Plasma miRNAome Profiling Reveals Candidate Biomarkers for Low- and High-Dose Whole-Body Ionizing Radiation Exposure

Endoscopic retrograde cholangiopancreatography (ERCP) requires radiation. This study aimed to assess the clinical factors influencing radiation exposure and devise a scoring model for predicting high-dose radiation exposure. Endoscopic retrograde cholangiopancreatography cases recorded between 2016 and 2019 in a single tertiary teaching hospital were retrospectively reviewed. A scoring model was created by bootstrap method in a derivation cohort (2016-2018) and was assessed in a validation cohort (2019). Out of 4223 ERCPs, 2983 and 1240 cases were included in the derivation and validation cohorts, respectively. In the derivation cohort, 746 cases (top 25%) comprised the high-dose exposure group, and 2237 cases (bottom 75%) comprised the low-dose exposure group. Nine clinical parameters associated with high-dose exposure were male, pancreatic sphincterotomy, balloon dilatation, biliary or pancreatic drainage, procedures with contrast dye, endoscopist, in-hospital ERCP, and spot image. Stone removal was included by bootstrap analysis. As presented in a nomogram, the weight score of each variable was as follows: male, 1; pancreatic sphincterotomy, 3; balloon dilatation, 7; stone removal, 3; biliary or pancreatic drainage, 5; procedures with contrast dye, 1; endoscopist B, 4; endoscopist C, 5; in-hospital procedure, 3; and spot image, 3. A total score≥15 suggested a high-dose radiation exposure. The sensitivity and specificity of the model for high-dose exposure were 0.562 and 0.813, respectively. In the validation cohort, the model showed reasonable predictability. Various factors were associated with radiation exposure. The simple scoring system in this study could guide endoscopists in predicting the risk of high-dose radiation exposure.

One of the earliest cellular responses to radiation-induced DNA damage is the phosphorylation of the histone variant H2AX (gamma-H2AX). gamma-H2AX facilitates the local concentration and focus formation of numerous repair-related proteins within the vicinity of DNA DSBs. Previously, we have shown that low-dose hyper-radiosensitivity (HRS), the excessive sensitivity of mammalian cells to very low doses of ionizing radiation, is a response specific to G(2)-phase cells and is attributed to evasion of an ATM-dependent G(2)-phase cell cycle checkpoint. To further define the mechanism of low-dose hyper-radiosensitivity, we investigated the relationship between the recognition of radiation-induced DNA double-strand breaks as defined by gamma-H2AX staining and the incidence of HRS in three pairs of isogenic cell lines with known differences in radiosensitivity and DNA repair functionality (disparate RAS, ATM or DNA-PKcs status). Marked differences between the six cell lines in cell survival were observed after high-dose exposures (>1 Gy) reflective of the DNA repair capabilities of the individual six cell lines. In contrast, the absence of functional ATM or DNA-PK activity did not affect cell survival outcome below 0.2 Gy, supporting the concept that HRS is a measure of radiation sensitivity in the absence of fully functional repair. No relationship was evident between the initial numbers of DNA DSBs scored immediately after either low- or high-dose radiation exposure with cell survival for any of the cell lines, indicating that the prevalence of HRS is not related to recognition of DNA DSBs. However, residual DNA DSB damage as indicated by the persistence of gamma-H2AX foci 4 h after exposure was significantly correlated with cell survival after exposure to 2 Gy. This observation suggests that the persistence of gamma-H2AX foci could be adopted as a surrogate assay of cellular radiosensitivity to predict clinical radiation responsiveness.

Second Solid Cancers After Radiation Therapy: A Systematic Review of the Epidemiologic Studies of the Radiation Dose-Response Relationship

Purpose: Human beings encounter radiation in many different situations – from proximity to radioactive waste sites to participation in medical procedures using X-rays etc. Limits for radiation exposures are legally regulated; however, current radiation protection policy does not explicitly acknowledge that biological, cellular and molecular effects of low doses and low dose rates of radiation differ from effects induced by medium and high dose radiation exposures. Recent technical developments in biology and medicine, from single cell techniques to big data computational research, have enabled new approaches for study of biology of low doses of radiation. Results of the work done so far support the idea that low doses of radiation have effects that differ from those associated with high dose exposures; this work, however, is far from sufficient for the development of a new theoretical framework needed for the understanding of low dose radiation exposures.Conclusions: Mechanistic understanding of radiation effects at low doses is necessary in order to develop better radiation protection policy.

High-dose radiation exposures of humans occur every year around the world, and may lead to harmful tissue reactions. This review aims to look at the available information sources that can help answering the question of how often these events occur yearly on a global scale. In the absence of comprehensive databases of global occurrence, publications on radiation accidents in all uses of radiation and on rates of high-dose events in different medical uses of radiation have been reviewed. Most high-dose radiation exposures seem to occur in the medical uses of radiation, reflecting the high number of medical exposures performed. In therapeutic medical uses, radiation doses are purposely often given at levels known to cause deterministic effects, and there is a very narrow range in which the medical practitioner can operate without causing severe unacceptable outcomes. In interventional medical uses, there are scenarios in which the radiation dose given to a patient may reach or exceed a threshold for skin effects, where this radiation dose may be unavoidable, considering all benefits and risks as well as benefits and risks of any alternative procedures. Regardless of if the delivered dose is unintended, unnecessary or unavoidable, there are estimates published of the rates of high-dose events and of radiation-induced tissue injuries occurring in medical uses. If this information is extrapolated to a global scenario, noting the inherent limitations in doing so, it does not seem unreasonable to expect that the global number of radiation-induced injuries every year may be in the order of hundreds, likely mainly arising from medical uses of radiation, and in particular from interventional fluoroscopy procedures and external beam radiotherapy procedures. These procedures are so frequently employed throughout the world that even a very small rate of radiation-induced injuries becomes a substantial number when scaled up to a global level.

DNA strand breaks and DNA repair response in lymphocytes after chronic in vivo exposure to very low doses of ionizing radiation in mice

The aim was to develop a simple biodosimetry method for as rapid as possible estimation of absorbed radiation doses in victims of radiation accidents, in particular after high-dose exposure. Human peripheral blood lymphocytes (PBL) were gamma-irradiated in vitro with several doses up to 40 Gy stimulated with phytohaemagglutinin-P (PHA-P) for 2 days and their chromosomes condensed prematurely using 50 nm calyculin A. Chromosome lengths of Giemsa-stained G2 prematurely condensed chromosomes (PCC) were measured using image analysing software and the ratio of the longest/shortest chromosome length was calculated. The length ratio (LR) of the longest/shortest Giemsa-stained chromosome s increased with a good correlation to the square root of the radiation dose (D) up to 40 Gy, i.e. LR = (4.90 × D0.5) + 2.14. The LR of the longest/shortest chromosome might be used as an index for estimating the radiation dose. The blood samples should not be cooled until the start of separation/stimulation of the lymphocytes. A rapid and easy estimation of large doses after whole-body exposure was identified by measuring the ratio of the longest/shortest length of Giemsa-stained G2-PCC induced by calyculin A. This simple protocol will be particularly useful for making therapy decisions for victims of ionizing radiation exposure and has potential for use as a biodosimeter for partial-body exposure accidents.

Retrospective radiation dose estimations, whether based on physical or biological measurements, or on theoretical dose reconstruction, are limited in their precision and reliability, particularly for exposures that occurred many decades ago. Here, we studied living U.S. military test participants, believed to have received high-dose radiation exposures during nuclear testing-related activities approximately six decades ago, with two primary goals in mind. The first was to compare three different approaches of assessing past radiation exposures: 1. Historical personnel monitoring data alone; 2. Dose reconstruction based on varying levels of completeness of individual information, which can include film badge data; and 3. Retrospective biodosimetry using chromosome aberrations in peripheral blood lymphocytes. The second goal was to use the collected data to make the best possible estimates of bone marrow dose received by a group with the highest military recorded radiation doses of any currently living military test participants. Six nuclear test participants studied had been on Rongerik Atoll during the 1954 CASTLE Bravo nuclear test. Another six were present at the Nevada Test Site (NTS) and/or Pacific Proving Ground (PPG) and were believed to have received relatively high-dose exposures at those locations. All were interviewed, and all provided a blood sample for cytogenetic analysis. Military dose records for each test participant, as recorded in the Defense Threat Reduction Agency's Nuclear Test Review and Information System, were used as the basis for historical film badge records and provided exposure scenario information to estimate dose via dose reconstruction. Dose to bone marrow was also estimated utilizing directional genomic hybridization (dGH) for high-resolution detection of radiation-induced chromosomal translocations and inversions, the latter being demonstrated for the first time for the purpose of retrospective biodosimetry. As the true dose for each test participant is not known these many decades after exposure, this study gauged the congruence of different methods by assessing the degree of correlation and degree of systematic differences. Overall, the best agreement between methods, defined by statistically significant correlations and small systematic differences, was between doses estimated by a dose reconstruction methodology that exploited all the available individual detail and the biodosimetry methodology derived from a weighted average dose determined from chromosomal translocation and inversion rates. Employing such a strategy, we found that the Rongerik veterans who participated in this study appear to have received, on average, bone marrow equivalent doses on the order of 300-400 mSv, while the NTS/ PPG participants appear to have received approximately 250-300 mSv. The results show that even for nuclear events that occurred six decades in the past, biological signatures of exposure are still present, and when taken together, chromosomal translocations and inversions can serve as reliable retrospective biodosimeters, particularly on a group-average basis, when doses received are greater than statistically-determined detection limits for the biological assays used.

Thrombopoietin-Receptor Agonist Romiplostim Attenuates Hematopoietic System Injury By Promoting the Recovery of Early Hematopoiesis and the Hematopoietic Environment in the Bone Marrow and Spleen of Mice Exposed to Lethal Total Body γ-Irradiation

The epidermis is a physiological barrier that protects an organism against pathogens and chemical or physical damage. The degree of skin injuries caused by radiation influences the subsequent survival from and prognosis of such injuries. Recently, we have identified, using microarray technology, genes regulated by high-dose radiation exposure in normal human epidermal keratinocytes. Our results suggest the possible role of ATF3 in the apoptosis pathway in radiation injuries caused by high-dose radiation exposure in human skin. In the present study, we characterized ATF3 induction after X-ray irradiation in normal human skin cells. Our results showed that the induction of ATF3 mRNA is rapid, transient, and at least in part mediated through a transcriptional mechanism after X-irradiation of normal human keratinocytes. In addition, ATF3 was induced and accumulated in the nuclei of keratinocytes upon treatment with an apoptosis inducer, anisomycin. Our results also suggested that the induction mechanism of ATF3 mRNA by X-irradiation may be different not only between epidermal keratinocytes and dermal fibroblasts, but also between dermal fibroblasts and lung fibroblasts.

Purpose In case of a nuclear accident, individuals with high-dose radiation exposure (>1–2 Gy) should be rapidly identified. While ferredoxin reductase (FDXR) was recently suggested as a radiation-responsive gene, the use of a single gene biomarker limits radiation dose assessment. To overcome this limitation, we sought to identify reliable radiation-responsive gene biomarkers. Materials and methods Peripheral blood mononuclear cells (PBMCs) were isolated from mice after total body irradiation, and gene expression was analyzed using a microarray approach to identify radiation-responsive genes. Results In light of the essential role of the immune response following radiation exposure, we selected several immune-related candidate genes upregulated by radiation exposure in both mouse and human PBMCs. In particular, the expression of ACOD1 and CXCL10 increased in a radiation dose-dependent manner, while remaining unchanged following lipopolysaccharide (LPS) stimulation in human PBMCs. The expression of both genes was further evaluated in the blood of cancer patients before and after radiotherapy. CXCL10 expression exhibited a distinct increase after radiotherapy and was positively correlated with FDXR expression. Conclusions CXCL10 expression in irradiated PBMCs represents a potential biomarker for radiation exposure.

There are well-documented associations of glaucoma with high-dose radiation exposure, but only a single study suggesting risk of glaucoma, and less conclusively macular degeneration, associated with moderate-dose exposure. We assessed risk of glaucoma and macular degeneration associated with occupational eye-lens radiation dose, using participants from the US Radiologic Technologists Study, followed from the date of surveys in 1994–1998, 2003–2005 to the earliest of diagnosis of glaucoma or macular degeneration, cancer other than non-melanoma skin cancer, or date of last survey (2012–2014). We excluded those with baseline disease or previous radiotherapy history. Cox proportional hazards models with age as timescale were used. There were 1631 cases of newly self-reported doctor-diagnosed cases of glaucoma and 1331 of macular degeneration among 69,568 and 69,969 eligible subjects, respectively. Estimated mean cumulative eye-lens absorbed dose from occupational radiation exposures was 0.058 Gy. The excess relative risk/Gy for glaucoma was −0.57 (95% CI −1.46, 0.60, p = 0.304) and for macular degeneration was 0.32 (95% CI −0.32, 1.27, p = 0.381), suggesting that there is no appreciable risk for either endpoint associated with low-dose and low dose-rate radiation exposure. Since this is the first examination of glaucoma and macular degeneration associated with low-dose radiation exposure, this result needs to be replicated in other low-dose studies.

Despite some advances in the study of radiation injuries, effective methods of prevention and treatment of severe acute radiation syndrome or illness (ARS) are still lacking. Therefore, an in-depth understanding of the biological characteristics associated with high dose radiation is essential to reveal the mechanisms underlying the varied biological processes following high dose radiation and the development of novel potent radioprotective agents. In the present study, plasma metabolic characteristics were investigated using hematopoietic stem cell transplantation patients (n = 36) undergoing total body ionizing irradiation (TBI) utilizing gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). Plasma was collected pre-irradiation, 3 days after completion of fractionated radiation therapy with a total dose of 12 Gy delivered at a dose rate of 8 cGy min-1. These metabolic disorders involve the dysregulation of the gut microflora, a shift in energy supply from aerobic respiration toward ketogenesis, protein synthesis and metabolism in response to TBI. Furthermore, the panel of four metabolic markers with most potential consisting of PC (O-38:5), urate, ornithine, and GCDCS for radiation injury was chosen by combining multiple methods of data processing that included univariate analysis, partial least squares discriminant analysis (PLS-DA), and multivariable stepwise linear regression analysis. While similar patterns of metabolic alterations were observed in patients of different genders, disease types and ages, specific changes were also found in specific patients following high doses of exposure. These findings provide valuable information for selecting metabolic biomarker panels for radiation injury, clues for radiation pathology and therapeutic interventions involved in high-dose radiation exposure.

Computed tomography (CT) scans are commonly ordered during initial trauma care. CT scans obtained at referring institutions may fall outside Advanced Trauma Life Support (ATLS) guidelines; be of poor technical quality, requiring repeat imaging; or be performed without reduced-radiation protocols. There is growing concern that early, high-dose radiation exposure in children may increase the risk for certain hematologic malignancies. In addition, excess scanning delays trauma care and …

Without any doubt, high dose radiation exposure can induce hypothyroidism. However, there are open questions related to the mechanisms of its induction, corresponding dose thresholds and possible countermeasures. Therefore, this review addresses the aetiology, prevention and therapy of radiation induced hypothyroidism. External beam radiotherapy with several 10 Gy to the head and neck region and radioiodine therapy with several 100 Gy thyroid absorbed dose can destroy the thyroid gland and can induce autoantibodies against thyroid tissue. According to recent literature, clinical hypothyroidism is observed at threshold doses of ∼10 Gy after external beam radiotherapy and of ∼50 Gy after radioiodine therapy, children being more sensitive than adults. In children and adolescents exposed by the Chernobyl accident with mean thyroid absorbed doses of 500–800 mGy, subclinical hypothyroidism has been detected in 3%–6% of the cases with significant correlation to thyroid absorbed doses above 2.5 Gy. In case of nuclear emergencies, iodine thyroid blocking (ITB) is the method of choice to keep thyroid absorbed doses low. Large doses of stable iodine affect two different steps of internalization of radioiodine (transport and organification); perchlorate affecting the transport only may be an alternative to iodine. Administered before radioiodine incorporation, the effect of 100 mg iodide or more is still about 90% after 1 days, 80% after 2 days, and 50% or less after 3 days. If administered (too) late after exposure to radioiodine, the theoretically expected protective effect of ITB is about 50% after 6 h, 25% after 12 h, and about 6% after 24 h. In case of repeated or continuous exposure, repeated administration of 50 mg of iodide daily is indicated. If radiation-induced hypothyroidism cannot be avoided, thyroid hormone replacement therapy with individualized dosing and regular monitoring in order to maintain thyroid-stimulating hormone levels within the normal range ensures normal life expectancy.