LIFE09200604007 Tabish - Homi Bhabha National Institute

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Chapter 6 Summary and Conclusions
Summary and Conclusions Together, our data suggest that intermediate phenotypes of cancer susceptibility might be potentially useful in identifying UADT MPN risk subgroups. Identifying distinctive polymorphism based G Score signature can differentiate the study participants into two different subsets and its correlation with various phenotypic effects (indicating a gene-environment interaction) may have an important bearing on predisposing an individual to UADT MPN development. However one of the limitations of our study was that the 22 SNPs that were included were probably insufficient to account for the absolute risk prediction. It is quiet likely that several other genes and minor or major carcinogens exist that have not been evaluated in our study. Therefore it is possible that the addition of rare risk alleles with greater effects, or a larger number of common risk alleles with small individual effects, could improve discrimination. Nevertheless combination of our selected SNPs shows a correlation with phenotypes and make us believe that in near future if more number of such studies are conducted we can arrive on a panel of SNPs that probably can be used as a prediction marker for risk assessment of patients with a high risk of MPN development. Another limitation of the study was that our Genotype Score gave all alleles the same weight; this may not be a true reflection of the biological basis of UADT MPN etiology. One of the highlights of our study was that we have correlated risk genotype with adverse phenotypic characteristics and undertaken interaction between genes and the environment that might alter the genetic risk in exposed individuals that remains the cornerstone of approaches to predicting cancer risk. To the best of our knowledge our study provides the first molecular epidemiological evidence correlating 22 gene polymorphisms (falling in multiple pathways) with alteration in phenotypic effect under three categories (cell-cycle checkpoints, apoptosis and DNA repair capacity) on same subset of patients and generating a genotype and molecular phenotype correlation for understanding UADT MPN risk. Our findings emphasize the importance of assessing collective effects from a panel of polymorphisms in modulating phenotypic effects following genotoxic exposure. It is an important contribution to available literature wherein, for the first time SNPs in major metabolic and biological pathways implicated in carcinogenesis have been correlated with intermediate phenotype in order to analyse the functional significance of gene polymorphisms and cancer predisposition in the unique Indian UADT MPN cohort. 147
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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
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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 156 and 157: Discussion DNA repair genes and MPN
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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