LIFE09200604007 Tabish - Homi Bhabha National Institute

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Synopsis and develop a correlation. We genotyped 22 SNPs in 17 genes falling in important carcinogenesis pathways viz. carcinogen metabolism, DNA damage/repair, cell cycle regulation and apoptosis. To understand genotyping data we calculated a consolidated G Score on the basis of whether the subject had homozygous variant, heterozygous or homozygous wildtype form of a gene. A high G Score designated more number of risk alleles in an individual. Our assumption was that individuals with a high G Score might have a higher probability of MPN development as compared to those with the low G Score. Hence a higher G Score indicated magnitude of cancer predisposing genotype. A total G Score with all 22 SNPs, G Score of only DNA repair genes and G Score of MPN risk association signature, which included SNPs in genes that could predict the outcome of tobacco related MPN in our previous study 8 , was calculated and was found to be higher in MPN patient group as compared to control group. Although total G Score was not statistically significant between the two groups at the 5% level (p=0.12), G Score of DNA repair genes and MPN risk association signature was statistically significant, indicating that indeed there existed inter-individual difference at genetic level between MPN patients and controls at least in a subset of important genes falling in carcinogenesis pathways. A comparison of total G Score in all 22 SNPs, G Score of DNA repair genes and MPN risk association signature showed a negative correlation with percent cell death and percent G2 delay. This correlation was statistically significant for most of the groups. While a positive correlation was observed between G Score (all three groups) and percent H2AX positive cells at 4 h time point, although it was not significant. Our findings emphasize the importance of assessing the collective effects of a panel of polymorphisms in modulating phenotypic effects after genotoxic exposure. The genotype-phenotype correlation observed in this study supports our hypothesis that variations in important genes may alter phenotypic response and may contribute to UADT MPN risk. In the present state for understanding UADT MPN pathogenesis it is important to find association between multiple genetic combinations and cancer risks, which may otherwise remain undetectable in single SNP analysis. In summary our results clearly suggest that extent of DNA repair, percent cell death and cell cycle delay might be potentially useful in identifying susceptibility to UADT MPN. It also demonstrates that identifying distinctive polymorphism based G Score signature can differentiate the study participants into two separate subsets, and its correlation with various phenotypic effects (indicating a gene-environment interaction) 17
Synopsis may have an important bearing on predisposing an individual to UADT MPN development. The significance of this study lies in the fact that it guides us in identifying high risk individuals thus increasing the possibility of identifying cohort of patients of clinical relevance which can be undertaken for chemo preventive studies although larger prospective studies are needed to verify these findings. 18
Page 1: Genotype-Molecular Phenotype Correl
Page 7 and 8: CONTENTS Page No Synopsis 1 List of
Page 9 and 10: Synopsis
Page 11 and 12: Synopsis Genotype-Molecular Phenoty
Page 13 and 14: Synopsis Materials and Methods: 1.
Page 15 and 16: Synopsis loading control. PCR produ
Page 17 and 18: Synopsis 7.1 Percent cell death aft
Page 19 and 20: Synopsis slides were then dried and
Page 21 and 22: Synopsis range 41.77% - 90.95% at 5
Page 23 and 24: Synopsis 5. Genotyping of genes: Ge
Page 25: Synopsis G2/M arrest and delaying e
Page 29 and 30: Synopsis References: 1. Bobba, R.;
Page 31 and 32: Abbreviations MOPS : 3-(N-morpholin
Page 33 and 34: List of Figures Fig. 28: Percent re
Page 35 and 36: Chapter 1 Introduction
Page 37 and 38: Introduction In previous studies fr
Page 39 and 40: Introduction important carcinogenes
Page 41 and 42: Review of Literature The yet undeci
Page 43 and 44: Review of Literature Fig. 2: Incide
Page 45 and 46: Review of Literature sustained angi
Page 47 and 48: Review of Literature 2.6 Genotype p
Page 49 and 50: Review of Literature 2.7.2 Biologic
Page 51 and 52: Review of Literature Table 1: Steps
Page 53 and 54: Review of Literature future analysi
Page 55 and 56: Review of Literature Inefficient ce
Page 57 and 58: Review of Literature XRCC1 (X-ray r
Page 59 and 60: Review of Literature 2.9.2 Gene inv
Page 61 and 62: Review of Literature MPO gene polym
Page 63 and 64: Review of Literature important role
Page 65 and 66: Materials and Methods Source of che
Page 67 and 68: Materials and Methods Method: EBV-t
Page 69 and 70: Materials and Methods Immunophenoty
Page 71 and 72: Materials and Methods with 500 μl
Page 73 and 74: Materials and Methods cDNA it can b
Page 75 and 76: 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
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Results 4.1.5 Expression of ATM gen
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Results Objective 2 To compare the
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Results Fig. 17: Standardization of
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Results Fig. 19: Standardisation of
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Results The cells were incubated fu
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Results 4.2.3.1 Percent G2 delay af
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Results 4.2.3.2 Effect of BPDE expo
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Results Fig. 29: Comparison of perc
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Results Fig. 31: Percent cell death
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Results normalization with baseline
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Results 4.2.5.2 Real time PCR valid
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Results homozygous wild-type, heter
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Results Fig. 36b: Electrophoresis o
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Results Fig. 37a: Representative el
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Results Table 13: Consolidated geno
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Results LCL Genes NAT2(1) NAT2(2) N
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Results Fig. 38: Distribution of Ge
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Results Fig. 39: Various combinatio
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Results Table 14: Genotype-phenotyp
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Discussion Introduction Squamous ce
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Discussion stimulated lymphocytes w
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Discussion H2AX is currently the mo
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Discussion or G2/M phase arrest. As
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Discussion differential expression
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Discussion DNA repair genes and MPN
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Chapter 6 Summary and Conclusions
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Summary and Conclusions Statistical
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Bibliography 1. Dikshit, R.; Gupta,
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Bibliography 43. Lei, D.; Sturgis,
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Bibliography 76. Fry, R. C.; Svenss
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Bibliography 115. Kote-Jarai, Z.; M
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Bibliography 149. Hashibe, M.; Bren
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Bibliography 183. Bergamaschi, D.;
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Bibliography 216. Bondy, M. L.; Wan
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Indian J Med Res 135, June 2012, pp
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822 INDIAN J MED RES, JUNE 2012 mar
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824 INDIAN J MED RES, JUNE 2012 (h)
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826 INDIAN J MED RES, JUNE 2012 Tab
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828 INDIAN J MED RES, JUNE 2012 lik
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CASE REPORT Eben L. Rosenthal, MD,
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FIGURE 2. Chromosomal breakage anal
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FA along with ataxia telangiectasia
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