Results from our recent studies have led to the novel hypothesis that radiation-induced coagulopathy (RIC) and associated hemorrhage occurring as part of the acute radiation syndrome (ARS) is a major cause of death resulting from radiation exposure in large mammals, including humans. This article contains information related to RIC, as well as potential strategies for the prevention and treatment of RIC. In addition, new findings are reported here on the occurrence of RIC biomarkers in humans exposed to radiation. To determine whether irradiated humans have RIC biomarkers, blood samples were obtained from radiotherapy patients who received treatment for different types of malignancies. Blood samples from allogeneic hematopoietic cell transplantation (allo-HCT) patients obtained before, during and after irradiation indicated that exposure led to prolonged clot formation times, increased levels of thrombin-antithrombin III (TAT) complex and increased circulating nucleosome/histone (cNH) levels, which suggest potential coagulopathies in the allo-HCT patients. Since these allo-HCT patients received chemotherapy prior to radiotherapy, it is possible that the chemical agents could have influenced the observed results. Frozen plasma samples from radiotherapy patients with prostate, lung and breast cancer were also obtained for analyses of cNH levels. The results indicated that some of these patients had very high cNH blood levels. Analysis of cNH levels in plasma samples from irradiated ferrets also indicated increased cNH levels compared to preirradiation baseline levels. The results from irradiated animals and some radiotherapy patients suggest the possibility that anti-histone antibodies, which block the toxic effects of elevated cNH levels in the blood, might be useful as therapeutic agents for adverse biological radiation-induced effects. The detection of increased levels of cNH in some radiotherapy patient blood samples demonstrates its potential as a biomarker for diagnosing and/or predicting the propensity for developing coagulopathies/hemorrhage, offering possible treatment options with personalized medicine therapies for cancer patients.

Radiation Research publishes work dealing with radiation effects and related subjects in the areas of physics, chemistry, biology and medicine.

Triage and medical intervention strategies for unanticipated exposure during a radiation incident benefit from the early, rapid and accurate assessment of dose level. Radiation exposure results in complex and persistent molecular and cellular responses that ultimately alter the levels of many biological markers, including the metabolomic phenotype. Metabolomics is an emerging field that promises the determination of radiation exposure by the qualitative and quantitative measurements of small molecules in a biological sample. This review highlights the current role of metabolomics in assessing radiation injury, as well as considerations for the diverse range of bioanalytical and sampling technologies that are being used to detect these changes. The authors also address the influence of the physiological status of an individual, the animal models studied, the technology and analysis employed in interrogating response to the radiation insult, and variables that factor into discovery and development of robust biomarker signatures. Furthermore, available databases for these studies have been reviewed, and existing regulatory guidance for metabolomics are discussed, with the ultimate goal of providing both context for this area of radiation research and the consideration of pathways for continued development.

Biomarkers are important indicators of biological processes in health or disease. For this reason, they play a critical role in advanced development of radiation biodosimetry tools and medical countermeasures (MCMs). They can aid in the assessment of radiation exposure level, extent of radiation-induced injury, and/or efficacy of a MCM. This meeting report summarizes the presentations and discussions from the 2020 workshop titled, “Biomarkers in Radiation Biodosimetry and Medical Countermeasures” sponsored by the Radiation and Nuclear Countermeasures Program (RNCP) within the National Institute of Allergy and Infectious Diseases (NIAID). The main goals of this meeting were to: 1. Provide an overview on biomarkers and to focus on the state of science with regards to biomarkers specific to radiation biodosimetry and MCMs; 2. Understand developmental challenges unique to the role of biomarkers in the fields of radiation biodosimetry and MCM development; and 3. Identify existing gaps and needs for translational application.

Natural history studies have been informative in dissecting radiation injury, isolating its effects, and compartmentalizing injury based on the extent of exposure and the elapsed time post-irradiation. Although radiation injury models are useful for investigating the mechanism of action in isolated subsyndromes and development of medical countermeasures (MCMs), it is clear that ionizing radiation exposure leads to multi-organ injury (MOI). The Radiation and Nuclear Countermeasures Program within the National Institute of Allergy and Infectious Diseases partnered with the Biomedical Advanced Research and Development Authority to convene a virtual two-day meeting titled 'Radiation-Induced Multi-Organ Injury' on June 7-8, 2022. Invited subject matter experts presented their research findings in MOI, including study of mechanisms and possible MCMs to address complex radiation-induced injuries. This workshop report summarizes key information from each presentation and discussion by the speakers and audience participants. Understanding the mechanisms that lead to radiation-induced MOI is critical to advancing candidate MCMs that could mitigate the injury and reduce associated morbidity and mortality. The observation that some of these mechanisms associated with MOI include systemic injuries, such as inflammation and vascular damage, suggests that MCMs that address systemic pathways could be effective against multiple organ systems.

The public health and medical response to a radiological or nuclear incident requires the capability to sort, assess, treat, triage and ultimately discharge, as well as to refer or transport people to their next step in medical care. The Public Health Emergency Medical Countermeasures Enterprise (PHEMCE), directed by the U.S. Department of Health and Human Services (HHS), facilitates a comprehensive, multi-agency effort to develop and deploy radiation biodosimetry tests. Within HHS, discovery and development of biodosimetry tests includes the National Institute of Allergy and Infectious Diseases (NIAID) National Institutes of Health (NIH), the Office of the Assistant Secretary of Preparedness and Response (ASPR), Biomedical Advanced Research and Development Authority (BARDA), and the Food and Drug Administration (FDA) as primary partners in this endeavor. The study of radiation biodosimetry has advanced significantly, with expansion into the fields of cytogenetics, genomics, proteomics, metabolomics, lipidomics and transcriptomics. In addition, expansion of traditional cytogenetic assessment methods using automated platforms, and development of laboratory surge capacity networks have helped to advance biodefense preparedness. This article describes various programs and coordinating efforts between NIAID, BARDA and FDA in the development of radiation biodosimetry approaches to respond to radiological and nuclear threats.