Armed forces Radiobiology Research Institute

Bethesda, MD, United States

Armed forces Radiobiology Research Institute

Bethesda, MD, United States

The Armed Forces Radiobiology Research Institute is a triservice laboratory in Bethesda, Maryland, USA, and was chartered by the U.S. Congress in 1961. It conducts research in the field of radiobiology and related matters which are essential to the operational and medical support of the U.S. Department of Defense and the U.S. military services. AFRRI provides services and performs cooperative research with other federal and civilian agencies and institutions. Wikipedia.

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Singh V.K.,Armed forces Radiobiology Research Institute | Singh V.K.,Uniformed Services University of the Health Sciences | Newman V.L.,Armed forces Radiobiology Research Institute | Seed T.M.,Technology Micro Services
Cytokine | Year: 2015

One of the greatest national security threats to the United States is the detonation of an improvised nuclear device or a radiological dispersal device in a heavily populated area. As such, this type of security threat is considered to be of relatively low risk, but one that would have an extraordinary high impact on health and well-being of the US citizenry. Psychological counseling and medical assessments would be necessary for all those significantly impacted by the nuclear/radiological event. Direct medical interventions would be necessary for all those individuals who had received substantial radiation exposures (e.g., > 1. Gy). Although no drugs or products have yet been specifically approved by the United States Food and Drug Administration (US FDA) to treat the effects of acute radiation syndrome (ARS), granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), and pegylated G-CSF have been used off label for treating radiation accident victims. Recent threats of terrorist attacks using nuclear or radiologic devices makes it imperative that the medical community have up-to-date information and a clear understanding of treatment protocols using therapeutically effective recombinant growth factors and cytokines such as G-CSF and GM-CSF for patients exposed to injurious doses of ionizing radiation. Based on limited human studies with underlying biology, we see that the recombinants, G-CSF and GM-CSF appear to have modest, but significant medicinal value in treating radiation accident victims. In the near future, the US FDA may approve G-CSF and GM-CSF as 'Emergency Use Authorization' (EUA) for managing radiation-induced aplasia, an ARS-related pathology. In this article, we review the status of growth factors for the treatment of radiological/nuclear accident victims. © 2014 Published by Elsevier Ltd.

Fukumoto R.,Armed forces Radiobiology Research Institute | Kiang J.G.,Armed forces Radiobiology Research Institute | Kiang J.G.,Uniformed Services University of the Health Sciences
Radiation Research | Year: 2011

Exposure to ionizing radiation induces p53, and its inhibition improves mouse survival. We tested the effect of 17-dimethylamino-ethylamino-17- demethoxygeldanamycin (17-DMAG) on p53 expression and function after radiation exposure. 17-DMAG, a heat-shock protein 90 (Hsp90) inhibitor, protects human T cells from ionizing radiation-induced apoptosis by inhibiting inducible nitric oxide synthase (iNOS) and subsequent caspase-3 activation. Using ex vivo human peripheral blood mononuclear cells, we found that ionizing radiation increased p53 accumulation, acute p53 phosphorylation, Bax expression and caspase-3/7 activation in a radiation dose-and time postirradiation-dependent manner. 17-DMAG inhibited these increases in a concentration-dependent manner (IC50  =  0.93 ± 0.01 M). Using in vitro models, we determined that inhibition of p53 by genetic knockout resulted in lower levels of caspase-3/7 activity 1 day after irradiation and enhanced survival at 10 days. Analysis of p53Hsp90 interaction in ex vivo cell lysates indicated that the binding between the two molecules occurred after irradiation but 17-DMAG prevented the binding. Taken together, these results suggest the presence of p53 phosphorylation and Hsp90-dependent p53 stabilization after acute irradiation. Hsp90 inhibitors such as 17-DMAG may prove useful with radiation-based cancer therapy as well as for general radioprotection. © 2011 by Radiation Research Society.

Kiang J.G.,Armed forces Radiobiology Research Institute | Kiang J.G.,Uniformed Services University of the Health Sciences | Ledney G.D.,Armed forces Radiobiology Research Institute
Oxidative Medicine and Cellular Longevity | Year: 2013

Skin injuries such as wounds or burns following whole-body γ -irradiation (radiation combined injury (RCI)) increase mortality more than whole-body γ -irradiation alone. Wound-induced decreases in survival after irradiation are triggered by sustained activation of inducible nitric oxide synthase pathways, persistent alteration of cytokine homeostasis, and increased susceptibility to systemic bacterial infection. Among these factors, radiation-induced increases in interleukin-6 (IL-6) concentrations in serum were amplified by skin wound trauma. Herein, the IL-6-induced stress proteins including C-reactive protein (CRP), complement 3 (C3), immunoglobulin M (IgM), and prostaglandin E(PGE were evaluated after skin injuries given following a mixed radiation environment that might be found after a nuclear incident. In this report, mice received 3 Gy of reactor-produced mixed field (n + γ -photons) radiations at 0.38 Gy/min followed by nonlethal skin wounding or burning. Both wounds and burns reduced survival and increased CRP, C3, and PGEin serum after radiation. Decreased IgM production along with an early rise in corticosterone followed by a subsequent decrease was noted for each RCI situation. These results suggest that RCI-induced alterations of corticosterone, CRP, C3, IgM, and PGEcause homeostatic imbalance and may contribute to reduced survival. Agents inhibiting these responses may prove to be therapeutic for RCI and improve related survival. © 2013 Juliann G. Kiang and G. David Ledney.

Xiao M.,Armed forces Radiobiology Research Institute
Health Physics | Year: 2016

Massive radiation-induced inflammatory factors released from injured cells may cause innate and acquired immune reactions that can further result in stress response signal activity-induced local and systemic damage. IL-1 family members IL-1β, IL-18, and IL-33 play key roles in inflammatory and immune responses and have been recognized to have significant influences on the pathogenesis of diseases. IL-1β, IL-18, and IL-33 share similarities of cytokine biology, but differences exist in signaling pathways. A key component of the inflammatory reaction is the inflammasome, which is a caspase-1-containing multiprotein oligomer. Pathological stimuli such as radiation can induce inflammasome and caspase-1 activation, and subsequently cause maturation (activation) of pro-forms of IL-1 and IL-18 upon caspase-1 cleavage. This caspase-1 dependent and IL-1 and IL-18 associated cell damage is defined as pyroptosis. Activated IL-1 and IL-18 as proinflammatory cytokines drive pathology at different immune and inflammatory disorders through Toll-like receptor (TLR) signaling. While the mechanisms of IL-1β-induced pathophysiology of diseases have been well studied, IL-18 has received less attention. The author recently reported that gamma radiation highly increased IL-1β, IL-18 and IL-33 expression in mouse thymus, spleen and/or bone marrow cells; also circulating IL-18 can be used as a radiation biomarker to track radiation injury in mice, minipigs, and nonhuman primates. This mini-review focuses on the role of IL-18 in response to gamma radiation-induced injury. © 2016 Health Physics Society.

Kiang J.G.,Armed forces Radiobiology Research Institute
Health Physics | Year: 2016

Recent understanding of the cellular and molecular signaling activations in adult mesenchymal stem cells (MSCs) has provided new insights into their potential clinical applications, particularly for tissue repair and regeneration. This review focuses on these advances, specifically in the context of self-renewal for tissue repair and recovery after radiation injury. Thus far, MSCs have been characterized extensively and shown to be useful in mitigation and therapy for acute radiation syndrome and cognitive dysfunction. Use of MSCs for treating radiation injury alone or in combination with additional trauma is foreseeable. © 2016 Health Physics Society.

Kalinich J.F.,Armed forces Radiobiology Research Institute
Health Physics | Year: 2012

The terrorist use of a radiological dispersal device (RDD) has been described as "not if, but when" (Conklin and Liotta 2005). Exposures from such an event could occur by a number of routes including inhalation, wound contamination, or embedded fragments. Several of the radionuclides thought to be potential RDD components are metals or ceramic material. The use of such material would increase the potential for wounds from embedded fragments of radioactive material. To date, most research in this area has focused on inhalation exposures, while the consequence of embedded fragment exposure has not been investigated. This study modified a previously used rodent model in order to determine the biokinetics of intramuscularly implanted nonradioactive surrogate RDD material. Cobalt, iridium, or strontium titanate was embedded into the gastrocnemius muscle of Sprague Dawley rats. The rats were euthanized at 1, 3, or 6 mo post-implantation. Tissue metal analysis showed that iridium did not solubilize from the implanted pellet, while cobalt and strontium did so rapidly. Cobalt was found in all tissues analyzed, but it was localized mainly to kidney and liver as well as being excreted in the urine. Strontium was found in lung, liver, and spleen, as well as being deposited in bone. However, the greatest strontium concentrations were found in the popliteal lymph nodes, the lymph nodes responsible for draining the area of the gastrocnemius. These results indicate that, depending upon the material, a variety of treatment strategies will be needed when dealing with embedded fragment wounds from a radiological dispersal device event. Copyright © 2012 Health Physics Society.

Ghosh S.P.,Armed forces Radiobiology Research Institute
Journal of radiation research | Year: 2012

The aim of the present study was to assess recovery from hematopoietic and gastrointestinal damage by Ex-RAD(®), also known as ON01210.Na (4-carboxystyryl-4-chlorobenzylsulfone, sodium salt), after total body radiation. In our previous study, we reported that Ex-RAD, a small-molecule radioprotectant, enhances survival of mice exposed to gamma radiation, and prevents radiation-induced apoptosis as measured by the inhibition of radiation-induced protein 53 (p53) expression in cultured cells. We have expanded this study to determine best effective dose, dose-reduction factor (DRF), hematological and gastrointestinal protection, and in vivo inhibition of p53 signaling. A total of 500 mg/kg of Ex-RAD administered at 24 h and 15 min before radiation resulted in a DRF of 1.16. Ex-RAD ameliorated radiation-induced hematopoietic damage as monitored by the accelerated recovery of peripheral blood cells, and protection of granulocyte macrophage colony-forming units (GM-CFU) in bone marrow. Western blot analysis on spleen indicated that Ex-RAD treatment inhibited p53 phosphorylation. Ex-RAD treatment reduces terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay (TUNEL)-positive cells in jejunum compared with vehicle-treated mice after radiation injury. Finally, Ex-RAD preserved intestinal crypt cells compared with the vehicle control at 13 and 14 Gy. The results demonstrated that Ex-RAD ameliorates radiation-induced peripheral blood cell depletion, promotes bone marrow recovery, reduces p53 signaling in spleen and protects intestine from radiation injury.

Sandgren D.J.,Armed forces Radiobiology Research Institute
Health Physics | Year: 2014

Nuclear accidents or terrorist attacks could expose large numbers of people to ionizing radiation. Early biomarkers of radiation injury will be critical for triage, treatment, and follow-up of such individuals. The authors evaluated the utility of multiple blood biomarkers for early-response assessment of radiation exposure using a murine (CD2F1, males) total-body irradiation (TBI) model exposed to Co γ rays (0.6 Gy min) over a broad dose range (0-14 Gy) and timepoints (4 h-5 d). Results demonstrate: 1) dose-dependent changes in hematopoietic cytokines: Flt? 3 ligand (Flt3L), interleukin 6 (IL? 6), granulocyte colony stimulating factor (G-CSF), thrombopoietin (TPO), erythropoietin (EPO), and acute phase protein serum amyloid A (SAA); 2) dose-dependent changes in blood cell counts: lymphocytes, neutrophils, platelets, and ratio of neutrophils to lymphocytes; 3) protein results coupled with peripheral blood cell counts established very successful separation of groups irradiated to different doses; and 4) enhanced separation of dose was observed as the number of biomarkers increased. Results show that the dynamic changes in the levels of SAA, IL? 6, G-CSF, and Flt3L reflect the time course and severity of acute radiation syndrome (ARS) and may function as prognostic indicators of ARS outcome. These results also demonstrate proof-in-concept that plasma proteins show promise as a complimentary approach to conventional biodosimetry for early assessment of radiation exposures and, coupled with peripheral blood cell counts, provide early diagnostic information to manage radiation casualty incidents effectively, closing a gap in capabilities to rapidly and effectively assess radiation exposure early, especially needed in case of a mass-casualty radiological incident. Copyright © 2014 Health Physics Society.

Ossetrova N.I.,Armed forces Radiobiology Research Institute | Sandgren D.J.,Armed forces Radiobiology Research Institute | Blakely W.F.,Armed forces Radiobiology Research Institute
Radiation Protection Dosimetry | Year: 2014

Development and validation of early-response radiation injury biomarkers are critical for effective triage and medical management of irradiated individuals. Plasma protein and haematological profiles were evaluated using multivariate linear-regression analysis to provide dose-response calibration curves for photon-radiation dose assessment in 30 rhesus macaques total-bodyirradiated to 1-8.5 Gy with 60Co gamma rays (0.55 Gy min-1). Equations for radiation dose received were established based on different combinations of protein biomarkers [i.e. C-reactive protein (CRP), serum amyloid A (SAA), interleukin 6 (IL-6) and Flt3 Ligand (Flt3L)] at samples collection time-points 6 h, 1, 2, 3, 4 and 7 d post-total-body irradiation. Dynamic changes in the levels of CRP, SAA, IL-6 and Flt3L may function as prognostic indicators of the time course and severity of acute radiation sickness (ARS). The combination of protein biomarkers provides greater accuracy for early radiation assessment than any one biomarker alone. © The Author 2014. Published by Oxford University Press. All rights reserved.

Ledney G.D.,Armed forces Radiobiology Research Institute | Elliott T.B.,Armed forces Radiobiology Research Institute
Health Physics | Year: 2010

Combined injuries, which are expected after a radiation dispersal device release or nuclear weapon detonation, are the combination of radiation exposure and tissue injuries from blast and thermal energy. To determine the impact of such trauma, mice were used to (1) evaluate the consequences of skin tissue injuries after various qualities and doses of radiation and (2) document substances that increase survival from radiation injury. Female 12- to 20-wk-old mice weighing 23 ± 3 g received dorsal skin burns or wounds (15% total body skin surface) under methoxyflurane anesthesia before or after irradiation in this study approved by the Armed Forces Radiobiology Research Institute (AFRRI) Institutional Animal Care and Use Committee. Methoxyflurane is analgesic up to 48 h after injury. The radiations used in these studies included Co gamma photons (1.25 MeV) and research-reactor-produced neutrons with an average energy of 0.96 MeV in either an enriched-field [n/(n + γ) = 0.95] configuration at 4.2 kW or a mixed-field [n/(n + γ) = 0.67] configuration operated at 45 kW. Dose rates averaged 0.4 Gy/min. Endpoints included survival, LD50/30s (lethal dose to produce 50% mortality in 30 d), dose modifying factors, relative biological effectiveness values, tissue alterations, susceptibility to bacterial challenge, and countermeasure efficacies. Countermeasures evaluated included S-3-(3-methylaminopropylamino) propylthiophosphorothioic acid (WR-151327), antibiotics, immune modulators, and bone marrow transplantation. Of these treatments, survival was improved by WR-151327, antibiotics, synthetic trehalose discorynomycolate, and bone marrow transplantation. Because trauma to irradiated personnel and medical countermeasures may affect biodosimetric measurements, it will be necessary to quickly determine radiation dose in order to implement appropriate therapy. © 2010 Health Physics Society.

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