LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

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CHAPTER 4 DISCUSSION Numerous studies have implicated extracellular secreted signaling proteins in mediating the bystander effect [289], but the strongest contenders have been reactive oxygen and nitrogen species [299]. To investigate what factors are involved in radiation induced bystander effect, the cells were treated with either L-NAME (NOS inhibitor) or cPTIO (NO scavenger). The effect of cPTIO and L-NAME in bystander response between similar cell (EL-4 Vs EL-4) was different in the fact that treatment with L-NAME reduces the bystander induction of NF-κB as well as iNOS gene expression in EL-4 cells receiving medium from irradiated EL-4 cells (Fig. 3.4.5a, Lane 4) but the treatment with cPTIO reduces the bystander induction of only NF-κB gene expression and not iNOS gene expression (Fig. 3.4.5a, Lane 5). The above results demonstrate that the activated NOS in the irradiated cell is essential for gene expression in the bystanding cell. The addition of either L-NAME or cPTIO reduces the bystander induction of NF-κB as well as iNOS gene expression in EL-4 cells receiving medium from LPS stimulated and irradiated RAW 264.7 cells (Fig. 3.4.5a, Lane 6 and 7), indicating that both activation of iNOS in the irradiated cell and NO production play a role in cross bystander effect. The treatment with L-NAME or cPTIO also reduces the bystander induction of DNA damage in EL-4 cells receiving medium from irradiated EL-4 cells or LPS stimulated and irradiated RAW 264.7 cells (Fig. 3.4.5b, Lane 4, 5, 6 and 7), demonstrating that NO contributes to the DNA damage in bystander EL-4 cells. NO is generated endogeneously from L-arginine by inducible NO synthases [300, 301] that can be stimulated by radiation in mammalian cells [302]. It is believed that NO itself does not induce DNA strand breaks, although one of its oxidation product, peroxynitrite is toxic and can cause DNA damage by both attacking deoxyribose and direct oxidation of purine and pyrimidine [303]. Radiation induced NO has the possibility of 207
CHAPTER 4 DISCUSSION attacking nearby cells within their diffusion distance of less than 0.5mm [304, 305]. However, because of their having very short half-lives, they may not be direct contributors to the cellular damage in the bystander population. This is confirmed by the fact that inclusion of cPTIO in the medium only marginally inhibits the bystander response in similar cells (Fig. 3.4.5a, Lane 5). Contrarily, it has also been reported that NO is involved in the bystander responses caused by the conditioned medium harvested from irradiated cells [306]. Therefore, some long-lived bioactive factors downstream of NO are most likely involved in this bystander response. 4.5 Summary and Conclusion Summary: The irradiation of cells with fractionated doses led to a signaling response that was different from a single dose of irradiation. A549 cells were found to be relatively more radioresistant if the 10Gy dose was delivered as a fractionated regimen. Microarray analysis showed upregulation of DNA repair and cell cycle arrest genes in the cells exposed to fractionated irradiation. There was intense activation of DNA repair pathway (DNA-PK, ATM, Rad52, MLH1 and BRCA1), efficient DNA repair and phospho-p53 was found to be translocated to the nucleus of A549 cells exposed to fractionated irradiation. MCF-7 cells responded differently in fractionated regimen. Silencing of the Rad52 gene in fractionated group of A549 cells made the cells radiosensitive. The reasons for the radioresistance of the A549 cells lay in the repair pathway, the Rad52, the 208
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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.3.3.1.6 Phosp
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CHAPTER 3 RESULTS Fig.3.3.1.7b Phos
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Page 178 and 179: CHAPTER 3 RESULTS PMA stimulated U9
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Page 182 and 183: CHAPTER 3 RESULTS up-regulation of
Page 184 and 185: CHAPTER 3 RESULTS Fig.3.4.3.2 NO pr
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Page 190 and 191: CHAPTER 3 RESULTS Fig.3.4.4b DNA da
Page 192 and 193: CHAPTER 3 RESULTS Fig.3.4.5a Gene e
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Page 196 and 197: CHAPTER 4 DISCUSSION directly expos
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Page 222 and 223: CHAPTER 5 REFERENCES [1] Khan, F. T
Page 224 and 225: CHAPTER 5 REFERENCES [19] Woo, R. A
Page 226 and 227: CHAPTER 5 REFERENCES [35] Nghiem, P
Page 228 and 229: CHAPTER 5 REFERENCES [52] McKay, B.
Page 230 and 231: CHAPTER 5 REFERENCES [69] Cary, R.
Page 232 and 233: CHAPTER 5 REFERENCES [84] Uziel, T.
Page 234 and 235: CHAPTER 5 REFERENCES [98] Liu, Y.;
Page 236 and 237: CHAPTER 5 REFERENCES [111] Fei, P.;
Page 238 and 239: CHAPTER 5 REFERENCES [127] Frank, K
Page 240 and 241: CHAPTER 5 REFERENCES [141] Pierce,
Page 242 and 243: CHAPTER 5 REFERENCES [156] Roots, R
Page 244 and 245: CHAPTER 5 REFERENCES [171] Xia, Z.;
Page 246 and 247: CHAPTER 5 REFERENCES (MAP) kinase c
Page 248 and 249: CHAPTER 5 REFERENCES phosphorylatio
Page 250 and 251: CHAPTER 5 REFERENCES [211] Anderson
Page 252 and 253: CHAPTER 5 REFERENCES [229] Konca, K
Page 254 and 255: CHAPTER 5 REFERENCES [245] Kastan,
Page 256 and 257: CHAPTER 5 REFERENCES [261] Miralbel
Page 258 and 259: CHAPTER 5 REFERENCES [278] Weizman,
Page 260 and 261: CHAPTER 5 REFERENCES [294] Zhou, H.
Page 262 and 263: PUBLICATIONS AND PRESENTATIONS Publ
Page 264 and 265: Mutation Research 729 (2012) 61-72
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S. Ghosh, M. Krishna / Mutation Res
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Mutation Research 716 (2011) 10-19
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12 S. Ghosh et al. / Mutation Resea
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Mutation Research 723 (2011) 190-19
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Cancer Invest Downloaded from infor
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1568 I. J. Radiation Oncology d Bio
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