LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

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18 S. Ghosh et al. / Mutation Research 716 (2011) 10–19 Since, with high LET radiation yield of ROS is very low as compared to low LET radiation [38–40], the early activation of ERK was not expected with high LET radiation. However, complete absence of ERK activation even hours after high LET radiation suggests that repair pathways are neither feeding into nor being fed upon by intracellular cytoprotective signaling. However, the pro-apoptotic JNK pathway was found to be activated after high LET radiation. BRCA1 induced apoptotic responses have also been shown to be via activation of JNK [41]. Thus, after carbon irradiation, DNA damage induced activation of repair components are being fed into by cytotoxic signaling rather than cytoprotective responses and was evident in the form of early induction of apoptosis (Fig. 8). Since, cellular decisions are summation of all the activated pathways, the final response after high LET radiation tips towards death. 5. Conclusions In summary, our results suggest that the subtle differences leading to different outcomes due to radiation quality seem to lie in different macromolecular complexes of crucial DNA damage response proteins and activation of other intracellular pathways in A549 lung adenocarcinoma cell line. Analysis of functionality of these macromolecular complexes as a whole rather than individual proteins and holistic study involving intracellular survival pathways could help in revealing the mechanistic details of complex DNA damage responses. Conflict of interest The authors declare that there are no conflicts of interest. Acknowledgments This work was funded by Board of Research in Nuclear Sciences, Department of Atomic Energy [DAE], Government of India, through a project sanctioned to one of the authors, A. Sarma, bearing sanction number 2007/37/37/BRNS. All the authors are thankful to the Director, IUAC, New Delhi for providing radiation facility for the work. We would also like to extend our thanks to all the members of Pelletron group of IUAC and Harminder Kaur, Radiation Biology Laboratory, IUAC for their sincere help during irradiation. Authors would like to thank Mr. Manjoor Ali and Mr. Paresh Khadilkar, RB&HSD, BARC for their help in Confocal Microscopy and Lab work respectively. References [1] F.A. Cucinotta, M. Durante, Cancer risk from exposure to galactic cosmic rays: implications for space exploration by human beings, Lancet Oncol. 7 (2006) 431–435. [2] F.A. Cucinotta, H. Wu, M.R. Shavers, K. George, Radiation dosimetry and biophysical models of space radiation effects, Gravit. Space Biol. Bull. 16 (2003) 11–18. [3] D.T. Goodhead, The initial physical damage produced by ionizing radiations, Int. J. Radiat. Biol. 56 (1989) 623–634. [4] F.A. Cucinotta, H. Nikjoo, D.T. Goodhead, Model for radial dependence of frequency distributions for energy imparted in nanometer volumes from HZE particles, Radiat. Res. 153 (2000) 459–468. [5] E.A. Blakely, A. Kronenberg, Heavy-ion radiobiology: new approaches to delineate mechanisms underlying enhanced biological effectiveness, Radiat. Res. 150 (1998) S126–S145. [6] F.A. Cucinotta, R. Katz, J.W. Wilson, Radial distribution of electron spectra from high-energy ions, Radiat. Environ. Biophys. 37 (1998) 259–265. [7] B.M. Sutherland, P.V. Bennett, O. Sidorkina, J. Laval, Clustered DNA damages induced in isolated DNA and in human cells by low doses of ionizing radiation, Proc. Natl. Acad. Sci. U.S.A. 97 (2000) 103–108. [8] B. Rydberg, B. Cooper, P.K. Cooper, W.R. Holley, A. Chatterjee, Dose-dependent misrejoining of radiation-induced DNA double-strand breaks in human fibroblasts: experimental and theoretical study for high- and low-LET radiation, Radiat. Res. 163 (2005) 526–534. [9] D. Schulz-Ertner, A. Nikoghosyan, C. Thilmann, T. Haberer, O. Jakel, C. Karger, G. Kraft, M. Wannenmacher, J. Debus, Results of carbon ion radiotherapy in 152 patients, Int. J. Radiat. Oncol. Biol. Phys. 58 (2004) 631–640. [10] T. Miyamoto, N. Yamamoto, H. Nishimura, M. Koto, H. Tsujii, J.E. Mizoe, T. Kamada, H. Kato, S. Yamada, S. Morita, K. Yoshikawa, S. Kandatsu, T. Fujisawa, Carbon ion radiotherapy for stage I non-small cell lung cancer, Radiother. Oncol. 66 (2003) 127–140. [11] S.P. Jackson, Sensing and repairing DNA double-strand breaks, Carcinogenesis 23 (2002) 687–696. [12] E.P. Rogakou, D.R. Pilch, A.H. Orr, V.S. Ivanova, W.M. Bonner, DNA doublestranded breaks induce histone H2AX phosphorylation on serine 139, J. Biol. Chem. 273 (1998) 5858–5868. [13] O. Fernandez-Capetillo, A. Lee, M. Nussenzweig, A. Nussenzweig, H2AX: the histone guardian of the genome, DNA Repair (Amst.) 3 (2004) 959–967. [14] N. Desai, E. Davis, P. O’Neill, M. Durante, F.A. Cucinotta, H. Wu, Immunofluorescence detection of clustered gamma-H2AX foci induced by HZE-particle radiation, Radiat. Res. 164 (2005) 518–522. [15] L.J. Chappell, M.K. Whalen, S. Gurai, A. Ponomarev, F.A. Cucinotta, J.M. Pluth, Analysis of flow cytometry DNA damage response protein activation kinetics after exposure to X rays and high-energy iron nuclei, Radiat. Res. 174 (2010) 691–702. [16] M.K. Whalen, S.K. Gurai, H. Zahed-Kargaran, J.M. Pluth, Specific ATM-mediated phosphorylation dependent on radiation quality, Radiat. Res. 170 (2008) 353–364. [17] R. Ugenskiene, K. Prise, M. Folkard, J. Lekki, Z. Stachura, M. Zazula, J. Stachura, Dose response and kinetics of foci disappearance following exposure to highand low-LET ionizing radiation, Int. J. Radiat. Biol. 85 (2009) 872–882. [18] K. Valerie, A. Yacoub, M.P. Hagan, D.T. Curiel, P.B. Fisher, S. Grant, P. Dent, Radiation-induced cell signaling: inside-out and outside-in, Mol. Cancer Ther. 6 (2007) 789–801. [19] S.E. Golding, E. Rosenberg, S. Neill, P. Dent, L.F. Povirk, K. Valerie, Extracellular signal-related kinase positively regulates ataxia telangiectasia mutated, homologous recombination repair, and the DNA damage response, Cancer Res. 67 (2007) 1046–1053. [20] K.E. Keating, N. Gueven, D. Watters, H.P. Rodemann, M.F. Lavin, Transcriptional downregulation of ATM by EGF is defective in ataxia-telangiectasia cells expressing mutant protein, Oncogene 20 (2001) 4281–4290. [21] N. Weizman, Y. Shiloh, A. Barzilai, Contribution of the ATM protein to maintaining cellular homeostasis evidenced by continuous activation of the AP-1 pathway in ATM-deficient brains, J. Biol. Chem. 278 (2003) 6741–6747. [22] A. Asaithamby, N. Uematsu, A. Chatterjee, M.D. Story, S. Burma, D.J. Chen, Repair of HZE-particle-induced DNA double-strand breaks in normal human fibroblasts, Radiat. Res. 169 (2008) 437–446. [23] A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu, T. Murray, M.J. Thun, Cancer statistics, CA Cancer J. Clin. 58 (2008) 71–96. [24] S. Ghosh, N.N. Bhat, S. Santra, R.G. Thomas, S.K. Gupta, R.K. Choudhury, M. Krishna, Low energy proton beam induces efficient cell killing in A549 lung adenocarcinoma cells, Cancer Invest. 28 (2010) 615–622. [25] J.F. Ziegler, M.D. Ziegler, J.P. Biersack, SRIM – The stopping and range of ions in matter, Nucl. Instrum. Meth. B 268 (2010) 1818–1823. [26] H. Narang, M. Krishna, Effect of nitric oxide donor and gamma irradiation on MAPK signaling in murine peritoneal macrophages, J. Cell. Biochem. 103 (2008) 576–587. [27] W.S. Rasband, ImageJ, U.S. National Institutes of Health, Bethesda, USA, 1997–2006, http://rsb.info.nih.gov/ij/. [28] K.M. Prise, M. Pinto, H.C. Newman, B.D. Michael, A review of studies of ionizing radiation-induced double-strand break clustering, Radiat. Res. 156 (2001) 572–576. [29] F.A. Cucinotta, J.M. Pluth, J.A. Anderson, J.V. Harper, P. O’Neill, Biochemical kinetics model of DSB repair and induction of gamma-H2AX foci by nonhomologous end joining, Radiat. Res. 169 (2008) 214–222. [30] S. Ghosh, H. Narang, A. Sarma, H. Kaur, M. Krishna, Activation of DNA damage response signaling in lung adenocarcinoma A549 cells following oxygen beam irradiation, Mutat. Res. 723 (2011) 190–198. [31] A.L. Ponomarev, S.V. Costes, F.A. Cucinotta, Stochastic properties of radiationinduced DSB: DSB distributions in large scale chromatin loops the HPRT gene and within the visible volumes of DNA repair foci, Int. J. Radiat. Biol. 84 (2008) 916–929. [32] E.R. Foster, J.A. Downs, Histone H2A phosphorylation in DNA double-strand break repair, FEBS J. 272 (2005) 3231–3240. [33] N.F. Lowndes, G.W. Toh, DNA repair: the importance of phosphorylating histone H2AX, Curr. Biol. 15 (2005) R99–R102. [34] K.H. Karlsson, B. Stenerlow, Focus formation of DNA repair proteins in normal and repair-deficient cells irradiated with high-LET ions, Radiat. Res. 161 (2004) 517–527. [35] S.E. Golding, E. Rosenberg, A. Khalil, A. McEwen, M. Holmes, S. Neill, L.F. Povirk, K. Valerie, Double strand break repair by homologous recombination is regulated by cell cycle-independent signaling via ATM in human glioma cells, J. Biol. Chem. 279 (2004) 15402–15410. [36] A.L. Ponomarev, J. Huff, F.A. Cucinotta, The analysis of the densely populated patterns of radiation-induced foci by a stochastic, Monte Carlo model of DNA double-strand breaks induction by heavy ions, Int. J. Radiat. Biol. 86 (2010) 507–515. [37] C.X. Deng, BRCA1: cell cycle checkpoint genetic instability, DNA damage response and cancer evolution, Nucleic Acids Res. 34 (2006) 1416–1426.
S. Ghosh et al. / Mutation Research 716 (2011) 10–19 19 [38] A. Kuppermann, Diffusion kinetics in radiation chemistry: an assessment, in: R.D. Cooper, R.W. Wood (Eds.), Physical Mechanisms in Radiation Biology, Springfield, Virginia, 1974, pp. 155–183. [39] D.E. Watt, Absolute biological effectiveness of neutrons and photons, Radiat. Prot. Dosim. 23 (1988) 63–67. [40] M. Spotheim-Maurizot, M. Charlier, R. Sabattier, DNA radiolysis by fast neutrons, Int. J. Radiat. Biol. 57 (1990) 301–313. [41] S. Lafarge, V. Sylvain, M. Ferrara, Y.J. Bignon, Inhibition of BRCA1 leads to increased chemoresistance to microtubule-interfering agents, an effect that involves the JNK pathway, Oncogene 20 (2001) 6597–6606.
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RADIATION INDUCED SIGNALING IN MAMM
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DECLARATION I, hereby declare that
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CONTENTS Page No. SYNOPSIS………
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2.11 Measurement of NO production
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PREAMBLE SYNOPSIS Ionising radiatio
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SYNOPSIS Aims and Objectives: To St
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SYNOPSIS 2.6 Immunofluorescence sta
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SYNOPSIS ATM gene expression, which
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SYNOPSIS Percentage Survival 100 80
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SYNOPSIS Ratio of Rad52 to Actin Ra
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Relative Phosphorylation 45 40 35 3
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SYNOPSIS Fig. 3.3A Clonogenic Cell
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SYNOPSIS (A) Av No. of phospho BRCA
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SYNOPSIS Percentage Survival 120 10
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SYNOPSIS Fig.3.4B. Existance of cro
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SYNOPSIS Fig. 3.4EDNA damage in EL-
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SYNOPSIS subsequent cytotoxicity ca
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SYNOPSIS [4] Hall, E. J. Radiobiolo
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CHAPTER 1 INTRODUCTION INTRODUCTION
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CHAPTER 1 INTRODUCTION 15.8% 9.56%
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CHAPTER 1 INTRODUCTION far apart an
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CHAPTER 1 INTRODUCTION and are more
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CHAPTER 1 INTRODUCTION 1.3 DNA dama
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CHAPTER 1 INTRODUCTION associates w
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CHAPTER 1 INTRODUCTION are unable t
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CHAPTER 1 INTRODUCTION Perhaps one
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CHAPTER 1 INTRODUCTION occurs at DS
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CHAPTER 1 INTRODUCTION related prot
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CHAPTER 1 INTRODUCTION damage must
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CHAPTER 1 INTRODUCTION At the prese
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CHAPTER 1 INTRODUCTION predominant
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CHAPTER 1 INTRODUCTION provide a me
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CHAPTER 1 INTRODUCTION hypersensiti
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CHAPTER 1 INTRODUCTION cycle-specif
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CHAPTER 1 INTRODUCTION 1.4 Overview
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CHAPTER 1 INTRODUCTION 1.4.1 Radiat
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CHAPTER 1 INTRODUCTION interaction
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CHAPTER 1 INTRODUCTION p90S6 kinase
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CHAPTER 1 INTRODUCTION CD4 (formerl
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CHAPTER 1 INTRODUCTION unrepaired d
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CHAPTER 1 INTRODUCTION well to the
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CHAPTER 1 INTRODUCTION 1.6 Radiatio
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CHAPTER 1 INTRODUCTION becomes pote
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CHAPTER 2 MATERIALS AND METHODS MAT
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CHAPTER 2 MATERIALS AND METHODS 2.2
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CHAPTER 2 MATERIALS AND METHODS res
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CHAPTER 2 MATERIALS AND METHODS Arr
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CHAPTER 2 MATERIALS AND METHODS PBS
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CHAPTER 2 MATERIALS AND METHODS the
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CHAPTER 2 MATERIALS AND METHODS 2.1
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CHAPTER 3 RESULTS RESULTS 93
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CHAPTER 3 RESULTS fractionated regi
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CHAPTER 3 RESULTS On comparison of
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CHAPTER 3 RESULTS Table 3.1.2A List
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CHAPTER 3 RESULTS 80 NM_002185 IL7R
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CHAPTER 3 RESULTS SAA2 149 AU134977
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CHAPTER 3 RESULTS 221 LOC643167 RNA
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CHAPTER 3 RESULTS 299 BF244402 FBXO
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CHAPTER 3 RESULTS CDK4) 57 AU152107
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CHAPTER 3 RESULTS 134 AL045793 METT
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CHAPTER 3 RESULTS 58 AF237813 ABAT
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CHAPTER 3 RESULTS 127 AI809749 ORMD
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CHAPTER 3 RESULTS 31 BE615699 UNC84
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CHAPTER 3 RESULTS 47 AF026303 SULT1
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CHAPTER 3 RESULTS 117 BF062193 CYor
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CHAPTER 3 RESULTS 187 AL036662 ---
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CHAPTER 3 RESULTS 52 AV686514 EMP2
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CHAPTER 3 RESULTS exposed to 10 Gy
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CHAPTER 3 RESULTS Fig.3.1.4 Gene ex
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CHAPTER 3 RESULTS Fig. 3.1.6 Radiat
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CHAPTER 3 RESULTS Fig. 3.1.7 Transl
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CHAPTER 3 RESULTS 3.1.9 Stabilizati
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CHAPTER 3 RESULTS 23±1.5% (Fig. 3.
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CHAPTER 3 RESULTS whereas only the
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CHAPTER 3 RESULTS with equal doses
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CHAPTER 3 RESULTS Fig.3.3.1.2 Forma
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CHAPTER 3 RESULTS Fig.3.3.1.3 Phosp
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CHAPTER 3 RESULTS (7.5±0.64) (Fig.
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CHAPTER 3 RESULTS Fig.3.3.1.7b Phos
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CHAPTER 3 RESULTS 3.3.2 Oxygen beam
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CHAPTER 3 RESULTS in all the cells.
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CHAPTER 3 RESULTS 3.3.2.3 Radiation
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CHAPTER 3 RESULTS Fig.3.3.2.7 Apopt
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CHAPTER 3 RESULTS PMA stimulated U9
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CHAPTER 3 RESULTS Fig.3.4.2. Exista
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CHAPTER 3 RESULTS up-regulation of
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CHAPTER 3 RESULTS Fig.3.4.3.2 NO pr
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CHAPTER 3 RESULTS 3.4.3.4 Apoptotic
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CHAPTER 3 RESULTS 3.4.4 Bystander e
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CHAPTER 3 RESULTS Fig.3.4.4b DNA da
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CHAPTER 3 RESULTS Fig.3.4.5a Gene e
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CHAPTER 4 DISCUSSION DISCUSSION 185
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CHAPTER 4 DISCUSSION directly expos
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CHAPTER 4 DISCUSSION dose is delive
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CHAPTER 4 DISCUSSION A clear cause
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CHAPTER 4 DISCUSSION 4.2 Proton bea
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CHAPTER 4 DISCUSSION Although the e
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CHAPTER 4 DISCUSSION Similar number
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CHAPTER 4 DISCUSSION the mechanism
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CHAPTER 4 DISCUSSION Thus unlike th
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CHAPTER 4 DISCUSSION different from
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CHAPTER 4 DISCUSSION upregulates ma
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CHAPTER 4 DISCUSSION Numerous studi
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CHAPTER 4 DISCUSSION inhibition of
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CHAPTER 4 DISCUSSION The survival o
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CHAPTER 5 REFERENCES [1] Khan, F. T
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CHAPTER 5 REFERENCES [19] Woo, R. A
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CHAPTER 5 REFERENCES [35] Nghiem, P
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CHAPTER 5 REFERENCES [52] McKay, B.
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CHAPTER 5 REFERENCES [69] Cary, R.
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CHAPTER 5 REFERENCES [84] Uziel, T.
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