Our CMCR is focused on the development of medical countermeasures to assess, diagnose, and treat those exposed to radiation by developing (1) methods for rapid, high throughput assessment or measurement of radiation exposure through both bioassays and instruments, and (2) agents for mitigation and treatment of radiation effects with an emphasis on early and late side effects in non-hematopoietic tissues. Given both the urgent need to develop and validate medical countermeasures to seemingly imminent radiological and nuclear threats, and the dearth of available assessment tools or therapies, our short-term Center goal has been to develop and validate a number of therapeutic agents and radiation exposure assessment devices as quickly as possible, at least to the point of usefulness and availability for an emergency situation. Such a requirement is driven by the need for emergency/disaster response teams to be able to rapidly identify those who are contaminated with radioactive material and reassure those who are not, assess the extent/dose of radiation exposure, and administer appropriate treatment. Our expectation is to accelerate the development of our dosimeters and discriminators (methods of screening for radiation exposure which do not measure dose) as well as 2 or 3 of our most promising therapeutic agents that can be offered to victims (and rescue workers) to mitigate early and/or late non-hematopoietic effects.
PROJECT 1
Project 1 has demonstrated early progress with a number of agents that may prove useful in radiation mitigation and/or treatment. These include EsA as a lung and skin radiation protector, which is undergoing acquisition of intellectual property (international patent). In addition, testing of customized Curcumin analogs and customized FGF analogs has suggested that these agents may provide both protection and mitigation of the acute gastrointestinal syndrome in addition to both early and late cutaneous radiation toxicity.
PROJECT 2
Cytokine profiles using bead arrays have generated a panel of cytokines and growth factors in the C57BL/6 mouse and these may provide information for biodosimetric analysis. Most exciting has been the demonstration that juvenile mice have greatly different responses than their more mature counterparts. This added complexity will be important as we attempt to develop agents that mitigate radiation toxicity for the general population. We believe this to be the first discovered difference in radiobiological marker response in a juvenile population.
PROJECT 3
The instrument at Dartmouth is being cloned so that comprehensive measurements can be made in a clinical situation. This instrument should be ready for routine operation on schedule at the close of year 2. In addition, finger-nail dosimetry using EPR appears promising, and unlike most biological measures is relatively stable in time and available without a lag time. The collection of samples should also be very simple and safe. Thus this approach will be studied further at Dartmouth and concurrently with additional technologies via a pilot project grant at Rochester.
PROJECT 4
The 3-D human bone marrow culture is essential to the support of MN-RET as radiation dose estimate in humans. It holds great promise as an ex vivo culture systems to investigate the potential effects by either mitigating agents or growth factors on human bone marrows.
PROJECT 5
An exciting development has been the detection and characterization of gamma-H2AX foci after irradiation at low doses. These studies can now be done by a number of methods including in vitro and in vivo models.
Recent CBARMFI Communications
After-the-Fact Measurement of Clinically Significant Acute Radiation
Exposures. H.M. Swartz, Y. Sakata, B. Williams, A.
Sucheta, P. Lesniewski, R. Dong, M. Kmiec, E. Demidenko, A. Romanyukha,
P. Starewicz. ASTRO/Radiation Research Society Meeting, Philadelphia,
Pennsylvania. November 4-7, 2006 (oral presentation).
A. Wieser, E. Vasilenko, P. Fattibene, S. Bayankin, N. El-Faramawy,
D. Ivanov, P. Jacob, V. Knyazev, S. Onori, M.C. Pressello, A. Romanyukha,
M. Smetanin and A. Ulanovsky, “Comparison of EPR Occupational
Lifetime External Dose Assessments for Mayak Nuclear Workers and Film
Badge Dose Data.” Radiat Environ Biophys. 44, 279-288 (2006)
A.A. Romanyukha, D.A. Schauer and Y.K. Malikov, “Analysis of Current
Assessments and Perspectives of ESR Tooth Dosimetry for Radiation Dose
Reconstruction of the Population Residing Near the Semipalatinsk Nuclear
Test Site.” J. Radiat. Res. 47, A55-A60 (2006).
Dertinger SD, Hyrien O, Chen Y. Flow cytometric scoring
of radiation-induced micronuclei: reticulocyte- and lymphocyte-based
approaches. Environmental Mutagen Society, Atlanta, Oct. 2007 (invited
lecture).
Dertinger SD, MacGregor JT, Hyrien O, Chen Y. Micronucleated
CD71-positive reticulocytes: A cross-species bridging endpoint. 8th
International Symposium on Chromosomal Aberrations, Awaji Island, Hyogo,
Japan, Oct. 2007 (invited lecture).
Dertinger SD, Miller RK, Brewer K, Smudzin T, Torous DK, Roberts DJ,
Avlasevich SL, Bryce SM, Sugunan S, Chen Y. Automated
human blood micronucleated reticulocyte measurements for rapid assessment
of chromosomal damage. Mutat Res. 2007;626(1-2):111-9.
E. Tielewuhan, K. Tanaka, S. Toyoda, A. Kadoma, S. Endo, A. Romanyukha,
O. Tarasov and M. Hoshi, “90Sr Concentration in Cow Teeth from
South Ural Region, Russia, Using Monte Carlo Simulation.” J. Radiat.
Res. 47, A117-A120 (2006).
J.P. Williams, C. Johnston, E. Hernady, C. Reed, J.N.
Finkelstein. Cytokines and radiation treatment: mitigators
or mitigating targets. 13th International Congress of Radiation Research,
San Francisco, July 8-12, 2007 (invited lecture).
J.P. Williams, E Hernady, C Johnston, C Reed, G Oberdörster,
P Okunieff, JN Finkelstein. Early
alterations in cytokine expression after low dose radiation: markers
or mediators? 53rd Annual meeting of the Radiation Research Society,
Philadelphia, November 5-8, 2006 (oral presentation).
Okunieff P, Xu J, Hu D, Liu W, Zhang L, Morrow G, Pentland
A, Ryan JL, Ding I. Curcumin protects against radiation-induced acute
and chronic cutaneous toxicity in mice and decreases mRNA expression
of inflammatory and fibrogenic cytokines. Int J Radiat Oncol Biol Phys.
2006;65(3):890-8.
R.A. Kleinerman, A.A. Romanyuka, D.A. Schauer, and J.D. Tucker, “Retrospective
Assessment of Radiation Exposure using Biological Dosimetry: Chromosome
Painting, Electron Paramagnetic Resonance and the Glycophorin - A Mutation
Assay.” Radiat. Res. 166, 287-302 (2006).
S. Toyoda, H. Imata, A. Romanyukha and M. Hoshi, “Toward High
Sensitivity ESR Dosimetry of Mammal Teeth: The Effect of Chemical Treatment.”
J. Radiat. Res., 47, A71-A74 (2006).
Xiao Z, Su Y, Yang S, Yin L, Wang W, Yi Y, Fenton BM, Zhang L, Okunieff
P. Protective effect of esculentoside A on radiation-induced
dermatitis and fibrosis. Int J Radiat Oncol Biol Phys. 2006;65(3):882-9.
