evidence that non-leukaemic lymphoid malignancies are radiogenic. As radiation-related cancer risks are generally higher after childhood exposure, we analysed pooled lymphoid neoplasm data in nine cohorts first exposed to external radiation aged  0.4). In six cohorts with estimates of lymphatic tissue dose, borderline significant increased risks (p-trend = 0.02-0.07) were observed for NHL + CLL, NHL, and CLL. Further pooled epidemiological studies are needed with longer follow-up, central outcome review by expert hematopathologists, and assessment of radiation doses to lymphoid tissues.

In this study, it was aimed to evaluate the effect of ethanol extract of Annona Muricata (AM) leaves in the prevention of brain damage caused by ionizing radiation (IR). This study was conducted in the Experimental Animal Research Unit of a university with 28 adults female Wistar Albino rats. The experimental groups were as follows: Control group (n = 8), AM group (n = 6), IR group (n = 8), AM + IR group (n = 6). In the IR group, astrocyte hypertrophy, microglial reaction and inflammatory reaction levels were significantly higher than the control and AM groups (P

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In radiopharmaceutical treatmentsα-particles are employed to treat tumor cells. However, the mechanism that drives the biological effect induced is not well known. Being ionizing radiation,α-particles can affect biological organisms by producing damage to the DNA, either directly or indirectly. Following the principle that microdosimetry theory accounts for the stochastic way in which radiation deposits energy in sub-cellular sized volumes via physical collisions, we postulate that microdosimetry represents a reasonable framework to characterize the statistical nature of direct damage induction byα-particles to DNA. We used the TOPAS-nBio Monte Carlo package to simulate direct damage produced by monoenergetic alpha particles to different DNA structures. In separate simulations, we obtained the frequency-mean lineal energy (yF) and dose-mean lineal energy (yD) of microdosimetric distributions sampled with spherical sites of different sizes. The total number of DNA strand breaks, double strand breaks (DSBs) and complex strand breaks per track were quantified and presented as a function of eitheryForyD.The probability of interaction between a track and the DNA depends on how the base pairs are compacted. To characterize this variability on compactness, spherical sites of different size were used to match these probabilities of interaction, correlating the size-dependent specific energy (z) with the damage induced. The total number of DNA strand breaks per track was found to linearly correlate withyFandzFwhen using what we defined an effective volume as microdosimetric site, while the yield of DSB per unit dose linearly correlated withyDorzD,being larger for compacted than for unfolded DNA structures. The yield of complex breaks per unit dose exhibited a quadratic behavior with respect toyDand a greater difference among DNA compactness levels. Microdosimetric quantities correlate with the direct damage imparted on DNA.

IntroductionA step-up endoscopic or percutaneous approach improves outcomes in necrotizing pancreatitis (NP). However, these require multiple radiographic studies and fluoroscopic procedures, which use low-dose ionizing radiation. The cumulative radiation exposure for treatment of NP has not been well defined.MethodsWe conducted a retrospective study of consecutive patients with NP admitted to University of California San Francisco Medical Center from January 2011 to June 2019. We calculated effective doses for fluoroscopic procedures using the dose area product and used the National Cancer Institute tool for computed tomography studies. The primary outcome was the cumulative effective dose (CED). Multivariable logistic regression was used to evaluate risk factors of high exposure (CED > 500 mSv).ResultsOne hundred seventy-one patients with NP (mean follow-up 40 ± 18 months) underwent a median of 7 (interquartile range [IQR] 5-11) computed tomography scans and 7 (IQR 5-12) fluoroscopic procedures. The median CED was 274 mSv (IQR 177-245) and 30% (51) of patients received high exposure. Risk factors of high exposure include multiorgan failure (aOR 3.47, 95%-CI: 1.53-9.88, P = 0.003), infected necrosis (adjusted odds ratio [aOR] 3.89 95%-CI:1.53-9.88, P = 0.005), and step-up endoscopic approach (aOR 1.86, 95%-CI: 1.41-1.84, P = 0.001) when compared with step-up percutaneous approach.DiscussionPatients with NP were exposed to a substantial amount of ionizing radiation (257 mSv) as a part of their treatment, and 30% received more than 500 mSv, which corresponds with a 5% increase in lifetime cancer risk. Severity of NP and a step-up endoscopic approach were associated with CED > 500 mSv. Further studies are needed to help develop low-radiation treatment protocols for NP, particularly in patients receiving endoscopic therapy.

The antitumor effects of ionizing radiation (IR) are mediated in part through activation of innate and adaptive immunity. Here we report that gut microbiota influences tumor control following IR. Vancomycin decreased the abundance of butyrate-producing gut bacteria and enhanced antitumor responses to IR. Oral administration of Lachnospiraceae, a family of vancomycin-sensitive bacteria, was associated with increased systemic and intratumoral butyric acid levels and impaired the efficacy of IR in germ-free (GF) mice. Local butyrate inhibited STING-activated type I IFN expression in dendritic cells (DCs) through blockade of TBK1 and IRF3 phosphorylation, which abrogated IR-induced tumor-specific cytotoxic T cell immune responses without directly protecting tumor cells from radiation. Our findings demonstrate that the selective targeting of butyrate-producing microbiota may provide a novel therapeutic option to enhance tumor radiation sensitivity.

Optical property modulation induced by ionizing radiation is a promising approach for ultra-fast, lower time jitter detection of photon arrival time. If successful, this method can be utilized in time-of-flight positron emission tomography to achieve a coincidence time resolution approaching 10 ps. In this work, the optical property modulation based method is further developed with focus on a detection setup based on two crossed polarizers. Previous work demonstrated that such an optical setup could be utilized in radiation detection, though its detection sensitivity needed improvement. This work investigates the angle between polarizers and electric field distribution within the detection crystal to understand and improve the detection sensitivity of an optical polarization modulation based method. For this work, cadmium telluride (CdTe) was studied as the detector crystal . The magic angle (i.e. optimal working angle) of the two crossed polarizers based optical setup with CdTe were explored theoretically and experimentally. The experimental results show that the detection sensitivity could be improved by around 10% by determining the appropriate magic angle. We then studied the dependence of detection sensitivity on electric field distribution as well as on the bias voltage across the detector crystal using CdTe crystals. The experimental results show that a smaller electrode on the detector crystal, or a more concentrated electric field distribution could improve detection sensitivity. For CdTe, a detector crystal sample with 2.5 mm × 2.5 mm square electrode has twice the detection sensitivity of a detector crystal with 5 mm × 5 mm square electrode. Increasing the bias voltage before saturation for CdTe could further enhance the modulation strength and thus, the sensitivity. Our investigations demonstrated that by determining the proper working angle of polarizers and bias electrical distribution to the detector, we could improve the sensitivity of the proposed optical setup.

Introduction: Computed tomography angiography (CTA) represents the gold standard as a method for the diagnosis of carotid artery diseases. The current topic is the use of CTA for the evaluation of carotid arteries with a reduction in the dose of contrast agent and dose of ionizing radiation, which, with adequate preparation, would enable the use of this method in some risk groups. The aim of this study was to evaluate the feasibility and image quality of a new low-dose CTA protocol in comparison with a standard protocol. Methods: Forty patients with recumbent ischemic stroke were included in the study, twenty of whom underwent lowdose CTA, and the remaining twenty underwent a standard CTA protocol of the carotid arteries. Results: No significant difference was found between the mean values of CT number (Hounsfield unit), signal-to-noise ratio, contrast-to-noise ratio, and subjective assessment of image quality in the comparison of the control and experimental groups. CT dose index, volume, and dose length product were significantly lower in patients who underwent lowdose carotid CTA. There was no significant difference in the degree of carotid stenosis between color Doppler and CTA. Conclusion: The use of the low-dose protocol for carotid CTA allows the application of this method in risk groups, in which it was previously not possible to perform, with the same image quality in comparison with the standard protocol.

Introduction: Computed tomography angiography (CTA) represents the gold standard as a method for the diagnosis of carotid artery diseases. The current topic is the use of CTA for the evaluation of carotid arteries with a reduction in the dose of contrast agent and dose of ionizing radiation, which, with adequate preparation, would enable the use of this method in some risk groups. The aim of this study was to evaluate the feasibility and image quality of a new low-dose CTA protocol in comparison with a standard protocol. Methods: Forty patients with recumbent ischemic stroke were included in the study, twenty of whom underwent lowdose CTA, and the remaining twenty underwent a standard CTA protocol of the carotid arteries. Results: No significant difference was found between the mean values of CT number (Hounsfield unit), signal-to-noise ratio, contrast-to-noise ratio, and subjective assessment of image quality in the comparison of the control and experimental groups. CT dose index, volume, and dose length product were significantly lower in patients who underwent lowdose carotid CTA. There was no significant difference in the degree of carotid stenosis between color Doppler and CTA. Conclusion: The use of the low-dose protocol for carotid CTA allows the application of this method in risk groups, in which it was previously not possible to perform, with the same image quality in comparison with the standard protocol. [ABSTRACT FROM AUTHOR]

BackgroundEvidence linking risk of lymphoma and B-cell lymphoma subtypes to ionizing radiation is inconclusive, particularly at low exposure levels.MethodsWe investigated risk of lymphoma (all subtypes), B-cell lymphomas, and its major subtypes, associated with low-level occupational exposure to ionizing radiation, in 2346 lymphoma cases and 2463 controls, who participated in the multicenter EpiLymph case-control study. We developed a job-exposure matrix to estimate exposure to ionizing radiation, distinguishing between internal and external radiation, and we applied it to the lifetime occupational history of study subjects, We calculated the Odds Ratio (OR) and its 95% confidence interval (95% CI) for lymphoma (all subtypes combined), B-cell lymphoma, and its major subtypes using unconditional, polytomous logistic regression adjusting for age, gender, and education.ResultsWe did not observe an association between exposure metrics of external and internal radiation and risk of lymphoma (all subtypes), nor with B-cell lymphoma, or its major subtypes, at the levels regularly experienced in occupational settings. An elevated risk of diffuse large B cell lymphoma was observed among the most likely exposed study subjects with relatively higher exposure intensity, which would be worth further investigation.ConclusionsFurther investigation is warranted on risk of B cell lymphoma subtypes associated with low-level occupational exposure to external ionizing radiation, and to clarify whether lymphoma should be included among the cancer outcomes related to ionizing radiation.

A meta-analytic summary effect estimate often is calculated as an inverse-variance-weighted average of study-specific estimates of association. The variances of published estimates of association often are derived from their associated confidence intervals under assumptions typical of Wald-type statistics, such as normality of the parameter. However, in some research areas, such as radiation epidemiology, epidemiological results typically are obtained by fitting linear relative risk models, and associated likelihood-based confidence intervals are often asymmetric; consequently, reasonable estimates of variances associated with study-specific estimates of association may be difficult to infer from the standard approach based on the assumption of a Wald-type interval. Here, a novel method is described for meta-analysis of published results from linear relative risk models that uses a parametric transformation of published results to improve on the normal approximation used to assess confidence intervals. Using simulations, it is illustrated that the meta-analytic summary obtained using the proposed approach yields less biased summary estimates, with better confidence interval coverage, than the summary obtained using the more classical approach to meta-analysis. The proposed approach is illustrated using a previously published example of meta-analysis of epidemiological findings regarding circulatory disease following exposure to low-level ionizing radiation.

Bone can become brittle when exposed to ionizing radiation across a wide range of clinically relevant doses that span from radiotherapy (accumulative 50 Gy) to sterilization (~35,000 Gy). While irradiation-induced embrittlement has been attributed to changes in the collagen molecular structure, the relative role of collagen fragmentation versus non-enzymatic collagen crosslinking remains unclear. To better understand the effects of radiation on the bone material without cellular activity, we conducted an ex vivo x-ray radiation experiment on excised mouse lumbar vertebrae. Spinal tissue from twenty-week old, female, C57BL/6J mice were randomly assigned to a single x-ray radiation dose of either 0 (control), 50, 1000, 17,000, or 35,000 Gy. Measurements were made for collagen fragmentation, non-enzymatic collagen crosslinking, and both monotonic and cyclic-loading compressive mechanical properties. We found that the group differences for mechanical properties were more consistent with those for collagen fragmentation than for non-enzymatic collagen crosslinking. Monotonic strength at 17,000 and 35,000 Gy was lower than that of the control by 50% and 73% respectively, (p

PurposePotential acute exposure to ionizing radiation in nuclear or radiological accidents presents complex mass casualty scenarios that demand prompt triage and treatment decisions. Due to delayed symptoms and varied response of radiation victims, there is an urgent need to develop robust biomarkers to assess the extent of injuries in individuals.Experimental designThe transcription factor Nrf2 is the master of redox homeostasis and there is transcriptional evidence of Nrf2-dependent antioxidant response activation upon radiation. The biomarker potential of Nrf2-dependent downstream target enzymes is investigated by measuring their response in bone marrow extracted from C57Bl/6 and C3H mice of both genders for up to 4 days following 6 Gy total body irradiation using targeted MS.ResultsOverall, C57Bl/6 mice have a stronger proteomic response than C3H mice. In both strains, male mice have more occurrences of upregulation in antioxidant enzymes than female mice. For C57Bl/6 male mice, three proteins show elevated abundances after radiation exposure: catalase, superoxide dismutase 1, and heme oxygenase 1. Across both strains and genders, glutathione S-transferase Mu 1 is consistently decreased.Conclusions and clinical relevanceThis study provides the basis for future development of organ-specific protein biomarkers used in diagnostic blood test for radiation injury.

PurposeRadiotherapy (RT) constitutes an important part of breast cancer treatment. However, triple negative breast cancers (TNBC) exhibit remarkable resistance to most therapies, including RT. Developing new ways to radiosensitize TNBC cells could result in improved patient outcomes. The M2 isoform of pyruvate kinase (PK-M2) is believed to be responsible for the re-wiring of cancer cell metabolism after oxidative stress. The aim of the study was to determine the effect of ionizing radiation (IR) on PK-M2-mediated metabolic changes in TNBC cells, and their survival. In addition, we determine the effect of PK-M2 activators on breast cancer stem cells, a radioresistant subpopulation of breast cancer stem cells.MethodsGlucose uptake, lactate production, and glutamine consumption were assessed. The cellular localization of PK-M2 was evaluated by western blot and confocal microscopy. The small molecule activator of PK-M2, TEPP46, was used to promote its pyruvate kinase function. Finally, effects on cancer stem cell were evaluated via sphere forming capacity.ResultsExposure of TNBC cells to IR increased their glucose uptake and lactate production. As expected, PK-M2 expression levels also increased, especially in the nucleus, although overall pyruvate kinase activity was decreased. PK-M2 nuclear localization was shown to be associated with breast cancer stem cells, and activation of PK-M2 by TEPP46 depleted this population.ConclusionsRadiotherapy can induce metabolic changes in TNBC cells, and these changes seem to be mediated, at least in part by PK-M2. Importantly, our results show that activators of PK-M2 can deplete breast cancer stem cells in vitro. This study supports the idea of combining PK-M2 activators with radiation to enhance the effect of radiotherapy in resistant cancers, such as TNBC.

Bone can become brittle when exposed to ionizing radiation across a wide range of clinically relevant doses that span from radiotherapy (accumulative 50 Gy) to sterilization (~35,000 Gy). While irradiation-induced embrittlement has been attributed to changes in the collagen molecular structure, the relative role of collagen fragmentation versus non-enzymatic collagen crosslinking remains unclear. To better understand the effects of radiation on the bone material without cellular activity, we conducted an ex vivo x-ray radiation experiment on excised mouse lumbar vertebrae. Spinal tissue from twenty-week old, female, C57BL/6J mice were randomly assigned to a single x-ray radiation dose of either 0 (control), 50, 1000, 17,000, or 35,000 Gy. Measurements were made for collagen fragmentation, non-enzymatic collagen crosslinking, and both monotonic and cyclic-loading compressive mechanical properties. We found that the group differences for mechanical properties were more consistent with those for collagen fragmentation than for non-enzymatic collagen crosslinking. Monotonic strength at 17,000 and 35,000 Gy was lower than that of the control by 50% and 73% respectively, (p

Resistance to ionizing radiation (IR), which is a conventional treatment for osteosarcoma that cannot be resected, undermines the efficacy of this therapy. However, the mechanism by which IR induces radioresistance in osteosarcoma is not defined. Here, we report that CR6-interacting factor-1 (CRIF1) is highly expressed in osteosarcoma and undergoes nuclear-cytoplasmic shuttling of cyclin-dependent kinase 2 (CDK2) after IR. Osteosarcoma cells lacking CRIF1 show increased sensitivity to IR, which is associated with delayed DNA damage repair, inactivated G1/S checkpoint, and mitochondrial dysfunction. CRIF1 interacts with the DNA damage checkpoint regulator CDK2, and CRIF1 and CDK2 colocalize in the nucleus after IR. Nuclear localization of CDK2 is associated with phosphorylation changes that promote DNA repair and activation of the G1/S checkpoint. CRIF1 knockdown synergized with IR in an in vivo osteosarcoma model, leading to tumor regression. Based on these findings, we identify CRIF1 as a potential therapeutic target in osteosarcoma that can increase the efficacy of radiotherapy. More broadly, our findings may provide insights into the mechanism for other types of radioresistant cancers and be exploited for therapeutic ends.

Resistance to ionizing radiation (IR), which is a conventional treatment for osteosarcoma that cannot be resected, undermines the efficacy of this therapy. However, the mechanism by which IR induces radioresistance in osteosarcoma is not defined. Here, we report that CR6-interacting factor-1 (CRIF1) is highly expressed in osteosarcoma and undergoes nuclear-cytoplasmic shuttling of cyclin-dependent kinase 2 (CDK2) after IR. Osteosarcoma cells lacking CRIF1 show increased sensitivity to IR, which is associated with delayed DNA damage repair, inactivated G1/S checkpoint, and mitochondrial dysfunction. CRIF1 interacts with the DNA damage checkpoint regulator CDK2, and CRIF1 and CDK2 colocalize in the nucleus after IR. Nuclear localization of CDK2 is associated with phosphorylation changes that promote DNA repair and activation of the G1/S checkpoint. CRIF1 knockdown synergized with IR in an in vivo osteosarcoma model, leading to tumor regression. Based on these findings, we identify CRIF1 as a potential therapeutic target in osteosarcoma that can increase the efficacy of radiotherapy. More broadly, our findings may provide insights into the mechanism for other types of radioresistant cancers and be exploited for therapeutic ends.

PURPOSE:Quantitative susceptibility mapping (QSM) MRI is a tool that can characterize changes in susceptibility, an intrinsic property which is associated with compositional changes in the tissue. Current QSM estimation of cortical bone is challenging because conventional clinical MRI cannot acquire signal in cortical bone. This study aimed to implement Cones 3D ultrashort echo time MRI (UTE-MRI) for ex vivo QSM measurements in human tibial cortical bone, investigating the correlations of QSM with volumetric intracortical bone mineral density (BMD). MATERIALS AND METHODS:Nine tibial midshaft cortical bone specimens (25 mm long specimens cut at the mid-point of tibial shaft, 67 ± 20 years old, 5 women and 4 men) were scanned on a clinical 3 T MRI scanner for QSM measurement. The specimens were also scanned on a high-resolution micro-computed tomography (μCT) scanner for volumetric BMD estimation. QSM and μCT results were compared at approximately nine regions of interest (ROIs) per specimen. RESULTS:Average 3D UTE-MRI QSM showed significantly strong correlation with volumetric BMD (R = -0.82, P

Ionizing radiation exposure to the brain is common for patients with a variety of CNS related malignancies. This exposure is known to induce structural and functional alterations to the brain, impacting dendritic complexity, spine density and inflammation. Over time, these changes are associated with cognitive decline. However, many of these impacts are only observable long after irradiation. Extracellular vesicles (EVs) are shed from cells in nearly all known tissues, with roles in many disease pathologies. EVs are becoming an important target for identifying circulating biomarkers. The aim of this study is to identify minimally invasive biomarkers of ionizing radiation damage to the CNS that are predictors of late responses that manifest as persistent cognitive impairments. Using a clinically relevant 9 Gy irradiation paradigm, we exposed mice to cranial (head only) irradiation. Using metabolomic and lipidomic profiling, we analyzed their plasma and plasma-derived EVs two days and two weeks post-exposure to detect systemic signs of damage. We identified significant changes associated with inflammation in EVs. Whole-plasma profiling provided further evidence of systemic injury. These studies are the first to demonstrate that profiling of plasma-derived EVs may be used to study clinically relevant markers of ionizing radiation toxicities to the brain.

Stem cell heterogeneity is recognized as functionally relevant for tissue homeostasis and repair. The identity, context dependence, and regulation of skeletal muscle satellite cell (SC) subsets remains poorly understood. We identify a minor subset of Pax7+ SCs that is indelibly marked by an inducible Mx1-Cre transgene in vivo, is enriched for Pax3 expression, and has reduced ROS (reactive oxygen species) levels. Mx1+ SCs possess potent stem cell activity upon transplantation but minimally contribute to endogenous muscle repair, due to their relative low abundance. In contrast, a dramatic clonal expansion of Mx1+ SCs allows extensive contribution to muscle repair and niche repopulation upon selective pressure of radiation stress, consistent with reserve stem cell (RSC) properties. Loss of Pax3 in RSCs increased ROS content and diminished survival and stress tolerance. These observations demonstrate that the Pax7+ SC pool contains a discrete population of radiotolerant RSCs that undergo clonal expansion under severe stress.

In previous work (D. R. Harris et al., J Bacteriol 191:5240-5252, 2009, https://doi.org/10.1128/JB.00502-09; B. T. Byrne et al., Elife 3:e01322, 2014, https://doi.org/10.7554/eLife.01322), we demonstrated that Escherichia coli could acquire substantial levels of resistance to ionizing radiation (IR) via directed evolution. Major phenotypic contributions involved adaptation of organic systems for DNA repair. We have now undertaken an extended effort to generate E. coli populations that are as resistant to IR as Deinococcus radiodurans After an initial 50 cycles of selection using high-energy electron beam IR, four replicate populations exhibit major increases in IR resistance but have not yet reached IR resistance equivalent to D. radiodurans Regular deep sequencing reveals complex evolutionary patterns with abundant clonal interference. Prominent IR resistance mechanisms involve novel adaptations to DNA repair systems and alterations in RNA polymerase. Adaptation is highly specialized to resist IR exposure, since isolates from the evolved populations exhibit highly variable patterns of resistance to other forms of DNA damage. Sequenced isolates from the populations possess between 184 and 280 mutations. IR resistance in one isolate, IR9-50-1, is derived largely from four novel mutations affecting DNA and RNA metabolism: RecD A90E, RecN K429Q, and RpoB S72N/RpoC K1172I. Additional mechanisms of IR resistance are evident.IMPORTANCE Some bacterial species exhibit astonishing resistance to ionizing radiation, with Deinococcus radiodurans being the archetype. As natural IR sources rarely exceed mGy levels, the capacity of Deinococcus to survive 5,000 Gy has been attributed to desiccation resistance. To understand the molecular basis of true extreme IR resistance, we are using experimental evolution to generate strains of Escherichia coli with IR resistance levels comparable to Deinococcus Experimental evolution has previously generated moderate radioresistance for multiple bacterial species. However, these efforts could not take advantage of modern genomic sequencing technologies. In this report, we examine four replicate bacterial populations after 50 selection cycles. Genomic sequencing allows us to follow the genesis of mutations in populations throughout selection. Novel mutations affecting genes encoding DNA repair proteins and RNA polymerase enhance radioresistance. However, more contributors are apparent.

Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death in women. Radioresistance remains one of the most critical barriers in radiation therapy for breast cancer. In this study, we employed a parallel-reaction monitoring (PRM)-based targeted proteomic method to examine the reprogramming of the heat shock proteome during the development of radioresistance in breast cancer. In particular, we investigated the differential expression of heat shock proteins (HSPs) in two pairs of matched parental/radioresistant breast cancer cell lines. We were able to quantify 43 and 42 HSPs in the MCF-7 and MDA-MB-231 pairs of cell lines, respectively. By analyzing the commonly altered proteins, we found that several members of the HSP70 and HSP40 subfamilies of HSPs exhibited substantially altered expression upon development of radioresistance. Moreover, the expression of HSPB8 is markedly elevated in the radioresistant lines relative to the parental MCF-7 and MDA-MB-231 cells. Together, our PRM-based targeted proteomics method revealed the reprogramming of the heat shock proteome during the development of radioresistance in breast cancer cells and offered potential targets for sensitizing breast cancer cells toward radiation therapy.

The purpose of this study is to show the actual recommendations for dose management and provide an overview of the available options for dose tracking and dose optimization. The legal institutions that supervise the radiological exposure of patients and their most important directives are presented. A literature review of existing diagnostic reference levels for computed tomography (CT), interventional radiology, radiography, paediatric radiography, mammography, and fluoroscopy in Europe and Poland was carried out. It has been shown that, in Poland, it is necessary to verify and determine the new diagnostic reference levels (DRLs) for each imaging modality because the existing ones are adapted from other countries and are not determined on the basis of data from Polish hospitals. They have not been updated for 11-17 years, although it is recommended to update them every 3-5 years. Many countries in Europe have already determined DRLs based on the analysis of their own dosage data (e.g. Austria and Germany). Analysing the existing DRLs for CT in Poland, it was noticed that they concern only a single anatomical region. It is necessary to determine the DRLs for multi-region CT (i.e. chest-abdomen-pelvis and neck-chest-abdomen-pelvis) examinations because these examinations account for about 60% of all oncological CT examinations-based on data collected from The Maria Sklodowska-Curie National Research Institute of Oncology in Warsaw. [ABSTRACT FROM AUTHOR]

Background: Radiation-induced hematopoietic suppression and myelotoxicity can occur due to the nuclear accidents, occupational irradiation and therapeutic interventions. Bone marrow dysfunction has always been one of the most important causes of morbidity and mortality after ionizing irradiation. Objective: This study aims to investigate the protective effect of telmisartan against radiation-induced bone marrow injuries in a Balb/c mouse model.Material and Methods: In this experimental study, male Balb/c mice were divided into four groups as follow: group 1: mice received phosphate buffered saline (PBS) without irradiation, group 2: mice received a solution of telmisartan in PBS without irradiation, group 3: mice received PBS with irradiation, and group 4: mice received a solution of telmisartan in PBS with irradiation. A solution of telmisartan was prepared and administered orally at 12 mg/kg body weight for seven consecutive days prior to whole body exposing to a single sub-lethal dose of 5 Gy X-rays. Protection of bone marrow against radiation induced damage was investigated by Hematoxylin-Eosin (HE) staining assay at 3, 9, 15 and 30 days after irradiation. Results: Histopathological analysis indicated that administration of telmisartan reduced X-radiation-induced damage and improved bone marrow histology. The number of different cell types in bone marrow, including polymorphonuclear /mononuclear cells and megakaryocytes significantly increased in telmisartan treated group compared to the only irradiated group at all-time points. Conclusion: The results of the present study demonstrated an efficient radioprotective effect of telmisartan in mouse bone marrow against sub-lethal X-irradiation.

It is well known that ionizing radiation-induced toxicity to normal tissue has functional consequences in the brain. However, the underlying molecular alterations have yet to be elucidated. We have previously reported cognitive impairments with concomitant changes in dendritic complexity, spine density and inflammation in mice at 6-24 weeks postirradiation. The goal of this study was to determine whether metabolic changes in the mouse hippocampus after whole-body (4 Gy) or cranial (9 Gy) X-ray irradiation might trigger some of the incipient changes contributing to the persisting pathology in the radiation-injured brain. Metabolomic and lipidomic profiling of hippocampal tissue revealed that radiation induced dyslipidemia in mice at two days and two weeks postirradiation. Strikingly, significant changes were also observed in metabolites of the hexosamine biosynthesis pathway, a finding that was further confirmed using orthogonal methodologies. We hypothesize that these changes in hexosamine metabolism could induce endoplasmic reticulum stress and contribute to radiation-induced cognitive impairments. Taken together, our results show that molecular phenotyping is a valuable approach to identify potentially detrimental pathway perturbations that manifest significantly earlier than gross structural and functional changes in the irradiated brain.

There has been enormous recent progress in understanding how human cells respond to oxidative stress, such as that caused by exposure to ionizing radiation. We have witnessed a significant deciphering of the events that underlie how antioxidant responses counter pro-oxidant damage to key biological targets in all cellular compartments, including the genome and mitochondria. These cytoprotective responses include: 1. The basal cellular repertoire of antioxidant capabilities and its supporting cast of facilitator enzymes; and 2. The inducible phase of the antioxidant response, notably that mediated by the Nrf2 transcription factor. There has also been frenetic progress in defining how reactive electrophilic species swamp existing protective mechanisms to augment DNA damage, events that are embodied in the cellular "DNA-damage response", including cell cycle checkpoint activation and DNA repair, which occur on a time scale of hours to days, as well as the implementation of cellular responses such as apoptosis, autophagy, senescence and reprograming that extend the time period of damage sensing and response into weeks, months and years. It has become apparent that, in addition to the initial oxidative insult, cells typically undergo further waves of secondary reactive oxygen/nitrogen species generation, DNA damage and signaling and that these may reemerge long after the initial events have subsided, probably being driven, at least in part, by persisting DNA damage. These reactive oxygen/nitrogen species are an integral part of the pathological consequences of radiation exposure and may persist across multiple cell divisions. Because of the pervasive nature of oxidative stress, a cell will manifest different responses in different subcellular compartments and to different levels of stress injury. Aspects of these compartmentalized responses can involve the same proteins (such as ATM, p53 and p21) but in different functional guises, e.g., in cytoplasmic versus nuclear responses or in early- versus late-phase events. Many of these responses involve gene activation and new protein synthesis as well as a plethora of post-translational modifications of both basal and induced response proteins. It is these responses that we focus on in this review.

Ionizing radiation (IR) not only activates DNA damage response (DDR) in irradiated cells but also induces bystander effects (BE) in cells not directly targeted by radiation. How DDR pathways activated in irradiated cells stimulate BE is not well understood. We show here that extracellular vesicles secreted by irradiated cells (EV-IR), but not those from unirradiated controls (EV-C), inhibit colony formation in unirradiated cells by inducing reactive oxygen species (ROS). We found that µEV-IR from Abl nuclear localization signal-mutated ( Abl-µNLS) cells could not induce ROS, but expression of wild-type Abl restored that activity. Because nuclear Abl stimulates miR-34c biogenesis, we measured miR-34c in EV and found that its levels correlated with the ROS-inducing activity of EV. We then showed that EV from miR-34c minigene-transfected, but unirradiated cells induced ROS; and transfection with miR-34c-mimic, without radiation or EV addition, also induced ROS. Furthermore, EV-IR from miR34-family triple-knockout cells could not induce ROS, whereas EV-IR from wild-type cells could cause miR-34c increase and ROS induction in the miR-34 triple-knockout cells. These results establish a novel role for extracellular vesicles in transferring nuclear Abl-dependent and radiation-induced miR-34c into unirradiated cells to cause bystander oxidative stress.

Radiation therapy is critical for the control of many tumors and lung is an important dose-limiting organ that impacts radiation dose prescribed to avoid irreversible pulmonary fibrosis in cancer survivors. Idiopathic pulmonary fibrosis (IPF) is a chronic, irreversible lung disease caused by aberrantly activated lung (myo)fibroblasts. The presence of pro-fibrotic, apoptosis-resistant fibroblasts in IPF promotes progressive fibrosis and may have a role in other diseases, if these resistant cells are selected for as a consequence of treatment. However, the pathological response of IPF fibroblasts to radiation compared to non-IPF lung fibroblasts is not known. To address this, we examined fibroblast viability following radiation in lung fibroblasts from IPF and non-IPF patients and the underlying mechanism that protects IPF fibroblasts from radiation-induced death. IPF fibroblasts are significantly more resistant to apoptosis compared to non-IPF lung fibroblasts, suggesting that resistance to radiation-induced cell death is a predominant mechanism leading to lung fibrosis. Analysis of γH2AX induction demonstrated that radiation-induced DNA damage is reduced in IPF fibroblasts and correlates to the activation of the transcription factor forkhead box M1 (FoxM1) and subsequent upregulation of DNA repair proteins RAD51 and BRCA2. FoxM1 activation occurs secondary to FoxO3a suppression in IPF fibroblasts while restoration of FoxO3a function sensitizes IPF fibroblasts to radiation-induced cell death and downregulates FoxM1, RAD51, and BRCA2. Our findings support that increased FoxO3a/FoxM1-dependent DNA repair may be integral to the preservation of death-resistant fibrotic fibroblasts after radiation and that selective targeting of radioresistant fibroblasts may mitigate fibrosis.

Purpose: The standard treatment for organ-confined prostate cancer is surgery or radiation, and locally advanced prostate cancer is typically treated with radiotherapy alone or in combination with androgen deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double-strand DNA break repair in prostate cancer, and whether Stat5 inhibition may provide a novel strategy to sensitize prostate cancer to radiotherapy.Experimental Design: Stat5a/b regulation of DNA repair in prostate cancer was evaluated by comet and clonogenic survival assays, followed by assays specific to homologous recombination (HR) DNA repair and nonhomologous end joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in prostate cancer cells, xenograft tumors, and patient-derived prostate cancers ex vivo in 3D explant cultures. Stat5a/b induction of Rad51 and HR DNA repair and responsiveness to radiation were evaluated in vivo in mice bearing prostate cancer xenograft tumors.Results: Stat5a/b is critical for Rad51 expression in prostate cancer via Jak2-dependent mechanisms by inducing Rad51 mRNA levels. Consistent with this, genetic knockdown of Stat5a/b suppressed HR DNA repair while not affecting NHEJ DNA repair. Pharmacologic Stat5a/b inhibition potently sensitized prostate cancer cell lines and prostate cancer tumors to radiation, while not inducing radiation sensitivity in the neighboring tissues.Conclusions: This work introduces a novel concept of a pivotal role of Jak2-Stat5a/b signaling for Rad51 expression and HR DNA repair in prostate cancer. Inhibition of Jak2-Stat5a/b signaling sensitizes prostate cancer to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues. Clin Cancer Res; 24(8); 1917-31. ©2018 AACR.

Salivary gland acinar cells are routinely destroyed during radiation treatment for head and neck cancer that results in a lifetime of hyposalivation and co-morbidities. A potential regenerative strategy for replacing injured tissue is the reactivation of endogenous stem cells by targeted therapeutics. However, the identity of these cells, whether they are capable of regenerating the tissue, and the mechanisms by which they are regulated are unknown. Using in vivo and ex vivo models, in combination with genetic lineage tracing and human tissue, we discover a SOX2+ stem cell population essential to acinar cell maintenance that is capable of replenishing acini after radiation. Furthermore, we show that acinar cell replacement is nerve dependent and that addition of a muscarinic mimetic is sufficient to drive regeneration. Moreover, we show that SOX2 is diminished in irradiated human salivary gland, along with parasympathetic nerves, suggesting that tissue degeneration is due to loss of progenitors and their regulators. Thus, we establish a new paradigm that salivary glands can regenerate after genotoxic shock and do so through a SOX2 nerve-dependent mechanism.