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M. Prakash Hande - One of the best experts on this subject based on the ideXlab platform.
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Hydrogen peroxide induced genomic instability in nucleotide excision repair-deficient lymphoblastoid cells.
Genome integrity, 2010Co-Authors: Kalpana Gopalakrishnan, Aloysius Poh Leong Ting, Grace Kah Mun Low, Prarthana Srikanth, Predrag Slijepcevic, M. Prakash HandeAbstract:Background: The Nucleotide Excision Repair (NER) pathway specialises in UV-induced DNA damage repair. Inherited defects in the NER can predispose individuals to Xeroderma Pigmentosum (XP). UV-induced DNA damage cannot account for the manifestation of XP in organ systems not directly exposed to sunlight. While the NER has recently been implicated in the repair of oxidative DNA lesions, it is not well characterised. Therefore we sought to investigate the role of NER Factors Xeroderma Pigmentosum A (XPA), XPB and XPD in oxidative DNA damage-repair by subjecting lymphoblastoid cells from patients suffering from XP-A, XP-D and XP-B with Cockayne Syndrome to hydrogen peroxide (H2O2). Results: Loss of functional XPB or XPD but not XPA led to enhanced sensitivity towards H2O2-induced cell death. XP-deficient lymphoblastoid cells exhibited increased susceptibility to H2O2-induced DNA damage with XPD showing the highest susceptibility and lowest repair capacity. Furthermore, XPB- and XPD-deficient lymphoblastoid cells displayed enhanced DNA damage at the telomeres. XPA- and XPB-deficient lymphoblastoid cells also showed differential regulation of XPD following H2O2 treatment. Conclusions: Taken together, our data implicate a role for the NER in H2O2-induced oxidative stress management and further corroborates that oxidative stress is a significant contributing Factor in XP symptoms. Resistance of XPAdeficient lymphoblastoid cells to H2O2-induced cell death while harbouring DNA damage poses a potential Cancer Risk Factor for XPA patients. Our data implicate XPB and XPD in the protection against oxidative stress-induced DNA damage and telomere shortening, and thus premature senescence.
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Oxidative damage induced genotoxic effects in human fibroblasts from Xeroderma Pigmentosum group A patients.
The International Journal of Biochemistry & Cell Biology, 2008Co-Authors: Aloysius Poh Leong Ting, M. Prakash HandeAbstract:Xeroderma Pigmentosum A protein plays a pivotal role in the nucleotide excision repair pathway. Through site-directed binding of rigidly kinked double-stranded DNA, it verifies damaged DNA for subsequent excision and incision. Although Xeroderma Pigmentosum A-deficient cells have shown to be defective in oxidative base-lesion repair, the effects of oxidative assault on such cells have not been fully explored. Therefore, we sought to determine the involvement of Xeroderma Pigmentosum A in oxidative DNA damage-repair by treating primary fibroblasts from a patient suffering from Xeroderma Pigmentosum A with sodium arsenite and hydrogen peroxide. Our results show dose-dependent increase in genotoxicity with little change in cytotoxicity with both arsenite and H2O2 in Xeroderma Pigmentosum A-deficient cells compared to control cells. Xeroderma Pigmentosum A-deficient cells displayed increased susceptibility and reduced repair capacity when subjected to DNA damage induced by oxidative stress. Superarray results of apoptotic genes revealed differential expression of ∼10 genes between Xeroderma Pigmentosum A-deficient and normal cells following arsenite treatment. Interestingly, we noted that arsenite did not inflict as much damage in the cells compared to H2O2. Lack of functional Xeroderma Pigmentosum A seems to increase the susceptibility of oxidative stress-induced genotoxicity while retaining cell viability posing as a potential Cancer Risk Factor of Xeroderma Pigmentosum A patients.
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Oxidative damage induced genotoxic effects in human fibroblasts from Xeroderma Pigmentosum group A patients.
The international journal of biochemistry & cell biology, 2008Co-Authors: Grace Kah Mun Low, Aloysius Poh Leong Ting, Edwin Dan Zhihao Fok, M. Prakash HandeAbstract:Xeroderma Pigmentosum A protein plays a pivotal role in the nucleotide excision repair pathway. Through site-directed binding of rigidly kinked double-stranded DNA, it verifies damaged DNA for subsequent excision and incision. Although Xeroderma Pigmentosum A-deficient cells have shown to be defective in oxidative base-lesion repair, the effects of oxidative assault on such cells have not been fully explored. Therefore, we sought to determine the involvement of Xeroderma Pigmentosum A in oxidative DNA damage-repair by treating primary fibroblasts from a patient suffering from Xeroderma Pigmentosum A with sodium arsenite and hydrogen peroxide. Our results show dose-dependent increase in genotoxicity with little change in cytotoxicity with both arsenite and H2O2 in Xeroderma Pigmentosum A-deficient cells compared to control cells. Xeroderma Pigmentosum A-deficient cells displayed increased susceptibility and reduced repair capacity when subjected to DNA damage induced by oxidative stress. Superarray results of apoptotic genes revealed differential expression of approximately 10 genes between Xeroderma Pigmentosum A-deficient and normal cells following arsenite treatment. Interestingly, we noted that arsenite did not inflict as much damage in the cells compared to H2O2. Lack of functional Xeroderma Pigmentosum A seems to increase the susceptibility of oxidative stress-induced genotoxicity while retaining cell viability posing as a potential Cancer Risk Factor of Xeroderma Pigmentosum A patients.
Ben Schottker - One of the best experts on this subject based on the ideXlab platform.
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investigation on potential associations of oxidatively generated dna rna damage with lung colorectal breast prostate and total Cancer incidence
Scientific Reports, 2019Co-Authors: Bernd Holleczek, Ankita Anusruti, Yang Xuan, Yiwei Xu, Ben Schottker, Hermann Brenner, Yan ZhangAbstract:Oxidative stress has been linked to Cancer development in previous studies. However, the association between pre-diagnostic oxidatively generated DNA/RNA damage levels and incident Cancer has rarely been investigated. Urinary oxidized guanine/guanosine (OxGua) concentrations, including 8-hydroxy-2′-deoxyguanosine, were assessed in 8,793 older adults in a population-based German cohort. 1,540 incident Cancer cases, including 207 lung, 196 colorectal, 218 breast and 245 prostate Cancer cases were diagnosed during over 14 years of follow-up. Associations of OxGua levels with Cancer outcomes were not observed in the total population in multi-variable adjusted Cox regression models. However, in subgroup analyses, colorectal Cancer incidence increased by 8%, 9% and 8% with one standard deviation increase in OxGua levels among current non-smokers, female and non-obese participants, respectively. Additionally, among non-smokers, overall and prostate Cancer incidences statistically significantly increased by 5% and 13% per 1 standard deviation increase in OxGua levels, respectively. In contrast, OxGua levels were inversely associated with the Risk of prostate Cancer among current smokers. However, none of the subgroup analyses had p-values below a threshold for statistical significance after correction for multiple testing. Thus, results need to be validated in further studies. There might be a pattern that oxidatively generated DNA/RNA damage is a weak Cancer Risk Factor in the absence of other strong Risk Factors, such as smoking, obesity and male sex.
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Investigation on potential associations of oxidatively generated DNA/RNA damage with lung, colorectal, breast, prostate and total Cancer incidence.
Scientific Reports, 2019Co-Authors: Bernd Holleczek, Ankita Anusruti, Yang Xuan, Yiwei Xu, Hermann Brenner, Yan Zhang, Ben SchottkerAbstract:Oxidative stress has been linked to Cancer development in previous studies. However, the association between pre-diagnostic oxidatively generated DNA/RNA damage levels and incident Cancer has rarely been investigated. Urinary oxidized guanine/guanosine (OxGua) concentrations, including 8-hydroxy-2′-deoxyguanosine, were assessed in 8,793 older adults in a population-based German cohort. 1,540 incident Cancer cases, including 207 lung, 196 colorectal, 218 breast and 245 prostate Cancer cases were diagnosed during over 14 years of follow-up. Associations of OxGua levels with Cancer outcomes were not observed in the total population in multi-variable adjusted Cox regression models. However, in subgroup analyses, colorectal Cancer incidence increased by 8%, 9% and 8% with one standard deviation increase in OxGua levels among current non-smokers, female and non-obese participants, respectively. Additionally, among non-smokers, overall and prostate Cancer incidences statistically significantly increased by 5% and 13% per 1 standard deviation increase in OxGua levels, respectively. In contrast, OxGua levels were inversely associated with the Risk of prostate Cancer among current smokers. However, none of the subgroup analyses had p-values below a threshold for statistical significance after correction for multiple testing. Thus, results need to be validated in further studies. There might be a pattern that oxidatively generated DNA/RNA damage is a weak Cancer Risk Factor in the absence of other strong Risk Factors, such as smoking, obesity and male sex.
Aloysius Poh Leong Ting - One of the best experts on this subject based on the ideXlab platform.
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Hydrogen peroxide induced genomic instability in nucleotide excision repair-deficient lymphoblastoid cells.
Genome integrity, 2010Co-Authors: Kalpana Gopalakrishnan, Aloysius Poh Leong Ting, Grace Kah Mun Low, Prarthana Srikanth, Predrag Slijepcevic, M. Prakash HandeAbstract:Background: The Nucleotide Excision Repair (NER) pathway specialises in UV-induced DNA damage repair. Inherited defects in the NER can predispose individuals to Xeroderma Pigmentosum (XP). UV-induced DNA damage cannot account for the manifestation of XP in organ systems not directly exposed to sunlight. While the NER has recently been implicated in the repair of oxidative DNA lesions, it is not well characterised. Therefore we sought to investigate the role of NER Factors Xeroderma Pigmentosum A (XPA), XPB and XPD in oxidative DNA damage-repair by subjecting lymphoblastoid cells from patients suffering from XP-A, XP-D and XP-B with Cockayne Syndrome to hydrogen peroxide (H2O2). Results: Loss of functional XPB or XPD but not XPA led to enhanced sensitivity towards H2O2-induced cell death. XP-deficient lymphoblastoid cells exhibited increased susceptibility to H2O2-induced DNA damage with XPD showing the highest susceptibility and lowest repair capacity. Furthermore, XPB- and XPD-deficient lymphoblastoid cells displayed enhanced DNA damage at the telomeres. XPA- and XPB-deficient lymphoblastoid cells also showed differential regulation of XPD following H2O2 treatment. Conclusions: Taken together, our data implicate a role for the NER in H2O2-induced oxidative stress management and further corroborates that oxidative stress is a significant contributing Factor in XP symptoms. Resistance of XPAdeficient lymphoblastoid cells to H2O2-induced cell death while harbouring DNA damage poses a potential Cancer Risk Factor for XPA patients. Our data implicate XPB and XPD in the protection against oxidative stress-induced DNA damage and telomere shortening, and thus premature senescence.
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Oxidative damage induced genotoxic effects in human fibroblasts from Xeroderma Pigmentosum group A patients.
The International Journal of Biochemistry & Cell Biology, 2008Co-Authors: Aloysius Poh Leong Ting, M. Prakash HandeAbstract:Xeroderma Pigmentosum A protein plays a pivotal role in the nucleotide excision repair pathway. Through site-directed binding of rigidly kinked double-stranded DNA, it verifies damaged DNA for subsequent excision and incision. Although Xeroderma Pigmentosum A-deficient cells have shown to be defective in oxidative base-lesion repair, the effects of oxidative assault on such cells have not been fully explored. Therefore, we sought to determine the involvement of Xeroderma Pigmentosum A in oxidative DNA damage-repair by treating primary fibroblasts from a patient suffering from Xeroderma Pigmentosum A with sodium arsenite and hydrogen peroxide. Our results show dose-dependent increase in genotoxicity with little change in cytotoxicity with both arsenite and H2O2 in Xeroderma Pigmentosum A-deficient cells compared to control cells. Xeroderma Pigmentosum A-deficient cells displayed increased susceptibility and reduced repair capacity when subjected to DNA damage induced by oxidative stress. Superarray results of apoptotic genes revealed differential expression of ∼10 genes between Xeroderma Pigmentosum A-deficient and normal cells following arsenite treatment. Interestingly, we noted that arsenite did not inflict as much damage in the cells compared to H2O2. Lack of functional Xeroderma Pigmentosum A seems to increase the susceptibility of oxidative stress-induced genotoxicity while retaining cell viability posing as a potential Cancer Risk Factor of Xeroderma Pigmentosum A patients.
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Oxidative damage induced genotoxic effects in human fibroblasts from Xeroderma Pigmentosum group A patients.
The international journal of biochemistry & cell biology, 2008Co-Authors: Grace Kah Mun Low, Aloysius Poh Leong Ting, Edwin Dan Zhihao Fok, M. Prakash HandeAbstract:Xeroderma Pigmentosum A protein plays a pivotal role in the nucleotide excision repair pathway. Through site-directed binding of rigidly kinked double-stranded DNA, it verifies damaged DNA for subsequent excision and incision. Although Xeroderma Pigmentosum A-deficient cells have shown to be defective in oxidative base-lesion repair, the effects of oxidative assault on such cells have not been fully explored. Therefore, we sought to determine the involvement of Xeroderma Pigmentosum A in oxidative DNA damage-repair by treating primary fibroblasts from a patient suffering from Xeroderma Pigmentosum A with sodium arsenite and hydrogen peroxide. Our results show dose-dependent increase in genotoxicity with little change in cytotoxicity with both arsenite and H2O2 in Xeroderma Pigmentosum A-deficient cells compared to control cells. Xeroderma Pigmentosum A-deficient cells displayed increased susceptibility and reduced repair capacity when subjected to DNA damage induced by oxidative stress. Superarray results of apoptotic genes revealed differential expression of approximately 10 genes between Xeroderma Pigmentosum A-deficient and normal cells following arsenite treatment. Interestingly, we noted that arsenite did not inflict as much damage in the cells compared to H2O2. Lack of functional Xeroderma Pigmentosum A seems to increase the susceptibility of oxidative stress-induced genotoxicity while retaining cell viability posing as a potential Cancer Risk Factor of Xeroderma Pigmentosum A patients.
Arto Mannermaa - One of the best experts on this subject based on the ideXlab platform.
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Matriptase-2 gene (TMPRSS6) variants associate with breast Cancer survival, and reduced expression is related to triple-negative breast Cancer.
International journal of cancer, 2013Co-Authors: Hanna Tuhkanen, Gloria Velasco, Jaana M. Hartikainen, Ylermi Soini, Reijo Sironen, Timo K. Nykopp, Vesa Kataja, Matti Eskelinen, Veli-matti Kosma, Arto MannermaaAbstract:Matriptase-2 (TMPRSS6) has been identified as a breast Cancer Risk Factor. Here, we examined relationships between TMPRSS6 genetic variations and breast Cancer Risk and survival, and determined the gene and protein expressions in breast tumors and assessed their clinical importance. Thirteen TMPRSS6 polymorphisms were genotyped in 462 invasive breast Cancer cases and 458 controls. Gene expression was analyzed from 83 tumors and protein expression from 370 tumors. We then assessed the statistical significance of associations among genotypes, clinicopathological characteristics and survival. The TMPRSS6 variant rs2543519 was associated with breast Cancer Risk (p = 0.032). Multivariate analysis showed that four variants had effects on survival—rs2543519 (p = 0.017), rs2235324 (p = 0.038), rs14213212 (p = 0.044) and rs733655 (p = 0.021)—which were used to create a group variable that was associated with poorer prognosis correlating with more alleles related to reduced survival (p = 0.006; Risk ratio, 2.375; 95% confidence interval, 1.287–4.382). Low gene expression was related to triple-negative breast Cancer (p = 0.0001), and lower protein expression was detected in undifferentiated (p = 0.019), large (p = 0.014) and ductal or lobular tumors (p = 0.036). These results confirm the association of TMRRSS6 variants with breast Cancer Risk and survival. Matriptase-2 levels decrease with tumor progression, and lower gene expression is seen in poor-prognosis-related triple-negative breast Cancers. Our study is the first to show that matriptase-2 gene variants are related to breast Cancer prognosis, supporting matriptase-2 involvement in tumor development.
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Refinement of the 22q12-q13 Breast Cancer–Associated Region: Evidence of TMPRSS6 as a Candidate Gene in an Eastern Finnish Population
Clinical cancer research : an official journal of the American Association for Cancer Research, 2006Co-Authors: Jaana M. Hartikainen, Hanna Tuhkanen, Vesa Kataja, Matti Eskelinen, Veli-matti Kosma, Matti Uusitupa, Arto MannermaaAbstract:Although many Risk Factors for breast Cancer are known, most of the genetic background and molecular mechanisms still remain to be elucidated. We have previously published an autosome-wide microsatellite scan for breast Cancer association and here we report a follow-up study for one of the detected regions. Ten single nucleotide polymorphisms (SNP) were genotyped in an Eastern Finnish population sample of 497 breast Cancer cases and 458 controls to refine the 550-kb region on 22q12-q13 and identify the breast Cancer-associated gene(s) in this region. We also studied 22q12-q13 for allelic imbalance for the detection of a possible tumor suppressor gene and to see whether the breast Cancer association and allelic imbalance in this region could be connected. A SNP (rs733655) in matriptase-2 gene (TMPRSS6) was detected to associate with breast Cancer Risk. The genotype frequencies of rs733655 differed significantly between cases and controls in the entire sample and in the geographically and genetically more homogeneous subsample with P = 0.044 and P = 0.0003, respectively. The heterozygous genotype TC was observed to be the Risk genotype in both samples (odds ratios, 1.39; 95% confidence intervals, 1.06-1.83 and odds ratios, 2.11; 95% confidence intervals, 1.46-3.05). An associated two-marker haplotype involving SNP rs733655 (empirical P = 0.041) provides further evidence for breast Cancer Risk Factor locating on 22q12-q13, possibly being TMPRSS6. Our results suggest that matriptase-2 gene is associated with breast Cancer Risk in the Eastern Finnish population.
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refinement of the 22q12 q13 breast Cancer associated region evidence of tmprss6 as a candidate gene in an eastern finnish population
Clinical Cancer Research, 2006Co-Authors: Jaana M. Hartikainen, Hanna Tuhkanen, Vesa Kataja, Veli-matti Kosma, Matti Uusitupa, M Eskelinen, Arto MannermaaAbstract:Although many Risk Factors for breast Cancer are known, most of the genetic background and molecular mechanisms still remain to be elucidated. We have previously published an autosome-wide microsatellite scan for breast Cancer association and here we report a follow-up study for one of the detected regions. Ten single nucleotide polymorphisms (SNP) were genotyped in an Eastern Finnish population sample of 497 breast Cancer cases and 458 controls to refine the 550-kb region on 22q12-q13 and identify the breast Cancer-associated gene(s) in this region. We also studied 22q12-q13 for allelic imbalance for the detection of a possible tumor suppressor gene and to see whether the breast Cancer association and allelic imbalance in this region could be connected. A SNP (rs733655) in matriptase-2 gene (TMPRSS6) was detected to associate with breast Cancer Risk. The genotype frequencies of rs733655 differed significantly between cases and controls in the entire sample and in the geographically and genetically more homogeneous subsample with P = 0.044 and P = 0.0003, respectively. The heterozygous genotype TC was observed to be the Risk genotype in both samples (odds ratios, 1.39; 95% confidence intervals, 1.06-1.83 and odds ratios, 2.11; 95% confidence intervals, 1.46-3.05). An associated two-marker haplotype involving SNP rs733655 (empirical P = 0.041) provides further evidence for breast Cancer Risk Factor locating on 22q12-q13, possibly being TMPRSS6. Our results suggest that matriptase-2 gene is associated with breast Cancer Risk in the Eastern Finnish population.
Graham A Colditz - One of the best experts on this subject based on the ideXlab platform.
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body size from birth through adolescence in relation to Risk of benign breast disease in young women
Breast Cancer Research and Treatment, 2017Co-Authors: Catherine S Berkey, Adetunji T Toriola, Rulla M. Tamimi, Martha Hickey, Walter C Willett, Bernard Rosner, Lindsay A Frazier, Graham A ColditzAbstract:Purpose Body size, from birth throughout adulthood, is associated with breast Cancer Risk, but few studies have investigated early-life body size and benign breast disease (BBD), a well-established breast Cancer Risk Factor. We consider whether prenatal Factors and size at birth, 10, 18 year, and intervening growth, are related to BBD Risk.
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Physical activity and mammographic breast density: a systematic review
Breast cancer research and treatment, 2012Co-Authors: Lusine Yaghjyan, Graham A Colditz, Kathleen Y. WolinAbstract:Studies show a protective relationship between physical activity and breast Cancer Risk across the life course from menarche to postmenopausal years. Mammographic breast density is a known and strong breast Cancer Risk Factor. Whether the association of physical activity with breast Cancer Risk is mediated through mammographic breast density is poorly understood. This systematic review summarizes published studies that investigated the association between physical activity and mammographic breast density and discusses the methodological issues that need to be addressed. We included in this review studies that were published before October 31, 2011 that were accessible in full-text format and were published in English. We identified 20 studies through the PubMed Central, BioMed Central, Embase, and Scopus and using the search terms “physical activity and breast density” and “exercise and breast density” as well as through manual searches of the bibliographies of the articles identified in electronic searches. We found no evidence of association between physical activity and breast density across the studies by grouping them first by the timing of physical activity assessment (in adolescence, current/recent, past, and lifetime) and then by women’s menopausal status (premenopausal and postmenopausal). Given the strength of the relationship between physical activity and breast Cancer and the null findings of this review, it is unlikely that the effect of physical activity is mediated through an effect on breast density.
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Vitamin D and mammographic breast density: a systematic review
Cancer Causes & Control, 2012Co-Authors: Lusine Yaghjyan, Graham A Colditz, Bettina DrakeAbstract:Studies suggest a protective relationship between Vitamin D and breast Cancer Risk. Several studies assessed the association of Vitamin D with mammographic breast density, a known and strong breast Cancer Risk Factor. Understanding the potential role of Vitamin D in the modification of breast density might open new avenues in breast Cancer prevention. This systematic review summarizes published studies that investigated the association between Vitamin D and mammographic breast density and offers suggestions for strategies to advance our scientific knowledge.
