Targets for protection and mitigation of radiation injury.

Protection of normal tissues against toxic effects of ionizing radiation is a critical issue in clinical and environmental radiobiology. Investigations in recent decades have suggested potential targets that are involved in the protection against radiation-induced damages to normal tissues and can be proposed for mitigation of radiation injury. Emerging evidences have been shown to be in contrast to an old dogma in radiation biology; a major amount of reactive oxygen species (ROS) production and cell toxicity occur during some hours to years after exposure to ionizing radiation. This can be attributed to upregulation of inflammatory and fibrosis mediators, epigenetic changes and disruption of the normal metabolism of oxygen. In the current review, we explain the cellular and molecular changes following exposure of normal tissues to ionizing radiation. Furthermore, we review potential targets that can be proposed for protection and mitigation of radiation toxicity.

Early-response multiple-parameter biodosimetry and dosimetry: risk predictions.

The accepted generic multiple-parameter and early-response biodosimetry and dosimetry assessment approach for suspected high-dose radiation (i.e. life-threatening) exposure includes measuring radioactivity associated with the exposed individual (if appropriate); observing and recording prodromal signs/symptoms; obtaining serial complete blood counts with white-blood-cell differential; sampling blood for the chromosome-aberration cytogenetic bioassay using the 'gold standard' dicentric assay (premature chromosome condensation assay for exposures >5 Gy photon acute doses equivalent), measurement of proteomic biomarkers and gene expression assays for dose assessment; bioassay sampling, if appropriate, to determine radioactive internal contamination; physical dose reconstruction, and using other available opportunistic dosimetry approaches. Biodosimetry and dosimetry resources are identified and should be setup in advance along with agreements to access additional national, regional, and international resources. This multifaceted capability needs to be integrated into a biodosimetry/dosimetry 'concept of operations' for use in a radiological emergency. The combined use of traditional biological-, clinical-, and physical-dosimetry should be use in an integrated approach to provide: (a) early-phase diagnostics to guide the development of initial medical-management strategy, and (b) intermediate and definitive assessment of radiation dose and injury. Use of early-phase (a) clinical signs and symptoms, (b) blood chemistry biomarkers, and (c) triage cytogenetics shows diagnostic utility to predict acute radiation injury severity.

Mitigation of acute radiation syndrome (ARS) with human umbilical cord blood.

PURPOSE: The growing concern over potential unintended nuclear accidents or malicious activities involving nuclear/radiological devices cannot be overstated. Exposure to whole-body doses of radiation can result in acute radiation syndrome (ARS), colloquially known as "radiation sickness," which can severely damage various organ systems. Long-term health consequences, such as cancer and cardiovascular disease, can develop many years post-exposure. Identifying effective medical countermeasures and devising a strategic medical plan represents an urgent, unmet need. Various clinical studies have investigated the therapeutic use of umbilical cord blood (UCB) for a range of illnesses, including ARS. The objective of this review is to thoroughly discuss ARS and its sub-syndromes, and to highlight recent findings regarding the use of UCB for radiation injury. UCB, a rich source of stem cells, boasts numerous advantages over other stem cell sources, like bone marrow, owing to its ease of collection and relatively low risk of severe graft-versus-host disease. Preclinical studies suggest that treatment with UCB, and often UCB-derived mesenchymal stromal cells (MSCs), results in improved survival, accelerated hematopoietic recovery, reduced gastrointestinal tract damage, and mitigation of radiation-induced pneumonitis and pulmonary fibrosis. Interestingly, recent evidence suggests that UCB-derived exosomes and their microRNAs (miRNAs) might assist in treating radiation-induced damage, largely by inhibiting fibrotic pathways. CONCLUSION: UCB holds substantial potential as a radiation countermeasure, and future research should focus on establishing treatment parameters for ARS victims.

Severity scoring systems for radiation-induced GI injury - prioritization for use of GI-ARS medical countermeasures.

PURPOSE: Severity scoring systems for ionizing radiation-induced gastrointestinal injury have been used in animal radiation models, human studies involving the use of radiation therapy, and human radiation accidents. Various radiation exposure scenarios (i.e. total body irradiation, total abdominal irradiation, etc.) have been used to investigate ionizing radiation-induced gastrointestinal injury. These radiation-induced gastrointestinal severity scoring systems are based on clinical signs and symptoms and gastrointestinal-specific biomarkers (i.e. citrulline, etc.). In addition, the time course for radiation-induced changes in blood citrulline levels were compared across various animal (i.e. mice, minipigs, Rhesus Macaque, etc.) and human model systems. CONCLUSIONS: A worksheet tool was developed to prioritize individuals with severe life-threatening gastrointestinal acute radiation syndrome, based on the design of the Exposure and Symptom Tool addressing hematopoietic acute radiation syndrome, to rescue individuals from potential gastrointestinal acute radiation syndrome injury. This tool provides a triage diagnostic approach to assist first responders to assess individuals suspected of showing gastrointestinal acute radiation syndrome severity to guide medical management, hence enhancing medical readiness for managing radiological casualties.

Looking for the phoenix: the current research on radiation countermeasures.

PURPOSE: Ionizing radiation (IR) is widely applied in radiotherapy for the treatment of over 50% of cancer patients. IR is also intensively used in medical diagnostics on a daily basis in imaging. Moreover, recent geopolitical events have re-ignited the real threat of the use of nuclear weapons. Medical radiation countermeasures represent one of the effective protection strategies against the effects of IR. The aim of this review was to summarize the most commonly used strategies and procedures in the development of radiation countermeasures and to evaluate the current state of their research, with a focus on those in the clinical trial phase. METHODS: Clinical trials for this review were selected in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. The search was performed in the clinicaltrials.gov database as of May 2022. RESULTS: Our search returned 263 studies, which were screened and of which 25 were included in the review. 10 of these studies had been completed, 3 with promising results: KMRC011 increased G-CSF, IL-6, and neutrophil counts suggesting potential for the treatment of hematopoietic acute radiation syndrome (H-ARS); GC4419 reduced the number of patients with severe oral mucositis and its duration; the combination of enoxaparin, pentoxifylline, and ursodeoxycholic acid reduced the incidence of focal radiation-induced liver injury. CONCLUSION: The agents discovered so far show significant side effects or low efficacy, and hence most of the tested agents terminate in the early stages of development. In addition, the low profitability of this type of drug demotivates the private sector to invest in such research. To overcome this problem, there is a need to involve more public resources in funding. Among the technological opportunities, a deeper use of in silico approaches seems to be prospective.

Delayed renal injury in survivors of hematologic acute radiation syndrome.

PURPOSE: A mass casualty disaster involving radiological or nuclear agents continues to be a public health concern which requires consideration of both acute and late tissue toxicities in exposed victims. With the advent of advanced treatment options for the mitigation of hematological injuries, there are likely to be survivors of total body irradiation (TBI) exposures as high as 8-10 Gy. These survivors are at risk for a range of delayed multi-organ morbidities including progressive renal failure. MATERIAL AND METHODS: Here, we established the WAG/RijCmcr rat as an effective model for the evaluation of medical countermeasures (MCM) for acute hematologic radiation syndrome (H-ARS). The LD50/30 dose for adult and pediatric WAG/RijCmcr rats was determined for both sexes. We then confirmed the FDA-approved MCM pegfilgrastim (peg-GCSF, Neulasta®) mitigates H-ARS in adult male and female rats. Finally, we evaluated survival and renal dysfunction up to 300 d post-TBI in male and female adult rats. RESULTS: In the WAG/RijCmcr rat model, 87.5% and 100% of adult rats succumb to lethal hematopoietic acute radiation syndrome (H-ARS) at TBI doses of 8 and 8.5 Gy, respectively. A single dose of the hematopoietic growth factor peg-GCSF administered at 24 h post-TBI improved survival during H-ARS. Peg-GCSF treatment improved 30 d survival from 12.5% to 83% at 8 Gy and from 0% to 63% at 8.5 Gy. We then followed survivors of H-ARS through day 300. Rats exposed to TBI doses greater than 8 Gy had a 26% reduction in survival over days 30-300 compared to rats exposed to 7.75 Gy TBI. Concurrent with the reduction in long-term survival, a dose-dependent impairment of renal function as assessed by blood urea nitrogen (BUN) and urine protein to urine creatinine ratio (UP:UC) was observed. CONCLUSION: Together, these data show survivors of H-ARS are at risk for the development of delayed renal toxicity and emphasize the need for the development of medical countermeasures for delayed renal injury.

Haptoglobin is an early indicator of survival after radiation-induced severe injury and bone marrow transplantation in mice.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is the main treatment for acute radiation sickness, especially after fatal radiation. The determination of HSCT for radiation patients is mainly based on radiation dose, hemogram and bone marrow injury severity. This study aims to explore a better biomarker of acute radiation injury from the perspective of systemic immune response. METHODS: C57BL/6J female mice were exposed to total body irradiation (TBI) and partial body irradiation (PBI). Changes in haptoglobin (Hp) level in plasma were shown at different doses and time points after the exposure and treatment with amifostine or bone marrow transplantation. Student's t-test/two tailed test were used in two groups. To decide the Hp levels as a predictor of the radiation dose in TBI and PBI, multiple linear regression analysis were performed. The ability of biomarkers to identify two groups of different samples was determined by the receiver operating characteristic (ROC) curve. The results were expressed as mean ± standard deviation (SD). Significance was set at P value < 0.05, and P value < 0.01 was set as highly significant. Survival distribution was determined by log-rank test. RESULTS: In this study, we found that Hp was elevated dose-dependently in plasma in the early post-irradiation period and decreased on the second day, which can be used as a molecular indicator for early dose assessment. Moreover, we detected the second increase of Hp on the 3rd and 5th days after the lethal irradiation at 10 Gy, which was eliminated by amifostine, a radiation protection drug, while protected mice from death. Most importantly, bone marrow transplantation (BMT) on the 3rd and 5th day after 10 Gy radiation improved the 30-days survival rate, and effectively accelerated the regression of secondary increased Hp level. CONCLUSIONS: Our study suggests that Hp can be used not only as an early molecule marker of radiation injury, but also as an important indicator of bone marrow transplantation therapy for radiation injury, bringing new scientific discoveries in the diagnosis and treatment of acute radiation injury from the perspective of systemic immunity.

Developing and comparing models of hematopoietic-acute radiation syndrome in Göttingen and Sinclair minipigs.

PURPOSE: Current animal models of hematopoietic-acute radiation syndrome (H-ARS) are resource intensive and have limited translation to humans, thereby inhibiting the development of effective medical countermeasures (MCM)s for radiation exposure. MATERIALS AND METHODS: To improve the MCM pipeline, we developed models of H-ARS in male Göttingen and Sinclair minipigs. Weight matched Göttingens and Sinclairs received total body irradiation (TBI; 1.50-2.10 Gy and 1.94-2.90 Gy, respectively), were observed for up to 45 days with blood collections for clinical pathology analysis, and were examined during gross necropsy. RESULTS: The lethal dose for 50% of the population over the course of 45 days (LD50/45) with 'field' supportive care (primarily antibiotics and hydration support) and implanted vascular access ports was 1.89 and 2.53 Gy for Göttingens and Sinclairs, respectively. Both minipig strains exhibited prototypical H-ARS characteristics, experiencing thrombocytopenia and neutropenia, and nadirs approximately 14 days following irradiation, slightly varying with dose. Both strains experienced increased bruising, petechia, and signs of internal hemorrhage in the lungs, GI, heart, and skin. All observations were noted to correlate with dose more closely in Sinclairs than in Göttingens. CONCLUSION: The results of this study provide a template for future MCM development in an alternate species, and support further development of the Göttingen and Sinclair minipig H-ARS models.

Use of CT simulation and 3-D radiation therapy treatment planning system to develop and validate a total-body irradiation technique for the New Zealand White rabbit.

PURPOSE: Well-controlled ionizing radiation injury animal models for testing medical countermeasure efficacy require robust radiation physics and dosimetry to ensure accuracy of dose-delivery and reproducibility of the radiation dose-response relationship. The objective of this study was to establish a simple, convenient, robust and accurate technique for validating total body irradiation (TBI) exposure of the New Zealand White rabbit. METHODS: We use radiotherapy techniques such as computed tomography simulation and a 3 D-conformal radiation therapy treatment planning system (TPS) on three animals to comprehensively design and preplan a TBI technique for rabbits. We evaluate the requirement for bolus, treatment geometry, bilateral vs anterior-posterior treatment delivery, the agreement between monitor units calculated using the TPS vs a traditional hand calculation to the mid-plane, and resulting individual organ doses. RESULTS: The optimal technique irradiates animals on the left-decubitus position using two isocentric bilateral parallel-opposed 6 MV x-ray beams. Placement of a 5 mm bolus and 8.5 mm beam spoiler was shown to increase the dose to within ≤5 mm of the surface, improving dose homogeneity throughout the body of the rabbit. A simple hand calculation formalism, dependent only on mid-abdominal separation, could be used to calculate the number of monitor units (MUs) required to accurately deliver the prescribed dose to the animal. For the representative animal, the total body volume receiving > 95% of the dose, V95% > 99%, V100% > 95%, and V107% < 20%. The area of the body receiving >107% of the prescribed dose was mainly within the limbs, head, and around the lungs of the animal, where the smaller animal width reduces the x-ray attenuation. Individual organs were contoured by an experienced dosimetrist, and each received doses within 95-107% of the intended dose, with mean values ∼104%. Only the bronchus showed a maximal dose >107% (113%) due to the decreased attenuation of the lungs. To validate the technique, twenty animals were irradiated with four optically-stimulated luminescence dosimeters (OSLDs) placed on the surface of each animal (two on each side in the center of the radiation beam). The average dose over all animals was within <0.1% from intended values, with no animal receiving an average dose more than ±3.1% from prescription. CONCLUSION: The TBI technique developed in this pilot study was successfully used to establish the dose-response relationship for 45-day lethality across the dose-range to induce the hematopoietic-subsyndrome of the acute radiation syndrome (ARS).

Impact analysis of age on radiation casualty estimations for nuclear detonation scenarios.

Purpose: The purpose of this research was to demonstrate the impact of accounting for age-based radiation response when estimating radiation casualties in a nuclear detonation scenario.Materials and methods: Three nuclear device detonation scenarios were simulated using densely populated regions to compare traditional casualty estimates with age-dependent casualty estimates. Fatalities were estimated using age-based dose-response curves. The surviving population was assumed injured (requiring medical care) if their dose exceeded a lower bound, represented by the minimum dose required to cause deterministic effects, for each age group.Results: In each of the three scenarios, the affected area increased significantly for radiosensitive age groups. In two of the three scenarios, accounting for age-dependent radiosensitivity resulted in up to a 10% increase in fatalities and up to a 12% increase in radiation injuries compared to traditional estimates. This study demonstrates that the differences in casualty estimates are dependent on the relative density and location of radiosensitive populations.Conclusions: These results demonstrate that the inclusion of age-based demographic data and associated dose responses may result in significantly higher estimates of casualties depending on the location and age of the affected population. This information could be useful for the emergency management planning community.

Informing CONOPS and medical countermeasure deployment strategies after an improvised nuclear device detonation: the importance of delayed treatment efficacy data.

Purpose: In the wake of a nuclear detonation, individuals with acute radiation syndrome will be a significant source of morbidity and mortality. Mathematical modeling can compare response strategies developed for real-world chaotic conditions after a nuclear blast in order to identify optimal strategies for administering effective treatment to these individuals. To maximize responders' abilities to save lives it is critical to understand how treatment efficacy is impacted by real-world conditions and levels of supportive care. To illustrate the importance of these factors, we developed a mathematical model of cytokine administration 24 h after the blast with varying levels of supportive care described in the primary literature.Conclusion: The results highlight the proportionally higher life-saving benefit of administering cytokines to individuals with a moderate to high dose of radiation exposure, compared to those with a lower dose. However, the fidelity of mathematical models is dependent on the primary data informing them. We describe the data needed to fully explore the impact of timing, dosage, and fractional benefit of cytokines and supportive care treatment in non-optimal situations that could be seen after a nuclear detonation. Studies addressing these types of knowledge gaps are essential to evaluating the relative efficacy of countermeasures to refine existing plans and help develop new strategies and priorities.

Pharmacodynamics of romiplostim alone and in combination with pegfilgrastim on acute radiation-induced thrombocytopenia and neutropenia in non-human primates.

Purpose: Evaluation of the pharmacodynamics (PD) and pharmacokinetics (PK) of romiplostim alone and in combination with pegfilgrastim in a non-human primate (NHP) model of acute radiation syndrome (ARS).Materials and methods: Male and female rhesus macaques were subjected to Cobalt-60 γ irradiation, at a dose of 550 cGy 24 h prior to subcutaneous administration of either romiplostim alone as a single (2.5 or 5.0 mg/kg on Day 1) or repeat dose (5.0 mg/kg on Days 1 and 8), pegfilgrastim alone as a repeat dose (0.3 µg/kg on Day 1 and 8), or a combination of both agents (romiplostim 5.0 mg/kg on Day 1; pegfilgrastim 0.3 µg/kg on Days 1 and 8). Clinical outcome, hematological parameters and PK were assessed throughout the 45 d study period post-irradiation.Results: Administration of romiplostim, pegfilgrastim or the combination of both resulted in significant improvements in hematological parameters, notably prevention of severe thrombocytopenia, compared with irradiated, vehicle control-treated NHPs. The largest hematologic benefit was observed when romiplostim and pegfilgrastim were administered as a combination therapy with much greater effects on both platelet and neutrophil recovery following irradiation compared to single agents alone.Conclusions: These results indicate that romiplostim alone or in combination with pegfilgrastim is effective at improving hematological parameters in an NHP model of ARS. This study supports further study of romiplostim as a medical countermeasure to improve primary hemostasis and survival in ARS.

Alleviation of acute radiation-induced bone marrow failure in mice with human fetal placental stromal cell therapy.

PURPOSE: Selected placental mesenchymal stromal cells isolated from the fetal mesenchymal placental tissues (f-hPSCs) were tested as cell therapy of lethal acute radiation syndrome (ARS) with bone marrow regeneration and induced extramedullary hematopoiesis. METHODS AND MATERIALS: f-hPSCs were isolated from the chorionic plate of human placentae and further expanded in regular culture conditions. 2 × 106 f-hPSCs were injected on days 1 and 4 to 8-Gy total body irradiated (TBI) C3H mice, both intramuscularly and subcutaneously. Pre-splenectomized TBI mice were used to test the involvement of extramedullary spleen hematopoiesis in the f-hPSC-induced hematopoiesis recovery in the TBI mice. Weight and survival of the mice were followed up within the morbid period of up to 23 days following irradiation. The role of hematopoietic progenitors in the recovery of treated mice was evaluated by flow cytometry, blood cell counts, and assay of possibly relevant growth factors. RESULTS AND CONCLUSIONS: The survival rate of all groups of TBI f-hPSC-treated mice at the end of the follow-up was dramatically elevated from < 10% in untreated to ~ 80%, with a parallel regain of body weight, bone marrow (BM) recovery, and elevated circulating progenitors of blood cell lineages. Blood erythropoietin levels were elevated in all f-hPSC-treated mice. Extramedullary splenic hematopoiesis was recorded in the f-hPSC-treated mice, though splenectomized mice still had similar survival rate. Our findings suggest that the indirect f-hPSC life-saving therapy of ARS may also be applied for treating other conditions with a failure of the hematopoietic system and severe pancytopenia.

Research progress in hematopoietic stem cell transplantation for bone marrow acute radiation syndrome / 中国辐射卫生

As is known, the nuclear accident resulting from the explosion of a nuclear weapon or the release of nuclear material could cause acute radiation syndrome within a short time. The study had found that the dose of > 0.7 Gy radiation on human body can result in persistent myelosuppression, a kind of acute radiation syndrome, leading to pancytopenia, bleeding, infection and other injuries. Several evidences also have shown that hematopoietic stem cell is conducive to repair hematopoietic injury in bone marrow, improve hematopoietic microenvironment and promote hematopoietic reconstruction. Therefore, hematopoietic stem cell transplantation is widely considered as the main treatment of the bone marrow acute radiation syndrome. However, before a surgery of hematopoietic stem cell transplantation, it still needs more research on donor selection, formulation of preconditioning and prevention of complications such as graft-versus-host disease. This paper mainly summarizes the application and research progress of hematopoietic stem cell transplantation in treating radiation injury.

Radiologists: The Unsuspecting Subject Matter Experts.

The social and political climates are changing rapidly in the United States and the world at large. The threat of a chemical, biologic, radiologic, and/or nuclear event is a rising concern to many. The current Ebola crisis has shed light on health care providers' preparedness for such an event. Radiologists, including radiation oncologists, nuclear medicine specialists, and all radiology subspecialists are considered "subject matter experts" in this area and are likely to be called upon in response to a radiation incident. Although others, such as radiation safety officers, provide important expertise, the clinical leadership will be the responsibility of physicians and other health care providers. However, many radiologists are unaware that they are considered subject matter experts who may be called on to assist, should their local hospital's emergency department need to take care of casualties from a radiation incident. A mass-casualty situation with hundreds of patients would require the immediate assistance of all available medical providers. Radiologists are primed and positioned to take the lead in ensuring preparedness of their local hospital and community, through emergency planning for a radiologic incident, given their combined medical and radiation physics knowledge. Therefore, increasing the skills of radiologists first is the more prudent approach in such planning. This preparation can be done through understanding of the critical components of such scenarios: the threat, types of radiation incidents, contamination, detection, decontamination, and acute radiation syndrome and its treatment. Once the necessary knowledge supplementation has been completed, radiologists can participate in educating their fellow medical colleagues and health care staff, and assist in the radiation-related aspects of an "all hazards" emergency department response, decreasing "radiophobia" in the process.