Gastrointestinal Acute Radiation Syndrome: Mechanisms, Models, Markers, and Medical Countermeasures.

There have been a number of reported human exposures to high dose radiation, resulting from accidents at nuclear power plants (e.g., Chernobyl), atomic bombings (Hiroshima and Nagasaki), and mishaps in industrial and medical settings.

Advanced Technologies in Radiation Research.

The U.S. Government is committed to maintaining a robust research program that supports a portfolio of scientific experts who are investigating the biological effects of radiation exposure.

Radiation-induced multi-organ injury.

Purpose: 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).

Methods: 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.

Immune Dysfunction from Radiation Exposure.

The hematopoietic system is highly sensitive to ionizing radiation. Damage to the immune system may result in opportunistic infections and hemorrhage, which could lead to mortality. Inflammation triggered by tissue damage can also lead to additional local or widespread tissue damage.

The NIAID/RNCP Biodosimetry Program: An Overview.

Established in 2004, the Radiation and Nuclear Countermeasures Program (RNCP), within the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health has the central mission to advance medical countermeasure mitigators/therapeutics, and biomarkers and technologies to assess, triage, and inform medical management of patients experiencing acute radiation syndrome and/or the delayed effects of acute radiation exposure. The RNCP biodosimetry mission space encompasses: (1) basic research to elucidate novel approaches for rapid and accurate assessment of radiation exposure, (2) studies to support advanced development for US Food and Drug Administration (FDA) clearance of promising triage or treatment devices/approaches, (3) characterization of biomarkers and/or assays to determine degree of tissue or organ dose that can predict outcome of radiation injuries (i.e.

Immune Dysfunction from Radiation Exposure.

Exposure to ionizing radiation causes acute damage and loss of bone marrow and peripheral immune cells that can result in high mortality due to reduced resistance to infections and hemorrhage. Besides these acute effects, tissue damage from radiation can trigger inflammatory responses, leading to progressive and chronic tissue damage by radiation-induced loss of immune cell types that are required for resolving tissue injuries. Understanding the mechanisms involved in radiation-induced immune system injury and repair will provide new insights for developing medical countermeasures that help restore immune homeostasis.

Minimum reporting standards should be expected for preclinical radiobiology irradiators and dosimetry in the published literature.

The cornerstones of science advancement are rigor in performing scientific research, reproducibility of research findings and unbiased reporting of design and results of the experiments. For radiation research, this requires rigor in describing experimental details as well as the irradiation protocols for accurate, precise and reproducible dosimetry. Most institutions conducting radiation biology research in in vitro or animal models do not have describe experimental irradiation protocols in sufficient details to allow for balanced review of their publication nor for other investigators to replicate published experiments.

Considerations of Medical Preparedness to Assess and Treat Various Populations During a Radiation Public Health Emergency.

During a radiological or nuclear public health emergency, given the heterogeneity of civilian populations, it is incumbent on medical response planners to understand and prepare for a potentially high degree of interindividual variability in the biological effects of radiation exposure. A part of advanced planning should include a comprehensive approach, in which the range of possible human responses in relation to the type of radiation expected from an incident has been thoughtfully considered. Although there are several reports addressing the radiation response for special populations (as compared to the standard 18-45-year-old male), the current review surveys published literature to assess the level of consideration given to differences in acute radiation responses in certain sub-groups.

Animal Care in Radiation Medical Countermeasures Studies.

Animal models are necessary to demonstrate the efficacy of medical countermeasures (MCM) to mitigate/treat acute radiation syndrome and the delayed effects of acute radiation exposure and develop biodosimetry signatures for use in triage and to guide medical management. The use of animal models in radiation research allows for the simulation of the biological effects of exposure in humans. Robust and well-controlled animal studies provide a platform to address basic mechanistic and safety questions that cannot be conducted in humans.

Development of Biomarkers for Radiation Biodosimetry and Medical Countermeasures Research: Current Status, Utility, and Regulatory Pathways.

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.

Acute Radiation Syndrome and the Microbiome: Impact and Review.

Study of the human microbiota has been a centuries-long endeavor, but since the inception of the National Institutes of Health (NIH) Human Microbiome Project in 2007, research has greatly expanded, including the space involving radiation injury. As acute radiation syndrome (ARS) is multisystemic, the microbiome niches across all areas of the body may be affected. This review highlights advances in radiation research examining the effect of irradiation on the microbiome and its potential use as a target for medical countermeasures or biodosimetry approaches, or as a medical countermeasure itself.

Metabolomics in Radiation Biodosimetry: Current Approaches and Advances.

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.

Therapeutic and space radiation exposure of mouse brain causes impaired DNA repair response and premature senescence by chronic oxidant production.

Despite recent epidemiological evidences linking radiation exposure and a number of human ailments including cancer, mechanistic understanding of how radiation inflicts long-term changes in cerebral cortex, which regulates important neuronal functions, remains obscure. The current study dissects molecular events relevant to pathology in cerebral cortex of 6 to 8 weeks old female C57BL/6J mice two and twelve months after exposure to a γ radiation dose (2 Gy) commonly employed in fractionated radiotherapy. For a comparative study, effects of 1.

An in vitro DNA double-strand break repair assay based on end-joining of defined duplex oligonucleotides.

DNA double-strand breaks (DSBs) are caused by endogenous cellular processes such as oxidative metabolism, or by exogenous events like exposure to ionizing radiation or other genotoxic agents. Repair of these DSBs is essential for the maintenance of cellular genomic integrity. In human cells, and cells of other higher eukaryotes, DSBs are primarily repaired by the nonhomologous end-joining (NHEJ) DSB repair pathway.

Radiation-generated short DNA fragments may perturb non-homologous end-joining and induce genomic instability.

Cells exposed to densely ionizing radiation (high-LET) experience more severe biological damage than do cells exposed to sparsely ionizing radiation (low-LET). The prevailing hypothesis is that high-LET radiations induce DNA double strand-breaks (DSB) that are more complex and clustered, and are thereby more challenging to repair. Here, we present experimental data obtained by atomic force microscopy imaging, DNA-dependent protein kinase (DNA-PK) activity determination, DNA ligation assays, and genomic studies to suggest that short DNA fragments are important products of radiation-induced DNA lesions, and that the lengths of DNA fragments may be significant in the cellular responses to ionizing radiation.

Base damage immediately upstream from double-strand break ends is a more severe impediment to nonhomologous end joining than blocked 3'-termini.

Radiation-induced DNA double-strand breaks (DSBs) are critical cytotoxic lesions that are typically repaired by nonhomologous end joining (NHEJ) in human cells. Our previous work indicated that the highly cytotoxic DSBs formed by (125)I decay possess base damage clustered within 8 to 10 bases of the break and 3'-phosphate (P) and 3'-OH ends. This study examined the effect of such structures on NHEJ in in vitro assays employing either (125)I decay-induced DSB linearized plasmid DNA or structurally defined duplex oligonucleotides.

Coincident In Vitro Analysis of DNA-PK-Dependent and -Independent Nonhomologous End Joining.

In mammalian cells, DNA double-strand breaks (DSBs) are primarily repaired by nonhomologous end joining (NHEJ). The current model suggests that the Ku 70/80 heterodimer binds to DSB ends and recruits DNA-PK(cs) to form the active DNA-dependent protein kinase, DNA-PK. Subsequently, XRCC4, DNA ligase IV, XLF and most likely, other unidentified components participate in the final DSB ligation step.

DNA-PKcs deficiency leads to persistence of oxidatively induced clustered DNA lesions in human tumor cells.

DNA-dependent protein kinase (DNA-PK) is a key non-homologous-end-joining (NHEJ) nuclear serine/threonine protein kinase involved in various DNA metabolic and damage signaling pathways contributing to the maintenance of genomic stability and prevention of cancer. To examine the role of DNA-PK in processing of non-DSB clustered DNA damage, we have used three models of DNA-PK deficiency, i.e.

In vitro non-homologous DNA end joining assays--the 20th anniversary.

DNA double-strand breaks (DSBs) are the most serious forms of DNA damage in cells. Unrepaired or misrepaired DSBs account for some of the genetic instabilities that lead to mutations or cell death, and consequently, to cancer predisposition. In human cells non-homologous DNA end joining (NHEJ) is the main repair mechanism of these breaks.

Determination and analysis of site-specific 125I decay-induced DNA double-strand break end-group structures.

End groups contribute to the structural complexity of radiation-induced DNA double-strand breaks (DSBs). As such, end-group structures may affect a cell's ability to repair DSBs. The 3'-end groups of strand breaks caused by gamma radiation, or oxidative processes, under oxygenated aqueous conditions have been shown to be distributed primarily between 3'-phosphoglycolate and 3'-phosphate, with 5'-phosphate ends in both cases.

Molecular analysis of base damage clustering associated with a site-specific radiation-induced DNA double-strand break.

Base damage flanking a radiation-induced DNA double-strand break (DSB) may contribute to DSB complexity and affect break repair. However, to date, an isolated radiation-induced DSB has not been assessed for such structures at the molecular level. In this study, an authentic site-specific radiation-induced DSB was produced in plasmid DNA by triplex forming oligonucleotide-targeted (125)I decay.