Effect of Age at Time of Irradiation, Sex, Genetic Diversity, and Granulopoietic Cytokine Radiomitigation on Lifespan and Lymphoma Development in Murine H-ARS Survivors.

Acute, high-dose radiation exposure results in life-threatening acute radiation syndrome (ARS) and debilitating delayed effects of acute radiation exposure (DEARE). The DEARE are a set of chronic multi-organ illnesses that can result in early death due to malignancy and other diseases. Animal models have proven essential in understanding the natural history of ARS and DEARE and licensure of medical countermeasures (MCM) according to the FDA Animal Rule.

Where are the medical countermeasures against the ARS and DEARE? A current topic relative to an animal model research platform, radiation exposure context, the acute and delayed effects of acute exposure, and the FDA animal rule.

Purpose: A question echoed by the National Biodefense Science Board (NBSB) in 2010, remains a reasonable question in 2023; 'Where are the Countermeasures?'. A critical path for development of medical countermeasures (MCM) against acute, radiation-induced organ-specific injury within the acute radiation syndrome (ARS) and the delayed effects of acute radiation exposure (DEARE) requires the recognition of problems and solutions inherent in the path to FDA approval under the Animal Rule. Keep Rule number one in mind, It's not easy.

Age and Sex Divergence in Hematopoietic Radiosensitivity in Aged Mouse Models of the Hematopoietic Acute Radiation Syndrome.

The hematopoietic system is highly sensitive to stress from both aging and radiation exposure, and the hematopoietic acute radiation syndrome (H-ARS) should be modeled in the geriatric context separately from young for development of age-appropriate medical countermeasures (MCMs). Here we developed aging murine H-ARS models, defining radiation dose response relationships (DRRs) in 12-month-old middle-aged and 24-month-old geriatric male and female C57BL/6J mice, and characterized diverse factors affecting geriatric MCM testing. Groups of approximately 20 mice were exposed to ∼10 different doses of radiation to establish radiation DRRs for estimation of the LD50/30.

Semi-Supervised Segmentation of Radiation-Induced Pulmonary Fibrosis From Lung CT Scans With Multi-Scale Guided Dense Attention.

Computed Tomography (CT) plays an important role in monitoring radiation-induced Pulmonary Fibrosis (PF), where accurate segmentation of the PF lesions is highly desired for diagnosis and treatment follow-up. However, the task is challenged by ambiguous boundary, irregular shape, various position and size of the lesions, as well as the difficulty in acquiring a large set of annotated volumetric images for training. To overcome these problems, we propose a novel convolutional neural network called PF-Net and incorporate it into a semi-supervised learning framework based on Iterative Confidence-based Refinement And Weighting of pseudo Labels (I-CRAWL).

Rat Models of Partial-body Irradiation with Bone Marrow-sparing (Leg-out PBI) Designed for FDA Approval of Countermeasures for Mitigation of Acute and Delayed Injuries by Radiation.

The goal of this study was to develop rat models of partial body irradiation with bone-marrow sparing (leg-out PBI) to test medical countermeasures (MCM) of both acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE) under the FDA animal rule. The leg-out PBI models were developed in female and male WAG/RijCmcr rats at doses of 12.5-14.

Effect of Radiation on the Essential Nutrient Homeostasis and Signaling of Retinoids in a Non-human Primate Model with Minimal Bone Marrow Sparing.

High-dose radiation exposure results in hematopoietic (H) and gastrointestinal (GI) acute radiation syndromes (ARS) followed by delayed effects of acute radiation exposure (DEARE), which include damage to lung, heart, and GI. Whereas DEARE includes inflammation and fibrosis in multiple tissues, the molecular mechanisms contributing to inflammation and to the development of fibrosis remain incompletely understood. Reports that radiation dysregulates retinoids and proteins within the retinoid pathway indicate that radiation disrupts essential nutrient homeostasis.

Metabolomics of Multiorgan Radiation Injury in Non-human Primate Model Reveals System-wide Metabolic Perturbations.

Exposure to ionizing radiation following a nuclear or radiological incident results in potential acute radiation syndromes causing sequelae of multi-organ injury in a dose- and time-dependent manner. Currently, medical countermeasures against radiation injury are limited, and no biomarkers have been approved by regulatory authorities. Identification of circulating plasma biomarkers indicative of radiation injury can be useful for early triage and injury assessment and in the development of novel therapies (medical countermeasures).

Acute Proteomic Changes in Lung after Radiation: Toward Identifying Initiating Events of Delayed Effects of Acute Radiation Exposure in Non-human Primate after Partial Body Irradiation with Minimal Bone Marrow Sparing.

Radiation-induced lung injury is a delayed effect of acute radiation exposure resulting in pulmonary pneumonitis and fibrosis. Molecular mechanisms that lead to radiation-induced lung injury remain incompletely understood. Using a non-human primate model of partial body irradiation with minimal bone marrow sparing, lung was analyzed from animals irradiated with 12 Gy at timepoints every 4 d up to 21 d after irradiation and compared to non-irradiated (sham) controls.

Complementary Lipidomic, Proteomic, and Mass Spectrometry Imaging Approach to the Characterization of the Acute Effects of Radiation in the Non-human Primate Mesenteric Lymph Node after Partial-body Irradiation with Minimal Bone Marrow Sparing.

Radiation sequelae is complex and characterized by multiple pathologies, which occur over time and nonuniformly throughout different organs. The study of the mesenteric lymph node (MLN) due to its importance in the gastrointestinal system is of particular interest. Other studies have shown an immediate post-irradiation reduction in cellularity due to the known effects of irradiation on lymphoid cell populations, but the molecular and functional mechanisms that lead to these cellular alterations remain limited.

Multi-omic Analysis of Non-human Primate Heart after Partial-body Radiation with Minimal Bone Marrow Sparing.

High-dose radiation exposure results in hematopoietic and gastrointestinal acute radiation syndromes followed by delayed effects of acute radiation exposure, which encompasses multiple organs, including heart, kidney, and lung. Here we sought to further characterize the natural history of radiation-induced heart injury via determination of differential protein and metabolite expression in the heart. We quantitatively profiled the proteome and metabolome of left and right ventricle from non-human primates following 12 Gy partial body irradiation with 2.

Acute Proteomic Changes in Non-human Primate Kidney after Partial-body Radiation with Minimal Bone Marrow Sparing.

Near total body exposure to high-dose ionizing radiation results in organ-specific sequelae, including acute radiation syndromes and delayed effects of acute radiation exposure. Among these sequelae are acute kidney injury and chronic kidney injury. Reports that neither oxidative stress nor inflammation are dominant mechanisms defining radiation nephropathy inspired an unbiased, discovery-based proteomic interrogation in order to identify mechanistic pathways of injury.

AEOL 10150 Alleviates Radiation-induced Innate Immune Responses in Non-human Primate Lung Tissue.

To study the molecular and cellular mechanisms of radiation-induced lung injury (RILI) in a non-human primate model, Rhesus macaques were irradiated with lethal doses of radiation to the whole thorax. A subset of the irradiated animals was treated with AEOL 10150, a potent catalytic scavenger of reactive oxygen and nitrogen species. Lung tissues were collected at necropsy for molecular and immunohistochemical (IHC) studies.

Acute Radiation Effects, the H-ARS in the Non-human Primate: A Review and New Data for the Cynomolgus Macaque with Reference to the Rhesus Macaque.

Medical countermeasure development under the US Food and Drug Administration animal rule requires validated animal models of acute radiation effects. The key large animal model is the non-human primate, rhesus macaque. To date, only the rhesus macaque has been used for both critical supportive data and pivotal efficacy trials seeking US Food and Drug Administration approval.

The Natural History of Acute Radiation-induced H-ARS and Concomitant Multi-organ Injury in the Non-human Primate: The MCART Experience.

The dose response relationship and corresponding values for mid-lethal dose and slope are used to define the dose- and time-dependent parameters of the hematopoietic acute radiation syndrome. The characteristic time course of mortality, morbidity, and secondary endpoints are well defined. The concomitant comorbidities, potential mortality, and other multi-organ injuries that are similarly dose- and time-dependent are less defined.

Recent advances in medical countermeasure development against acute radiation exposure based on the US FDA animal rule.

Recent advances in medical countermeasures (MCMs) has been dependent on the Food and Drug Administration (FDA) animal rule (AR) and the final guidance document provided for industry on product development. The criteria outlined therein establish the path for approval under the AR. The guidance document, along with the funding and requirements from the federal agencies provided the basic considerations for animal model development in assessing radiation effects and efficacy against the potential lethal effects of acute radiation injury and the delayed effects of acute exposure.

Establishing Pediatric Mouse Models of the Hematopoietic Acute Radiation Syndrome and the Delayed Effects of Acute Radiation Exposure.

Medical countermeasures (MCMs) for hematopoietic acute radiation syndrome (H-ARS) should be evaluated in well-characterized animal models, with consideration of at-risk populations such as pediatrics. We have developed pediatric mouse models of H-ARS and delayed effects of acute radiation exposure (DEARE) for efficacy testing of MCMs against radiation. Male and female C57BL/6J mice aged 3, 4, 5, 6, 7 and 8 weeks old (±1 day) were characterized for baseline hematopoietic and gastrointestinal parameters, radiation response, efficacy of a known MCM, and DEARE at six and 12 months after total-body irradiation (TBI).

Acute Radiation-induced Lung Injury in the Non-human Primate: A Review and Comparison of Mortality and Co-morbidities Using Models of Partial-body Irradiation with Marginal Bone Marrow Sparing and Whole Thorax Lung Irradiation.

The nonhuman primate, rhesus macaque, is a relevant animal model that has been used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality of radiation-induced lung injury. Herein, a literature review of published studies showing the evolution of lethal lung injury characteristic of the delayed effects of acute radiation exposure between the two significantly different exposure protocols, whole thorax lung irradiation and partial-body irradiation with bone marrow sparing in the nonhuman primate, is provided. The selection of published data was made from the open literature.

Immune Reconstitution and Thymic Involution in the Acute and Delayed Hematopoietic Radiation Syndromes.

Lymphoid lineage recovery and involution after exposure to potentially lethal doses of ionizing radiation have not been well defined, especially the long-term effects in aged survivors and with regard to male/female differences. To examine these questions, male and female C57BL/6 mice were exposed to lethal radiation at 12 wk of age in a model of the Hematopoietic-Acute Radiation Syndrome, and bone marrow, thymus, spleen, and peripheral blood examined up to 24 mo of age for the lymphopoietic delayed effects of acute radiation exposure. Aged mice showed myeloid skewing and incomplete lymphocyte recovery in all lymphoid tissues.

Proteomic Evaluation of the Natural History of the Acute Radiation Syndrome of the Gastrointestinal Tract in a Non-human Primate Model of Partial-body Irradiation with Minimal Bone Marrow Sparing Includes Dysregulation of the Retinoid Pathway.

Exposure to ionizing radiation results in injuries of the hematopoietic, gastrointestinal, and respiratory systems, which are the leading causes responsible for morbidity and mortality. Gastrointestinal injury occurs as an acute radiation syndrome. To help inform on the natural history of the radiation-induced injury of the partial body irradiation model, we quantitatively profiled the proteome of jejunum from non-human primates following 12 Gy partial body irradiation with 2.

Proteomics of Non-human Primate Plasma after Partial-body Radiation with Minimal Bone Marrow Sparing.

High-dose radiation exposure results in organ-specific sequelae that occurs in a time- and dose-dependent manner. The partial body irradiation with minimal bone marrow sparing model was developed to mimic intentional or accidental radiation exposures in humans where bone marrow sparing is likely and permits the concurrent analysis of coincident short- and long-term damage to organ systems. To help inform on the natural history of the radiation-induced injury of the partial body irradiation model, we quantitatively profiled the plasma proteome of non-human primates following 12 Gy partial body irradiation with 2.

Evaluation of Plasma Biomarker Utility for the Gastrointestinal Acute Radiation Syndrome in Non-human Primates after Partial Body Irradiation with Minimal Bone Marrow Sparing through Correlation with Tissue and Histological Analyses.

Exposure to total- and partial-body irradiation following a nuclear or radiological incident result in the potentially lethal acute radiation syndromes of the gastrointestinal and hematopoietic systems in a dose- and time-dependent manner. Radiation-induced damage to the gastrointestinal tract is observed within days to weeks post-irradiation. Our objective in this study was to evaluate plasma biomarker utility for the gastrointestinal acute radiation syndrome in non-human primates after partial body irradiation with minimal bone marrow sparing through correlation with tissue and histological analyses.

A Systematic Review of the Hematopoietic Acute Radiation Syndrome (H-ARS) in Canines and Non-human Primates: Acute Mixed Neutron/Gamma vs. Reference Quality Radiations.

A systematic review of relevant studies that determined the dose response relationship (DRR) for the hematopoietic (H) acute radiation syndrome (ARS) in the canine relative to radiation quality of mixed neutron:gamma radiations, dose rate, and exposure uniformity relative to selected reference radiation exposure has not been performed. The datasets for rhesus macaques exposure to mixed neutron:gamma radiation are used herein as a species comparative reference to the canine database. The selection of data cohorts was made from the following sources: Ovid Medline (1957-present), PubMed (1954-present), AGRICOLA (1976-present), Web of Science (1954-present), and US HHS RePORT (2002-present).

Lack of Cellular Inflammation in a Non-human Primate Model of Radiation Nephropathy.

Inflammation is commonly cited as a mechanism of delayed effects of acute radiation exposure (DEARE). Confirmation of its presence could provide significant insight to targeted use of treatments or mitigators of DEARE. We sought to quantify the presence of cellular inflammation in kidneys of non-human primates that developed acute and chronic kidney injury after a partial body irradiation exposure.