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Michael P. Dempsey , PhD, MT(ASCP) Major, USAF, BSC SAFMLS 2010 San Diego, CA 25 MARCH 2010. AFRRI A Unique National Resource Who We Are and What We Do. Presentation Objectives. Provide introduction to AFRRI’s history and mission

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AFRRI A Unique National Resource Who We Are and What We Do


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    1. Michael P. Dempsey, PhD, MT(ASCP) Major, USAF, BSC SAFMLS 2010 San Diego, CA25 MARCH 2010 AFRRIA Unique National Resource Who We Are and What We Do

    2. Presentation Objectives • Provide introduction to AFRRI’s history and mission • Introduce on-going scientific research and education at AFRRI • Describe AFRRI assignment opportunities for DoD laboratory scientists

    3. Established 1960

    4. Background • AFRRI is the only medical nuclear/radiological defense Research and Development Institute in DoD. • We are strategically aligned with the Uniformed Services University of Health Sciences.

    5. The Threat • Accidents • Radiological dispersal devices • Radiation-emitting devices • Nuclear weapons

    6. AFRRI Mission Medical R&D • Conductradiobiology research and develop medical countermeasures for DoD. Medical Education • Trainmedical personnel in ionizing radiation countermeasures. Medical Emergency Response Team • Advise JCS (J-4 Medical), Combatant Commands, and others on radiological matters. Consultation • Answer questions from federal agencies and participate with them as subject matter experts.

    7. AFRRI Research in Radiation Biology

    8. Medical Consequences ofAcute Radiation Injury Gastrointestinal (5-20 Gy) Cardio- vascular Hematopoietic (1-6 Gy) CNS (>20 Gy) Subclinical Increasing Dose

    9. Detonation Casualties

    10. Research Gaps in Medical Preparedness • Countermeasures • The only FDA-approved radioprotectant, amifostine, has toxicity that makes military use not feasible • Biodosimetry • Biodosimetric tools for triage are limited in speed and physiologic predictive power • Mitigation/Therapy • No drug has an FDA-approved indication for radiation-induced hematopoietic or GI injury

    11. Protection Assessment Treatment • Candidate screening • Drug evaluation • Biodosimetry: Cytogenetics and Molecular markers • Automation • Drug evaluation • Combined effects • Heavy metal toxicity Scientific Program SURVIVAL Prophylaxis Therapy

    12. Scientific Functional Schematic Scientific Director Scientific Research Department Radiation Countermeasures Biological Dosimetry Veterinary Sciences Department Radiation Sciences Department Research Support Group Radiation Neutralization Radiation Combined Injury Internal Contamination & Metal Toxicity

    13. Radiation Sciences DepartmentUnique Radiation Facilities

    14. 1 Megawatt TRIGA Mark F Reactor Phillips Industrial X-Ray Facility 100 Curie Cesium Calibration Facility Chronic Irradiation Facility 450,000 Curie Co-60 Panoramic Irradiator

    15. 450 K curies Provides researchers large, uniform gamma-ray fields with a wide array of exposure configurations

    16. Veterinary Sciences DepartmentResources • Animal facility designed to support radiation & surgery studies (32K ft2) • State-of-the-art environmental controls & monitoring • Histopathology, Microbiology, and Clinical Pathology Labs • AAALAC-accredited animal care and use program • Supports AFRRI, SOM, WRAMC, and Navy studies • All protocols IACUC approved

    17. Veterinary Sciences Department Staffing • Currently 27 Staff Members • 4 Veterinarians: Department Head, Laboratory Animal Medicine Resident, Contract Clinical Veterinarian, and Veterinary Pathologist • 5 Veterinary Technicians: 3 Army and 2 Civilian • 12 Government Husbandry Personnel • 3 Pathology Lab Staff (2 GS; 1 Air Force) • 3 Administrative Personnel

    18. Research Support Group • The Research Support Group (RSG) • Formed per recommendations from the Scientific Directorate (SD) strategic planning team. • The transformation to a principal investigator-centric organization allows RSG to provide support to our scientists and minimize the growing demands that keep them out of the laboratory. • RSG staff (5 employees) • Cooperateve Research and Development Agreements (CRDA) • Intramural/extramural proposals (pre & post award), budgets, and Gov’t credit cards. • Works with contracts, equipment/service agreements as well as Good Laboratory Practices (GLP) development. Some of AFRRI’s Extramural Sponsors NIAID, DTRA, NIH, NASA, DARPA, BARDA

    19. Scientific Program Areas

    20. Biological Dosimetry Program • Mission: Todevelop rapid, high-precision methods that determine radiation exposure of radiological casualties for use in triage and medical management addressing: William F. Blakely, PhD Program Advisor • Automation and field deployability for rapid battlefield dose assessment • Enhancement of reference biodosimetry capability • Identification and validation of radiation specific biomarkers for early phase, organ-specific, and late effects. Website for research program: http://www.afrri.usuhs.mil/research/biodos.htm Website for biodosimetry tools: http://www.afrri.usuhs.mil/outreach/biodostools.htm

    21. Focus Areas and Staffing • Identification, optimization, and validation of integrated biodosimetry assays for military and civilian applications with the following emphases: • Development of medical recording and software-based applications to manage radiation dose and injury assessment • Characterization of prodromal clinical signs and symptoms for radiation exposure diagnostics • Automation of cytogenetic assays for radiation dose assessment • Identification of radiation bioassays using i) nucleic-acid based methodology and ii) for early-expressed and persistent radiation late effects • Combined use of hematology biomarkers with clinical signs/symptoms for radiation dose assessment • Validation of blood proteomic, metabeolomic, and urinary biomarkers for early-phase and organ-specific radiation injury and dose assessment • Integration of multi-parameter early-phase clinical biodosimetry • Staff: 3 primary and 3 associated PIs, 1 doctoral level Investigator, 2 Programmers, 2 Postdocs, 2 masters level Research Associates, 2 primary and 2 associated Laboratory Technicians, 2 volunteers (Total: 19)

    22. Recent Accomplishments • Patents and IDE • U.S. patent filed (March 2009); international patent filed (October 2009) • Pre-IDE meeting with FDA (regulation of automated sample processing for cytogenetic dose assessment) • Other • Medical Communications for Combat Casualty Care (MC4) deployed AFRRI’s BAT software application to CONUS and OCONUS (see website: www.mc4.army.mil). • In 2010, 3 of 9 BARDA contract awardees collaborating with AFRRI scientists on a radiation-responsive proteomic diagnostic concept for rapid & early-phase biodosimetry device(s). • Participation in international cytogenetic biodosimetry inter-comparison study and the development of a cytogenetic network concept to enhance sample analysis from a mass-casualty radiological incident. • In 2009 AFRRI BD scientists established a nonhuman-primate radiation dose-response model at AFRRI for the purpose of validating candidate novel and multiple biodosimetry assays, critical for obtaining necessary FDA approvals. • Additional products and accomplishments of the AFRRI’s BD Research Group are available at website: www.afrri.usuhs.mil/research/biodos.htm

    23. Selected Recent Publications • Ossetrova NI et al. (2010) Combined approach of hematological biomarkers and plasma protein SAA for improvement of radiation dose assessment in triage biodosimetry applications. Health Physics 98(2):204–8. • Prasanna PGS et al. (2010). Triage dose assessment for partial-body exposure: Dicentric analysis. Health Physics 98(2):244–51. • Blakely WF, Ossetrova NI et al. (2010) Multiple parameter radiation injury assessment using a nonhuman primate radiation model—biodosimetry applications. Health Physics 98(2):153–9. • Prasanna PGS, Blakely WF et al. (2010) Synopsis of partial-body radiation diagnostic biomarkers and medical management of radiation injury workshop. Radiation Research 173(2):245–53. • Ossetrova NI, Blakely WF (2009) Multiple blood-proteins approach for early-response exposure assessment using an in vivomurine radiation model. International Journal of Radiation Biology 85(10):837–850. • Blakely WF, Carr Z et al. (2009) WHO 1st Consultation on the Development of a Global Biodosimetry Laboratories Network for Radiation Emergencies (BioDoseNet). Radiation Research 171(1):127–139. • Waller E, Millage K, Blakely WF et al. (2009) Overview of hazard assessment and emergency planning software of use to RN first responders. Health Physics, 97(2):145–156. • Pathak R, Ramakumar A, Subramanian U, Prasanna PG. (2009) Differential radio-sensitivities of human chromosomes 1 and 2 in one donor in interphase- and metaphase-spreads after 60Co gamma-irradiation. BMC Medical Physics 9:6 8-pages (open access journal, website: www.biomedcentral.com/1756-6649/9/6).

    24. Radiation Countermeasures Program • Mission: To develop pharmacological countermeasures to radiation injury that can be used by • Military personnel and • Emergency responders Mark H Whitnall, PhD Program Advisor

    25. Focus Areas and Staffing • Developing radiation countermeasure drugs in 8 individual research programs with the following emphases: • Gamma-Tocotrienol, Intracellular Signaling, Screening Drugs with In Vivo Mouse Model • Ex-Rad, Gamma-Tocotrienol, Intracellular Signaling • Genistein, BIO300, In Vivo Hematopoiesis • Cancer prevention, Intracellular Signaling • Alpha-Tocopherol Succinate, CBLB502, Myeloid Progenitor Cells, Cytokine Expression • Delta-Tocotrienol, SOD Mimetic, TPO Mimetic, Screening Drugs with In Vivo Mouse Model, Mitochondrial Metabolism • In Vitro Hematopoietic Niche Model, Intracellular Signaling, Neutron/Gamma Fields, Minipig Model for Drug Development • In Vitro Hematopoietic Niche Model, Delta-Tocotrienol, Intracellular Signaling, In Vivo Hematopoiesis • Staff: 8 PIs, 11 Doctoral Level Investigators, 1 Masters Level Investigator, 25 Laboratory Technicians, 1 Intern, 2 Administrative (Total: 48)

    26. A B Intracellular Signaling Pathways: DT3 TPO Mimetic Enhances Survival in Mice DT3 AKT ERK Radiation X mTOR Survival (%) P 4EBP S6K eIF4E A: 30 day mouse survival after whole-body gamma-irradiation: Effect of a thrombopoietin (TPO) mimetic (sc, 24 h before irradiation). B: Intracellular signaling pathways modulated by Delta-Tocotrienol (DT3). C: Mouse bone marrow, 8 days after whole-body gamma irradiation (7 Gy). D: As in C, but mouse treated with Alpha-Tocopherol Succinate (sc, 24 h before irradiation). S6 Protein translation Cell survival and growth Time Post-Irradiation (Days) C D

    27. Recent Accomplishments • Patent approval: Landauer et al., “Phytoestrogenic isoflavone compositions … for protection against and treatment of radiation injury” • Other • Developed minipig model for advanced radiation countermeasure development • Integrated mechanistic and applied research with advanced drug development • Working with companies to pursue advanced development of countermeasure candidates (large animal trials, attend FDA meetings, etc.) • All four radiation countermeasures with FDA IND status are AFRRI products

    28. Selected Recent Publications • Merlot R, Huang G, Houpert H, Miller AC, Lison P. The Inhibitory Action of Epigallocatechin gallate, a DNA Methyltransferase Inhibitor, on Neoplastic Transformation. Anti-Cancer Research. Epub Mar 1, 2010 • Singh VK, Brown DS, Kao TC: Alpha-tocopherol succinate protects mice from gamma-radiation by induction of granulocyte-colony stimulating factor. Int J Rad Biol. 86: 12-21, 2010. • Ghosh SP, Kulkarni S, Hieber K, Toles R, Romanyukha L, Kao TC, Hauer-Jensen M, Kumar KS. Gamma-tocotrienol, a tocol antioxidant as a potent radioprotector. Int J Radiat Biol 85: 598-606, 2009. • Singh VK, Grace MB, Parekh VI, Whitnall MH, Landauer MR: Effects of genistein administration on cytokine induction in whole-body gamma irradiated mice. Int Immunopharmacol. 9: 1401-1410, 2009. • Xiao M, Inal CE, Parekh VI, Li XH, Whitnall MH. Role of NF-kappaB in hematopoietic niche function of osteoblasts after radiation injury. Exp Hematol 37: 52-64, 2009. • Srinivasan V, Doctrow S, Singh VK, Whitnall MH. Evaluation of EUK-189, a synthetic superoxide dismutase/catalase mimetic as a radiation countermeasure. Immunopharmacol Immunotoxicol 30: 271-290, 2008.

    29. Radiation Combined Injury Program Mission: To develop medical treatments for irradiated personnel whose exposure is compounded by traumatic wounds, burns, hemorrhage, and/or infection. Treatment strategies under investigation include biological response modifiers, new antimicrobial agents, probiotics, and stem cells, used individually or in combination. Juliann G. Kiang, PhD Program Advisor

    30. Focus Areas and Staffing Recent Accomplishments • Two patents and one MTA • Developing radiation countermeasure drugs in 6 individual research programs with the following emphases: • 17-DMAG, Intracellular Signaling, Screening Drugs with Mouse Model and In Vitro Model • ARA290, S-TDCM combined with levofloxacin, and Bone Marrow Mesenchymal Stem Cells, Screening Drugs with Mouse Model • A Novel In Vivo Combined Injury Model to be established • Levofloxacin, Pharmacodynamics and Pharmacokinetics • Staff: 3 PIs, 3 military officers, 5 Doctoral Level Investigators, 1 Master Level Investigator, 6 Laboratory Technicians, 3 Interns (Total: 21)

    31. A. Survival % Survival Postirradiation (Days) D. IL-6 B. Wound C. CI IL-6 (pg/ml) ** * * Postirradiation (Days) B6D2F1 mice received 9.75 Gy Co-60 gamma irradiation followed by body surface wounding. B. A good size of the healing bud in wounded area. C. Irradiation reduces the healing bud in wounded area, causes degeneration of adipocytes, and eliminates neutrophils and macrophages. D. Wounding enhances irradiation-induced increases in IL-6 levels. A.B6D2F1/J mice received 8.5 or 9.75 Gy Co-60 gamma irradiation followed by 15% total body surface area wounding. The survival in % 30 days after irradiation or irradiation+wounding: Sham -100%; Wound - 100%; 8.5 Gy - 100%; 8.5 Gy+Wounding -70%; 9.75 Gy – 60%; 9.75 Gy+wounding - 10%

    32. Selected Recent Publications Kiang JG, Garrison BR, Gorbunov NV. Radiation combined injury: DNA damage, apoptosis, and autophagy. Adapt Med 2: 000-000, 2010 (in press). Kiang JG, Jiao W, Cary L, Mog SR, Elliott TB, Pellmar TC, Ledney GD. Wound trauma increases radiation-induced mortality by increasing iNOS, cytokine concentrations, and bacterial infections. Radiate Res 173: 000-000, 2010 (in press). Kiang JG, Smith JA, and Agravante NG. Geldanamycin analog 17-DMAG inhibits iNOS and caspases in gamma irradiated human T cells. Radiat Res 172: 321-330, 2009. Gorbunov NV, Kiang JG. Up-regulation of Autophagy in the Small Intestine Paneth Cell in Response to Total-Body γ-Irradiation. J Pathol 219: 242-252, 2009. Jiao W, Kiang JG, Cary L, Elliott TB, Pellmar TC, Ledney GD. COX-2 inhibitors are contraindicated for therapy of combined injury. Radiat Res 172: 686-697, 2009. Ledney GD, Elliott TB. Combined injury: factors with potential to impact radiation dose assessments. Health Phys 98:145-152, 2009.

    33. Internal Contamination and Metal Toxicity Program Mission: To determine whether the short-term and long-term radiological and toxicological risks of embedded metals warrant changes in the current combat and postcombat fragment removal policies for military personnel and, in the case of internalized radiological hazards, investigate treatment strategies to enhance elimination of these metals from the body. John F. Kalinich, Ph.D. Program Advisor

    34. Focus Areas and Staffing • Health effect of embedded metal fragments, including DU and tungsten alloy, with a focus on carcinogenicity and transgenerational effects. • Identification of biomarkers of exposure to internalized radionuclides and development of high-throughput analytical systems. • Decorporation procedures for the enhanced elimination of radionuclides from the body as a result of a nuclear explosion or “dirty bomb” event. Staff: 2 PIs, 2 Research Associates, 2 Lab Technicians

    35. A B Photomicrograph of J774 cells untreated (Panel A) or treated with depleted uranium (Panel B) for 24 h then stained with 2-(5-bromo-2-pyridylazo)-5-diethylaminophenol to indicate uranium deposits.

    36. Selected Recent Publications • Military Medicine 174: 265-269 (2009) • Biochemie 91: 1328-1330 (2009) • Toxicology In Vitro 23: 356-359 (2009) • Military Medicine 173: 754-758 (2008) • Radiation Measurements 42: 1029-1032 (2007) • Reviews on Environmental Health 22: 75-89 (2007) • Environmental Health Perspectives 113: 729-734 (2005) • Molecular and Cellular Biochemistry 279: 97-104 (2005)

    37. Radiobiology Education and Training Opportunities • USU Department of Radiation Biology – PhD program coming • PhD in Molecular and Cellular Biology: Radiation Biology track • Operational Support Training: MEIR

    38. Operational Support Training Medical Effects of Ionizing Radiation Course • CME / CNE /CHE credit • Required training for contingency personnel • Target Audience • Physicians • Nurses • Medical Response Personnel • 30 - 40 courses presented worldwide annually with approximately 1000 individuals trained • Courses are customizable (1-day focused courses)

    39. AFRRI CIVILIAN PERSONNEL SUMMARY *Onboard totals as of 3/1/10 **30 under contract, 18 under grants

    40. AFRRI Authorized Military Billets *Onboard totals as of 3/1/10

    41. Types of Military and Civilian Positions

    42. Perspectives of an AFRRI Enlisted Military Lab Technician HM2(SW) Sergio Gallego

    43. AFFRI’s Opportunities • Opportunity to contribute to the DoD’s effort in finding means to counter the effects of ionizing radiation. • Be part of developing new protocol/testing procedures to be used in the future, out in the field environment or in combat setting. • Learn how to perform research and understand the different stages of research while working with world renowned scientists.

    44. AFRRI’s Opportunities (con’t) • Learn new laboratory procedures and operate highly sophisticated equipment not normally available in basic clinical lab setting: - Protein assays / Western Blots - PCR/Molecular biology procedure – Bio Rad IQ5 - Cell counting / Flow Cytometry – Guava 8HT - Automated RNA isolation & purification – Qiagen Bio Robot 8000 - Immunohistochemical staining - Stem Cell Isolation and culture (bone marrow)

    45. AFRRI’s Uniqueness • Perform various veterinary procedures such as obtaining tissue/fluid samples and administering therapeutics. • Perform animal survival studies and irradiate experimental animals using different radiation sources. • See the stages of your work as it progresses from start to end.

    46. Operations Bushmaster and Kerkesner • This field exercise is unique to USU's medical school curriculum and is designed to ensure that USU graduates are well prepared to practice "good medicine in bad places." • Students are trained to deal with wartime casualties, national disasters, emerging infectious diseases and other public health emergencies.

    47. Why AFRRI? • Tri-Service Experience • Joint Service/DoD Awards • Continuing Education Opportunities • USUHS Affiliation • WRNMMC as MHS epicenter in 2011 • DC and surrounding area, including NIH

    48. Acknowledgements COL Patricia Lillis-Hearne Director COL Donald Hall Deputy Director Dr. Christopher Lissner Interim Scientific Director CDR John Gilstad Head, Scientific Research Dept. MAJ Larry Shelton Head, Veterinary Science Dept. Mr. Steve Miller Head, Radiation Science Dept. LT Matthew Deshazo Head, Admin Support Dept. SAFMLS Presentation Team: Maj Michael Dempsey CPT Nabil Latif CPT Anthony Kang HM1 Neal Agravante HM2 Sergio Gallego For more information go to: www.afrri.usuhs.mil

    49. AFRRI STAFF