LIFE09200604007 Tabish - Homi Bhabha National Institute

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Discussion DNA repair genes and MPN risk signature between the two groups (data not shown). Although the difference between the G Score of MPN and control group was not huge a significant difference between the G Score of patient and control samples in all the three categories was observed with our earlier data set also, signifying the importance of measuring G Score for MPN risk assessment. This emphasizes our present observation and demonstrates that combination of risk alleles probably is a risk factor with modest discriminatory ability between patient and control group. G Score – phenotype correlation Gene polymorphisms have long been associated with cancer risk; however the real implication of these gene polymorphisms with increased cancer risk can only be interpreted if they have any functional significance. This approach of understanding effect of gene polymorphisms at functional level has been phenomenal and has been applied to deduce the functional significance of genetic predisposition in cancer risk 49- 52, 201 . Many such genotype-phenotype correlation studies have been conducted on lung cancer. Comparable to our study, apoptotic capacity was found to be a risk factor for lung cancer development and the risk was observed to be modulated by the Fas - A 670 G polymorphism 51 . Similarly apoptosis, DNA repair and decreased G2/M cell cycle check point function are found to be compromised in lung cancer with variations in ATM, CDKN1A, BRCA2, ERCC6, TP53, and TP53BP1 genes 53, 201 . On the contrary in another report XPA gene polymorphism, a DNA binding protein in the nucleotide excision repair pathway, has been observed to modulate repair capacity and associated with decreased lung cancer risk, especially in the presence of exposure to tobacco carcinogens 52 . Other than lung cancer, analogous reports are available for breast cancer where polymorphisms in nucleotide excision repair genes and DNA repair capacity phenotype has been associated with breast cancer risk 54, 55 . In another report by Minard et al. evaluation of glutathione S-transferase polymorphisms and mutagen sensitivity as risk factors for the development of second primary tumours in 303 patients previously diagnosed with early-stage head and neck cancer has been done 49 . These studies demonstrate the functional significance of genetic variation in different individuals and then their probable implication on various phenotypes and eventually 145
Discussion cancer risk, hence emphasizing the importance of undertaking genotype-phenotype correlation studies in understanding UADT MPN pathogenesis. When we correlated G Score with phenotypic responses after radiation / BPDE exposure, a negative correlation was observed between the total G Score in all 22 SNPs, G Score of DNA repair genes and MPN risk association signature, and percent cell death and percent G2 delay. This was statistically significant for most of the groups. As higher G Score corresponds to more number of risk alleles in an individual and improper apoptotic and cell cycle response designate enhanced carcinogenesis phenotypes in a cell, our results emphasize the notion that polymorphisms in certain genes modify cellular intermediate phenotypic responses after genotoxic exposure that may have an important bearing on neoplastic evolution. Thus the genotype-phenotype associations observed in this study support our hypothesis that polymorphisms in genes involved in well regulated pathways like DNA repair, cell cycle check point, carcinogen metabolism and apoptosis can affect important cellular functions like, DNA repair capacity, cell cycle regulation and apoptosis. 146
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Genotype-Molecular Phenotype Correl
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CONTENTS Page No Synopsis 1 List of
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Synopsis
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Synopsis Genotype-Molecular Phenoty
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Synopsis Materials and Methods: 1.
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Synopsis loading control. PCR produ
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Synopsis 7.1 Percent cell death aft
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Synopsis slides were then dried and
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Synopsis range 41.77% - 90.95% at 5
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Synopsis 5. Genotyping of genes: Ge
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Synopsis G2/M arrest and delaying e
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Synopsis may have an important bear
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Synopsis References: 1. Bobba, R.;
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Abbreviations MOPS : 3-(N-morpholin
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List of Figures Fig. 28: Percent re
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Chapter 1 Introduction
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Introduction In previous studies fr
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Introduction important carcinogenes
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Review of Literature The yet undeci
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Review of Literature Fig. 2: Incide
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Review of Literature sustained angi
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Review of Literature 2.6 Genotype p
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Review of Literature 2.7.2 Biologic
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Review of Literature Table 1: Steps
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Review of Literature future analysi
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Review of Literature Inefficient ce
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Review of Literature XRCC1 (X-ray r
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Review of Literature 2.9.2 Gene inv
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Review of Literature MPO gene polym
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Review of Literature important role
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Materials and Methods Source of che
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Materials and Methods Method: EBV-t
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Materials and Methods Immunophenoty
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Materials and Methods with 500 μl
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Materials and Methods cDNA it can b
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Materials and Methods Cobalt-60 iso
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Materials and Methods specific bind
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Materials and Methods h half of the
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Materials and Methods phenol and th
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Materials and Methods 7. Filter ste
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Materials and Methods viz. EXO-SAP
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Materials and Methods Table 2: List
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Materials and Methods SMAD6 AREG HM
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Materials and Methods 3.9 Effect of
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Materials and Methods fresh eppendo
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Materials and Methods Power SYBR Gr
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Results Objective 1 To generate EBV
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Results Fig. 8: Frequency of second
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Results Table 6: Demographics of he
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Results Fig. 10: Cell population do
Page 106 and 107: Results Fig. 12: Cell surface marke
Page 108 and 109: Results 4.1.5 Expression of ATM gen
Page 110 and 111: Results Objective 2 To compare the
Page 112 and 113: Results Fig. 17: Standardization of
Page 114 and 115: Results Fig. 19: Standardisation of
Page 116 and 117: Results The cells were incubated fu
Page 118 and 119: Results 4.2.3.1 Percent G2 delay af
Page 120 and 121: Results 4.2.3.2 Effect of BPDE expo
Page 122 and 123: Results Fig. 29: Comparison of perc
Page 124 and 125: Results Fig. 31: Percent cell death
Page 126 and 127: Results normalization with baseline
Page 128 and 129: Results 4.2.5.2 Real time PCR valid
Page 130 and 131: Results homozygous wild-type, heter
Page 132 and 133: Results Fig. 36b: Electrophoresis o
Page 134 and 135: Results Fig. 37a: Representative el
Page 136 and 137: Results Table 13: Consolidated geno
Page 138 and 139: Results LCL Genes NAT2(1) NAT2(2) N
Page 140 and 141: Results Fig. 38: Distribution of Ge
Page 142 and 143: Results Fig. 39: Various combinatio
Page 144 and 145: Results Table 14: Genotype-phenotyp
Page 146 and 147: Discussion Introduction Squamous ce
Page 148 and 149: Discussion stimulated lymphocytes w
Page 150 and 151: Discussion H2AX is currently the mo
Page 152 and 153: Discussion or G2/M phase arrest. As
Page 154 and 155: Discussion differential expression
Page 158 and 159: Chapter 6 Summary and Conclusions
Page 160 and 161: Summary and Conclusions Statistical
Page 162 and 163: Bibliography 1. Dikshit, R.; Gupta,
Page 164 and 165: Bibliography 43. Lei, D.; Sturgis,
Page 166 and 167: Bibliography 76. Fry, R. C.; Svenss
Page 168 and 169: Bibliography 115. Kote-Jarai, Z.; M
Page 170 and 171: Bibliography 149. Hashibe, M.; Bren
Page 172 and 173: Bibliography 183. Bergamaschi, D.;
Page 174 and 175: Bibliography 216. Bondy, M. L.; Wan
Page 176 and 177: Indian J Med Res 135, June 2012, pp
Page 178 and 179: 822 INDIAN J MED RES, JUNE 2012 mar
Page 180 and 181: 824 INDIAN J MED RES, JUNE 2012 (h)
Page 182 and 183: 826 INDIAN J MED RES, JUNE 2012 Tab
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Page 186 and 187: CASE REPORT Eben L. Rosenthal, MD,
Page 188 and 189: FIGURE 2. Chromosomal breakage anal
Page 190 and 191: FA along with ataxia telangiectasia
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LIFE09200604007 Tabish - Homi Bhabha National Institute

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