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., organ failure, morbidity, and/or mortality), and (4) outreach efforts to facilitate interactions with researchers developing cutting edge biodosimetry approaches. Thus far, no biodosimetry device has been FDA cleared for use during a radiological/nuclear incident. At NIAID, advancement of radiation biomarkers and biodosimetry approaches is facilitated by a variety of funding mechanisms (grants, contracts, cooperative and interagency agreements, and Small Business Innovation Research awards), with the objective of advancing devices and assays toward clearance, as outlined in the FDA's Radiation Biodosimetry Medical Countermeasure Devices Guidance. The ultimate goal of the RNCP biodosimetry program is to develop and establish accurate and reliable biodosimetry tools that will improve radiation preparedness and ultimately save lives during a radiological or nuclear incident.

Laboratory-acquired vaccinia virus infection in a recently immunized person--Massachusetts, 2013.

On November 26, 2013, the CDC poxvirus laboratory was notified by the Boston Public Health Commission (BPHC) of an inadvertent inoculation of a recently vaccinated (ACAM2000 smallpox vaccine) laboratory worker with wild type vaccinia virus (VACV) Western Reserve. A joint investigation by CDC and BPHC confirmed orthopoxvirus infection in the worker, who had reported a needle stick in his thumb while inoculating a mouse with VACV. He experienced a non-tender, red rash on his arm, diagnosed at a local emergency department as cellulitis. He subsequently developed a necrotic lesion on his thumb, diagnosed as VACV infection. Three weeks after the injury, the thumb lesion was surgically debrided and at 2 months post-injury, the skin lesion had resolved. The investigation confirmed that the infection was the first reported VACV infection in the United States in a laboratory worker vaccinated according to the Advisory Committee on Immunization Practices (ACIP) recommendations. The incident prompted the academic institution to outline biosafety measures for working with biologic agents, such as biosafety training of laboratory personnel, vaccination (if appropriate), and steps in incident reporting. Though vaccination has been shown to be an effective measure in protecting personnel in the laboratory setting, this case report underscores the importance of proper safety measures and incident reporting.

Design and synthesis of 2-nitroimidazoles with variable alkylating and acylating functionality.

The synthesis of a small series of 2-nitroimidazoles in which the ß-amino alcohol side chain was amidated with a range of alkylating/acylating functionality is described. Synthetic methodologies were developed that generally provided for selective N-acyl versus N,O-bisacyl products. In vitro, target analogs showed minimal radiosensitization activity, with only a few exhibiting a sensitizer enhancement ratio (SER) >2.0 and C(1.6) values comparable to reference agents RB-6145 and RSU-1069. In an assay to determine potential to alkylate biomolecules, representative analogs showed <1% of the alkylating activity of RSU-1069. In vivo, one analog showed an enhancement ratio of 1.6 relative to vehicle control when tested in B6C3F1 mice with an implanted KHT sarcoma. The data reinforce prior findings that there is a correlation between alkylation potential and in vivo activity.

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. The need to increase and improve dosimetry standards, traceability to National Institute of Standards and Technology (NIST) standard beamlines, and to provide dosimetry harmonization within the radiation biology community has been noted for over a decade both within the United States and France. To address this requirement subject matter experts have outlined minimum reporting standards that should be included in published literature for preclinical irradiators and dosimetry.

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. On August 17 and 18, 2023, the Radiation and Nuclear Countermeasures Program, within the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), partnered with the National Cancer Institute, NIH, the National Aeronautics and Space Administration, and the Radiation Injury Treatment Network to convene a workshop titled, Advanced Technologies in Radiation Research (ATRR), which focused on the use of advanced technologies under development or in current use to accelerate radiation research. This meeting report provides a comprehensive overview of the research presented at the workshop, which included an assembly of subject matter experts from government, industry, and academia. Topics discussed during the workshop included assessments of acute and delayed effects of radiation exposure using modalities such as clustered regularly interspaced short palindromic repeats (CRISPR) - based gene editing, tissue chips, advanced computing, artificial intelligence, and immersive imaging techniques. These approaches are being applied to develop products to diagnose and treat radiation injury to the bone marrow, skin, lung, and gastrointestinal tract, among other tissues. The overarching goal of the workshop was to provide an opportunity for the radiation research community to come together to assess the technological landscape through sharing of data, methodologies, and challenges, followed by a guided discussion with all participants. Ultimately, the organizers hope that the radiation research community will benefit from the workshop and seek solutions to scientific questions that remain unaddressed. Understanding existing research gaps and harnessing new or re-imagined tools and methods will allow for the design of studies to advance medical products along the critical path to U.S. Food and Drug Administration approval.

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. Invited subject matter experts presented their research findings in MOI, including study of mechanisms and possible MCMs to address complex radiation-induced injuries. RESULTS: This workshop report summarizes key information from each presentation and discussion by the speakers and audience participants. CONCLUSIONS: 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.

Update on Managing the Risks of Exposure to Lentiviral and Retroviral Vectors.

OBJECTIVE: This paper aims to review the risks associated with using lentiviral and retroviral vectors in research and clinical settings and to propose an update to an effective treatment plan. METHODS: Risks of exposure were evaluated based on vector design, safety features, viral tropism, transgene, and means and modes of transmission. These risks were weighed against the potential risks and benefits of current HIV medications. RESULTS: We recommend the following post-exposure prophylactic treatment for significant lentiviral vector exposures: 1) dolutegravir 50 mg. taken once a day for 7 days; and 2) tenofovir disoproxil fumarate 300 mg. taken once a day for 7 days (28 days of both medications for replication-competent vectors). CONCLUSIONS: Due to the highly efficient delivery of transgenes by modern lentiviral and retroviral vectors, post-exposure prophylaxis is indicated to prevent vector integration and oncogenic risks.

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. If absorbed radiation doses are high enough, evolution of acute radiation syndromes (ARS) will likely impact both the bone marrow as well as the gastrointestinal (GI) tract. Damage incurred in the latter can lead to nutrient malabsorption, dehydration, electrolyte imbalance, altered microbiome and metabolites, and impaired barrier function, which can lead to septicemia and death. To prepare for a medical response should such an incident arise, the National Institute of Allergy and Infectious Diseases (NIAID) funds basic and translational research to address radiation-induced GI-ARS, which remains a critical and prioritized unmet need. Areas of interest include identification of targets for damage and mitigation, animal model development, and testing of medical countermeasures (MCMs) to address GI complications resulting from radiation exposure. To appropriately model expected human responses, it is helpful to study analogous disease states in the clinic that resemble GI-ARS, to inform on best practices for diagnosis and treatment, and translate them back to inform nonclinical drug efficacy models. For these reasons, the NIAID partnered with two other U.S. government agencies (the Biomedical Advanced Research and Development Authority, and the Food and Drug Administration), to explore models, biomarkers, and diagnostics to improve understanding of the complexities of GI-ARS and investigate promising treatment approaches. A two-day workshop was convened in August 2022 that comprised presentations from academia, industry, healthcare, and government, and highlighted talks from 26 subject matter experts across five scientific sessions. This report provides an overview of information that was presented during the conference, and important discussions surrounding a broad range of topics that are critical for the research, development, licensure, and use of MCMs for GI-ARS.

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. For these reasons, The Radiation and Nuclear Countermeasures Program (RNCP) and the Basic Immunology Branch (BIB) under the Division of Allergy, Immunology, and Transplantation (DAIT) within the National Institute of Allergy and Infectious Diseases (NIAID) convened a two-day workshop, along with partners from the Biomedical Advanced Research and Development Authority (BARDA), and the Radiation Injury Treatment Network (RITN). This workshop, titled "Immune Dysfunction from Radiation Exposure," was held virtually on September 9-10, 2020; this Commentary provides a high-level overview of what was discussed at the meeting.

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. The authors attempt to bring clarity to the complex nature of human biology in the context of radiation to facilitate a path forward for radiation medical countermeasure (MCM) development that may be appropriate and effective in special populations. Consequently, the focus is on the medical (as opposed to logistical) aspects of preparedness and response. Populations identified for consideration include obstetric, pediatric, geriatric, males, females, individuals of different race/ethnicity, and people with comorbidities. Relevant animal models, biomarkers of radiation injury, and MCMs are highlighted, in addition to underscoring gaps in knowledge and the need for consistent and early inclusion of these populations in research. The inclusion of special populations in preclinical and clinical studies is essential to address shortcomings and is an important consideration for radiation public health emergency response planning. Pursuing this goal will benefit the population at large by considering those at greatest risk of health consequences after a radiological or nuclear mass casualty incident.

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 immune system is responsible for tissue repair and restoration, which is made more challenging when it is in the process of self-recovery. Because of these challenges, the Radiation and Nuclear Countermeasures Program (RNCP) and the Basic Immunology Branch (BIB) under the Division of Allergy, Immunology, and Transplantation (DAIT) within the National Institute of Allergy and Infectious Diseases (NIAID), along with partners from the Biomedical Advanced Research and Development Authority (BARDA), and the Radiation Injury Treatment Network (RITN) sponsored a two-day meeting titled Immune Dysfunction from Radiation Exposure held on September 9-10, 2020. The intent was to discuss the manifestations and mechanisms of radiation-induced immune dysfunction in people and animals, identify knowledge gaps, and discuss possible treatments to restore immune function and enhance tissue repair after irradiation.

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. 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.

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. The U.S. Department of Health and Human Services has tasked the National Institute of Allergy and Infectious Diseases (NIAID) with identifying and funding early- through advanced-stage MCM development for radiation-induced injuries; and advancement of biodosimetry platforms and exploration of biomarkers for triage, definitive dose, and predictive purposes. Some of these NIAID-funded projects may transition to the Biomedical Advanced Research and Development Authority (BARDA), a component of the Office of the Assistant Secretary for Preparedness and Response in the U.S. Department of Health and Human Services, which is tasked with the advanced development of MCMs to include pharmacokinetic, exposure, and safety assessments in humans. Guided by the U.S. Food and Drug Administration's (FDA) Animal Rule, both NIAID and BARDA work closely with researchers to advance product and device development, setting them on a course for eventual licensure/approval/clearance of their approaches by the FDA. In August 2020, NIAID partnered with BARDA to conduct a workshop to discuss currently accepted animal care protocols and examine aspects of animal models that can influence outcomes of studies to explore MCM efficacy for potential harmonization. This report provides an overview of the two-day workshop, which includes a series of special topic presentations followed by panel discussions with subject-matter experts from academia, industry partners, and select governmental agencies.

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. The authors also address animal model considerations for designing studies, and the potential to use the microbiome as a biomarker to assess radiation exposure and predict outcome. Recent research has shown that the microbiome holds enormous potential for mitigation of radiation injury, in the context of both radiotherapy and radiological/nuclear public health emergencies. Gaps still exist, but the field is moving forward with much promise.

Commonalities Between COVID-19 and Radiation Injury.

As the multi-systemic components of COVID-19 emerge, parallel etiologies can be drawn between SARS-CoV-2 infection and radiation injuries. While some SARS-CoV-2-infected individuals present as asymptomatic, others exhibit mild symptoms that may include fever, cough, chills, and unusual symptoms like loss of taste and smell and reddening in the extremities (e.g., "COVID toes," suggestive of microvessel damage). Still others alarm healthcare providers with extreme and rapid onset of high-risk indicators of mortality that include acute respiratory distress syndrome (ARDS), multi-organ hypercoagulation, hypoxia and cardiovascular damage. Researchers are quickly refocusing their science to address this enigmatic virus that seems to unveil itself in new ways without discrimination. As investigators begin to identify early markers of disease, identification of common threads with other pathologies may provide some clues. Interestingly, years of research in the field of radiation biology documents the complex multiorgan nature of another disease state that occurs after exposure to high doses of radiation: the acute radiation syndrome (ARS). Inflammation is a key common player in COVID-19 and ARS, and drives the multi-system damage that dramatically alters biological homeostasis. Both conditions initiate a cytokine storm, with similar pro-inflammatory molecules increased and other anti-inflammatory molecules decreased. These changes manifest in a variety of ways, with a demonstrably higher health impact in patients having underlying medical conditions. The potentially dramatic human impact of ARS has guided the science that has identified many biomarkers of radiation exposure, established medical management strategies for ARS, and led to the development of medical countermeasures for use in the event of a radiation public health emergency. These efforts can now be leveraged to help elucidate mechanisms of action of COVID-19 injuries. Furthermore, this intersection between COVID-19 and ARS may point to approaches that could accelerate the discovery of treatments for both.

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. 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.

Low serum uric acid level is a risk factor for death in incident hemodialysis patients.

BACKGROUND: A reverse epidemiology of classic cardiovascular risk factors was observed in hemodialysis patients with a high comorbidity burden. We hypothesized that uric acid, a novel cardiovascular risk factor, also has an altered association with survival in these patients. METHODS: A retrospective study was conducted on 168 consecutive outpatient hemodialysis patients over a 6-year period. Serum uric acid, albumin levels and relevant laboratory information were recorded monthly. The disease severity was assessed using Comorbidity Index (CoI) scores. Patients were stratified into 3 groups according to their serum uric acid concentrations: group I was the lowest quintile, group II was the middle 3 quintiles and group III was the highest quintile. The risks of death were calculated utilizing a Cox regression model. RESULTS: Using group II as a reference group, the hazard ratio of group I was 2.23 [95% confidence interval (CI) 1.21-4.11, p = 0.01] and group III was 0.89 (95% CI 0.47-1.71, p = 0.74). The serum uric acid levels correlated inversely with CoI scores (r = -0.31, 95% CI -0.44 to -0.17, p < 0.0001) and positively with serum albumin levels (r = 0.35, 95% CI 0.21-0.48, p < 0.0001). CONCLUSION: Low serum uric acid is a mortality risk factor in incident hemodialysis patients with a high comorbidity burden and hypoalbuminemia.

P2Y1 receptor antagonists as novel antithrombotic agents.

The P2Y(1) and P2Y(12) purinergic receptors are responsible for mediating adenosine diphosphate (ADP) dependent platelet aggregation. Evidence from P2Y(1) knockout studies as well as from nucleotide-based small molecule P2Y(1) antagonists has suggested that the antagonism of this receptor may offer a novel and effective method for the treatment of thrombotic disorders. Herein, we report the identification and optimization of a series of non-nucleotide P2Y(1) antagonists that are potent and orally bioavailable.

Substituted oxazolidinones as novel NPC1L1 ligands for the inhibition of cholesterol absorption.

Cholesterol absorption inhibition (CAI) represents an important treatment option for hypercholesterolemia. Herein, we report the design and evaluation of a series of substituted oxazolidinones as ligands for the Niemann Pick C1 Like 1 (NPC1L1) protein, a key mediator of cholesterol transport. Novel analogs were initially evaluated in a brush border membrane NPC1L1 binding assay; subsequently, promising compounds were evaluated in vivo for acute inhibition of cholesterol absorption. These studies identified analogs with low micromolar NPC1L1 binding affinity and acute in vivo efficacy of >50% absorption inhibition at 3mg/kg.