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. Synthesis and use patents for D12, D13, and D68 had their 1-year finalization in May 2008 and a disclosure has been sent for the synthesis and use of FGF-P and a patent has been applied for.
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. Our top accomplishment in 2008 involves the initial studies using radioactive cesium particles. These studies were logistically difficult to begin, but in collaboration with our Radiation Safety personnel, the distribution and elimination of injected particles has been assessed, and tissues, including blood, are being analyzed. Data suggests that this model may have additional utility for evaluating bone marrow effects.
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. The most significant accomplishment in 2008 was reaching an understanding of the nature and characteristics of the mechanically induced signal in fingernails, which should make it more feasible to utilize fingernails as dosimeters.
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. The major accomplishments in 2008 were (1) three potential deliverables as described, (2) elucidating the mechanism of radiation injury to erythroid progenitor and precursor cells by the in vivo and ex vivo comparisons in C57BL/6 mice, and (3) elucidating the cell kinetics of precursor and progenitor cells in human bone marrow using the 3-D culture system for human bone marrow.
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. The top accomplishments of 2008 were the elucidation of a dose response relationship for the micronucleus (MN) assay and, significantly, the development of robust technique for in vivo analysis of IRIF
Recent CBARMFI Communications
CBARMFI Publications (2007-present)
1. Bristow RG, Hill RP. Hypoxia and metabolism. Hypoxia, DNA repair
and genetic instability. Nat Rev Cancer. 2008 Mar;8(3):180-92.
2. Robert G. Bristow, Hilmi Ozcelik, Farid Jalali, Norman Chan and Danny
Vesprini. Homologous Recombination and Prostate Cancer: Prostate Cancer
as a Model for Novel DNA Repair Targets and Therapies. Radiother Oncol
2007 Jun; 83(3): 220-30.
3. Norman Chan, Michael Milosevic, Robert Bristow. Hypoxia, DNA Repair
and Prostate Cancer: New targets and New Strategies. Future Oncol 2007
Jun; 3(3): 329-41.
4. Demidenko E, Williams BB, Sucheta A, Dong R, Swartz HM. Radiation
dose reconstruction from L-band in vivo EPR spectroscopy of intact teeth:
Comparison of methods. Radiat Meas. 2007 Jul;42(6-7):1089-1098.
5. 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.
6. Dertinger SD, Tsai Y, Nowak I, Hyrien O, Sun H, Bemis JC, Torous
DK, Keng P, Palis J, Chen Y. Reticulocyte and micronucleated reticulocyte
responses to gamma irradiation: dose-response and time-course profiles
measured by flow cytometry. Mutat Res 634:119-125, 2007.
7. DiCarlo AL, Hatchett RJ, Kaminski JM, Ledney GD, Pellmar TC, Okunieff
P, Ramakrishnan N. Medical countermeasures for radiation combined injury:
radiation with burn, blast, trauma and/or sepsis. report of an NIAID
Workshop, March 26-27, 2007. Radiat Res. 2008 Jun;169(6):712-21.
8. Flood AB, Bhattacharyya S, Nicolalde RJ, Swartz HM. Implementing
EPR Dosimetry for Life-Threatening Incidents: Factors Beyond Technical
Performance. Radiat Meas. 2007 Jul;42(6-7):1099-1109.
9. Fujii H, Sakata K, Katsumata Y, Sato R, Kinouchi M, Someya M, Masunaga
S, Hareyama M, Swartz HM, Hirata H. Tissue oxygenation in a murine SCC
VII tumor after X-ray irradiation as determined by EPR spectroscopy.
Radiother Oncol. 2008 Mar;86(3):354-60.
10. Gurung A, Uddin F, Hill RP, Ferguson PC, Alman BA. Beta-catenin
is a mediator of the response of fibroblasts to irradiation. Am J Pathol.
2009 Jan;174(1):248-55.
11. Carl J. Johnston, Eric Hernady, Christina Reed, Bruce M. Fenton,
Jacob N. Finkelstein, Jacqueline P. Williams. Role of IL-1 and inflammatory
cell recruitment in radiation-induced pulmonary late effects. 2009.
Submitted to Radiation Research. Under revision.
12. Carl J. Johnston, Eric Hernady, Christina Reed, Sally Thurston,
Jacob N. Finkelstein, and Jacqueline P. Williams, Ph.D. Early alterations
in pulmonary interleukin expression: surrogate markers in adult versus
children following a terrorist event. 2009. Submitted to International
Journal of Radiation Oncology, Biology and Physics. Under review.
13. Carl Johnston, Eric Hernady, Christina Reed, Sally Thurston, Thomas
Morgan, Jacqueline P. Williams, Jacob N. Finkelstein. Pulmonary response
to internal contamination: a model for a RDD. Submitted to 54th Annual
Meeting of Radiation Research Society, Boston, September 20-24, 2008.
14. R. P Hill. P. Kaspler, A.M. Griffin, B. O’Sullivan, C. Catton,
H. Alasti, A Abbas, M Heydarian, P. Ferguson, J.S. Wunder and R. S.
Bell. Studies of the in vivo radiosensitivity of human skin fibroblasts.
Radiother Oncol. 2007 Jul; 84(1): 75-83.
15. Ibragimova MI, Petukhov VY, Zheglov EP, Khan N, Hou H, Swartz HM,
Konjukhov GV, Nizamov RN. Quinoid radio-toxin (QRT) induced metabolic
changes in mice: an ex vivo and in vivo EPR investigation. Nitric Oxide.
2008 May;18(3):216-22.
16. Mishra KP, Ahmed M, Hill RP. Low-dose radiation effects on human
health with implications to radioprotection and cancer radiotherapy.
Int J Radiat Biol. 2008 May;84(5):441-4.
17. Okunieff P, Yuhchyau Chen, David J. Maguire, Amy K. Huser. Molecular
Markers of Radiation-related Normal Tissue Toxicity. Clinical and Metastasis
Reviews. 2008 Sep;27(3):363-74.
18. Okunieff P, Swarts S, Keng P, Sun W, Wang W, Kim J, Yang S, Zhang
H, Liu C, Williams JP, Huser AK, Zhang L. Antioxidants reduce consequences
of radiation exposure. Adv Exp Med Biol 2008; 614: 165-78.
19. Pintilie M, Iakovlev V, Fyles A, Hedley D, Milosevic M, Hill RP.
Heterogeneity and Power in Clinical Biomarker Studies. J Clin Oncol.
2009 Feb 9. [Epub ahead of print]
20. Reyes RA, Romanyukha A, Trompier F, Mitchell CA, Clairand I, De
T, Benevides LA, Swartz HM. Electron paramagnetic resonance in human
fingernails: the sponge model implication. Radiat Environ Biophys. 2008
Nov;47(4):515-26.
21. Romanyukha A, Mitchell CA, Schauer DA, Romanyukha L, Swartz HM.
Q-band EPR biodosimetry in tooth enamel microsamples: feasibility test
and comparison with x-band. Health Phys. 2007 Dec;93(6):631-5.
22. Romanyukha A, Trompier F, Leblanc B, Calas C, Clairand I, Mitchell
CA, Smirniotopoulos JG, Swartz HM. EPR dosimetry in chemically treated
fingernails. Radiat Meas. 2007 Aug;42(6-7):1110-1113.
23. Sato, B.A. Filas, S.S. Eaton, G.R. Eaton, A.A. Romanyukha, R. Hayes,
and A.M. Rossi, “Electron Spin Relaxation of Radicals in Irradiated
Tooth Enamel and Synthetic Hydroxyapatite.” Radiation Measurements.
In Press (2007).
24. D.A. Schauer, A. Iwasaki, A.A. Romanyukha, H.M. Swartz and S. Onori,
"Electron Paramagnetic Resonance (EPR) in Medical Dosimetry,"
Radiation Measurements. In Press (2007).
25. S.L. Simon, I. Bailiff, A. Bouville, P. Fattibene, R.A. Kleinerman,
D.C. Lloyd, S.W.S. McKeever, A. Romanyukha, A.V. Sevan'kaev, J.D. Tucker,
“Methods to Evaluate Radiation Doses at Long Times After Exposure.”
Radiation Measurements. In Press (2007).
26. Su Y, Yang S, Xiao Z, Wang W, Okunieff P, Zhang L. Triptolide alters
mitochondrial functions. Adv Exp Med Biol. 2007;599:139-46.
27. Sun W, Wang W, Kim J, Keng P, Yang S, Zhang H, Liu C, Okunieff P,
Zhang L. Anti-cancer effect of resveratrol is associated with induction
of apoptosis via a mitochondrial pathway alignment. Adv Exp Med Biol
2008; 614: 179-86.
28. Swartz HM, Burke G, Coey M, Demidenko E, Dong R, Grinberg O, Hilton
J, Iwasaki A, Lesniewski P, Kmiec M, Lo KM, Nicolalde RJ, Ruuge A, Sakata
Y, Sucheta A, Walczak T, Williams BB, Mitchell C, Romanyukha A, Schauer
DA. In Vivo EPR For Dosimetry. Radiat Meas. 2007 Jul;42(6-7):1075-1084.
29. Trompier F, Kornak L, Calas C, Romanyukha A, Leblanc B, Mitchell
CA, Swartz HM, Clairand I. Protocol for emergency EPR dosimetry in fingernails.
Radiat Meas. 2007 Aug;42(6-7):1085-1088.
30. Veenema TG, Walden B, Feinstein N, Williams JP. Factors affecting
hospital-based nurses' willingness to respond to a radiation emergency.
Disaster Med Public Health Prep. 2008 Dec;2(4):224-9.
31. Williams BB, Sucheta A, Dong R, Sakata Y, Iwasaki A, Burke G, Grinberg
O, Lesniewski P, Kmiec M, Swartz HM. Experimental Procedures for Sensitive
and Reproducible In Situ EPR Tooth Dosimetry. Radiat Meas. 2007 Jul;42(6-7):1094-1098.
32. Zhang, Hengshan, Steven B. Zhang, Weimin Sun, Shanmin Yang, Mei
Zhang, Wei Wang, Chaomei Liu, Kunzhong Zhang, Steven Swarts, , Bruce
M. Fenton, Peter Keng, David Maguire, Paul Okunieff, and Lurong Zhang.
B1 Sequence-based real-time Quantitative PCR: A sensitive method for
direct measurement of mouse plasma DNA levels after gamma irradiation.
Revision under review: Int J Radiat Oncol Biol Phys (2009).
