LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

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CHAPTER 4 DISCUSSION directly exposed to the radiation but are juxtaposed to the irradiated cells are also affected because of signals transduced from the ‘hit’ cell. The classical paradigm of radiation biology asserts that all radiation effects on cells, tissues and organisms are due to the direct action of radiation. However, there has been a recent growth of interest in the indirect actions of radiation including the radiation-induced adaptive response, the bystander effect, low-dose hypersensitivity, and genomic instability, which are specific modes of stress exhibited in response to low-dose/low-dose rate radiation. 4.1 Fractionated irradiation induced signaling and repair in mammalian cells. It is known that cellular response to ionising radiation is a complex phenomenon where the dose, dose rate and its fractionation play an equally important role in deciding the fate of the cell. Extensive work has been done and published on the response of the cell to single doses of radiation which are reflected as lesions in the DNA and non DNA targets. Among the latter are the signaling proteins that act to signal that the DNA is damaged as well as to regulate processes such as cell cycle progression and DNA repair. These pathways are also intricately linked with the intrinsic radioresistance of the cell [237, 238]. In recent years these signaling proteins are being exploited as targets to enhance tumor radiosensitivity [238-240]. The targets have been chosen based on their activation following a single dose of radiation. Since signaling, as it is now known, is not a linear activation of a pathway but a complex network where both positive and negative signals are activated simultaneously following exposure to stress , it is quite likely that the signaling factors that are being targeted may not be activated in a cancer cell that has undergone radiotherapy. The study of the ultimate radioresistant phenotype is undoubtedly a very important aspect but the immediate response of the signaling factors to repeated doses of 187
CHAPTER 4 DISCUSSION radiation are yet unknown. More information about the response of these signaling factors at clinically relevant doses during and after a fractionated regimen is needed to understand their role. In the present study human lung adenocarcinoma A549 cells were found to be more radioresistant if 10 Gy dose was delivered as fractionated dose (Fig.3.1.1). Although fractionation is supposed to play an important role in inducing an adaptive response and deciding the fate of cells, the mechanism by which it does so can be many and innumerable factors could be responsible. In microarray analysis, most of the pathways which were up-regulated in A549 cells exposed to fractionated irradiation in all comparisons were associated with the survival or repair of the A549 cells. This indicated that fractionated irradiation could induce up-regulation of survival/repair related pathways in cancer cells. Previous reports concerning radioresistant non–small-cell lung cancer and HeLa cells indicated that cell cycle signaling pathways, mismatch repair, homologous recombination were up-regulated [241, 242]. In this study, some of these genes were previously known to be associated with responsiveness to radiation, such as p21 and GADD45α, but others were novel. These novel genes can be expected to be involved in radioresistance, but the precise function of each gene remains unclear; so further study was necessary to clarify the nature of associations. Microarray data had shown that p53 signaling pathway was up-regualted in A549 cells that had been exposed to fractionated irradiation; it was of interest to look at the phosphorylation of p53 and its translocation to the nucleus of A549 cells. Lung adenocarcinoma A549 cells typically express wild-type p53 protein [243] and would be expected to be sensitive to the DNAdamaging agents used for cancer therapy; however, these cells are radioresistant if the radiation 188
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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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Page 170 and 171: CHAPTER 3 RESULTS 3.3.2.3 Radiation
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Page 178 and 179: CHAPTER 3 RESULTS PMA stimulated U9
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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 222 and 223: CHAPTER 5 REFERENCES [1] Khan, F. T
Page 224 and 225: CHAPTER 5 REFERENCES [19] Woo, R. A
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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
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CHAPTER 5 REFERENCES (MAP) kinase c
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CHAPTER 5 REFERENCES phosphorylatio
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CHAPTER 5 REFERENCES [211] Anderson
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CHAPTER 5 REFERENCES [229] Konca, K
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CHAPTER 5 REFERENCES [245] Kastan,
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CHAPTER 5 REFERENCES [261] Miralbel
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CHAPTER 5 REFERENCES [278] Weizman,
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CHAPTER 5 REFERENCES [294] Zhou, H.
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PUBLICATIONS AND PRESENTATIONS Publ
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Mutation Research 729 (2012) 61-72
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S. Ghosh, M. Krishna / Mutation Res
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Cancer Invest Downloaded from infor
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1568 I. J. Radiation Oncology d Bio
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