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Sample records for genes ercc2 xrcc3

  1. Polymorphisms in the genes ERCC2, XRCC3 and CD3EAP influence treatment outcome in multiple myeloma patients undergoing autologous bone marrow transplantation

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    Vangsted, Annette; Gimsing, Peter; Klausen, Tobias W

    2007-01-01

    ) of polymorphism in the DNA repair genes ERCC1, ERCC2 and XRCC3, and in the apoptotic genes PPP1R13L and CD3EAP in 348 patients with multiple myeloma undergoing autologous bone marrow transplantation. Carriers of the variant C-allele of ERCC2 K751Q, the variant T-allele of XRCC3 T241M and the variant A...

  2. Influence of DNA repair gene polymorphisms of hOGG1, XRCC1, XRCC3, ERCC2 and the folate metabolism gene MTHFR on chromosomal aberration frequencies.

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    Skjelbred, Camilla Furu; Svendsen, Marit; Haugan, Vera; Eek, Anette Kildal; Clausen, Kjell Oskar; Svendsen, Martin Veel; Hansteen, Inger-Lise

    2006-12-01

    We have studied the effect of genetic polymorphisms in the DNA repair genes hOGG1, XRCC1, XRCC3, ERCC2 and the MTHFR gene in the folate metabolism on the frequencies of cells with chromosomal aberrations (CA), chromosome-type aberrations (CSA), chromatid-type aberrations (CTA), chromatid breaks (CTB) and chromatid gaps (CTG) scored in peripheral blood lymphocytes from 651 Norwegian subjects of Caucasian descendant. DNA was extracted from fixed cell suspensions. The log-linear Poisson regression model was used for the combined data which included age, smoking, occupational exposure and genotype for 449 subjects. Our results suggest that individuals carrying the hOGG1 326Cys or the XRCC1 399Gln allele have an increased risk of chromosomal damage, while individuals carrying the XRCC1 194Trp or the ERCC2 751Gln allele have a reduced risk regardless of smoking habits and age. Individuals carrying the XRCC1 280His allele had an increased risk of CSA which was only apparent in non-smokers. This was independent of age. A protective effect of the XRCC3 241Met allele was only found in the older age group in non-smokers for CA, CSA and CTA, and in smokers for CSA. In the youngest age group, the opposite effect was found, with an increased risk for CA, CTA and CTG in smokers. Carrying the MTHFR 222Val allele gave an increased risk for chromosome and chromatid-type aberrations for both non-smokers and smokers, especially for individuals in the older age group, and with variable results in the youngest age group. The variables included in the different regression models accounted, however, for only 4-10% of the variation. The frequency ratio for CTG was significantly higher than for CTA and CTB for only 7 of the 43 comparisons performed. Some of the gap frequencies diverge from the trend in the CA, CSA, CTA and CTB results.

  3. Identification of Damaging nsSNVs in HumanERCC2 Gene.

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    Fang, Shuo; Zhang, Yuntong; Xu, Miao; Xue, Chunyu; He, Lin; Cai, Lei; Xing, Xin

    2016-09-01

    The hERCC2 gene is an important DNA repair molecule for initiating Cutaneous melanoma (CM). Therefore, it is advisable to study the possible functional SNVs in hERCC2. To achieve this goal, we collected total 2, 253 SNVs in hERCC2from the EMBL website, of which 303 are non-synonymous single nucleotide variants (nsSNVs). Then, SIFT and PolyPhen were used to predict the damaging nsSNVs, and four nsSNVs (rs368866996, rs377739017, rs370819591, and rs121913022) were suggested to be damaging mutations. Since I-Mutant2.0 showed a decrease in stability for the mutants containing each of the four nsSNVs, a 3D protein structure was modeled. Based on the comparison of the energy after minimization, RMSD and stabilizing residues between the native and mutant proteins' structure, rs121913022 was proposed to be the most damaging variant among the nsSNVs in hERCC2 gene by decreasing the stability of protein. The mutant G713R of hERCC2 protein caused by rs121913022 was found to have less expression level than native hERCC2 protein in melanoma cells. These results suggest that rs121913022 may have potentially important clinical and drug target implications.

  4. Enhancing alkylating agent resistance through ERCC2 gene transfection in human glioma cell line

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    CHEN Zhongping 陈忠平; ZHANG Junying 张俊英; Gérard MOHR

    2003-01-01

    Objective To confirm the enhancing effect of excision repair cross complementing rodent repair deficiency gene 2 (ERCC2) on alkylating agents resistance. Methods The authors constructed a pcDNA3-ERCC2 plasmid. The pcDNA3-ERCC2 was transfected into a selected ERCC2 negative human glioma cell line, SKMG-4, using liposome-mediated transfection. After G418 selection, a stable transfected cell line was obtained and tested for cytotoxicity of several alkylating agents. Results The stable transfectant was obtained and confirmed by RT-PCR as well as Western blot analysis to be strongly expressing ERCC2 at both mRNA and protein levels. The IC90 (μmol/L) of two alkylating agents, cisplatin and melphalan, increased from 1.0 to 1.75 (75%) and 5.6 to 9.0 (61%), respectively, compared with control cell line. Conclusion The present data provided evidences and confirmed the authors' previous results that ERCC2 contributes, at least partially, to alkylating agent resistance in human glioma cell line.

  5. XRCC3 Gene Polymorphism Is Associated with Survival in Japanese Lung Cancer Patients

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    Yoshiaki Kido

    2012-12-01

    Full Text Available We focused on OGG1 Ser326Cys, MUTYH Gln324His, APEX1 Asp148Glu, XRCC1 Arg399Gln, and XRCC3 Thr241Met and examined the relationship between the different genotypes and survival of Japanese lung cancer patients. A total of 99 Japanese lung cancer patients were recruited into our study. Clinical data were collected, and genotypes of the target genes were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP. Survival analysis to verify the impact of these gene polymorphisms on the clinical outcome of lung cancer showed that lung squamous cell carcinoma patients with the Thr/Met genotype at XRCC3 had a significantly shorter survival time than those with the Thr/Thr genotype (13 months versus 48 months; log-rank test, p < 0.0001. Cox regression analysis showed that the carriers of XRCC3 genotypes were at a significantly higher risk [adjusted hazard ratio (HR = 9.35, 95% confidence interval (CI = 2.52–34.68, p = 0.001; adjusted HR = 9.05, 95% CI = 1.89–44.39, p = 0.006]. Our results suggest that XRCC3 Thr241Met may act as a favorable prognostic indicator for lung squamous cell carcinoma patients. 

  6. Polymorphisms of the DNA repair genes XRCC1 and XRCC3 in a Brazilian population

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    Duarte Márcia Cristina

    2005-01-01

    Full Text Available In several DNA repair genes, polymorphisms may result in reduced repair capacity, which has been implicated as a risk factor for various types of cancer. The frequency of the polymorphic alleles varies among populations, suggesting an ethnic distribution of genotypes. We genotyped 300 healthy Southeastern Brazilian individuals (262 of European ancestry and 38 of African ancestry for polymorphisms of codons 194 and 399 of the XRCC1 base excision repair pathway gene and of codon 241 of the XRCC3 homologous recombination repair pathway gene. The allele frequencies were 0.07 for the Arg194Trp and 0.33 for the Arg399Gln codons of the XRCC1 gene and 0.35 for the Thr241Met codon of the XRCC3 gene. The genotypic frequencies were within Hardy-Weinberg equilibrium. These frequencies showed ethnic variability when compared with those obtained for different populations from several countries.

  7. Polymorphisms in DNA repair genes XRCC2 and XRCC3 risk of gastric cancer in Turkey

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    İlhami Gok

    2014-09-01

    Full Text Available We studied the prevalence of polymorphisms in genes XRCC2 and XRCC3 in stomach cancer patients who lived in North Eastern Turkey. A total of 61 cancer patients and 78 controls were included in this study. Single nucleotide changes were studied in XRCC2 and XRCC3 genes at locus Arg188His and Thr241Met. Blood samples were taken from the patients and controls, and DNA was isolated. The regions of interest were amplified using a polymerase chain reaction method. After amplification, we used restriction enzymes (HphI and NcoI to digest the amplified product. Digested product was then run through gel electrophoresis. We identified changes in the nucleotides in these specific regions. It was found that the Arg188His polymorphism of the XRCC2 gene was about 39% (24 out of the 61 among cancer patients. However, only 15% (12 out of 78 of the control group indicated this polymorphism. We also observed that 18 of the 61 cancer patients (29% carried the Thr241Met polymorphism of the XRCC3 gene whereas 11 of the 78 (14% individuals in the control group had the polymorphism. Our results showed a significant difference in polymorphism ratios between the cancer patients and health control group for the regions of interest. This result clearly showed that these polymorphisms increase the risk of stomach cancer and might be a strong marker for early diagnosis of gastric cancer.

  8. Relationship between XRCC3 gene polymorphisms and lung cancer%XRCC3基因多态性与肺癌的关联

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    黄萌; 陈星; 邱月锋; 樊丽辉; 陈俊磊; 蔡琳

    2011-01-01

    Objective To explore the relationship between XRCC3 and lung cancer after selecting tag SNPs from HapMap database and reconstructing haplotypes.Methods Using case-control study design, smoking condition were surveyed by questionare.Peripheral blood of cases and saliva or buccal cell for controls were collected, and then their DNA were extracted.XRCC3 tagSNPs were genotyped by PCR-RFLP.TagSNPs were selected by Haploview, HWE and LD were checked by LDA.Best genetic model and relationship between tagSNPs and lung cancer were analysed by SPSS, and haplotype frequencies and effects were computed by THESIAS.Results Carriers of rs861537 AG or AA genotype had a statistically significantly increased risk for lung cancer ( OR =1.48,95% CI: 1.17 -1.86).Carriers of rs1799794 per G allele had a statistically significantly decreased risk for lung cancer (OR =0.83,95% CI: 0.72 -0.97 ); no significant association was observed between rs861539 and lung cancer.Smoke interacted with rs861537 polymorphism.Compared with CGG haplotype, carriers of CAA had a statistically significantly increased risk for lung cancer ( OR = 1.32,95% CI 1.11 - 1.57).Conclusion XRCC3 gene polymorphisms were associated with lung cancer.%目的 利用HapMap数据库筛选标签SNPs,构建单体型,探讨XRCC3基因多态性与肺癌的关联.方法 采用病例对照研究设计,以问卷调查获取研究对象的吸烟状况.采集病例的外周血与对照的唾液和口腔细胞,提取DNA,以PCR-RFLP技术对XRCC3的SNPs分型.应用Haploview挑选标签SNPs,LDA检验HWE与LD,SPSS分析最优遗传模型及SNPs与肺癌的关联,THESIAS推断单体型频率及其对肺癌的影响.结果 XRCC3的rs861537 AG或AA携带者的肺癌风险较GG携带者高(OR=1.48,95%CI 1.17~1.86);携带一个rs1799794 G,肺癌风险即降低(OR=0.83,95%CI0.72~0.97);rs861539多态性与肺癌无明显关联.吸烟与rs861537变异存在交互作用.以单体型CGG为参照,携带CAA增加了肺癌风险(OR=1

  9. Polymorphisms in DNA Repair Gene XRCC3 and Susceptibility to Breast Cancer in Saudi Females

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    Alaa Mohammed Ali

    2016-01-01

    Full Text Available We investigated three common polymorphisms (SNPs in the XRCC3 gene (rs861539, rs1799794, and rs1799796 in 143 Saudi females suffering from breast cancer (median age = 51.4 years and 145 age matched normal healthy controls. DNA was extracted from whole blood and genotyping was conducted using PCR-RFLP. rs1799794 showed significant association, where AA and AA+AG occurred at a significantly higher frequency in the cancer patients compared to the control group (OR: 28.1; 95% CI: 3.76–21.12; χ2: 22.82; pT and rs1799796 A>G did not show a significant difference when the results in the patients and controls were compared. However, the frequency of rs1799796 differed significantly in patients with different age of diagnosis, tumor grade, and ER and HER2 status. The wild type A allele occurred at a higher frequency in the ER− and HER2− group. Our results among Saudis suggest that some variations in XRCC3 may contribute to breast cancer susceptibility. In conclusion, the results obtained during this study suggest that rs1799794 in XRCC3 shows strong association with breast cancer development in Saudi females.

  10. Polymorphism of XRCC1, XRCC3, and XPD Genes and Risk of Chronic Myeloid Leukemia

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    Claudia Bănescu

    2014-01-01

    Full Text Available The genetic polymorphisms of X-ray repair cross complementing group 1 (XRCC1, X-ray repair cross complementing group 3 (XRCC3, and xeroderma pigmentosum complementation group D (XPD repair genes may lead to genetic instability and leukemogenesis. The purpose of the study was to evaluate the association between XRCC1 Arg399Gln, Arg280His and Arg194Trp, XRCC3 Thr241Met, and XPD Lys751Gln polymorphisms and the risk of developing CML in Romanian patients. A total of 156 patients diagnosed with CML and 180 healthy controls were included in this study. We found no association between CML and XRCC1 or XRCC3 variant genotypes in any of the investigated cases. A significant difference was observed in the variant genotype frequencies of the XPD Lys751Gln polymorphism between the patients with CML and control group (for variant homozygous genotypes, OR=2.37; 95% CI=1.20–4.67; P value = 0.016 and for combined heterozygous and variant homozygous genotypes, OR=1.72; 95% CI=1.10–2.69; P value = 0.019. This was also observed when analyzing the variant 751Gln allele (OR=1.54; 95% CI=1.13–2.11; P value = 0.008. Our results suggest that the XPD Lys751Gln variant genotype increases the risk of CML.

  11. Polymorphism of XRCC1, XRCC3, and XPD genes and risk of chronic myeloid leukemia.

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    Bănescu, Claudia; Trifa, Adrian P; Demian, Smaranda; Benedek Lazar, Erzsebeth; Dima, Delia; Duicu, Carmen; Dobreanu, Minodora

    2014-01-01

    The genetic polymorphisms of X-ray repair cross complementing group 1 (XRCC1), X-ray repair cross complementing group 3 (XRCC3), and xeroderma pigmentosum complementation group D (XPD) repair genes may lead to genetic instability and leukemogenesis. The purpose of the study was to evaluate the association between XRCC1 Arg399Gln, Arg280His and Arg194Trp, XRCC3 Thr241Met, and XPD Lys751Gln polymorphisms and the risk of developing CML in Romanian patients. A total of 156 patients diagnosed with CML and 180 healthy controls were included in this study. We found no association between CML and XRCC1 or XRCC3 variant genotypes in any of the investigated cases. A significant difference was observed in the variant genotype frequencies of the XPD Lys751Gln polymorphism between the patients with CML and control group (for variant homozygous genotypes, OR = 2.37; 95% CI = 1.20-4.67; P value = 0.016 and for combined heterozygous and variant homozygous genotypes, OR = 1.72; 95% CI = 1.10-2.69; P value = 0.019). This was also observed when analyzing the variant 751Gln allele (OR = 1.54; 95% CI = 1.13-2.11; P value = 0.008). Our results suggest that the XPD Lys751Gln variant genotype increases the risk of CML.

  12. Contribution of DNA double-strand break repair gene XRCC3 genotypes to oral cancer susceptibility in Taiwan.

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    Tsai, Chia-Wen; Chang, Wen-Shin; Liu, Juhn-Cherng; Tsai, Ming-Hsui; Lin, Cheng-Chieh; Bau, Da-Tian

    2014-06-01

    The DNA repair gene X-ray repair cross complementing protein 3 (XRCC3) is thought to play a major role in double-strand break repair and in maintaining genomic stability. Very possibly, defective double-strand break repair of cells can lead to carcinogenesis. Therefore, a case-control study was performed to reveal the contribution of XRCC3 genotypes to individual oral cancer susceptibility. In this hospital-based research, the association of XRCC3 rs1799794, rs45603942, rs861530, rs3212057, rs1799796, rs861539, rs28903081 genotypes with oral cancer risk in a Taiwanese population was investigated. In total, 788 patients with oral cancer and 956 age- and gender-matched healthy controls were genotyped. The results showed that there was significant differential distribution among oral cancer and controls in the genotypic (p=0.001428) and allelic (p=0.0013) frequencies of XRCC3 rs861539. As for the other polymorphisms, there was no difference between case and control groups. In gene-lifestyle interaction analysis, we have provided the first evidence showing that there is an obvious joint effect of XRCC3 rs861539 genotype with individual areca chewing habits on oral cancer risk. In conclusion, the T allele of XRCC3 rs861539, which has an interaction with areca chewing habit in oral carcinogenesis, may be an early marker for oral cancer in Taiwanese.

  13. DNA repair gene ERCC2 polymorphisms and associations with breast and ovarian cancer risk

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    Rabiau Nadège

    2008-05-01

    Full Text Available Abstract Breast and ovarian cancers increased in the last decades. Except rare cases with a genetic predisposition and high penetrance, these pathologies are viewed as a polygenic disease. In this concept, association studies look for genetic variations such as polymorphisms in low penetrance genes, i.e. genes in interaction with environmental factors. DNA repair systems that protect the genome from deleterious endogenous and exogenous damages have been shown to have significantly reduced. In particular, enzymes of the nucleotide excision repair pathway are suspected to be implicated in cancer. In this study, 2 functional polymorphisms in a DNA repair gene ERCC2 were analyzed. The population included 911 breast cancer cases, 51 ovarian cancer cases and 1000 controls. The genotyping of 2 SNP (Single Nucleotide Polymorphism was carried out on the population with the MGB (Minor Groove Binder probe technique which consists of the use of the allelic discrimination with the Taqman® method. This study enabled us to show an increase in risk of breast cancer with no oral contraceptive users and with women exhibiting a waist-to-hip ratio (WHR > 0.85 for Asn homozygous for ERCC2 312.

  14. Polymorphism of the XRCC3 gene and risk of gastric cancer in a Kashmiri population: a case-control study.

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    Bashir, Haamid; Majid, Sabhiya; Hamid, Rabia; Farooq, Rabia; Wani, Hilal A; Shoib, Sheikh; Bhat, Arief A

    2015-05-01

    DNA repair plays a critical role in protecting the genome of the cell from the insults of cancer-causing agents. Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity, which may be associated with the risk of developing cancer. Inherited polymorphisms of DNA repair genes may contribute to variations in DNA repair capacity and genetic susceptibility to different cancers. The X-ray repair complementing defective repair in Chinese hamster cells 3 (XRCC3) gene is a member of the RAD51 gene family. It encodes an important protein that functions in the homologous recombination repair of a DNA double-strand break. For gastric cancer, the importance of mutations in mismatch repair genes has been well documented, but less is known about other DNA repair pathways in gastric carcinogenesis. In this study, we have focused on the XRCC3 gene, involved in homologous recombinational repair. The Kashmir valley has an increased incidence of gastric cancer and its etiology has not been understood fully as yet. As the Kashmiri population is ethnically and demographically different from that in other parts of the world, the aim of this study was to determine whether a single nucleotide polymorphism of the XRCC3 gene (Thr241Met) of exon 7 can influence the risk of gastric cancer in the population. As many as 80 histopathologically confirmed gastric cancer cases and 70 healthy controls, age, sex, and ethnicity matched for known genotypes of XRCC3 exon 7 were studied. We genotyped for this variant using PCR-restriction fragment length polymorphisms. The XRCC3 genotype and allele frequencies were not significantly different between cases and controls (P=0.92 for the genotype; P=0.72 for the allele). The XRCC3 241Met allele frequency (6.6%) was significantly lower in healthy Kashmiri controls than reported previously in healthy US White controls (38.9%). Compared with the XRCC3 241Thr/Thr genotype, the variant XRCC3 241Thr/Met and Met

  15. Association of C722T polymorphism in XRCC3 gene with larynx cancer: a meta-analysis.

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    Li, Dong; You, Hui-Hua; Jia, Yuan-Jing; Guo, Jian-Dong; Du, Huan-Le

    2014-06-01

    Several case-control studies indicated that XRCC3 genetic polymorphism (C722T) was associated with larynx cancer. The present study aimed to further evaluate the relation between the XRCC3 gene C722T polymorphism and larynx cancer. We selected five case-control studies related to XRCC3 gene C722T polymorphism and larynx cancer by searching PubMed, EMBase, Chinese CNKI, and Wanfang database. RevMan 5.0 software was used to perform the analysis. We directly utilized Q test and I (2) test to test the heterogeneity between each study. We utilized the fixed effects model to merge the odds ratio (OR) and 95 % confidence interval. There were 1,507 larynx cancer patients and 3,623 cancer-free control subjects included in the present study. By meta-analysis, we did not find any association of XRCC3 gene C722T polymorphism with larynx cancer [OR=1.54, 95 % CI (0.77-3.08); P=0.22]. The present study indicated that XRCC3 gene C722T polymorphism was not associated with larynx cancer.

  16. XRCC3 Thr241Met gene polymorphisms and lung cancer risk: a meta-analysis

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    Zhan Ping

    2013-01-01

    Full Text Available Abstract Many studies have examined the association between the XRCC3 Thr241Met gene polymorphism and lung cancer risk in various populations, but their results have been inconsistent. To assess this relationship more precisely, a meta-analysis was performed. The PubMed, Embase, Web of Science, and CNKI database was searched for case–control studies published up to July 2012. Data were extracted and pooled odds ratios (OR with 95% confidence intervals (CI were calculated. Ultimately, 17 studies, comprising 4123 lung cancer cases and 5597 controls were included. Overall, for T allele carriers (TC + TT versus the wild-type homozygotes (CC, the pooled OR was 0.95 (95% CI = 0.87-1.04 P = 0.228 for heterogeneity, for TT versus CC the pooled OR was 0.99 (95% CI = 0.86-1.15 P = 0.315 for heterogeneity. In the stratified analysis by ethnicity, histological types of lung cancer and smoking status, no any significantly risks were found for (C/T + T/T vs C/C or T/T vs C/C. No publication bias was found by using the funnel plot and Egger's test. Overall, there is no evidence showing a significant correlation between XRCC3 Thr241Met polymorphism and lung cancer risk stratified analysis by ethnicity, histology and smoking status.

  17. Lys751Gln polymorphism in ERCC2 gene is associated with lung cancer susceptibility in the Chinese population

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    Liang Geyu; Pu Yuepu; Yin Lihong

    2007-01-01

    The excision repair cross-complementing group 2 (ERCC2) gene encodes a DNA repair protein, which is absolutely necessary in nucleotide excision repair. A polymorphism in codon 751 that induces a Lys→Gln substitution has been suggested to reduce the DNA repair capacity. Therefore, we conducted a matched case-control study to investigate the role of ERCC2 Lys751Gln polymorphism in the development of lung cancer in the Chinese population. The genotype of ERCC2 gene was analyzed by di-allele-specific-amplification with artificially modified primers (diASA-AMP) in 200 original lung cancer cases and 200 controls. The results showed that carriers of Lys/Gln and Gln/Gln genotypes had a 3.32-fold higher risk of lung cancer compared with carriers of Lys/Lys genotype. Furthermore,the mutant genotype of 751Gln allele was found to be associated with an increased risk in both lung squamous cell carcinoma and lung adenocarcinoma. However, no significant interaction between 751Gln variants and smoking was observed after stratifying according to the smoking status in this study. The results suggest that the Lys751Gln polymorphism in ERCC2 gene is a potential biomarker for susceptibility of lung cancer in the Chinese population.

  18. The effect of a DNA repair gene on cellular invasiveness: XRCC3 over-expression in breast cancer cells.

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    Veronica L Martinez-Marignac

    Full Text Available Over-expression of DNA repair genes has been associated with resistance to radiation and DNA-damage induced by chemotherapeutic agents such as cisplatin. More recently, based on the analysis of genome expression profiling, it was proposed that over-expression of DNA repair genes enhances the invasive behaviour of tumour cells. In this study we present experimental evidence utilizing functional assays to test this hypothesis. We assessed the effect of the DNA repair proteins known as X-ray complementing protein 3 (XRCC3 and RAD51, to the invasive behavior of the MCF-7 luminal epithelial-like and BT20 basal-like triple negative human breast cancer cell lines. We report that stable or transient over-expression of XRCC3 but not RAD51 increased invasiveness in both cell lines in vitro. Moreover, XRCC3 over-expressing MCF-7 cells also showed a higher tumorigenesis in vivo and this phenotype was associated with increased activity of the metalloproteinase MMP-9 and the expression of known modulators of cell-cell adhesion and metastasis such as CD44, ID-1, DDR1 and TFF1. Our results suggest that in addition to its' role in facilitating repair of DNA damage, XRCC3 affects invasiveness of breast cancer cell lines and the expression of genes associated with cell adhesion and invasion.

  19. DNA repair gene XRCC3 241Met variant and breast cancer susceptibility of Azeri population in Iranian

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    Gohari-Lasaki Sahar

    2015-01-01

    Full Text Available DNA-repair systems are essential for repairing damage that occurs when there is recombination between homologous chromosomes. The gene XRCC3 (X-ray cross complementing group 3 encodes a member of the RecA/Rad51-related protein family that participates in homologous recombination to maintain chromosome stability and repair DNA damage. The Thr241Met XRCC3-18067C>T, rs861539 substitution, a C to T transition at codon 241 in exon7, thus plays critical roles in cancer development. The aim of this study was association between XRCC3 Thr241Met polymorphism and risk of sporadic breast cancer in Azari population. We analysed DNA samples from 100 sporadic breast cancer patients and 100 healthy women, for XRCC3 Thr241Met polymorphism using PCR-RFLP. Genotype specific risks were tested using chi-test with 95% confident intervals. Frequency of Thr/Thr at codon 241was 69% in controls and 70% in patients, Thr/Met frequency was 22% in controls and 13 % in patients, the Met/Met genotype was 9% incontrols and 17% in patients. No correlation between the genotype and allele distribution and increased susceptibility for breast Cancer. Our results suggested that in pre-menopausal women, breast cancer riskis not significantly associated with rs861539 in Azari population.

  20. Allelic variants of XRCC1 and XRCC3 repair genes and susceptibility of oral cancer in Brazilian patients

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    Dos Reis, Mariana Bisarro; Losi-Guembarovski, Roberta; de Souza Fonseca Ribeiro, Enilze Maria

    2013-01-01

    genes have been found to be associated with oral cancer. The aim of this study was to investigate the relationship between the presence of allelic variants Arg194Trp (rs:1799782) and Arg399Gln (rs: 25487) of XRCC1 gene and Thr241Met (rs: 861539) of XRCC3 gene and susceptibility to oral cancer. We also...... variants of the XRCC1 gene within codon 194 (OR 0.82, 95% CI: 0.44-1.51) and codon 399 (OR 0.94, 95% CI: 0.59-1.50) and within the XRCC3 gene (OR 0.72; 95% CI: 0.45-1.16) were not associated with an increased risk of oral cancer. A combinational analysis of SNPs in both genes indicated no association....... The presence of the allelic variants of these two genes had no statistically significant effect on tumor differentiation, lymph node invasion or tumor size. CONCLUSIONS: These results suggest that allelic variants of XRCC1 and XRCC3 are not suitable markers for susceptibility to carcinomas of the oral cavity...

  1. Analyzing Association of the XRCC3 Gene Polymorphism with Ovarian Cancer Risk

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    Cunzhong Yuan

    2014-01-01

    Full Text Available This meta-analysis aims to examine whether the XRCC3 polymorphisms are associated with ovarian cancer risk. Eligible case-control studies were identified through search in PubMed. Pooled odds ratios (ORs were appropriately derived from fixed effects models. We therefore performed a meta-analysis of 5,302 ovarian cancer cases and 8,075 controls from 4 published articles and 8 case-control studies for 3 SNPs of XRCC3. No statistically significant associations between XRCC3 rs861539 polymorphisms and ovarian cancer risk were observed in any genetic models. For XRCC3 rs1799794 polymorphisms, we observed a statistically significant correlation with ovarian cancer risk using the homozygote comparison (T2T2 versus T1T1: OR = 0.70, 95% CI = 0.54–0.90, P=0.005, heterozygote comparison (T1T2 versus T1T1: OR = 1.10, 95% CI = 1.00–1.21, P=0.04, and the recessive genetic model (T2T2 versus T1T1+T1T2: OR = 0.67, 95% CI = 0.52–0.87, P=0.002. For XRCC3 rs1799796 polymorphisms, we also observed a statistically significant correlation with ovarian cancer risk using the heterozygote comparison (T1T2 versus T1T1: OR = 0.91, 95% CI = 0.83–0.99, P=0.04. In conclusion, this meta-analysis shows that the XRCC3 were associated with ovarian cancer risk overall for Caucasians. Asian and African populations should be further studied.

  2. 检测ERCC2基因多态性在乳腺癌分子病理诊断中的应用%Application of ERCC2 gene polymorphism detection in molecular pathological diagnosis of breast cancer

    Institute of Scientific and Technical Information of China (English)

    王涛; 张永东; 郭欢; 李海宁; 李永辉; 郭红云; 苏海翔

    2015-01-01

    目的:探讨ERCC2基因rs3916840 C/T、rs1799793 G/A和rs238416 G/A多态性在乳腺癌分子病理诊断中的应用价值。方法应用聚合酶链反应-限制性片段长度多态性( polymerase chain reaction-restriction fragment length polymorphism, PCR-RFLP)法比较101例乳腺癌和101例正常对照组中ERCC2基因rs3916840、rs1799793和rs238416位点的多态性分布与乳腺癌易感性及临床病理特征之间的关系。结果 rs3916840位点的多态性分布与肿瘤大小显著相关(P=0.049);rs1799793位点的多态性分布与乳腺病理组织PR状态(P=0.037)及三阴性乳腺癌(P=0.037)显著相关,rs238416位点的多态性分布与p53蛋白表达显著相关,p53蛋白阳性的乳腺癌患者所携带的GA基因型频率显著低于 p53阴性乳腺癌患者( P=0.026)。缺失rs238416位点基因型GA的个体患乳腺癌的风险增加0.287倍(P0.05)。结论 rs3916840、rs1799793和rs238416位点的多态性分布分别与肿瘤大小、PR状态、三阴性乳腺癌以及p53蛋白表达相关,检测ERCC2基因的多态性在乳腺癌的早期诊断及预后中具有一定的应用价值。%Purpose To evaluate the application value of ERCC2 gene polymorphism ( rs3916840 C/T, rs1799793 G/A and rs238416 G/A) detection in molecular pathological diagnosis of breast cancer. Methods The polymorphisms of ERCC2 ( rs3916840, rs1799793 and rs238416) were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in 101 patients with breast cancer and in 101 cancer-free controls. Results Analysis of the data showed a 0. 287-fold increased risk of breast cancer due to the deletion of genotype GA at rs238416 (P0. 05). Furthermore, Heterozygous genotype of rs3916840 was significantly associated with tumor size (P=0. 049), heterozygous genotype of rs1799793 was significantly associated with PR sta-tus and triple negative breast cancer (P=0. 037). Remarkably, the genotype frequency of GA in p53

  3. Association of single nucleotide polymorphisms in ERCC2 gene and their haplotypes with esophageal squamous cell carcinoma.

    Science.gov (United States)

    Zhang, Yougai; Wang, Longzhi; Wang, Peng; Song, Chunhua; Wang, Kaijuan; Zhang, Jianying; Dai, Liping

    2014-05-01

    Esophageal squamous cell carcinoma (ESCC), one of the leading causes of cancer death worldwide, occurs at a relatively high frequency in China. To investigate whether common excision repair cross-complementing rodent repair group 2 (ERCC2) variants (rs3916874 G>C, rs238415 C>G, rs1618536 G>A, rs1799793 G>A, and rsl3181 A>C) were associated with ESCC risk, a case-control study was conducted, including 405 cases with ESCC and 405 age and sex 1:1 matched cancer-free controls. The result showed that rsl3181 AC/CC genotypes was associated with an increased risk of ESCC (OR: 1.45, 95% CI: 1.05-2.00), and two ERCC2 haplotypes Grs3916874Crs238415Grs1618536Grs1799793Crsl3181 (Hap5) and Grs3916874Grs238415Ars1618536Grs1799793Crsl3181 (Hap7) were associated with increased risk of ESCC (OR: 2.16, 95 % CI: 1.27-3.57 for Hap5 and OR: 3.72; 95 % CI: 1.89-6.63 for Hap7, respectively), while Grs3916874Grs238415Grs1618536Grs1799793Arsl3181 (Hap4) was associated with decreased risk of ESCC (OR: 0.47, 95% CI: 0.35-0.71). Gene-environment interaction analysis by multifactor dimensionality reduction (MDR) software showed that there was an interaction among rs238415, rs1618536, and family history of cancer with a P value under 0.0001 (OR: 3.23: 95% CI: 2.37-4.40). These results suggested that genetic variations in the ERCC2 gene were associated with risk of ESCC, and there was a significant interaction between gene polymorphisms and family history of cancer in the etiology of ESCC.

  4. Polymorphisms of DNA repair gene XRCC3 and susceptibility of colon carcinoma%DNA修复基因XRCC3多态性与结肠癌易感性的关系

    Institute of Scientific and Technical Information of China (English)

    张嘉炜; 孟翔凌

    2011-01-01

    目的 研究DNA修复基因XRCC3多态性及其与结肠癌易感性的关系.方法 选择80例经病理证实的结肠癌患者为肿瘤组,80例同期经门诊肠镜检查无异常的健康体检者为对照组,采用限制性片段长度多态性-聚合酶链反应(RFLP-PCR)法检测XRCC3基因C18607T的多态性分布,比较不同基因型与结肠癌易感性的关系.结果 XRCC3 C18607T基因型C/C(野生型纯合子)、C/T(杂合子)和T/T(突变型纯合子)在肿瘤组的分布频率为58.75%、38.75%、2.50%,在对照组的分布频率为76.25%、22.50%、1.25%.各基因型在肿瘤组和对照组中的分布频率符合Hardy-Weinberg平衡规律.与携带C/C的个体相比,携带T等位基因的变异基因型(C/T+T/T)的个体具有更高的结肠癌易感性.结论 XRCC3基因C18607T的多态性可能与结肠癌易感性相关.%To study the relationship between the polymorphisms of DNA repair gene XRCC3 and susceptibility of colon carcinoma. Methods Selected eighty colon carcinoma patients as tumor cases and eighty health people as control cases. The XRCC3 C18607T genotypes were detected by restriction fragment length polymor-phism-polymerase chain reaction( RFLP-PCR ), and explored the relationship between the different genotypes and the susceptibility of colon carcinoma. Results The frequency of the XRCC3 C18607T genotypes C/C, C/T and T/T was 58. 75% ,38. 75% and 2. 50% respectively in colon carcinoma patients, but the frequency was 76. 25% , 22. 50% and 1. 25% respectively in normal control. The distribution of genotypes in colon carcinoma patients and the health controls was up to Hardy-Weinberg law. Compared with C/C genotype, combination of C/T and T/T genotype both increased the risk of colon cancer. Conclusion The polymorphism of XRCC3 C18607T may be associated with the increased risk of colon carcinoma.

  5. Defects in the DNA repair and transcription gene ERCC2(XPD) in trichothiodystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Takayama, K.; Salazar, E.P.; Thompson, L.H. [Lawrence Livermore National Lab., CA (United States)] [and others

    1996-02-01

    Trichothiodystrophy (TTD) is a rare autosomal recessive disorder characterized by brittle hair with reduced sulfur content, ichthyosis, peculiar face, and mental and growth retardation. Clinical photosensitivity is present in {approximately}50% of TTD patients but is not associated with an elevated frequency of cancers. Previous complementation studies show that the photosensitivity in nearly all of the studied patients is due to a defect in the same genetic locus that underlies the cancer-prone genetic disorder xeroderma pigmentosum group D (XP-D). Nucleotide-sequence analysis of the ERCC2 cDNA from three TTD cell strains (TTD1VI, TTD3VI, and TTD1RO) revealed mutations within the region from amino acid 713-730 and within previously identified helicase functional domains. The various clinical presentations and DNA repair characteristics of the cell strains can be correlated with the particular mutations found in the ERCC2 locus. Mutations of Arg658 to either His or Cys correlate with TTD cell strains with intermediate UV-sensitivity, mutation of Arg722 to Trp correlates with highly UV-sensitive TTD cell strains, and mutation of Arg683 to Trp correlates with XP-D. Alleles with mutation of Arg616 to Pro or with the combined mutation of Leu461 to Val and deletion of 716-730 are found in both XP-D and TTD cell strains. 39 refs., 2 figs., 3 tabs.

  6. Polymorphisms of the XRCC1, XRCC3, & XPD genes, and colorectal cancer risk: a case-control study in Taiwan

    Directory of Open Access Journals (Sweden)

    Sung Fung-Chang

    2005-01-01

    Full Text Available Abstract Background Recent studies relating to the association between DNA repair-gene polymorphisms and colorectal cancer risk would, to the best of our knowledge, appear to be very limited. This study was designed to examine the polymorphisms associated with three DNA repair genes, namely: XRCC1 Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln, and investigate their role as susceptibility markers for colorectal cancer. Methods We conducted a case-control study including 727 cases of cancer and 736 hospital-based age- and sex-matched healthy controls to examine the role of genetic polymorphisms of three DNA-repair genes (XRCC1, XRCC3 and XPD in the context of colorectal cancer risk for the Taiwanese population. Genomic DNA isolated from 10 ml whole blood was used to genotype XRCC1 Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln by means of polymerase chain reaction (PCR and restriction fragment length polymorphism (RFLP analysis. Results The risk for colorectal cancer did not appear to differ significantly amongst individuals featuring the XRCC1 399Arg/Arg genotype (OR = 1.18; 95% CI, 0.96–1.45, the XRCC3 241Thr/Thr genotype (OR = 1.25; 95% CI, 0.88–1.79 or the XPD 751Gln allele (OR = 1.20; 95% CI, 0.90–1.61, although individuals featuring a greater number of risk genotypes (genotype with OR greater than 1 did experience a higher risk for colorectal cancer when compared to those who didn't feature any risk genotypes (Trend test P = 0.03. Compared with those individuals who didn't express any putative risk genotypes, individuals featuring all of the putative risk genotypes did experience a significantly greater cancer risk (OR = 2.43, 95% CI = 1.21–4.90, particularly for individuals suffering tumors located in the rectum (OR = 3.18, 95% CI = 1.29–7.82 and diagnosed prior to the age of 60 years (OR = 4.90, 95% CI = 1.72–14.0. Conclusions Our results suggest that DNA-repair pathways may simultaneously modulate the risk of colorectal cancer

  7. The influence of genetic polymorphisms in XRCC3 and ADH5 genes on the frequency of genotoxicity biomarkers in workers exposed to formaldehyde.

    Science.gov (United States)

    Ladeira, Carina; Viegas, Susana; Carolino, Elisabete; Gomes, Manuel C; Brito, Miguel

    2013-04-01

    The International Agency for Research on Cancer classified formaldehyde as carcinogenic to humans because there is "sufficient epidemiological evidence that it causes nasopharyngeal cancer in humans". Genes involved in DNA repair and maintenance of genome integrity are critically involved in protecting against mutations that lead to cancer and/or inherited genetic disease. Association studies have recently provided evidence for a link between DNA repair polymorphisms and micronucleus (MN) induction. We used the cytokinesis-block micronucleus (CBMN assay) in peripheral lymphocytes and MN test in buccal cells to investigate the effects of XRCC3 Thr241Met, ADH5 Val309Ile, and Asp353Glu polymorphisms on the frequency of genotoxicity biomarkers in individuals occupationally exposed to formaldehyde (n = 54) and unexposed workers (n = 82). XRCC3 participates in DNA double-strand break/recombination repair, while ADH5 is an important component of cellular metabolism for the elimination of formaldehyde. Exposed workers had significantly higher frequencies (P < 0.01) than controls for all genotoxicity biomarkers evaluated in this study. Moreover, there were significant associations between XRCC3 genotypes and nuclear buds, namely XRCC3 Met/Met (OR = 3.975, CI 1.053-14.998, P = 0.042) and XRCC3 Thr/Met (OR = 5.632, CI 1.673-18.961, P = 0.005) in comparison with XRCC3 Thr/Thr. ADH5 polymorphisms did not show significant effects. This study highlights the importance of integrating genotoxicity biomarkers and genetic polymorphisms in human biomonitoring studies. Copyright © 2013 Wiley Periodicals, Inc.

  8. XRCC3基因多态性与铅作业男工铅毒性易感性的关联研究%Relationship between XRCC3 gene polymorphism and susceptibility to lead poisoning in male lead-exposed workers

    Institute of Scientific and Technical Information of China (English)

    刘祥铨; 张忠

    2013-01-01

    Objective To investigate the relationship between genetic polymorphism of X-ray repair cross-complementing gene 3 (XRCC3) and susceptibility to lead poisoning in male lead-exposed workers.Methods Peripheral venous blood and morning urine samples were collected from 326 male lead-exposed workers in a storage battery factory in Fuzhou.Blood lead,urine lead,blood zinc protoporphyrin (ZPP),blood calcium,and blood iron were measured.The genotype of XRCC3 was determined by polymerase chain reactionrestriction fragment length polymorphism method.The relationship between XRCC3 gene polymorphism and susceptibility to lead poisoning in male lead-exposed workers was analyzed.Results Genetic polymorphism of XRCC3 was seen in the 326 subjects.The frequency distribution of XRCC3 genotypes,XRCC3-241CC (wild type),XRCC3-241CT (heterozygous mutation),and XRCC3-241TT (homozygous mutation),was in accordance with the Hardy-Weinberg equilibrium (P>0.05).There were no significant differences in urine lead,blood ZPP,blood calcium,and blood iron between the lead-exposed workers with different XRCC3 genotypes (P>0.05).The workers with XRCC3-241CT/TT had a significantly higher mean blood lead level than those with XRCC3-241CC (P<0.05).With a blood lead level of 1.90 μmol/L as the cutoff value,the chi-square test and logistic regression analysis showed that the proportion of workers with XRCC3-241CT/TT was significantly higher than that of workers with XRCC3-241CC in the subjects with high blood leads (P<0.05) and that the risk of high blood lead was significantly higher in the workers with XRCC3-241CT/TT than in those with XRCC3-241CC (OR =2.34,95% CI =1.61~5.13); the multivariate linear regression analysis showed that the workers with XRCC3-241CT/TT had high blood lead levels (β=0.116,P<0.05),the workers with smoking habit demonstrated marked lead absorption (β=0.188,P<0.05),good individual protection could reduce lead absorption (β=-0.247,P<0.05),and the individuals

  9. DNA repair genes XRCC1 and XRCC3 polymorphisms and their relationship with the level of micronuclei in breast cancer patients

    Directory of Open Access Journals (Sweden)

    Raquel A. Santos

    2010-01-01

    Full Text Available Breast cancer (BC is the most prevalent type worldwide, besides being one of the most common causes of death among women. It has been suggested that sporadic BC is most likely caused by low-penetrance genes, including those involved in DNA repair mechanisms. Furthermore, the accumulation of DNA damage may contribute to breast carcinogenesis. In the present study, the relationship between two DNA repair genes, viz., XRCC1 (Arg399Gln and XRCC3 (Thr241Met polymorphisms, and the levels of chromosome damage detected in 65 untreated BC women and 85 healthy controls, was investigated. Chromosome damage was evaluated through micronucleus assaying, and genotypes determined by PCR-RFLP methodology. The results showed no alteration in the risk of BC and DNA damage brought about by either XRCC1 (Arg399Gln or XRCC3 (Thr241Met action in either of the two groups. Nevertheless, on evaluating BC risk in women presenting levels of chromosome damage above the mean, the XRCC3 Thr241Met polymorphism was found to be more frequent in the BC group than in the control, thereby leading to the conclusion that there is a slight association between XRCC3 (241 C/T genotypes and BC risk in the subgroups with higher levels of chromosome damage.

  10. The relationship between XRCC1 and XRCC3 gene polymorphisms and lung cancer risk in northeastern Chinese.

    Directory of Open Access Journals (Sweden)

    Shujie Guo

    Full Text Available BACKGROUND: The prevalence of lung cancer in China will be the world's highest if allowed to proceed uncurbed. To unravel its genetic underpinnings, we sought to investigate the association of three well-characterized nonsynonymous polymorphisms in XRCC1 (Arg194Trp and Arg399Gln and XRCC3 (Thr241Met genes with lung cancer risk in northeastern Chinese. METHODOLOGY/PRINCIPAL FINDINGS: This study was hospital-based in design, encompassing 684 patients with lung cancer and 604 cancer-free controls. Genotyping was performed using the PCR-LDR (ligase detection reactions method. Data were analyzed by R language and multifactor dimensionality reduction (MDR software. Single-locus analysis identified significance in genotype distributions of polymorphism Arg194Trp (P = 0.002 and Arg399Gln (P = 0.017, and in allele distributions of Thr241Met (P = 0.005. Carriers of 399Gln/Gln genotype conferred a 147% increased risk relative to the non-carriers (odds ratio (OR: 2.47; 95% confidence interval (95% CI: 1.48-4.13; P<0.001. For Thr241Met, significance persisted under allelic (OR = 1.63; 95% CI: 1.14-2.33; P = 0.005, additive (OR = 1.64; 95% CI: 1.16-2.32; P = 0.005 and dominant (OR = 1.67; 95% CI: 1.17-2.38; P = 0.004 models. However, common allele combinations were comparable in frequency between patients and controls. In interaction analysis, the overall best MDR model included Arg399Gln and Thr241Met polymorphisms, with a maximal testing accuracy of 63.18% and a maximal cross-validation consistency of 10 out of 10 (P = 0.0175. CONCLUSIONS: Our study significantly demonstrated an independent and synergistic contribution of XRCC1 Arg399Gln and XRCC3 Thr241Met polymorphisms to lung cancer susceptibility in northeastern Chinese.

  11. Human INO80 chromatin-remodelling complex contributes to DNA double-strand break repair via the expression of Rad54B and XRCC3 genes.

    Science.gov (United States)

    Park, Eun-Jung; Hur, Shin-Kyoung; Kwon, Jongbum

    2010-10-15

    Recent studies have shown that the SWI/SNF family of ATP-dependent chromatin-remodelling complexes play important roles in DNA repair as well as in transcription. The INO80 complex, the most recently described member of this family, has been shown in yeast to play direct role in DNA DSB (double-strand break) repair without affecting the expression of the genes involved in this process. However, whether this function of the INO80 complex is conserved in higher eukaryotes has not been investigated. In the present study, we found that knockdown of hINO80 (human INO80) confers DNA-damage hypersensitivity and inefficient DSB repair. Microarray analysis and other experiments have identified the Rad54B and XRCC3 (X-ray repair complementing defective repair in Chinese-hamster cells 3) genes, implicated in DSB repair, to be repressed by hINO80 deficiency. Chromatin immunoprecipitation studies have shown that hINO80 binds to the promoters of the Rad54B and XRCC3 genes. Re-expression of the Rad54B and XRCC3 genes rescues the DSB repair defect in hINO80-deficient cells. These results suggest that hINO80 assists DSB repair by positively regulating the expression of the Rad54B and XRCC3 genes. Therefore, unlike yeast INO80, hINO80 can contribute to DSB repair indirectly via gene expression, suggesting that the mechanistic role of this chromatin remodeller in DSB repair is evolutionarily diversified.

  12. HapMap-based study of the DNA repair gene ERCC2 and lung cancer susceptibility in a Chinese population

    DEFF Research Database (Denmark)

    Yin, Jiaoyang; Vogel, Ulla Birgitte; Ma, Yegang

    2009-01-01

    (NER) pathway. To elucidate whether common ERCC2 variants are associated with lung cancer susceptibility, we conducted a case–control study consisting of 339 cases with primary lung cancer and 358 controls matched on age, gender and ethnicity in a Chinese population. Six haplotype tagging single...

  13. XRCC3遗传变异与喉癌和下咽癌发病风险相关研究%Association between genetic polymorphism in DNA repair genes XRCC3 and risks of laryngeal and hypopharyngeal carcinomas

    Institute of Scientific and Technical Information of China (English)

    温树信; 张雪梅; 唐平章; 赵丹; 郭永丽; 谭文; 林东昕

    2007-01-01

    目的 研究DNA修复基因XRCC3 Thr 241 Met遗传变异与喉癌和下咽癌风险的关系.方法 采用聚合酶链反应-限制性片段长度多态分析方法对175例喉癌及下咽癌患者和525名无肿瘤对照进行基因分型,采用多因素Logistic回归模型计算各基因型携带者喉癌和下咽癌的发病风险,以及与吸烟交互对喉癌下咽癌发病风险的影响.结果 XRCC3 241 Met等位基因增加了喉癌、下咽癌发病风险,与XRCC3 241 Thr/Thr基因型携带者相比,至少携带一个241 Met等位基因的个体罹患喉癌、下咽癌的比值比(odds ratio,OR)为2.26,95%可信区间(confidence interval,CI)为1.33~3.82.分别分析XRCC3多态与喉癌及下咽癌发病风险关系发现,XRCC3 241 Met等位基因均增加喉癌与下咽癌的发生风险,与XRCC3 241 Thr/Thr基因型携带者相比,至少携带一个XRCC3 241 Met等位基因的个体发生喉癌和下咽癌风险的OR值(95% CI)分别为2.27(1.26~4.09)和2.99(1.27~7.04).基因吸烟交互作用分析结果显示,重度吸烟和XRCC3 Thr 241 Met多态存在相乘交互作用,显著增加喉癌、下咽癌发病风险.至少携带一个XRCC3 241 Met等位基因的重度吸烟个体发生喉癌、下咽癌的OR值(95% CI)为19.09(7.38~49.40),大于至少携带一个XRCC3 241 Met等位基因的不吸烟个体(OR,0.91;95%CI,0.20~4.21)及重度吸烟但携带XRCC3 241 Thr/Thr基因型个体(OR,4.13;95%CI,2.38~7.17)的OR乘积.结论 XRCC3 Thr 241 Met单核苷酸多态是喉癌、下咽癌的遗传易感因素.

  14. Association between single nucleotide polymorphisms (SNPs) of XRCC2 and XRCC3 homologous recombination repair genes and ovarian cancer in Polish women.

    Science.gov (United States)

    Michalska, Magdalena M; Samulak, Dariusz; Romanowicz, Hanna; Jabłoński, Filip; Smolarz, Beata

    2016-04-01

    The variability, perceived in DNA repair genes, may be of clinical importance for evaluation of the risk of occurrence of a given type of cancer, its prophylactics and therapy. The aim of the present work was to evaluate associations between the risk of ovarian cancer and polymorphisms in the genes, encoding for two key proteins of homologous recombination: XRCC2 Arg188His (c. 563 G>A; rs3218536) and XRCC3 Thr241Met (c. 722 C>T; rs861539). The study consisted of 700 patients with ovarian cancer and 700 healthy subjects. Analysis of the gene polymorphisms was performed using PCR-RFLP (restriction length fragment polymorphism). We found a statistically significant increase of the 188His allele frequency (OR=4.01; 95% CI=3.40-4.72; pcancer compared to healthy controls. There were no differences in the genotype and allele distributions and odds ratios of the XRCC3 Thr241Met polymorphism between patient and control groups. Association of these genetic polymorphisms with histological grading showed increased XRCC2 188Arg/His (OR=33.0; 95% CI=14.51-75.05; p<.0001) and 188His/His genotypes (OR=9.37; 95% CI=4.79-18.32; p<.0001) and XRCC3 241Thr/Met (OR=24.28; 95% CI=12.38-47.61; p<.0001) and 241Met/Met genotype frequencies (OR=17.00; 95% CI=8.42-34.28; p<.0001) in grading 1 (G1) as well as 188His (OR=2.78; 95% CI=2.11-3.69; p<.0001) and 241Met allele overrepresentation (OR=2.59; 95% CI=2.08-3.22; p<.0001) in G1 ovarian patients. Finally, with clinical FIGO staging under evaluation, an increase in XRCC2 188His/His homozygote and 188Arg/His heterozygote frequencies in staging I (SI) and XRCC3 Thr/Met heterozygote frequencies in SI was observed. The obtained results indicate that XRCC2 Arg188His and XRCC3 Thr241Met polymorphisms may be positively associated with the incidence of ovarian carcinoma in the population of Polish women.

  15. 广西人群DNA修复基因XRCC3多态性与肝细胞癌遗传易感性关联分析%Association of the Thr241Met polymorphism of DNA repair gene XRCC3 with genetic susceptibility to AFB1-related hepatocellular carcinoma in Guangxi population

    Institute of Scientific and Technical Information of China (English)

    龙喜带; 马韵; 邓卓霖; 黄永秩; 韦妮波

    2008-01-01

    Objective To explore the association of the Thr241Met polymorphism of X-my cross-complementing group 3(xRcc3) gene with genetic susceptibility to aflatoxin B1(AFBl)-related hepatocellular carcinoma(HCC)in Guangxi population.Methods We conducted a hospital-based case-control study,including 257 HCC cascs and 711 controls without cancels or liver diseases.The XRCC3 Thr241Met polymorphism was analyzed by PCR.Results The XRCC3 genotypes XRCC3.Thr/Met or XRCC3-Met/Met were related with an elevated risk of HCC.The risk of HCC was associated with the number of mutant Met copies(adjusted OR were 2.20 and 8.56 for XRCC3.Thr/Met and Met/Met,respectively);moreover,there seemed tO be combined effects for HCC risk between the variant genotypes and AFBl DNA adduct levels from peripheral blood leukocytes(adjusted OR was 2.34 to 20.44,P<0.01).Conclusion These results suggested that XRCC3 polymorphism may be associated with the risk of AFBl-related HCC among the Guansxipopulation,and interacts with AFBl exposure in the development of HCC induced by AFBl.%目的 探讨DNA修复基因X线修复交叉互补因子3(X-ray cross-complementing group 3,XRCC3)基因Thr241Met多态性与黄曲霉毒素B1(aflatoxin B1,AFB1)相关性肝细胞癌(hepatocellular carcinoma,HCC)遗传易感性的相关性.方法 应用PCR技术对AFB1高污染区广西地区257例HCC患者和711名对照人群的XRCC3基因多态性进行检测,进行的病例对照研究.结果 (1)XRCC3 3种基因型(Thr/Thr、Thr/Met、Met/Met)中带有Met者与HCC的易感性相关,且这种相关性与Met数量呈正相关(校正风险值OR分别为2.20和8.56);(2)XRCC3突变基因型多态与血白细胞AFB1-DNA加合物水平在HCC发生过程中存在协同作用(校正OR:2.34~20.44,P<0.01).结论 XRCC3多态性与HCC易感性相关,且这种多态性与AFB1暴露水平在HCC发生中存在协同作用.

  16. XRCC3基因多态性与汉族人群膀胱癌的相关性%Relationship between XRCC3 gene polymorphism and bladder cancer in the Han population

    Institute of Scientific and Technical Information of China (English)

    郝钢跃; 张月英; 张维东; 杨明山; 贾青

    2008-01-01

    目的 探讨DNA修复基因XRCC3多态性与膀胱癌危险性的关系.方法 选择中国汉族人群中膀胱癌患者307例为病例组,316例非肿瘤泌尿系疾病患者为对照组,两组年龄性别构成均衡.以PCR-RFLP技术,检测病例组和对照组的XRCC3(Thr241Met)基因型,比较不同基因型与膀胱癌危险性以及膀胱癌临床特征的关系.结果 XRCC3基因型Thr/Thr、Thr/Met和Met/Met在病例组的分布频率分别为87.3%、12.1%和0.6%,在对照组的分布频率为92.4%、7.3%和0.3%.与携带Thr/Thr的个体相比,携带XRCC3变异基因型(Thr/Met和Met/Met)的个体具有更高的患癌风险(OR,1.77;95%CI,1.04~3.02).XRCC3基因型与吸烟没有交互作用,与膀胱癌的临床类型亦无相关性,但与浅表性膀胱癌的复发关系密切.携带XRCC3变异基因型的浅表性膀胱癌患者具有更高的复发风险(OR,3.08;95%CI,1.13~8.41).结论 XRCC3基因多态性与膀胱癌危险性有关,携带变异基因型的个体易患膀胱癌,而且XRCC3基因有可能成为一个预测膀胱癌复发的指标.

  17. DNA修复基因XPCC3多态性与子宫内膜异位症发病相关性分析%Research of the relationship between polymorphisms of DNA repair gene XRCC3 and endometriosis

    Institute of Scientific and Technical Information of China (English)

    邹丽红; 徐帅; 卢美松

    2012-01-01

    Objective To investigate the association of the polymorphisms in DNA repair gene XRCC3 with endometriosis risk. Methods The polymorphisms of DNA repair gene XRCC3 between endometriosis patients and controls were detected and whether XRCC3 were associated with the severity of endometriosis or not was evaluated. Genotypes of XRCC3 were analyzed by PCR-RELP. Results There was significantly difference between endometriosis and control groups of XRCC3 genetic polymorphism (P < 0. 05 ). The expression of Thr/Met gene was significantly enhanced in endometriosis ( P < 0. 05 ). There was not association between the distributions of genotypes or alleles of XRCC3 and the stage of endometriosis. Conclusion Patients with XRCC3 Thr/Met or Met α/lele genotype have susceptibility to endometriosis, but the genotype is not associated with the stage of endomtriosis.%目的 研究DNA修复基因XRCC3多态性与子宫内膜异位症发病风险的关系.方法 采用病例-对照研究的方法,应用PCR-RELP方法检测子宫内膜异位症患者与非子宫内膜异位症妇女XRCC3基因Thr241 Met的多态性分布,并分析其多态性与子宫内膜异位症疾病病理过程的关系.结果 XRCC3基因多态性在内异症组与对照组存在显著差异(P<0.05),Thr/Met基因表达在内异症组显著增强(P<0.05);Thr241 Met基因多态性与内异症病理分期无相关性.结论 具有XRCC3 Thr/Met基因型或Met等位基因的个体对内异症的发生有易感性,但与内异症的临床病理分期无关.

  18. DNA修复基因XRCC3多态性与卵巢癌相关性研究的meta分析%Correlation between polymorphisms of DNA repair gene XRCC3 and ovarian cancer: a meta-analysis

    Institute of Scientific and Technical Information of China (English)

    陈平平; 杨辰敏

    2015-01-01

    目的 研究DNA修复基因XRCC3的3种单核苷酸多态性(T241M、A4541G和A17893G)各自与卵巢癌易感性的关系并进行meta分析.方法 计算机全面检索数据库中相关文献,收集有关XRCC3基因多态性(T241M、A4541G和A17893G)与卵巢癌发病相关的病例对照研究,按照纳入文献质量评价标准,剔除不符合要求的文献,应用Stata 10.0软件计算OR及其95%CI,对各研究结果进行数据合并,比较XRCC3不同基因型以及基因多态性与卵巢癌易感性的关系,并检验一致性和评估发表偏倚.结果 纳入6项研究进行meta分析,包括卵巢癌病例组5 529例,对照组8 350例,均符合H-W遗传平衡.meta分析结果表明XRCC3 T241M中T和M等位基因、XRCC3 A4541G中A和G等位基因、XRCC3 A17893G中A和G等位基因在病例组和对照组的频率分布比较,差异均无统计学意义(P>0.05).XRCC3 T241M多态性与卵巢癌的发生风险均无明显相关(P>0.05).XRCC3 A4541G基因多态性与卵巢癌发病风险相关,其中GG/AA、GG/AG+ AA、AG/AA基因型与卵巢癌发病风险相关(P<0.05;OR =0.71,95%CI=0.56 ~0.90; OR =0.67,95%CI=0.53 ~0.87;OR=1.06,95% CI=1.00 ~1.14).XRCC3 A17893G基因多态性与卵巢癌的发病风险相关,其中GG+AG/AA和GG/AG+ AA基因型与卵巢癌发病风险相关(P<0.05;OR=0.81,95%CI=0.79~0.84; OR=1.14,95% CI=1.02 ~1.28).结论 XRCC3 A4541G和A17893G基因多态性与卵巢癌发病风险相关.

  19. Genetic polymorphisms in XRCC1, OGG1, APE1 and XRCC3 DNA repair genes, ionizing radiation exposure and chromosomal DNA damage in interventional cardiologists

    Energy Technology Data Exchange (ETDEWEB)

    Andreassi, Maria Grazia, E-mail: andreas@ifc.cnr.it [CNR Institute of Clinical Physiology, National Research Council, Pisa (Italy); Foffa, Ilenia [CNR Institute of Clinical Physiology, National Research Council, Pisa (Italy); Sant' Anna School of Advanced Studies, Pisa (Italy); Manfredi, Samantha; Botto, Nicoletta [CNR Institute of Clinical Physiology, National Research Council, Pisa (Italy); Cioppa, Angelo [Clinica Cardiologica ' Montevergine' , Mercogliano (Italy); Picano, Eugenio [CNR Institute of Clinical Physiology, National Research Council, Pisa (Italy); Clinica Cardiologica ' Montevergine' , Mercogliano (Italy)

    2009-06-18

    Interventional cardiologists working in high-volume cardiac catheterization laboratory are exposed to significant occupational radiation risks. Common single-nucleotide polymorphisms (SNPs) in DNA repair genes are thought to modify the effects of low-dose radiation exposure on DNA damage, the main initiating event in the development of cancer and hereditary disease. The aim of this study was to determine the relationship between XRCC1 (Arg194Trp and Arg399Gln), OGG1 (Ser326Cys), APE1 (Asp148Glu) and XRCC3 (Thr241Met) SNPs and chromosomal DNA damage. We enrolled 77 subjects: 40 interventional cardiologists (27 male, 41.3 {+-} 9.4 years and 13 female, 37.8 {+-} 8.4 years) and 37 clinical cardiologists (26 male, 39.4 {+-} 9.5 years and 11 female, 35.0 {+-} 9.8 years) without radiation exposure as the control group. Micronucleus (MN) assay was performed as biomarker of chromosomal DNA damage and an early predictor of cancer. MN frequency was significantly higher in interventional cardiologists than in clinical physicians (19.7 {+-} 7.8 per mille vs. 13.5 {+-} 6.3 per mille , p = 0.0003). Within the exposed group, individuals carrying a XRCC3 Met241 allele had higher frequency than homozygous XRCC3 Thr241 (21.2 {+-} 7.8 per mille vs. 16.6 {+-} 7.1 per mille , p = 0.03). Individuals with two or more risk alleles showed a higher MN frequency when compared to subjects with one or no risk allele (18.4 {+-} 6.6 per mille vs. 14.4 {+-} 6.1 per mille , p = 0.02). An interactive effect was found between smoking, exposure >10 years and the presence of the two or more risk alleles on the MN frequency (F = 6.3, p = 0.02). XRCC3 241Met alleles, particularly in combination with multiple risk alleles of DNA repair genes, contribute to chromosomal DNA damage levels in interventional cardiologists.

  20. Polymorphisms of DNA repair genes XRCC1 and XRCC3, interaction with environmental exposure and risk of chronic gastritis and gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Márcia Cristina Duarte; Jucimara Colombo; Andrea Regina Baptista Rossit; Alaor Caetano; Aldenis Albaneze Borim; Durval Wornrath; Ana Elizabete Silva

    2005-01-01

    AIM: To evaluate the association between polymorphisms XRCC1 Arg194Trp and Arg399Gln and XRCC3Thr241Met and the risk for chronic gastritis and gastric cancer, in a Southeastern Brazilian population.METHODS: Genotyping by PCR-RFLP was carried out on 202 patients with chronic gastritis (CG) and 160 patients with gastric cancer (GC), matched to 202 (C1) and 150(C2) controls, respectively.RESULTS: No differences were observed among the studied grou ps with regard to the genotype distribution of XRCC1 codons 194 and 399 and of XRCC3 codon 241. However, the combined analyses of the three variant alleles (194Trp, 399Gln and 241Met) showed an increased risk for chronic gastritis when compared to the GC group. Moreover, an interaction between the polymorphic alleles and demographic and environmental factors was observed in the CG and GC groups. XRCC1 194Trp was associated with smoking in the CG group,while the variant alleles XRCC1 399Gln and XRCC3241Met were related with gender, smoking, drinking and H pylori infection in the CG and GC groups.CONCLUSION: Our results showed no evidence of a rela-tionship between the polymorphisms XRCC1Arg194Trp and Arg399Gln and XRCC3 Thr241Met and the risk of chronic gastritis and gastric cancer in the Brazilian population, but the combined effect of these variants may interact to increase the risk for chronic gastritis,considered a premalignant lesion. Our data also indicate a gene-environment interaction in the susceptibility to chronic gastritis and gastric cancer.

  1. Correction of chromosomal instability and sensitivity to diverse mutagens by a cloned cDNA of the XRCC3 DNA repair gene

    Energy Technology Data Exchange (ETDEWEB)

    Tebbs, R.S.; Tucker, J.D.; Hwang, M. [Lawrence Livermore National Lab., CA (United States)] [and others

    1995-07-03

    The mutagen-sensitive CHO line irs1SF was previously isolated on the basis of hypersensitivity to ionizing radiation and was found to be chromosomally unstable as well as cross-sensitive to diverse kinds of DNA-damaging agents. The analysis of somatic cell hybrids formed between irs1SF and human lymphocytes implicated a human gene (defined as XRCC3; x-ray repair cross-complementing), which partially restored mitomycin C resistance to the mutant. A functional cDNA that confers mitomycin C resistance was transferred to irs1SF cells by transforming them with an expression cDNA library and obtaining primary and secondary transformants. Functional cDNA clones were recovered from a cosmid library prepared from a secondary transformant. Transformants also showed partial correction of sensitivity to displatin and {gamma}-rays, efficient correction of chromosomal instability, and substantially improved plating efficiency and growth rate. The XRCC3 cDNA insert is {approx} 2.5 kb and detects an {approx} 3.0-kb mRNA on Northern blots. The cDNA was mapped by fluorescence in situ hybridization to human chromosome 14q32.3, which was consistent with the chromosome concordance data of two independent hybrid clone panels. 30 refs., 5 figs., 2 tabs.

  2. Polymorphisms of Homologous Recombination RAD51, RAD51B, XRCC2, and XRCC3 Genes and the Risk of Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Maria Nowacka-Zawisza

    2015-01-01

    Full Text Available Genetic polymorphisms in DNA repair genes may induce individual variations in DNA repair capacity, which may in turn contribute to the risk of cancer developing. Homologous recombination repair (HRR plays a critical role in maintaining chromosomal integrity and protecting against carcinogenic factors. The aim of the present study was to evaluate the relationship between prostate cancer risk and the presence of single nucleotide polymorphisms (SNPs in the genes involved in HRR, that is, RAD51 (rs1801320 and rs1801321, RAD51B (rs10483813 and rs3784099, XRCC2 (rs3218536, and XRCC3 (rs861539. Polymorphisms were analyzed by PCR-RFLP and Real-Time PCR in 101 patients with prostate adenocarcinoma and 216 age- and sex-matched controls. A significant relationship was detected between the RAD51 gene rs1801320 polymorphism and increased prostate cancer risk. Our results indicate that the RAD51 gene rs1801320 polymorphism may contribute to prostate cancer susceptibility in Poland.

  3. Polymorphisms of Homologous Recombination RAD51, RAD51B, XRCC2, and XRCC3 Genes and the Risk of Prostate Cancer

    Science.gov (United States)

    Nowacka-Zawisza, Maria; Wiśnik, Ewelina; Wasilewski, Andrzej; Skowrońska, Milena; Forma, Ewa; Bryś, Magdalena; Różański, Waldemar; Krajewska, Wanda M.

    2015-01-01

    Genetic polymorphisms in DNA repair genes may induce individual variations in DNA repair capacity, which may in turn contribute to the risk of cancer developing. Homologous recombination repair (HRR) plays a critical role in maintaining chromosomal integrity and protecting against carcinogenic factors. The aim of the present study was to evaluate the relationship between prostate cancer risk and the presence of single nucleotide polymorphisms (SNPs) in the genes involved in HRR, that is, RAD51 (rs1801320 and rs1801321), RAD51B (rs10483813 and rs3784099), XRCC2 (rs3218536), and XRCC3 (rs861539). Polymorphisms were analyzed by PCR-RFLP and Real-Time PCR in 101 patients with prostate adenocarcinoma and 216 age- and sex-matched controls. A significant relationship was detected between the RAD51 gene rs1801320 polymorphism and increased prostate cancer risk. Our results indicate that the RAD51 gene rs1801320 polymorphism may contribute to prostate cancer susceptibility in Poland. PMID:26339569

  4. A correlation study of single nucleotide polymorphisms in XRCC3,HOGG1 gene of repair DNA and radiosensitivity in esophageal squamous cell carcinoma%修复基因XRCC3和HOGG1单核苷酸多态性与食管鳞癌放射敏感性相关性研究

    Institute of Scientific and Technical Information of China (English)

    张旭升; 曾敏; 张瑾熔; 伊斯坎达尔·阿不力米提; 阿合力·那斯肉拉; 葛峰

    2011-01-01

    Objective To study the relationship between the single nucleotide polymorphisms (SNP)of X-ray repair cross-complementing group-3(XRCC3),human 8-hydroxyguanine glycosylase-1 (HOGG1)gene of repair DNA and the radiosensitivity in esophageal squamous cell carcinoma(ESCC).Methotis Genome DNA was exracted from whole blood cells of ESCC patients.XRCC3 and HOGG1 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism method.The relationship was analyzed between SNP of XRCC3 Thr242 Met,HOGG1 Ser326 Cys and the response to radiotherapy in ESCC.Results Totally 199 ESCC patients were treated with radical radiotherapy.The response rate w88 81.4%.The response rate in patients with the XRCC3 Thr/Met genotype was significant higher than that in patients with Thr/Thr genotype(91.5%vs 77.1%,X2=5.67,P=0.017),with the same in HOGGlSet/Ser,Ser/Cys and Cys/Cys genotype(74.1%,84.2%,83.9%,X2=2.64,P=0.268).The esophageal radioactivity injury rate in patients with the XRCC3 Thr/Met genotype was also significant higher than that in patients with Thr/Thr genotype(35.6%vs 20.0%,X2=5.44,P= 0.020),with the same in HOGG1 Ser/Ser,Ser/Cys and Cys/Cys genotype(24.1%,24.6%,25.8%,X2=0.03,P=0.984).In Iogistic multivariate analysis,the SNP of XRCC3 was the independent influencing factor closely correlating with the mdiosensitivity of esophageal cancer(X2=16.12,4.43,P=0.009.0.035).No significant difierence was observed between the SNP in HOGG1 Ser326 Cys and the response rate of radiotherapy or the rate of esophageal radioactivity injury(X2=3.74,0.58,P=0.053,0.445).Conclusions SNP of XRCC3 Thr/Met is associated with the radiosensitivity in ESCC patients,which suggests that the XRCC3 Thr/Met SNP may be a predictor for ESCC patients who likely to response to radiotherapy.%目的 研究DNA修复基因X线交错互补修复组-3(XRCC3)、人类8-羟基鸟嘌呤糖苷酶-1(HOGG1)单核苷酸多态性与食管鳞状细胞癌放射敏感性关系.方法 采用聚合酶

  5. XRCC3、XPD 基因多态性与职业性慢性铅中毒易感性关系病例-对照研究%Matched case-control study on relationship between polymorphisms of gene XRCC3, XPD and the susceptibility of occupational chronic lead poisoning

    Institute of Scientific and Technical Information of China (English)

    刘祥铨; 吴小南; 吴京颖; 刘合焜

    2014-01-01

    目的:探讨X射线交错互补修复基因3(XRCC3) Thr241Met和人类着色性干皮病基因D (XPD) Asp312Asn及Lys751Gln与职业性慢性铅中毒的关系。方法选择103名蓄电池厂确诊为职业性慢性铅中毒的男性工人为病例组,按照工种和年龄1∶1匹配选择同厂无诊断为铅中毒的铅作业男性工人为对照组。采集2组人群周围静脉血,采用聚合酶链反应-限制性片段长度多态性技术检测XRCC3 Thr241Met、XPD Asp312Asn和XPD Lys751Gln位点的多态性,采用条件Logistic回归分析分析不同基因型与职业性慢性铅中毒的关系。结果2组人群中XRCC3 Thr241Met、XPD Asp312Asn和XPD Lys751Gln多态位点的基因型分布均符合遗传学Hardy-Weinberg平衡定律( P>0.05)。2组人群XRCC3 Thr241Met 3种基因型总体分布比较,差异有统计学意义( P<0.05)。2 组人群XPD Asp312Asn和XPD Lys751Gln 3种基因型总体分布分别比较,差异均无统计学意义(P>0.05)。 XRCC3 Thr241Met的CT和TT基因型均增加铅中毒易感性[校正比值比分别为2.44和3.37,95%可信区间为(1.17~5.09)和(1.09~11.14)],而XPD Asp312Asn 和 XPD Lys751Gln 不同基因型与铅中毒易感性无关( P >0.05)。结论 XRCC3 Thr241Met的CT或TT基因型与职业性慢性铅中毒相关;而XPD Asp312Asn和XPD Lys751Gln多态性与职业性慢性铅中毒易感性无关。%Objective To explore the relationship between polymorphisms of gene XRCC3 Thr241Met and XPD Asp312Asn, Lys751Gln and occupational chronic lead poisoning .Methods Based on 1∶1 matched case-control study, 103 couple lead-exposed male workers were selected as the case group ( occupational chronic lead poisoning patients ) and the control group ( workers without poisoning manifestations ) from storage battery factories , and their peripheral venous blood was collected .Single nucleotide polymorphisms of XRCC3 Thr241Met, XPD Asp312

  6. DNA修复基因XRCC3多态性与肺癌易感性的关系%Relationship between polymorphisms of DNA repair gene XRCC3 and susceptibility to lung cancer

    Institute of Scientific and Technical Information of China (English)

    张增利; 周彩存; 张颉; 唐亮; 粟波

    2007-01-01

    目的 研究DNA修复基因XRCC3多态性与肺癌易感性的关系.方法 采用病例-对照研究,于2006年9月至2007年1月收集上海肺科医院原发性肺癌患者291例及同期住院的非肿瘤患者273例,应用Taqman探针结合实时荧光PCR方法分析病例组和对照组XRCC3基因Thr241Met的多态性分布,比较不同基因型与肺癌易感性的关系以及基因多态性与吸烟对肺癌的交互作用.对照组与病例组的比较用x2检验,以调整比值比及95%可信区间表示相对危险度,所有统计检验均为双侧概率检验,所有资料均用SPSS软件进行统计.结果 与携带XRCC3密码子241野生纯合基因型(Thr/Thr)且不吸烟者相比,携带同样基因型且吸烟者患肺癌的风险会增加,其调整比值比(OR值)为2.47[95%可信区间(CI)为1.49~4.08,P<0.01];携带有杂合基因型(Thr/Met)且吸烟者患肺癌的风险也会增加,其调整OR值为2.28(95%CI为1.21~6.60,P=0.017).野生纯合基因型(Thr/Thr)且吸烟量少于30包年可能对肺腺癌有较弱的保护作用(OR=0.49,95%CI为0.26~0.93,P=0.03).携带有XRCC3密码子241Met等位基因且吸烟者患肺鳞癌的风险明显增加(调整OR=9.69,95%CI为3.27~28.72,P<0.01).携带241Met等位基因且吸烟剂量<30包年和≥30包年的患者患肺鳞癌的风险也不同,OR值分别为8.00(95%CI为1.97~32.52,P<0.01)和11.67(95%CI为2.98~45.73,P<0.01).结论 DNA修复基因XRCC3多态性可能对肺癌易感性产生影响,并可能与吸烟有一定的协同作用.

  7. Polymorphisms of the XRCC1, XRCC3 and XPD genes and risk of colorectal adenoma and carcinoma, in a Norwegian cohort: a case control study

    Directory of Open Access Journals (Sweden)

    Aase Steinar

    2006-03-01

    Full Text Available Abstract Background Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity, which may be associated with risk of developing cancer. For colorectal cancer the importance of mutations in mismatch repair genes has been extensively documented. Less is known about other DNA repair pathways in colorectal carcinogenesis. In this study we have focused on the XRCC1, XRCC3 and XPD genes, involved in base excision repair, homologous recombinational repair and nucleotide excision repair, respectively. Methods We used a case-control study design (157 carcinomas, 983 adenomas and 399 controls to test the association between five polymorphisms in these DNA repair genes (XRCC1 Arg194Trp, Arg280His, Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln, and risk of colorectal adenomas and carcinomas in a Norwegian cohort. Odds ratio (OR and 95% confidence interval (95% CI were estimated by binary logistic regression model adjusting for age, gender, cigarette smoking and alcohol consumption. Results The XRCC1 280His allele was associated with an increased risk of adenomas (OR 2.30, 95% CI 1.19–4.46. The XRCC1 399Gln allele was associated with a reduction of risk of high-risk adenomas (OR 0.62, 95% CI 0.41–0.96. Carriers of the variant XPD 751Gln allele had an increased risk of low-risk adenomas (OR 1.40, 95% CI 1.03–1.89, while no association was found with risk of carcinomas. Conclusion Our results suggest an increased risk for advanced colorectal neoplasia in individuals with the XRCC1 Arg280His polymorphism and a reduced risk associated with the XRCC1 Arg399Gln polymorphism. Interestingly, individuals with the XPD Lys751Gln polymorphism had an increased risk of low-risk adenomas. This may suggest a role in regression of adenomas.

  8. RAD51G135C 和XRCC3C241T基因型与急性髓系白血病疗效及预后相关性研究%Polymorphisms of RAD51G135C and XRCC3C241T genes and correlations thereof with prognosis and clinical outcomes of acute myeloid leukemia

    Institute of Scientific and Technical Information of China (English)

    刘亮; 杨琳; 张悦; 徐泽锋; 于明华; 王建祥; 肖志坚

    2008-01-01

    risk of hematuria of the patients with variant genotype was significantly higher than that of the patients with wild genotype(P=0.017).Conclusion The polymorphisms of XRCC3C241T and RAD51 G135C genes are significantly related to response to therapy,adverse effects,and prognosis of AML.Detection of the XRCC3C241T and RAD51 G135C genotypes may be useful in selecting individual chemotherapy regimens for patients with AML.%目的 探讨同源重组修复基因RAD51G135C和XRCC3C241T多态性位点基因型与急性髓系白血病(AML)疗效及预后的关系.方法 AML患者372例,用聚合酶链反应-限制性内切酶片段长度多态性(PCR-RFLP)方法分析RAD51 G135C、XRCC3C241T基因型,用多重PCR方法检测GSTT1和GSTM1基因.比较不同基因型患者的诱导治疗完全缓解(CR)率、总体生存期、无复发生存期及不良反应.结果 (1)在第一疗程诱导治疗过程中,XRCC3C241T基因型与AML伴t(15;17)/PML-RARα患者的早期病亡率有显著相关性(OR=8.750,P=0.046).XRCC3C241T、RAD51G135C分别与GSTY1、GSTM1联合存在变异时,非M3患者诱导缓解时CR率明显降低,(P=0.028).(2)XRCC3C241T、RAD51 G135C的基因型影响AML患者的平均生存期及平均无复发生存期:RAD51 G135C、GSTF1基因存在双变异及联合GSTM1基因均变异时,非M3的AML的生存期(OS)显著缩短(P<0.05).XRCC3C241T与GSTT1联合分析,双基因均野生型M4EO、M2患者的无复发生存期(RFS)明显长于双变异型患者的RFS期(均P<0.05).XRCC3C241T、GS3T1、GSTM1基因同时变异的M2患者的RFS期(10.0个月)明显短于3个基因野生型患者(64.2个月,P<0.005).RAD51 G135C、GSTFl双基因变异M4EO患者的平均RFS期明显缩短(P=0.047).(3)XRCC3C241T、RAD51G135C基因型与第一疗程诱导治疗过程中的不良反应(包括白细胞数、恶心呕吐、脱发和血尿)有明显的相关性(均P<0.05).结论 XRCC3C241T、RAD51G135C单独或与GSTT1,GSTM1基因型联合变异,与AML患者第一疗程诱导

  9. DNA修复基因XRCC3 Thr241Met多态性在四川汉族人群的分布%STUDY ON GENETIC POLYMORPHISM OF DNA REPAIR GENE XRCC3 THR241MET IN SICHUAN HAN POPULATION

    Institute of Scientific and Technical Information of China (English)

    戴穹; 杨志惠

    2007-01-01

    目的:研究DNA修复基因X线修复交叉互补基因3(XRCC3)Thr241Met位点多态性在四川汉族人群的分布,并与其它种族比较其分布特点.方法:采用聚合酶链反应-限制性片断长度多态性(PCR-RFLP)方法检测四川泸州地区220例健康无血缘关系个体Thr241Met位点基因型和等位基因频率分布.结果:共检测出两种基因型,Thr/Thr和Thr/Met,其频率分布为91.82%和8.18%,基因型频率分布符合Hardy-Weinberg平衡定律,其基因型频率分布与比利时、法国、美国、芬兰人群比较有统计学意义(P<0.05),而与中国南京人群比较无统计学意义(P>0.05).结论:XRCC3Thr241Met位点多态性分布在中国人群中无统计学意义,但与欧美人群比较有统计学意义,证实了多态性分布的种族和地域差异.

  10. DNA修复基因ERCC2 rs50871遗传多态性的实时荧光定量PCR检测%Detection of Polymorphism of DNA Repair Gene ERCC2 rs50871 by Real-Time PCR

    Institute of Scientific and Technical Information of China (English)

    祁荣; 马业罡; 刘峥嵘; 孙中芙; 郭丽; 尹娇杨

    2010-01-01

    目的 应用ABI 7300实时荧光定量PCR-单核苷酸多态(SNP)等位基因分型技术建立准确、快速、经济、适应大样本检测SNP等位基因分型的改良方法.方法 采用缩小反应的体系(由推荐的25μl PCR反应体系降至为10μl),降低探针的浓度和自动软件SNP分型方法,检测我国东北地区321例汉族无亲缘关系健康个体DNA样品的DNA修复基因ERCC2rs50871遗传多态性.结果 经改良方法检测获得了理想的等位基因分型,与DNA测序结果一致.ERCC2rs50871T等位基因频率为0.749,G等位基因频率为0.251,基因型分布符合Hardy-Weinberg平衡定律(x2=0.003,af=1,P=0.96).该位点等位基因频率分布与NCBI dbSNP数据库中中国北京汉族(HCB)群体的分布相似(P=0.06);但与HapMap-CEU(CEPH样品:祖先为北西欧人的犹他州居民)及HapMap-YRI(尼日利哑伊巴丹的约鲁巴人)的分布差异有统计学意义(均P<0.001).结论 本实验建屯的改良方法经济实用,适合人类群体遗传学及流行病学大样本调查.

  11. Polymorphisms in DNA Repair Genes (APEX1, XPD, XRCC1 and XRCC3 and Risk of Preeclampsia in a Mexican Mestizo Population

    Directory of Open Access Journals (Sweden)

    Ada Sandoval-Carrillo

    2014-03-01

    Full Text Available Variations in genes involved in DNA repair systems have been proposed as risk factors for the development of preeclampsia (PE. We conducted a case-control study to investigate the association of Human apurinic/apyrimidinic (AP endonuclease (APEX1 Asp148Glu (rs1130409, Xeroderma Pigmentosum group D (XPD Lys751Gln (rs13181, X-ray repair cross-complementing group 1 (XRCC Arg399Gln (rs25487 and X-ray repair cross-complementing group 3 (XRCC3 Thr241Met (rs861539 polymorphisms with PE in a Mexican population. Samples of 202 cases and 350 controls were genotyped using RTPCR. Association analyses based on a χ2 test and binary logistic regression were performed to determine the odds ratio (OR and a 95% confidence interval (95% CI for each polymorphism. The allelic frequencies of APEX1 Asp148Glu polymorphism showed statistical significant differences between preeclamptic and normal women (p = 0.036. Although neither of the polymorphisms proved to be a risk factor for the disease, the APEX1 Asp148Glu polymorphism showed a tendency of association (OR: 1.74, 95% CI = 0.96–3.14 and a significant trend (p for trend = 0.048. A subgroup analyses revealed differences in the allelic frequencies of APEX1 Asp148Glu polymorphism between women with mild preeclampsia and severe preeclampsia (p = 0.035. In conclusion, our results reveal no association between XPD Lys751Gln, XRCC Arg399Gln and XRCC3 Thr241Met polymorphisms and the risk of PE in a Mexican mestizo population; however, the results in the APEX1 Asp148Glu polymorphism suggest the need for future studies using a larger sample size.

  12. Association between DNA repair gene XRCC3 Thr241 Met single nucleotide polymorphisms and colorectal cancer susceptibility:a meta-analysis%DNA修复基因XRCC3Thr241Met多态性与结直肠癌易感的Meta分析

    Institute of Scientific and Technical Information of China (English)

    梁天伟; 孙轶; 卢永刚

    2011-01-01

    AIM: To evaluate the association between single nucleotide polymorphisms of the X-ray repair cross-complementing group 3 (XRCC3) gene and colorectal cancer susceptibility.METHODS: By searching EMBSE (1974-2010.11), Pubmed (1966-2010.11), CNKI (1994-2010.11) and CBM (1978-2010.11), We collected studies evaluating the association between XRCC3 gene polymorphisms and colorectal cancer susceptibility. The effect size was odds ratios (OR) of variant allele of XRCC3Thr241Met in the case and control groups. Random or fixed effect model was selected according to the results of heterogeneity test. The OR and publication bias were calculated using Review Manager 5.0 and STATA11.0 software.RESULTS: Nine case-control studies involving 3 294 cases and 3 947 controls were included. In the Met/Met versus Thr/Thr group, the odds ratio was 1.30 (95%CI: 0.86-1.98, P = 0.22). For the dominant genetic model, the OR in the Met/ Met+Met/Thr versus Thr/Thr group was 1.05 (95%CI: 0.67-1.66 P = 0.83). For the recessive genetic model, the OR in the Met/Met versus Thr/ Thr+Thr/Met group was 1.45 (95%CI: 0.94-2.25, P = 0.09).CONCLUSION: There was no close association between XRCC3 Thr241 Met single nucleotide polymorphisms and colorectal cancer susceptibility.%目的:探讨DNA 修复基因X线修复交叉互补因子3(XRCC3) Thr241Met 单核苷酸多态性与结直肠癌易感性的关系.方法:检索EMBASE(1974/2010-11)、PubMed (1966/2010-11)、中国期刊全文数据库CNKI (1994/2010-11)、中国生物医学文献数据库CBM(1978/2010-11)公开发表的DNA 修复基因XRCC3 Thr241Met 单核苷酸多态性与结直肠癌易感性关系的研究.病例组及对照组XRCC3 Thr241Met 等位基因分布的优势比(OR )为效应指标,根据异质性检验结果,选择随机效应模型或固定效应模型对OR 进行合并,同时进行偏倚评估.结果:共查到符合要求的文献9篇,病例组3 29 4例,对照组3 947 例.分析结果显示:XRCC3 Thr241Met点突变纯合子(Met/Met)

  13. Polymorphisms in XPC, XPD, XRCC1, and XRCC3 DNA repair genes and lung cancer risk in a population of Northern Spain

    Directory of Open Access Journals (Sweden)

    Tardón Adonina

    2007-08-01

    Full Text Available Abstract Background Polymorphisms in DNA repair genes have been associated to repair DNA lesions, and might contribute to the individual susceptibility to develop different types of cancer. Nucleotide excision repair (NER, base excision repair (BER, and double-strand break repair (DSBR are the main DNA repair pathways. We investigated the relationship between polymorphisms in two NER genes, XPC (poly (AT insertion/deletion: PAT-/+ and XPD (Asp312Asn and Lys751Gln, the BER gene XRCC1 (Arg399Gln, and the DSBR gene XRCC3 (Thr241Met and the risk of developing lung cancer. Methods A hospital-based case-control study was designed with 516 lung cancer patients and 533 control subjects, matched on ethnicity, age, and gender. Genotypes were determined by PCR-RFLP and the results were analysed using multivariate unconditional logistic regression, adjusting for age, gender and pack-years. Results Borderline association was found for XPC and XPD NER genes polymorphisms, while no association was observed for polymorphisms in BER and DSBR genes. XPC PAT+/+ genotype was associated with no statistically significant increased risk among ever smokers (OR = 1.40; 95%CI = 0.94–2.08, squamous cell carcinoma (OR = 1.44; 95%CI = 0.85–2.44, and adenocarcinoma (OR = 1.72; 95%CI = 0.97–3.04. XPD variant genotypes (312Asn/Asn and 751Gln/Gln presented a not statistically significant risk of developing lung cancer (OR = 1.52; 95%CI = 0.91–2.51; OR = 1.38; 95%CI = 0.85–2.25, respectively, especially among ever smokers (OR = 1.58; 95%CI = 0.96–2.60, heavy smokers (OR = 2.07; 95%CI = 0.74–5.75, and adenocarcinoma (OR = 1.88; 95%CI = 0.97–3.63. On the other hand, individuals homozygous for the XRCC1 399Gln allele presented no risk of developing lung cancer (OR = 0.87; 95%CI = 0.57–1.31 except for individuals carriers of 399Gln/Gln genotype and without family history of cancer (OR = 0.57; 95%CI = 0.33–0.98 and no association was found between XRCC3 Thr241Met

  14. Meta Analysis on DNA Repair Gene XRCC3 - 18067C > T Single Neucleotide Polymorphisms and Head and Neck Cancer Susceptibility%DNA修复基因XRCC3-18067C>T多态性与头颈部肿瘤易感性关系的系统评价

    Institute of Scientific and Technical Information of China (English)

    柯为洵; 李杰; 曹岐新; 嵇冰

    2011-01-01

    目的 采用系统评价的方法探讨DNA修复基因X线修复交叉互补因子3(x- ray cross - complementing group 3,XRCC3) 18067C>T位点单核苷酸多态性与头颈部肿瘤易感性的关系.方法 检索PubMed(1966~2010年)、EMBASE( 1974~2010年)、中国生物医学文献数据库CBM(1978~2010年)、中国期刊全文数据库CNKI(1994~2010年)公开发表的关于DNA修复基因XRCC3 - 18067C>T单核苷酸多态性与头颈部肿瘤易感性的研究.病例组及对照组XRCC3 - 18067C>T等位基因分布的比值比( odds ratio,OR)为效应指标,根据一致性检验的结果,选择固定效应模型或随机效应模型对OR进行合并,并进行偏倚评估.结果 共查到符合要求的文献9篇,病例组1872例,对照组3521例.分析结果显示:XRCC3 - 18067C >T位点突变纯合子(T/T)患头颈部肿瘤的风险与野生型纯合子(C/C)相比OR=L.16(95% CI:0.95 ~ 1.43,P=0.150);隐性模式下,18067C>T位点突变纯合子(T/T)患头颈部肿瘤的风险与野生型(纯合子+杂合子)(C/C)+(C/T)相比OR=1.16(95% CI:0.96~1.40,P=0.124);显性模式下,18067C>T位点突变个体(突变纯合子+突变杂合子)(T/T)+(C/T)患头颈部肿瘤的风险与野生型纯合子(C/C)相比OR=1.05(95% CI:0.93~1.19,P=0.426).结论 DNA修复基因XRCC3 18067C>T位点单核苷酸多态性与头颈部肿瘤易感性间存不在明显相关性.%Objective To evaluate the relationship between X - ray cross - complementing group 3 ( XRCC3 ) gene single neucleotide polymorphisms and head and neck cancer susceptibility. Methods By searching Medline, EMBSE, CBM and CNKI.et al, we collected studies about DNA X - ray cross - complementing group 3 ( XRCC3) gene polymorphisms and head and neck cancer susceptibility. The odds ratios (OR) of variant allele of XRCC3 - 18067C >T was calculated by using statistic software STATAU.O. Publication bias was also evaluated. Results Nine case -control studies were identified for the

  15. XRCC3基因Thr241Met(rs861539)位点单核苷酸多态性与鼻咽癌的相关性%The association between single nucleotide polymorphisms of XRCC3 gene Thr241Met (rs861539) site and nasopharyngeal carcinoma susceptibility

    Institute of Scientific and Technical Information of China (English)

    张应蒙; 叶尔佳; 王宏梅; 石玉生; 陈龙华

    2012-01-01

    目的:研究XRCC3基因Thr241Met (C/T,rs861539)位点多态性与广东鼻咽癌的相关性.方法:应用PCR方法对127例广州鼻咽癌患者和117例健康对照人群的DNA标本rs861539位点进行扩增、纯化及测序,再结合人群临床资料进行统计学分析.结果:rs861539 C>T,其中杂合型C/T基因型频率在对照组中分布较高(OR=0.473,95% CI=0.244~ 0.917,P<0.05);经年龄及性别分层分析,杂合子在年龄≤30岁(OR=0.071,95% CI=0.007~0.722,P<0.05)以及男性(OR=0.469,95% CI=0.232~0.947,P<0.05)人群中在对照组分布较高;而在年龄> 30岁以及女性人群中两组间分布均无统计学差异.纯和突变型T/T基因型在两组间分布差异无显著性(OR=1e9,95% CI=0~∞,P>0.05),经年龄及性别分层分析,在两组间仍无统计学差异.结论:XRCC3基因Thr241Met (C/T,rs861539)基因多态性可能与鼻咽癌易感性无显著相关性.%Objective The aim of this paper was to study the association between single nucleotide polymorphisms (SNP) of XRCC3 gene Thr241Met (rs861539) site and the susceptibility of nasopharyngeal carcinoma in Cantonese. Methods A total of 127 NPC patients and 117 age-matched and gender-matched healthy controls were enrolled in this study. C/T genotyping of the SNP locus rs861539 in XRCC3 gene was performed by PCR and DNA sequencing of the PCR products. Results The genotype frequency of heterozygote C/T was higher in healthy individuals (OR = 0.473,95% CI = 0.244-0.917 ,P < 0.05). And the difference only existed in age <30 (OR = 0.071, 95% CI = 0.007-0.722, P < 0.05) or male group (OR = 0.469, 95% CI = 0.232-0.947, P < 0.05) when analyzing after stratification by age and gender. No association was found for the homozygote variant T/T( OR = 1e9, 95% CI = 0-∞, P > 0.05) in two groups. Conclusion The SNP of XRCC3 gene Thr241Met (rs861539) site may be irrelevant to the genetic susceptibility of NPC in Cantonese.

  16. Association between genetic polymorphism in DNA repair genes XRCC3 and risks of laryngeal carcinoma%X线交叉互补修复基因3遗传变异与喉癌风险的相关性

    Institute of Scientific and Technical Information of China (English)

    尼力帕尔•阿力木; 王玲玲; 张波; 阿依恒•曲库尔汗

    2016-01-01

    OBJECTIVE To study the association between polymorphism of DNA repair gene XRCC3Thr 241 Met and the risks of developing laryngeal carcinoma. METHODS Sixty patients with laryngeal carcinoma and 120 cancer-free controls were genotyped for the polymorphism by Multiplex SNaPshot.The odds ratios (ORs) and 95% confidence intervals (Cls) were calculated using unconditional logistic regression model.RESULTS The XRCC3 241 Met allele increased the risks of developing laryngeal carcinoma.Comparing with subjects having the XRCC3241 Thr/Thr genotype,the subjects at least having one XRCC3 241 Met allele had OR of 4.27 (95%CI 1.49-12.18). CONCLUSION XRCC3 Thr 241 Met plays an important role in the development of laryngeal carcinoma.%目的:研究DNA修复基因XRCC3 Thr 241 Met (rs861539)遗传变异与喉癌风险的关系。方法采用Multiplex SNaPshot技术(多重单碱基延伸反应技术)对60例喉癌患者和120名正常人进行基因分型,采用多因素Logistic回归模型计算各基因型携带者喉癌的发病风险,以及与吸烟交互对喉癌发病风险的影响。结果XRCC3241 Met等位基因增加了喉癌发病风险,与XRCC3241 Thr/Thr基因型携带者相比,至少携带一个241 Met等位基因的个体罹患喉癌的OR为4.27,95%CI为1.49~12.18。结论XRCC3 Thr 241 Met单核苷酸多态是喉癌的遗传易感因素。

  17. ERCC2基因多态性与焦炉工DNA损伤及肺癌易感性的关联研究%Association of ERCC2 gene polymorphisms with DNA damage among coke oven workers and lung cancer susceptibility

    Institute of Scientific and Technical Information of China (English)

    王芳; 何越峰; 郭欢; 杨艳; 吴舟; 郑红艳

    2012-01-01

    Objective To investigate the relationship between ERCC2 gene polymorphisms and DNA damage and lung cancer susceptibility. Methods 821 workers, 1 152 primary lung cancer and 1 152 controls were enrolled in the study. Workers were divided into three groups including the exposure, recovery and control according to the working status and places. Urine 1-hydroxypyrene was determined by reversed phase high-performance liquid chromatography. Comet assay was used to evaluate DNA damage level and the level of DNA damage was measured by Olive Tail Moments (OTM). 5' nuclease allelic discrimination assay was used to genotype ERCC2 gene polymorphisms. Results The urine 1-hydroxypyrene level of workers in the exposure and recovery group (4. 41±1. 06 and 3. 79±1. 05) were significantly higher than that of the control (3. 33±1. 03), P<0.05. The OTM of workers in exposure group (-0. 86±0.70) was higher than that of the recovery and controls (-1. 18±0. 69 and -1. 14±0- 63, respectively), P<0.01. In the recovery group, the OTM of rs50871 GT carriers was significantly lower than that of the TT carriers (-1. 28 ± 0. 62 vs -1.11 ± 0. 71, P=0. 021). Similarly, carriers of rs50872 TC heterozygote had lower OTM than that of the CC homo-zygote (-1. 33±0. 69 vs -1.10±0. 67, P=0.003). No significant associations were found in other SNPs with DNA damage. No significance was found between rs50871 and rs50872 and lung cancer susceptibility. Conclusions The ERCC2 gene polymorphisms could modulate DNA damage of coke oven workers, but had no significant effects on lung cancer susceptibility.%目的 探讨ERCC2基因多态性与焦炉工DNA损伤及肺癌易感性的关联.方法 选取821例焦化工人、1 152例原发性肺癌患者为研究对象,1 152名健康体检者作为对照.焦化工人以工作状态和岗位分为暴露组、恢复组和对照组;使用反向高效液相色谱法测定尿1-羟基芘含量,采用彗星试验检测DNA损伤并以Olive尾矩(Olive Tail Moments

  18. The Polymorphism of DNA Repair Gene ERCC2/XPD Arg156Arg and Susceptibility to Breast Cancer in a Chinese Population

    DEFF Research Database (Denmark)

    Yin, J. Y.; Liang, D. H.; Vogel, Ulla Birgitte

    2009-01-01

    found between ERCC2/XPD Arg156Arg and risk of breast cancer (AA/AC versus CC: OR = 0.79, 95% CI = 0.49-1.28, P = 0.33; AA versus CC: OR = 0.89, 95% CI = 0.49-1.63, P = 0.72; AC versus CC: OR = 0.74, 95% CI = 0.44-1.24, P = 0.25). Breast cancer cases with the variant AA genotype were marginally younger...... the association between ERCC2/XPD Arg156Arg and susceptibility to breast cancer in a Chinese population, we conducted a hospital-based case-control study consisting of 129 patients with breast cancer and 205 controls matched by age, gender, and ethnicity. PCR-RFLP was used for genotyping. No associations were...... (mean age 45 years) than cases with the wild CC genotype (mean age 50 years) (P = 0.05). There were no differences in risk estimates in relation to menopause and occurrence of breast cancer. Our findings do not suggest that ERCC2/XPD Arg156Arg contributes to breast cancer susceptibility in a Chinese...

  19. Dose and polymorphic genes xrcc1, xrcc3, gst play a role in the risk of articledeveloping erythema in breast cancer patients following single shot partial breast irradiation after conservative surgery

    Directory of Open Access Journals (Sweden)

    Muti Paola

    2011-07-01

    Full Text Available Abstract Background To evaluate the association between polymorphisms involved in DNA repair and oxidative stress genes and mean dose to whole breast on acute skin reactions (erythema in breast cancer (BC patients following single shot partial breast irradiation (SSPBI after breast conservative surgery. Materials and Methods Acute toxicity was assessed using vers.3 criteria. single nucleotides polymorphisms(SNPs in genes: XRCC1(Arg399Gln/Arg194Trp, XRCC3 (A4541G-5'UTR/Thr241Met, GSTP1(Ile105Val, GSTA1 and RAD51(untranslated region. SNPs were determined in 57 BC patients by the Pyrosequencing analysis. Univariate(ORs and 95% CI and logistic multivariate analyses (MVA were performed to correlate polymorphic genes with the risk of developing acute skin reactions to radiotherapy. Results After SSPBI on the tumour bed following conservative surgery, grade 1 or 2 acute erythema was observed in 19 pts(33%. Univariate analysis indicated a higher significant risk of developing erythema in patients with polymorphic variant wt XRCC1Arg194Trp, mut/het XRCC3Thr241Met, wt/het XRCC3A4541G-5'UTR. Similarly a higher erythema rate was also found in the presence of mut/het of XRCC1Arg194Trp or wt of GSTA1. Whereas, a lower erythema rate was observed in patients with mut/het of XRCC1Arg194Trp or wt of XRCC1Arg399Gln. The mean dose to whole breast(p = 0.002, the presence of either mut/het XRCC1Arg194Trp or wt XRCC3Thr241Met (p = 0.006 and the presence of either mut/het XRCC1Arg194Trp or wt GSTA1(p = 0.031 were confirmed as predictors of radiotherapy-induced erythema by MVA. Conclusions The Whole breast mean dose together with the presence of some polymorphic genes involved in DNA repair or oxidative stress could explain the erythema observed after SSPBI, but further studies are needed to confirm these results in a larger cohort. Trial Registration ClinicalTrials.gov Identifier: NCT01316328

  20. DNA修复基因XRCC3多态性与晚期肺腺癌患者含铂方案化疗疗效的关系%Relationship between XRCC3 gene polymorphism and efficacy of platinum-based chemotherapy in patients with advanced lung adenocarcinoma

    Institute of Scientific and Technical Information of China (English)

    张增利; 陈婷; 朱晓良; 余勇; 杜紫燕; 周童; 邢宇斐; 施敏骅

    2014-01-01

    目的 探讨DNA修复基因XRCC3多态性与晚期肺腺癌患者含铂方案化疗疗效的关系.方法 应用Taqman探针结合实时荧光PCR方法检测70例晚期肺腺癌患者外周血XRCC3基因多态性分布,分析XRCC3 241多态性与晚期肺腺癌患者接受一线含铂方案化疗疗效及总体生存之间的关系.结果 70例晚期肺腺癌患者总体有效率25.7%,中位生存时间为17个月.XRCC3241多态性与疗效无显著相关性.与携带XRCC3 241野生纯合基因型(Thr/Thr)患者相比,携带XRCC3 241 Met突变等位基因的患者生存期延长(P<0.05).结论 XRCC3 241 Met等位基因可能与晚期肺腺癌接受含铂方案化疗后的生存时间延长有关.

  1. GSTM1 and XRCC3 Polymorphisms: Effects on Levels of Aflatoxin B1-DNA Adducts

    Institute of Scientific and Technical Information of China (English)

    Xi-dai Long; Yun Ma; Zhou-lin Deng

    2009-01-01

    Objective: Aflatoxin B1 (AFB1), which can cause the formation of AFB1-DNA adducts, is a known human carcinogen. AFB1-exposure individuals with inherited susceptible carcinogen-metabolizing or repairing genotypes may experience an increased risk of genotoxicity. This study was designed to investigate whether the polymorphisms of two genes, the metabolic gene Glutathione S-transferase M1 (GSTM1) and DNA repair gene x-ray repair cross-complementing group 3 (XRCC3), can affect the levels of AFB1-DNA adducts in Guangxi Population (n= 966) from an AFB1-exposure area.Methods: AFB1-DNA adducts were measured by ELISA, and GSTM1 and XRCC3 codon 241 genotypes were identified by PCR-RFLP.Results: The GSTM1-null genotype [adjusted odds ratio (OR) = 2.09; 95% confidence interval (CI) = 1.61(2.71] and XRCC3 genotypes with 241 Met alleles [i.e., XRCC3-TM and -MM, adjusted ORs (95% CI) were 1.43 (1.08(1.89) and 2.42 (1.13(5.22), respectively] were significantly associated with higher levels of AFB1-DNA adducts. Compared with those individuals who did not express any putative risk genotypes as reference (OR = 1), individuals featuring all of the putative risk genotypes did experience a significantly higher DNA-adduct levels (adjusted ORs were 2.87 for GSTM1-null and XRCC3-TM; 5.83 for GSTM1-null and XRCC3-MM). Additionally, there was a positive joint effect between XRCC3 genotypes and long-term AFB1 exposure in the formation of AFB1-DNA adducts.Conclusion: These results suggest that individuals with susceptible genotypes GSTM1-null, XRCC3-TM, or XRCC3-MM may experience an increased risk of DNA damage elicited by AFB1 exposure.

  2. Relationship between ERCC2 Polymorphism and Risk of Lung Cancer in Chinese Nonsmoker

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective: Excision repair cross-complimentary group 2 (ERCC2) is one of the important DNA repair genes.ERCC2 codon 751 polymorphism has been shown to modulate cancer risk. We therefore assessed the relationship between the ERCC2 polymorphism and the susceptibility to lung cancer in nonsmoking females via a hospital-based case-control study. Methods: There were 105 lung cancer cases and matched healthy controls in this study. Information concerning demographic and risk factors was obtained, each person donated 2 ml blood for biomarker testing. ERCC2 genotypes were determined by PCR-RFLP method. All of the statistical analyses were performed with SPSS (v 12.0). Results: All of the subjects in this study were nonsmoking females in Shenyang.There was significant difference between the frequencies of ERCC2 polymorphism in cancer cases and controls (P<0.05). The frequencies of ERCC2 751 Gin allele were 6.2% in controls and 13.8% in cancer cases. The individuals with Lys/Gln+Gln/Gln combined genotype were at an increased risk for lung cancer as compared with those carrying the Lys/Lys genotype (adjusted OR=2.80, 95%=CI 1.21-6.48). We analyzed the environmental risk factors for lung cancer in nonsmoking females. The cancer patients showed a higher prevalence of exposure to cooking fumes compared with controls (OR=2.44, P<0.05). Furthermore, an interaction between exposure to cooking fumes and the variant ERCC2 751 Gln allele on the risk of lung cancer was observed. Individuals with both risk genotype and exposure to cooking fumes had a higher risk of cancer than those with only one of them.Conclusion: The above findings indicate that the genetic polymorphism in the ERCC2 codon 751 is associated with the risk of lung cancer in nonsmoking females.

  3. Meta-analysis of the association between the polymorphism of Thr241Met in DNA damage repair gene XRCC3 and lung cancer susceptibility%DNA损伤修复基因XRCC3Thr241Met多态与肺癌易感性关系的Meta分析

    Institute of Scientific and Technical Information of China (English)

    周芳; 万军庭; 谭晓刚; 陈照丽; 赫捷

    2011-01-01

    目的:探讨DNA损伤修复基因X射线交叉互补修复基因3(XRCC3)Thr241Met多态性与肺癌易感性的关系.方法:查找中国医学文献数据库和PubMed,以得到XRCC3基因Thr241Met多态与肺癌易感性关系的病例-对照研究,根据纳入和排除标准筛选符合条件的研究进行Meta分析,合并XRCC3基因Thr241Met多态与肺癌易感性关系的OR值,然后进行亚组分析、敏感性分析和文献的发表偏倚检验.结果:本次Meta分析共纳入13篇文献,累计病例2 986例,对照4 495例,显性模型下TM+MM基因型相对于TT(TM=Thr/Met)基因型 OR值为0.96(95%CI为0.86~1.06),差异无统计学意义.结论:尚无足够证据证明XRCC3基因Thr241Met多态同肺癌易感性有关.%OBJECTIVE: To evaluate the association between XRCC3 (X-ray repair cross-complementing group 3)Thr241Met polymorphism and lung cancer susceptibility.METHODS: CBM disc and PubMed was searched to get the case-control study on the association between XRCC3 Thr241Met and lung cancer susceptibility, and pooled the OR of the association of XRCC3 Thr241Met and lung cancer susceptibility by meta-analysis according to the including and excluding standard. Then subgroup analysis, sensitivity analysis and publication bias test were performed. RESULTS: Thirteen studies with 2 986 cases and 4 495 controls were enrolled in this Metaanalysis. The pooled OR of TM+ MM compared to TT under dominant model was 0.96 without statistically significant association (95% CI:0.86 -1.06 ). CONCLUSION: The findings suggest that XRCC3 Thr241Met may not contribute to the susceptibility of lung cancer.

  4. A systematic gene-gene and gene-environment interaction analysis of DNA repair genes XRCC1, XRCC2, XRCC3, XRCC4, and oral cancer risk.

    Science.gov (United States)

    Yang, Cheng-Hong; Lin, Yu-Da; Yen, Ching-Yui; Chuang, Li-Yeh; Chang, Hsueh-Wei

    2015-04-01

    Oral cancer is the sixth most common cancer worldwide with a high mortality rate. Biomarkers that anticipate susceptibility, prognosis, or response to treatments are much needed. Oral cancer is a polygenic disease involving complex interactions among genetic and environmental factors, which require multifaceted analyses. Here, we examined in a dataset of 103 oral cancer cases and 98 controls from Taiwan the association between oral cancer risk and the DNA repair genes X-ray repair cross-complementing group (XRCCs) 1-4, and the environmental factors of smoking, alcohol drinking, and betel quid (BQ) chewing. We employed logistic regression, multifactor dimensionality reduction (MDR), and hierarchical interaction graphs for analyzing gene-gene (G×G) and gene-environment (G×E) interactions. We identified a significantly elevated risk of the XRCC2 rs2040639 heterozygous variant among smokers [adjusted odds ratio (OR) 3.7, 95% confidence interval (CI)=1.1-12.1] and alcohol drinkers [adjusted OR=5.7, 95% CI=1.4-23.2]. The best two-factor based G×G interaction of oral cancer included the XRCC1 rs1799782 and XRCC2 rs2040639 [OR=3.13, 95% CI=1.66-6.13]. For the G×E interaction, the estimated OR of oral cancer for two (drinking-BQ chewing), three (XRCC1-XRCC2-BQ chewing), four (XRCC1-XRCC2-age-BQ chewing), and five factors (XRCC1-XRCC2-age-drinking-BQ chewing) were 32.9 [95% CI=14.1-76.9], 31.0 [95% CI=14.0-64.7], 49.8 [95% CI=21.0-117.7] and 82.9 [95% CI=31.0-221.5], respectively. Taken together, the genotypes of XRCC1 rs1799782 and XRCC2 rs2040639 DNA repair genes appear to be significantly associated with oral cancer. These were enhanced by exposure to certain environmental factors. The observations presented here warrant further research in larger study samples to examine their relevance for routine clinical care in oncology.

  5. RAD51基因G135C和XRCC3基因T241M多态性与卵巢癌的相关性%Correlation between polymorphisms of RAD51 gene G135C and XRCC3 gene T241M and ovarian cancer

    Institute of Scientific and Technical Information of China (English)

    高志斌; 徐瑛; 王兆平; 傅家欣

    2015-01-01

    目的 研究RAD51基因G135C多态性和XRCC3基因T241M多态性与卵巢癌的相关性.方法 对70例卵巢癌和70例健康对照人群的样本分别进行DNA提取、RAD51基因和XRCC3基因扩增及测序,再结合人群临床资料进行统计学分析.结果 RAD51基因型G/G、G/C和C/C在病例组的分布频率分别为71.4%、20.0%和8.6%,在对照组的分布频率分别为91.4%、8.6%和0.病例组突变型频率显著高于对照组(P<0.05).XRCC3基因T/T、T/M和M/M在病例组的分布频率分别为88.6%、8.6%和2.9%,在对照组的分布频率分别为85.7%、14.3%和0;两组差异无统计学意义(P>0.05).RAD51基因型G/G在卵巢浆液性癌组和黏液性癌组中的分布频率分别为68.0%和80.0%,变异基因型(G/C+C/C)分别为32.0%和20.0%.RAD51 G135C基因型在不同的卵巢癌组织学类型间的分布频率差异无统计学意义(P>0.05).XRCC3基因T/T在卵巢浆液性癌组和黏液性癌组中的频率分别为92.0%和80.0%,变异基因型(T/M和M/M)分别为8.0%和20.0%.XRCC3基因T241M基因型在不同的卵巢癌组织学类型间的分布频率差异无统计学意义(P>0.05).结论 RAD51基因G135C多态性与卵巢癌发病有相关性,XRCC3基因T241M多态性与卵巢癌易感性无显著相关性.两基因的野生型及突变型与卵巢癌的组织学类型不相关.

  6. Relationship between GSTT1, GSTM1, NQO1, RAD51 and XRCC3 genes polymorphisms and chronic myeloid leukemia%GSTT1、GSTM1、NQO1、RAD51和XRCC3基因多态性与慢性粒细胞白血病发生关系的研究

    Institute of Scientific and Technical Information of China (English)

    杨琳; 徐世才; 刘旭平; 张美荣; 张悦; 肖志坚

    2006-01-01

    目的探讨GSTT1、GSTM1、NQO1、RAD51和XRCC3基因多态性与我国慢性粒细胞白血病(CML)发生遗传易感之间的关系.方法共120例CML患者和458名与患者无血缘关系的正常人,用多重PCR方法检测GSTT1和GSTM1基因型,用PCR-RFLP方法分析RAD51,XRCC3,NQO1基因型.结果CML患者GSTT1和GSTM1缺失型比例分别为50.8%和59.2%,与正常对照组无显著差异(分别为42.8%和53.1%).CML患者NQO1 C/T和T/T基因型的比例(60.0%)、RAD51 G135CG/C基因型比例(26.9%)和XRCC3-241Met杂合子缺失型(Thr/Met)的比例(9.2%)均与正常对照组(分别为65.3%,12.4%和9.2%)无统计学差异.结论本研究结果提示GSTT1、GSTM1、NQO1、RAD51和XRCC3基因型与我国CML的发生无显著相关性.

  7. DNA修复基因XRCC1和XRCC3多态性与慢性苯中毒易感性的关系%Association between genetic polymorphisms of DNA repair genes XRCC1, XRCC3 and susceptibility to chronic benzene poisoning

    Institute of Scientific and Technical Information of China (English)

    黄慧隆; 许建宁; 王全凯; 杨敏; 王雅文; 陈艳; 李桂兰

    2007-01-01

    目的 探讨DNA修复基因XRCC1、XRCC3多态性与慢性苯中毒遗传易感性的关联及其与慢性苯中毒潜伏期的关系.方法 采用病例-对照研究方法,以确诊并已脱离苯作业的80名慢性苯中毒患者为病例组,以同期接苯的62名苯作业工人为对照组,应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)分析技术,检测XRCC1基因C26304T(Arg194Trp)、G27466A(Arg280His)、G28152A(Arg399Gln)、G36189A(Gln632Gln)位点和XRCC3基因C18067T(Thr241Met)位点的多态性,并采用生存分析方法对慢性苯中毒的潜伏期进行分析.结果 携带XRCC3 18067C/T基因型的个体发生慢性苯中毒的危险性低于携带XRCC3 18067C/C基因型的个体(0R=0.233,95%CI:0.085~0.639,P=0.0046);携带XRCC1 27466G/G基因型的个体发生慢性苯中毒的潜伏期比携带27466G/A或A/A基因型的个体长6年.结论 在相同的苯作业暴露环境下,携带XRCC3 18067T变异等位基因的个体发生慢性苯中毒的危险性降低;在慢性苯中毒患者中,携带XRCC1 27466 G/G基因型的个体发生慢性苯中毒的潜伏期较长.

  8. The XRCC3 Thr241Met gene polymorphism and hepatocellular carcinoma susceptibility in a Chinese population:a meta-analysis%中国人群XRCC3 Thr241Met基因多态性与肝癌易感性的荟萃分析

    Institute of Scientific and Technical Information of China (English)

    范烨; 张闻; 闫书山; 张鹏军; 王平

    2013-01-01

    目的:探讨中国人群中DNA修复基因X线修复交叉互补因子3(X-ray cross-complementing group 3,XRCC3) 241位点(XRCC3 Thr241Met)的基因多态性与肝细胞癌(hepatocellular carcinoma,HCC)遗传易感性的关联关系.方法:利用PubMed、EMBASE、万方数据库、中国期刊全文数据库及维普数据库检索国内外公开发表的关于XRCC3 Thr241Met的多态性与HCC关系的所有文献.采用Meta分析的方法合并所有纳入研究的优势比(odds ratios,ORs)值及其95%可信区间(confidence intervals,CIs).根据人群分布地区及HBV慢性感染、吸烟暴露因素的不同进行亚组分析,并分析组间异质性的可能来源.结果:本文共纳入从2008~2012年发表的随机对照研究5篇,共计HCC患者1 741例,对照2 596例.①在中国人群中,XRCC3 Thr241Met的T等位基因及变异基因型与HCC的发生存在明显的相关生(ORT vs C=1.84,95%CI:1.19~2.85,POR=0.003;ORTT vs CC=4.71,95%CI:2.14~10.34,POR<0.001;ORCT vs CC=1.59,95% CI:1.07 ~2.36,POR=0.022;ORTT vs CC+CT=4.21,95% CI:2.21~8.00,POR<0.001;ORCT+TT vs CC =1.83,95%CI:1.11~3.00,POR=0.017);②在广西人群中,携带XRCC3 Thr241Met的变异等位基因及基因型的个体,其HCC的易感性明显升高(ORT vs C=2.23,95%CI:1.32~3.77,POR=0.003; ORTT vs CC=5.74,95%CI:2.33~14.14,POR< 0.001;ORCT vs CC=1.91,95%CI:1.23~2.99,POR=0.004;ORTT vs CC+CT=4.63,95%CI:2.20~9.76,POR< 0.001;ORCT+TT vs CC=2.29,95%CI:1.26~4.18,POR =0.007);③未发现XRCC3 Thr241Met的基因多态性与HCC发病的2种危险因素HBV慢性感染、吸烟之间存在交互作用.结论:在中国人群尤其是广西人群中,XRCC3 Thr241Met的基因多态性与HCC的发病风险有关,但不存在基因与环境的交互作用.

  9. 广西肝癌高发区人群XRCC3基因多态性与肝癌易感性研究%Correlation of polymorphism of DNA repair gene XRCC3 with susceptibility to hepatocellular carcinoma in regions of high HCC incidence rate in Guangxi

    Institute of Scientific and Technical Information of China (English)

    曾小云; 余红平; 仇小强; 纪龙; 李龙嫚

    2009-01-01

    目的:探讨XRCC3基因多态性与广西肝癌高发区人群肝癌易感性的关系.方法:采用以医院为基础的病例对照研究方法.选择来自广西肝癌高发区的肝癌新发病例545例;对照组按年龄、性别频数匹配,且与病例来自相同地区的非肿瘤患者515例.运用高通量的TaqMan MGB荧光定量实时PCR实验方法,检测XRCC3-241位点单核苷酸多态性,比较其不同基因型与肝癌易感性的关系.结果:本研究共纳入符合要求、资料完整的肝癌病例组500例,对照组507例.XRCC3-241位点3种基因型CC、CT和TT在病例组的分布频率分别为85.8%、13.2%和1.0%,在对照组的分布频率分别为87.2%、11.8%和1.0%,但两组差异无统计学意义(χ2=0.431,P=0.806).XRCC3-241基因多态性与HCC在调整民族、年龄、性别、职业、吸烟和饮酒状态等因素前后均无统计学关联.按是否有肝炎病史、吸烟、饮酒和是否有HBsAg慢性感染进行分层,均未能发现XRCC3-241基因多态性与HCC发病风险有关.与吸烟、饮酒和HBsAg慢性感染3种环境危险因素均存在交互作用,OR值分别为7.949(2.308~27.382)、5.950(2.554~13.865)和24.709(11.861~51.477).结论:XRCC3-241基因多态性与肝癌易感性无关联,可能不是广西肝癌高发区人群的高危因素,但存在基因与环境的交互作用.

  10. Association between genetic polymorphisms of DNA repair genes XRCC1, XPD, XRCC3 and the capacity of DNA repair induce by benzene%修复基因XRCC1、XPD和XRCC3多态性与苯致DNA损伤修复能力关系的研究

    Institute of Scientific and Technical Information of China (English)

    许建宁; 杨敏; 黄慧隆; 王全凯; 王雅文; 李桂兰

    2007-01-01

    目的 探讨XRCC1、XPD、XRCC3基因多态性与苯致DNA损伤修复能力的关系.方法 以确诊并已脱离苯作业的80名慢性苯中毒患者作为病例组,以同期接苯的62名苯作业工人为对照组,应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)分析技术,检测XRCC1 C26304T(Arg194Trp)、G27466A(Arg280His)、C28152A(Arg399Gln)、C36189A(Gln632Gln)和XPD C22541A(Arg156Arg)、C23591T(Asp312Asn)、A35931C(Lys751Gln)以及XRCC3 C18067T(Thr241Met)位点的多态性,采用细胞阻滞微核试验和碱性彗星试验分别从细胞水平和分子水平检测DNA修复能力.结果 携带XPD 35931 AC+CC变异基因型的个体、携带XPCC3 18067 C/T变异基因型的个体均比携带相应野生基因型个体的苯致DNA损伤修复能力强.结论 XRCC3基因多态性与苯致DNA损伤修复能力存在相关性.

  11. XRCC3基因Thr241Met多态性与中国人肺癌易感性关系的Meta分析%Association between Thr241Met Polymorphism in XRCC3 Gene and the Risk of Lung Cancer in Chinese Population: A Meta-Analysis

    Institute of Scientific and Technical Information of China (English)

    郑巧玲; 张含琼; 张承; 徐刚

    2013-01-01

    目的 系统评价XRCC3基因Thr241Met多态性与中国人肺癌发病风险的相关性.方法 计算机检索PubMed、EMbase、CNKI、VIP和WanFang Data,查找国内外关于XRCC3基因Thr241Met多态性与中国人群肺癌易感性关系的研究,检索时限均为建库至2013年8月20日.由2名评价者根据纳入与排除标准独立筛选文献,提取资料并评价质量后,采用RevMan 5.0软件和Stata 10.0软件进行Meta分析,采用Egger's线性回归法分析发表偏倚.结果 最终纳入5个研究,包括肺癌患者2999例,对照2994例.Meta分析结果显示:对于中国人群而言,携带XRCC3基因Thr241Met多态性突变基因型/等位基因的个体肺癌发病风险不会明显增加:Met/Met vs.Thr/Thr:OR=1.00,95%CI (0.38,2.59),P=0.99; Met/Met vs.Thr/Met:OR=1.06,95%CI (0.83,1.36),P=0.63; Met/Met vs.Thr/Met+Thr/Thr:OR=0.99,95%CI (0.38,2.57),P=0.98; Thr/Met+Met/Met vs.Thr/Thr:OR=1.06,95%CI (0.82,1.37),P=0.65; Met vs.Thr:OR=1.05,95%CI (0.82,1.35),P=0.68.结论 目前尚未发现XRCC3基因Thr241Met多态性与中国人群肺癌发病风险相关.受纳入研究数量的限制,上述结论需更多高质量大样本研究进一步验证.

  12. Association of single nucleotide polymorphisms of DNA repair gene XRCC3-241 with non-small cell lung cancer%人类XRCC3-241单核苷酸多态性与非小细胞性肺癌的易感性研究

    Institute of Scientific and Technical Information of China (English)

    夏文进; 张毅敏; 苏丹; 史锋

    2008-01-01

    目的 探讨人类DNA修复基因XRCC3-241单核苷酸多态性(SNP)与非小细胞性肺癌的发生关系.方法 103例非小细胞性肺癌患者(经病理检查证实)作为病例组,139例健康体检者作为对照组,采外周血.XRCC3-241基因分型检测采用Taqman探针PCR法,分析病例组和对照组的XRCC3-241的SNP.结果 在139例健康体检者中.118例为C/C基因型,占总数的84.9%,21例为C/T基因型,占总数的15.1%.在103例非小细胞性肺癌患者中,91例为C,C基因型,占总数的88.3%,12例为C/T基因型,占总数的11.6%.病例组和对照组均未检测到T/T基因型.结果 表明,携带T/C基因型的人患非小细胞性肺癌的风险性是C/C基因型的1.004倍(P>0.05).非小细胞性肺癌组吸烟个体的比例(68.9%)明显高于对照组(36.7%);吸烟可显著增加肺癌的发病风险(P<0.01).结论 XRCC3-241 SNP与非小细胞性肺癌发生的风险无相关性;吸烟显著增加非小细胞性肺癌的发病风险.

  13. DNA repair gene XRCC3 Thr241Met polymorphism and susceptibility to cardia and non-cardia gastric cancer: a case- control study%DNA损伤修复基因XRCC3 Thr241Met多态与贲门癌、非贲门部胃癌易感性关系的病例对照研究

    Institute of Scientific and Technical Information of China (English)

    黄贵培; 郑宗立; 蔡琳

    2006-01-01

    目的探讨福建人群DNA损伤修复基因XRCC3 Thr241Met多态与贲门癌、非贲门部胃癌易感性的关系,分析基因与环境因素在癌症发生中的联合作用.方法采用共同对照组的病例对照研究方法,应用PCR-RFLP技术检测基因型,应用非条件logistic回归计算OR值及其95%CI.结果 XRCC3三种基因型(野生型CC、杂合突变型CT、纯合突变型TT)在贲门癌组的分布频率分别为43.2%、46.5%、10.3%;在非贲门部胃癌组的分布频率为53.2%、40.9%、5.8%;在对照组的分布频率分别为59.6%、35.1%、5.3%.经多因素分析结果显示携带变异基因型(CT+TT)个体罹患贲门癌的风险增加(OR=1.76,95%CI:1.07~2.90).XRCC3变异基因型与饮酒、新鲜蔬菜摄入和慢性胃炎对贲门癌发生存在协同作用;与吸烟、慢性胃炎对非贲门部胃癌发生存在协同作用.结论XRCC3基因多态与贲门癌发生有关,贲门癌与非贲门部胃癌的危险因素不尽相同.

  14. Polymorphisms in DNA repair genes XRCC1 and XRCC3, occupational exposure to arsenic and sunlight, and the risk of non-melanoma skin cancer in a European case-control study.

    Science.gov (United States)

    Surdu, Simona; Fitzgerald, Edward F; Bloom, Michael S; Boscoe, Francis P; Carpenter, David O; Haase, Richard F; Gurzau, Eugen; Rudnai, Peter; Koppova, Kvetoslava; Vahter, Marie; Leonardi, Giovanni; Goessler, Walter; Kumar, Rajiv; Fletcher, Tony

    2014-10-01

    X-ray repair cross-complementing group 1 (XRCC1) and group 3 (XRCC3) polymorphisms are relatively frequent in Caucasian populations and may have implications in skin cancer modulation. A few studies have evaluated their association with non-melanoma skin cancer (NMSC), but the results are inconsistent. In the current study, we aim to assess the impact of XRCC1 R399Q and XRCC3 T241M polymorphisms on the risk of NMSC associated with sunlight and arsenic exposure. Study participants consist of 618 new cases of NMSC and 527 hospital-based controls frequency matched on age, sex, and county of residence from Hungary, Romania, and Slovakia. Adjusted effects are estimated using multivariable logistic regression. The results indicate an increased risk of squamous cell carcinoma (SCC) for the homozygous variant genotype of XRCC1 R399Q (OR 2.53, 95% CI 1.14-5.65) and a protective effect against basal cell carcinoma (BCC) for the homozygous variant genotype of XRCC3 T241M (OR 0.61, 95% CI 0.41-0.92), compared with the respective homozygous common genotypes. Significant interactions are detected between XRCC3 T241M and sunlight exposure at work, and between XRCC3 T241M and exposure to arsenic in drinking water (p-value for interaction exposure to sunlight or arsenic. Given the high prevalence of genetic polymorphisms modifying the association between exposure to environmental carcinogens and NMSC, these results are of substantial relevance to public health. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. ERCC1 and ERCC2 variants predict survival in gastric cancer patients.

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    Yangkai Li

    Full Text Available PURPOSE: ERCC1 and ERCC2 play critical roles in the nucleotide excision repair pathway that effectively repairs DNA damage induced by chemotherapeutic agents. Therefore, functional single nucleotide polymorphisms (SNPs in these genes could have an impact on clinical outcomes in cancer patients who received chemotherapy. However, few studies have simultaneously investigated the roles of ERCC1 and ERCC2 SNPs in clinical outcomes in gastric cancer patients. EXPERIMENTAL DESIGN: We genotyped by the TaqMan assay three common, potentially functional ERCC1 (rs3212986 and ERCC2 SNPs (rs13181 and rs1799793 in 360 gastric cancer patients. We used both Kaplan-Meier tests and Cox proportional hazards models to evaluate the effects of ERCC1 and ERCC2 genotypes and haplotypes on clinical outcomes. RESULTS: We found that, compared with ERCC2 rs1799793 GG+AG genotypes, the homozygous variant AA genotype was associated with significantly poorer overall survival (OS (AA vs. GG+AG, log-rank P=0.012 and significantly higher risk of death (AA vs. GG+AG, Adjusted hazards ratio [HR] 2.13; 95% CI, 1.28 to 3.56; P=0.004. In combined analyses, patients with any one of the three unfavorable genotypes (i.e. ERCC1 rs3212986 TT, ERCC2 rs13181 GG and rs1799793 AA had statistically significant hazards of poor prognosis (Adjusted HR, 1.54; 95% CI, 1.06 to 2.25; P=0.025, compared with those without any unfavorable genotypes. Furthermore, the haplotype A-G-G (rs1799793/rs13181/rs3212986 had a significant impact on OS (Adjusted HR, 1.57; 95% CI, 1.11 to 2.21; P=0.011, compared with the common haplotype G-T-G. CONCLUSION: ERCC1 and ERCC2 functional SNPs may jointly affect OS in Caucasian gastric cancer patients. Additional large prospective studies are essential to confirm our findings.

  16. Association Studies Between XRCC1, XRCC2, XRCC3 Polymorphisms and Differentiated Thyroid Carcinoma

    Directory of Open Access Journals (Sweden)

    Li Yan

    2016-03-01

    Full Text Available Background/Aims: DNA HRR pathway and BER pathway play vital roles in differentiated thyroid cancer (DTC development, thus we supposed that polymorphisms of XRCC1, XRCC2, XRCC3 DNA repair genes are associated with thyroid cancer risk and progression. Methods: We searched the NCBI database for relevant literatures to determine eight SNPs to be included in our study (XRCC1: rs25487, rs25489, rs1799782; XRCC2: rs3218536; XRCC3: rs1799794, rs56377012, rs1799796, rs861539. Results: SNP of rs25487 was linked with a 53% decrease in DTC risk (OR: 0.47; 95%CI: 0.268-0.82; P = 0.01. For SNP of rs1799782, the homozygous TT genotype indicated a statistically significant 2-fold increased risk of DTC (OR: 2.09; 95%CI: 1.27-3.43; P P P = 0.02 after multivariate adjustment. Similar results for most of the SNPs were obtained from subgroup analysis by different histological types of DTC. Haplotype analysis revealed that AGC and GGT haplotypes of XRCC1 polymorphisms were associated with DTC. Moreover, results from gene-gene interaction showed that XRCC1-rs25487, XRCC1- rs1799782 and XRCC3- rs861539 variants jointly contributed to a specifically increased risk of DTC, with the combination variant of rs1799782-CT heterozygote and rs861539-TT homozygote exhibiting a higher 3.66-fold risk of DTC (OR: 3.66; 95% CI: 1.476-9.091, P = 0.005. Conclusion: Polymorphisms of XRCC1 (rs25487, rs1799782 and XRCC3 (rs861539, may play a critical role in DTC development and progression. Furthermore, XRCC1 variant can interact with XRCC3 variant to significantly increase DTC susceptibility. Identifying these genetic risk markers could provide evidence for exploring the insight pathogenesis and develop novel therapeutic strategies for DTC.

  17. XRCC3 Thr241Met polymorphism and risk of acute myeloid leukemia in a Romanian population.

    Science.gov (United States)

    Bănescu, Claudia; Tilinca, Mariana; Benedek, Erzsebeth Lazar; Demian, Smaranda; Macarie, Ioan; Duicu, Carmen; Dobreanu, Minodora

    2013-09-10

    DNA repair systems have a critical role in maintaining the genome integrity and stability. DNA repair gene polymorphisms may influence the capacity to repair DNA damage, and thus lead to an increased cancer susceptibility. X-ray repair cross-complementing groups 3 (XRCC3), a DNA repair gene, may be involved in acute myeloid leukemia susceptibility. The objective of the current study was to investigate the association of Thr241Met polymorphism of XRCC3 gene with the risk of acute myeloid leukemia (AML). This study included 78 AML patients and 121 healthy individuals without cancer. We used polymerase chain reaction-restriction fragment length polymorphism assay to determine XRCC3 genotypes. The XRCC3 variant genotype (Thr/Met+Met/Met) was more frequent in AML patients than in healthy controls (OR=2.76, 95% CI: 1.52-4.98, P=0.001). Our study revealed a statistically significant association between variant genotype (Thr/Met+Met/Met) and AML de novo compared to secondary AML (P=0.007). No significant associations were found between any genotype and age at diagnosis, number of white blood cells and subtype of AML. Overall survival of patients with Thr/Thr genotype was better than those of variant Thr/Met and Met/Met genotypes. Our findings indicate that the XRCC3 Thr241Met polymorphism may be a genetic risk factor for AML, particularly in male patients with de novo AML from the central part of Romania. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. X射线交错互补修复基因3基因单体型与喉癌的关联分析%Haplotype analysis of XRCC3 gene and laryngeal

    Institute of Scientific and Technical Information of China (English)

    周旭; 戚颖

    2014-01-01

    目的:探讨X射线交错互补修复基因3(XRCC3)基因单体型和喉癌易感性的关联.方法:选择XRCC3基因4个标签SNP(rs12432907、rs861536、rs861537、rs861531),对310例喉癌患者(实验组)及310例健康人(对照组)进行基因分型.采用SHEsis软件构建单体型,比较基因型及单体型频率在2组之间的差异.结果:实验组、对照组rs12432907基因型频率比较,差异有统计学意义(P<0.05).单体型分析结果显示,CCAG单体型分布频率实验组明显高于对照组,TCAG和TTAG分布频率实验组明显低于对照组,差异有统计学意义(均P<0.05).结论:XRCC3基因单体型和喉癌的易感性具有明显关联.

  19. XRCC3 ATPase activity is required for normal XRCC3-Rad51C complex dynamics and homologous recombination

    Energy Technology Data Exchange (ETDEWEB)

    Yamada, N; Hinz, J; Kopf, V L; Segalle, K; Thompson, L

    2004-02-25

    Homologous recombinational repair is a major DNA repair pathway that preserves chromosomal integrity by removing double-strand breaks, crosslinks, and other DNA damage. In eukaryotic cells, the Rad51 paralogs (XRCC2, XRCC3, Rad51B, Rad51C, and Rad51D) are involved in this process, although their exact functions are largely undetermined. All five paralogs contain ATPase motifs, and XRCC3 appears to exist in a single complex with Rad51C. To begin to examine the function of this Rad51C-XRCC3 complex, we generated mammalian expression vectors that produce human wild-type XRCC3 or mutant XRCC3 with either a non-conservative mutation (K113A) or a conservative mutation (K113R) in the GKT Walker A box of the ATPase motif. The three vectors were independently transfected into Xrcc3-deficient irs1SF CHO cells. Wild-type XRCC3 complemented irs1SF cells, albeit to varying degrees, while ATPase mutants had no complementing activity, even when the mutant protein was expressed at comparable levels to that in wild-type-complemented clones. Because of the mutants' dysfunction, we propose that ATP binding and hydrolyzing activities of XRCC3 are essential. We tested in vitro complex formation by wild-type and mutant XRCC3 with His6-tagged Rad51C upon coexpression in bacteria, nickel affinity purification, and western blotting. Wild-type and K113A mutant XRCC3 formed stable complexes with Rad51C and co-purified with Rad51C, while the K113R mutant did not and was predominantly insoluble. Addition of 5 mM ATP, but not ADP, also abolished complex formation by the wild-type proteins. These results suggest that XRCC3 is likely to regulate the dissociation and formation of Rad51C-XRCC3 complex through ATP binding and hydrolysis, with both processes being essential for the complex's ability to participate in HRR.

  20. RAD51G135C和XRCC3C241T多态性与急性髓系白血病和骨髓增生异常综合征的发生及其染色体异常相关性研究%Relationship of RAD51G135C and XRCC3C241T gene polymorphisms with acute myeloid leukemia, myelodysplasfic symdromes and karyotype abnormalities

    Institute of Scientific and Technical Information of China (English)

    杨琳; 张美荣; 张悦; 徐世才; 刘旭平; 肖志坚

    2006-01-01

    目的 探索同源重组修复基因RAD51和XRCC3多态性与急性髓系白血病(AML)、骨髓增生异常综合征(MDS)发生及染色体异常之间的关系.方法 对306例AML患者、52例MDS患者和458名与患者无血缘关系的正常人,用聚合酶链反应-限制性内切酶片段长度多态性(PCR-RFLP)方法分析RAD51、XRCC3、NQO1基因型,用多重PCR方法检测GSTT1和GSTM1基因型.结果 AML患者RAD51 G135CG/C基因型比例(35.3%)与正常对照组(26.9%)比较差异有统计学意义(P=0.023),RAD51G135C G/C基因型患AML的相对风险性(OR值)为1.441(95%CI:1.052~1.973).inv(16)和(或)t(16;16)/CBFB-MYH11(+)患者,XRCC3C241T杂合子基因型的比例(41.2%)明显高于正常对照组(10.0%)(P=0.000),XRCC3C241T杂合子基因型患inv(16)和(或)t(16;16)AML的OR值为6.133(95%CI:2.227~16.887,P=0.000);且不同基因之间有显著的协同效应,XRCC3C241T和RAD51G135C同时为变异基因型,OR值增高至8.697,在此基础上同时GSTM1为缺失型,OR值增至12.656,同时NQO1 C609T为变异基因型,OR值增至17.091.MDS患者RAD51G135C和XRCC3C241T各基因型比例与正常对照组比较差异无统计学意义.结论 XRCC3C241T基因型与inv(16)和(或)t(16;16)/CBFB-MYH11(+)AML发生高度相关,此相关性与XRCC3C241T和RAD51G135C之间,及与GSTM1和NQO1 C609T基因之间存在显著的协同效应.RAD51G135C和XRCC3C241T基因型与MDS发生及MDS染色体异常之间未发现有相关性.

  1. Are genetic polymorphisms in OGG1, XRCC1 and XRCC3 genes predictive for the DNA strand break repair phenotype and genotoxicity in workers exposed to low dose ionising radiations?

    Energy Technology Data Exchange (ETDEWEB)

    Aka, Peter [Laboratory for Cell Genetics, Department of Biology, Free University of Brussels, Pleinlaan 2, B-1050 Brussels (Belgium)]. E-mail: paka@vub.ac.be; Mateuca, Raluca [Laboratory for Cell Genetics, Department of Biology, Free University of Brussels, Pleinlaan 2, B-1050 Brussels (Belgium); Buchet, Jean-Pierre [Unit of Industrial Toxicology and Occupational Medicine, Catholic University of Louvain, Clos Chapelle, Aux-Champs, B-1200 Brussels (Belgium); Thierens, Hubert [Department of Biomedical Physics and Radiation Protection, University of Ghent, Proeftuinstraat 86, B-9000 Ghent (Belgium); Kirsch-Volders, Micheline [Laboratory for Cell Genetics, Department of Biology, Free University of Brussels, Pleinlaan 2, B-1050 Brussels (Belgium)

    2004-11-22

    Identification of higher risk individuals carrying genetic polymorphisms responsible for reduced DNA repair capacity has substantial preventive implications as these individuals could be targeted for cancer prevention. We have conducted a study to assess the predictivity of the OGG1, XRCC1 and XRCC3 genotypes and the in vitro single strand break repair phenotype for the induction of genotoxic effects. At the population level, a significant contribution of the OGG1 genotypes to the in vitro DNA strand break repair capacity was found. At an individual level, the OGG1 variants Ser/Cys and Cys/Cys genotypes showed a slower in vitro DNA repair than the Ser/Ser OGG1genotype. A multivariate analysis performed with genotypes, age, cumulative dose, exposure status and smoking as independent variables indicated that in the control population, repair capacity is influenced by age and OGG1 polymorphisms. In the exposed population, DNA damage is greater in older men and in smokers. Repair capacity is slower in individuals with Ser/Cys or Cys/Cys OGG1 genotypes compared to those with the Ser/Ser OGG1 genotype. Micronuclei (MN) frequencies increased with age and the cumulative dose of {gamma}-rays. Analysis of the total population revealed that genetic polymorphisms in XRCC1 resulted in higher residual DNA (RDNA) values and the Met/Met variant of XRCC3 resulted in an increased frequency of micronuclei. The analysis confirms that MN frequencies are reliable biomarkers for the assessment of genetic effects in workers exposed to ionising radiation (IR). A combined analysis of the three genotypes, OGG1, XRCC1 and XRCC3 polymorphisms is advised in order to assess individual susceptibility to ionising radiation. As an alternative or complement, the in vitro DNA strand break repair phenotype which integrates several repair pathways is recommended. Smokers with OGG1 polymorphisms who are exposed to ionising radiation represent a specific population requiring closer medical surveillance

  2. ERCC2, ERCC1 polymorphisms and haplotypes, cooking oil fume and lung adenocarcinoma risk in Chinese non-smoking females

    Directory of Open Access Journals (Sweden)

    Li Xuelian

    2009-12-01

    Full Text Available Abstract Background Excision repair cross-complementing group 1 (ERCC1 and group 2 (ERCC2 proteins play important roles in the repair of DNA damage and adducts. Single nucleotide polymorphisms (SNPs of DNA repair genes are suspected to influence the risk of lung cancer. This study aimed to investigate the association between the ERCC2 751, 312 and ERCC1 118 polymorphisms and the risk of lung adenocarcinoma in Chinese non-smoking females. Methods A hospital-based case-control study of 285 patients and 285 matched controls was conducted. Information concerning demographic and risk factors was obtained for each case and control by a trained interviewer. After informed consent was obtained, each person donated 10 ml blood for biomarker testing. Three polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP method. Results This study showed that the individuals with the combined ERCC2 751AC/CC genotypes were at an increased risk for lung adenocarcinoma compared with those carrying the AA genotype [adjusted odds ratios (OR 1.64, 95% confidence interval (CI 1.06-2.52]. The stratified analysis suggested that increased risk associated with ERCC2 751 variant genotypes (AC/CC was more pronounced in individuals without exposure to cooking oil fume (OR 1.98, 95%CI 1.18-3.32 and those without exposure to fuel smoke (OR 2.47, 95%CI 1.46-4.18. Haplotype analysis showed that the A-G-T and C-G-C haplotypes were associated with increased risk of lung adenocarcinoma among non-smoking females (ORs were 1.43 and 2.28, 95%CIs were 1.07-1.91 and 1.34-3.89, respectively. Conclusion ERCC2 751 polymorphism may be a genetic risk modifier for lung adenocarcinoma in non-smoking females in China.

  3. ERCC2, ERCC1 polymorphisms and haplotypes, cooking oil fume and lung adenocarcinoma risk in Chinese non-smoking females

    Science.gov (United States)

    2009-01-01

    Background Excision repair cross-complementing group 1 (ERCC1) and group 2 (ERCC2) proteins play important roles in the repair of DNA damage and adducts. Single nucleotide polymorphisms (SNPs) of DNA repair genes are suspected to influence the risk of lung cancer. This study aimed to investigate the association between the ERCC2 751, 312 and ERCC1 118 polymorphisms and the risk of lung adenocarcinoma in Chinese non-smoking females. Methods A hospital-based case-control study of 285 patients and 285 matched controls was conducted. Information concerning demographic and risk factors was obtained for each case and control by a trained interviewer. After informed consent was obtained, each person donated 10 ml blood for biomarker testing. Three polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results This study showed that the individuals with the combined ERCC2 751AC/CC genotypes were at an increased risk for lung adenocarcinoma compared with those carrying the AA genotype [adjusted odds ratios (OR) 1.64, 95% confidence interval (CI) 1.06-2.52]. The stratified analysis suggested that increased risk associated with ERCC2 751 variant genotypes (AC/CC) was more pronounced in individuals without exposure to cooking oil fume (OR 1.98, 95%CI 1.18-3.32) and those without exposure to fuel smoke (OR 2.47, 95%CI 1.46-4.18). Haplotype analysis showed that the A-G-T and C-G-C haplotypes were associated with increased risk of lung adenocarcinoma among non-smoking females (ORs were 1.43 and 2.28, 95%CIs were 1.07-1.91 and 1.34-3.89, respectively). Conclusion ERCC2 751 polymorphism may be a genetic risk modifier for lung adenocarcinoma in non-smoking females in China. PMID:20003391

  4. The effect of tobacco, XPC, ERCC2 and ERCC5 genetic variants in bladder cancer development

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    Othman Fethi

    2011-03-01

    Full Text Available Abstract Background In this work, we have conducted a case-control study in order to assess the effect of tobacco and three genetic polymorphisms in XPC, ERCC2 and ERCC5 genes (rs2228001, rs13181 and rs17655 in bladder cancer development in Tunisia. We have also tried to evaluate whether these variants affect the bladder tumor stage and grade. Methods The patients group was constituted of 193 newly diagnosed cases of bladder tumors. The controls group was constituted of non-related healthy subjects. The rs2228001, rs13181 and rs17655 polymorphisms were genotyped using a polymerase chain reaction-restriction fragment length polymorphism technique. Results Our data have reported that non smoker and light smoker patients (1-19PY are protected against bladder cancer development. Moreover, light smokers have less risk for developing advanced tumors stage. When we investigated the effect of genetic polymorphisms in bladder cancer development we have found that ERCC2 and ERCC5 variants were not implicated in the bladder cancer occurrence. However, the mutated homozygous genotype for XPC gene was associated with 2.09-fold increased risk of developing bladder cancer compared to the control carrying the wild genotype (p = 0.03, OR = 2.09, CI 95% 1.09-3.99. Finally, we have found that the XPC, ERCC2 and ERCC5 variants don't affect the tumors stage and grade. Conclusion These results suggest that the mutated homozygous genotype for XPC gene was associated with increased risk of developing bladder. However we have found no association between rs2228001, rs13181 and rs17655 polymorphisms and tumors stage and grade.

  5. Xeroderma Pigmentosum-Trichothiodystrophy overlap patient with novel XPD/ERCC2 mutation

    Science.gov (United States)

    Kralund, Henrik H.; Ousager, Lilian; Jaspers, Nicolaas G.; Raams, Anja; Pedersen, Erling B.; Gade, Else; Bygum, Anette

    2013-01-01

    Xeroderma Pigmentosum (XP), Trichothiodystrophy (TTD) and Cockayne Syndrome (CS) are rare, recessive disorders caused by mutational defects in the Nucleotide Excision Repair (NER) pathway and/or disruption of basic cellular DNA transcription. To date, a multitude of mutations in the XPD/ERCC2 gene have been described, many of which give rise to NER- and DNA transcription related diseases, which share certain diagnostic features and few overlap patients have been described. Despite increasing understanding of the roles of XPD/ERCC2 in mammalian cells, there is still weak predictability of somatic outcome from many of these mutations. We demonstrate a patient, believed to represent an overlap between XP and TTD/CS. In addition to other organ dysfunctions, the young man presented with Photosensitivity, Ichthyosis, Brittle hair, Impaired physical and mental development, Decreased fertility and Short stature (PIBIDS) suggestive of TTD, but lacking the almost patognomonic “tiger tail” banding of the hair under polarized light. Additionally, he developed basal cell carcinoma aged 28, as well as adult onset kidney failure, features normally not associated with TTD but rather XP/CS. His freckled appearance also suggested XP, but fibroblast cultures only demonstrated x2 UV-sensitivity with expected NER and TFIIH-activity decrease. Genetic sequencing of the XPD/ERCC2 gene established the patient as heterozygote compound with a novel, N-terminal Y18H mutation and a known C-terminal (TTD) mutation, A725P. The possible interplay between gene products and the patient phenotype is discussed. PMID:25002996

  6. Progress of Relationship between XRCC3 Polymorphisms and Lung Cancer Susceptibility%XRCC3多态性与肺癌易感性关系的研究进展

    Institute of Scientific and Technical Information of China (English)

    杜国波

    2011-01-01

    XRCC3 is a gene involved in repair of DNA damage and it may change DNA repair capacity and efficiency, thus modulate cancer susceptibility.Many researches suggest that polymorphisms of XRCC3 have relationship with susceptibility of lung cancer,but some other researches suggest there is no relationship bet weew them.Different race and area may cause the different conclusion.%X线损伤修复的交叉互补基因3(XRCC3)是一种DNA损伤修复基因,其多态性能够改变DNA修复功能和效率、影响肿瘤易感性.许多研究报道XRCC3多态性可能与肺癌易感性有关,但也有二者无相关性的报道,结论不一致可能与种族、地域等多种因素有关.在此就二者的关系的研究进展予以综述.

  7. Arabidopsis RAD51, RAD51C and XRCC3 proteins form a complex and facilitate RAD51 localization on chromosomes for meiotic recombination.

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    Hang Su

    2017-05-01

    Full Text Available Meiotic recombination is required for proper homologous chromosome segregation in plants and other eukaryotes. The eukaryotic RAD51 gene family has seven ancient paralogs with important roles in mitotic and meiotic recombination. Mutations in mammalian RAD51 homologs RAD51C and XRCC3 lead to embryonic lethality. In the model plant Arabidopsis thaliana, RAD51C and XRCC3 homologs are not essential for vegetative development but are each required for somatic and meiotic recombination, but the mechanism of RAD51C and XRCC3 in meiotic recombination is unclear. The non-lethal Arabidopsis rad51c and xrcc3 null mutants provide an opportunity to study their meiotic functions. Here, we show that AtRAD51C and AtXRCC3 are components of the RAD51-dependent meiotic recombination pathway and required for normal AtRAD51 localization on meiotic chromosomes. In addition, AtRAD51C interacts with both AtRAD51 and AtXRCC3 in vitro and in vivo, suggesting that these proteins form a complex (es. Comparison of AtRAD51 foci in meiocytes from atrad51, atrad51c, and atxrcc3 single, double and triple heterozygous mutants further supports an interaction between AtRAD51C and AtXRCC3 that enhances AtRAD51 localization. Moreover, atrad51c-/+ atxrcc3-/+ double and atrad51-/+ atrad51c-/+ atxrcc3-/+ triple heterozygous mutants have defects in meiotic recombination, suggesting the role of the AtRAD51C-AtXRCC3 complex in meiotic recombination is in part AtRAD51-dependent. Together, our results support a model in which direct interactions between the RAD51C-XRCC3 complex and RAD51 facilitate RAD51 localization on meiotic chromosomes and RAD51-dependent meiotic recombination. Finally, we hypothesize that maintenance of RAD51 function facilitated by the RAD51C-XRCC3 complex could be highly conserved in eukaryotes.

  8. XRCC3 Thr241Met polymorphism and clinical outcomes of NSCLC patients receiving platinum-based chemotherapy: a systematic review and meta-analysis.

    Directory of Open Access Journals (Sweden)

    Xiao-yong Shen

    Full Text Available INTRODUCTION: X-ray repair cross-complementing protein 3 (XRCC3 is an essential gene involved in the double-strand break repair pathway. Published evidence has shown controversial results about the relationship between XRCC3 Thr241Met polymorphism and clinical outcomes of non-small cell lung cancer (NSCLC patients receiving platinum-based chemotherapy. METHODS: A systematic review and meta-analysis was performed to evaluate the predictive value of XRCC3 Thr241Met polymorphism on clinical outcomes of advanced NSCLC receiving platinum-based chemotherapy. Response to chemotherapy, overall survival (OS and progression-free survival (PFS were analyzed. RESULTS: A number of 11 eligible studies were identified according to the inclusion criteria. Carriers of the variant XRCC3 241Met allele were significantly associated with good response to platinum-based chemotherapy (ThrMet/MetMet vs. ThrThr: OR  = 1.509, 95% CI: 1.099-2.072, Pheterogeneity  = 0.618. The XRCC3 Thr241Met polymorphism was not associated with OS (MetMet vs. ThrThr, HR  = 0.939, 95% CI:0.651-1.356, Pheterogeneity  = 0.112 or PFS (MetMet vs. ThrThr, HR  = 0.960, 95% CI: 0.539-1.710, Pheterogeneity  = 0.198. Additionally, no evidence of publication bias was observed. CONCLUSIONS: This systematic review and meta-analysis shows that carriers of the XRCC3 241Met allele are associated with good response to platinum-based chemotherapy in advanced NSCLC, while the XRCC3 Thr241Met polymorphism is not associated with OS or PFS.

  9. XRCC3 C18067T polymorphism contributes a decreased risk to both basal cell carcinoma and squamous cell carcinoma: evidence from a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Xu Chen

    Full Text Available BACKGROUND: The X-ray repair cross-complementing group 3 (XRCC3 in homologous recombination repair (HRR pathway plays a very important role in DNA double-strand break repair (DSBR. Variations in the XRCC3 gene might lead to altered protein structure or function which may change DSBR efficiency and result in cancer. The XRCC3 C18067T polymorphism has been reported to be associated with skin cancer susceptibility, yet the results of these previous results have been inconsistent or controversial. To derive a more precise estimation of the association, we conducted a meta-analysis. METHODS: The quality of the studies was assessed according to a predefined scale. The association between the XRCC3 C18067T polymorphism and skin cancer risk was assessed by odds ratios (ORs together with their 95% confidence intervals (CIs. RESULTS: Overall, no significant association was observed between XRCC3 C18067T polymorphism and skin cancer risk in any genetic model. Stratified analyses according to tumor type, significant association was found in the relationship between XRCC3 C18067T polymorphism and nonmelanoma skin cancer risk (homozygote comparison TT versus CC: OR = 0.74, 95%CI = 0.61-0.90, P = 0.003; recessive model TT versus TC/CC: OR = 0.81, 95%CI = 0.68-0.95, P = 0.01. Furthermore, significant association was also observed in XRCC3 C18067T polymorphism with both basal cell carcinoma risk (homozygote comparison TT versus CC: OR = 0.70, 95%CI = 0.53-0.92, P = 0.011; recessive model TT versus. TC/CC: OR = 0.74, 95%CI = 0.60-0.92, P = 0.007 and squamous cell carcinoma risk (heterozygote comparison TT versus .CC: OR = 0.81, 95%CI = 0.67-0.99, P = 0.04; dominant model TT/TC versus .CC: OR = 0.81, 95%CI = 0.68-0.98, P = 0.029. CONCLUSION: The present meta-analysis demonstrates that XRCC3 C18067T polymorphism was not associated with risk of cutaneous melanoma but contributed a decreased risk to both basal cell carcinoma and squamous cell carcinoma.

  10. Correlation of rs1799793 polymorphism in ERCC2 and the clinical response to platinum-based chemotherapy in patients with triple negative breast cancer.

    Science.gov (United States)

    Lu, Jun; Zhao, Haitao; Li, Sha; Tian, Zhongze; Zhu, Xianghui; Wang, Hongyi; Fu, Hua

    2015-01-01

    Polymorphisms of DNA repair genes may affect the repair capacity of DNA damages and cause different responses towards chemotherapy. Excision repair cross-complementing group 2 (ERCC2) plays an important role in the nucleotide excision repair. The aim of this study was to investigate the association between ERCC2 single nucleotide polymorphisms (SNPs) and the response to platinum-based chemotherapy among patients with triple negative breast cancer. In total, 60 triple negative breast cancer patients treated with platinum-based chemotherapy were studied. The clinical, pathological and treatment data of them were collected. Sequenom's MassARRAY system was used in the detection of the SNPs of ERCC2. Finally, the association between genotypes and different clinical responses among patients was analyzed. All of the patients received a platinum-based chemotherapy for 4 cycles in median and achieved an overall response rate of 66.7%, showing a comparative good response towards platinum-based chemotherapy among triple negative breast cancer. Fifty-three of the 60 patients had got the results of ERCC2 rs1799793 polymorphisms after MassARRAY detection. The proportion of GG genotype and GA genotype was 81.1% and 18.9% respectively. The response rate of the rs1799793 GG genotype group was 69.8%, while the GA genotype group only had a response rate of 30.0%. It turned out that the GG genotype was associated with better response towards platinum-based chemotherapy (P=0.030). ERCC2 rs1799793 polymorphism may be associated with the clinical sensitivity of platinum-based chemotherapy and could be a potential predictive biomarker for triple negative breast cancer patients treated with platinum compounds.

  11. Effect of the XRCC1 and XRCC3 Genetic Polymorphisms on the Efficacy of Platinum-based Chemotherapy in Patients with Advanced Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Chong’an XU

    2011-12-01

    Full Text Available Background and objective DNA repair gene polymorphisms can be used to predict the sensitivity of platinum-based chemotherapy. Thus, such polymorphisms are important for the individual treatment of non-small cell lung cancer (NSCLC. The aim of this study is to investigate the relationship between X-ray repair cross complementing protein 1 (XRCC1 and X-ray repair cross complementing protein 3 (XRCC3 gene polymorphisms and the chemosensitivity of platinum-based chemotherapy in patients with advanced NSCLC. Methods Genomic DNA were extracted from the sera of a total of 130 patients with advanced NSCLC who received platinum-based chemotherapy. XRCC1 Arg194 Trp, Arg399 Gln, and XRCC3 Thr241 Met were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method, and the relationship between XRCC1 and XRCC3 polymorphisms and chemotherapy sensitivity was analyzed. Results A total of 130 patients with advanced NSCLC received platinum-based chemotherapy, with an overall response rate of 33.8% after two chemotherapy cycles. The XRCC1 194 and 399 genetic polymorphisms, but not XRCC3 241, were found to be related to the chemosensitivity. The objective response rate of the patients with at least one XRCC1 194 Trp allele was 2.5 times higher than that of Arg/Arg genotype carriers (42.1% vs 22.2%, OR=2.545, 95%CI: 1.159-5.590, P=0.020. The objective response rate of the XRCC1 399 Arg/Arg genotype carriers was significantly higher than that of the patients with at least one Gln allele (45.5% vs 21.9%, OR=0.336, 95%CI: 0.156-0.722, P=0.005. Combined effects between XRCC1 194 and XRCC1 399 were observed. The objective response rate of the patients with at least one XRCC1 194 Trp allele and a 399 Arg/Arg genotype was significantly higher than that of patients with 194 Arg/Arg and 399 Arg/Gln genotypes (44.4% vs 18.8%, OR=3.467, 95%CI: 1.223-9.782, P=0.019. Moreover, XRCC1 and XRCC3 have a combined effect in predicting chemosensitivity

  12. XRCC3 and RAD51 expression are associated with clinical factors in breast cancer.

    Directory of Open Access Journals (Sweden)

    Jia Hu

    Full Text Available AIMS: XRCC3 and RAD51 are two important members in homologous recombination repair pathway. This study was performed to detect the expressions of these two molecules in breast cancer and explore their correlations with clinicopathological factors. METHODS AND RESULTS: Immunohistochemistry was used to detect protein expressions of XRCC3 and RAD51 in 248 cases of breast cancer tissue and 78 cases of adjacent non-cancerous tissue. Data showed that expressions for both XRCC3 and RAD51 were significantly increased in breast cancer. High XRCC3 expression was associated with large tumor size and positive PR and HER2 status, while high RAD51 expression was associated with axillary lymph node metastasis and positive PR and HER2 status. The result of multivariate analysis demonstrated that HER2, PR and RAD51 were significantly association with XRCC3. And besides XRCC3, axillary lymph node metastasis and PR were significantly correlated with RAD51. CONCLUSIONS: XRCC3 and RAD51 were significantly associated with clinicopathological factors and they might play important roles in the development and progress of breast cancer.

  13. ABCC5, ERCC2, XPA and XRCC1 transcript abundance levels correlate with cisplatin chemoresistance in non-small cell lung cancer cell lines

    Directory of Open Access Journals (Sweden)

    Khuder Sadik A

    2005-05-01

    Full Text Available Abstract Background Although 40–50% of non-small cell lung cancer (NSCLC tumors respond to cisplatin chemotherapy, there currently is no way to prospectively identify potential responders. The purpose of this study was to determine whether transcript abundance (TA levels of twelve selected DNA repair or multi-drug resistance genes (LIG1, ERCC2, ERCC3, DDIT3, ABCC1, ABCC4, ABCC5, ABCC10, GTF2H2, XPA, XPC and XRCC1 were associated with cisplatin chemoresistance and could therefore contribute to the development of a predictive marker. Standardized RT (StaRT-PCR, was employed to assess these genes in a set of NSCLC cell lines with a previously published range of sensitivity to cisplatin. Data were obtained in the form of target gene molecules relative to 106 β-actin (ACTB molecules. To cancel the effect of ACTB variation among the different cell lines individual gene expression values were incorporated into ratios of one gene to another. Each two-gene ratio was compared as a single variable to chemoresistance for each of eight NSCLC cell lines using multiple regression. In an effort to validate these results, six additional lines then were evaluated. Results Following validation, single variable models best correlated with chemoresistance (p ERCC2/XPC, ABCC5/GTF2H2, ERCC2/GTF2H2, XPA/XPC and XRCC1/XPC. All single variable models were examined hierarchically to achieve two variable models. The two variable model with the highest correlation was (ABCC5/GTF2H2, ERCC2/GTF2H2 with an R2 value of 0.96 (p Conclusion These results provide markers suitable for assessment of small fine needle aspirate biopsies in an effort to prospectively identify cisplatin resistant tumors.

  14. Identification and Functional Testing of ERCC2 Mutations in a Multi-national Cohort of Patients with Familial Breast- and Ovarian Cancer.

    Directory of Open Access Journals (Sweden)

    Andreas Rump

    2016-08-01

    Full Text Available The increasing application of gene panels for familial cancer susceptibility disorders will probably lead to an increased proposal of susceptibility gene candidates. Using ERCC2 DNA repair gene as an example, we show that proof of a possible role in cancer susceptibility requires a detailed dissection and characterization of the underlying mutations for genes with diverse cellular functions (in this case mainly DNA repair and basic cellular transcription. In case of ERCC2, panel sequencing of 1345 index cases from 587 German, 405 Lithuanian and 353 Czech families with breast and ovarian cancer (BC/OC predisposition revealed 25 mutations (3 frameshift, 2 splice-affecting, 20 missense, all absent or very rare in the ExAC database. While 16 mutations were unique, 9 mutations showed up repeatedly with population-specific appearance. Ten out of eleven mutations that were tested exemplarily in cell-based functional assays exert diminished excision repair efficiency and/or decreased transcriptional activation capability. In order to provide evidence for BC/OC predisposition, we performed familial segregation analyses and screened ethnically matching controls. However, unlike the recently published RECQL example, none of our recurrent ERCC2 mutations showed convincing co-segregation with BC/OC or significant overrepresentation in the BC/OC cohort. Interestingly, we detected that some deleterious founder mutations had an unexpectedly high frequency of > 1% in the corresponding populations, suggesting that either homozygous carriers are not clinically recognized or homozygosity for these mutations is embryonically lethal. In conclusion, we provide a useful resource on the mutational landscape of ERCC2 mutations in hereditary BC/OC patients and, as our key finding, we demonstrate the complexity of correct interpretation for the discovery of "bonafide" breast cancer susceptibility genes.

  15. Identification and Functional Testing of ERCC2 Mutations in a Multi-national Cohort of Patients with Familial Breast- and Ovarian Cancer

    Science.gov (United States)

    Kuhlmann, Jan Dominik; Janavičius, Ramūnas; Foretová, Lenka; Lhota, Filip; Zemankova, Petra; Betcheva-Krajcir, Elitza; Mackenroth, Luisa; Lehmann, Janin; Nissen, Anke; DiDonato, Nataliya; Opitz, Romy; Thiele, Holger; Kast, Karin; Wimberger, Pauline; Holinski-Feder, Elke; Emmert, Steffen

    2016-01-01

    The increasing application of gene panels for familial cancer susceptibility disorders will probably lead to an increased proposal of susceptibility gene candidates. Using ERCC2 DNA repair gene as an example, we show that proof of a possible role in cancer susceptibility requires a detailed dissection and characterization of the underlying mutations for genes with diverse cellular functions (in this case mainly DNA repair and basic cellular transcription). In case of ERCC2, panel sequencing of 1345 index cases from 587 German, 405 Lithuanian and 353 Czech families with breast and ovarian cancer (BC/OC) predisposition revealed 25 mutations (3 frameshift, 2 splice-affecting, 20 missense), all absent or very rare in the ExAC database. While 16 mutations were unique, 9 mutations showed up repeatedly with population-specific appearance. Ten out of eleven mutations that were tested exemplarily in cell-based functional assays exert diminished excision repair efficiency and/or decreased transcriptional activation capability. In order to provide evidence for BC/OC predisposition, we performed familial segregation analyses and screened ethnically matching controls. However, unlike the recently published RECQL example, none of our recurrent ERCC2 mutations showed convincing co-segregation with BC/OC or significant overrepresentation in the BC/OC cohort. Interestingly, we detected that some deleterious founder mutations had an unexpectedly high frequency of > 1% in the corresponding populations, suggesting that either homozygous carriers are not clinically recognized or homozygosity for these mutations is embryonically lethal. In conclusion, we provide a useful resource on the mutational landscape of ERCC2 mutations in hereditary BC/OC patients and, as our key finding, we demonstrate the complexity of correct interpretation for the discovery of “bonafide” breast cancer susceptibility genes. PMID:27504877

  16. Association studies of OGG1, XRCC1, XRCC2 and XRCC3 polymorphisms with differentiated thyroid cancer

    Energy Technology Data Exchange (ETDEWEB)

    Garcia-Quispes, Wilser-Andres; Perez-Machado, Giselle; Akdi, Abdelmounaim [Grup de Mutagenesi, Departament de Genetica i de Microbiologia, Universitat Autonoma de Barcelona, Bellaterra (Spain); Pastor, Susana [Grup de Mutagenesi, Departament de Genetica i de Microbiologia, Universitat Autonoma de Barcelona, Bellaterra (Spain); CIBER Epidemiologia y Salud Publica, Instituto de Salud Carlos III (Spain); Galofre, Pere [Servei de Medicina Nuclear, Hospitals Universitaris Vall d' Hebron, Barcelona (Spain); Biarnes, Fina [Unitat d' Endocrinologia, Hospital Josep Trueta, Girona (Spain); Castell, Joan [Servei de Medicina Nuclear, Hospitals Universitaris Vall d' Hebron, Barcelona (Spain); Velazquez, Antonia [Grup de Mutagenesi, Departament de Genetica i de Microbiologia, Universitat Autonoma de Barcelona, Bellaterra (Spain); CIBER Epidemiologia y Salud Publica, Instituto de Salud Carlos III (Spain); Marcos, Ricard, E-mail: ricard.marcos@uab.es [Grup de Mutagenesi, Departament de Genetica i de Microbiologia, Universitat Autonoma de Barcelona, Bellaterra (Spain); CIBER Epidemiologia y Salud Publica, Instituto de Salud Carlos III (Spain)

    2011-05-10

    The role of the DNA repair genes OGG1, XRCC1, XRCC2 and XRCC3 on differentiated thyroid cancer (DTC) susceptibility was examined in 881 individuals (402 DTC and 479 controls). DNA repair genes were proposed as candidate genes, since the current data indicate that exposure to ionizing radiation is the only established factor in the development of thyroid cancer, especially when it occurs in early stages of life. We have genotyped DNA repair genes involved in base excision repair (BER) (OGG1, Ser326Cys; XRCC1, Arg280His and Arg399Gln), and homologous recombination repair (HRR) (XRCC2, Arg188His and XRCC3, ISV-14G). Genotyping was carried out using the iPLEX (Sequenom) technique. Multivariate logistic regression analyses were performed in a case-control study design. From all the studied polymorphism, only a positive association (OR = 1.58, 95% CI 1.05-2.46, P = 0.027) was obtained for XRCC1 (Arg280His). No associations were observed for the other polymorphisms. No effects of the histopathological type of tumor were found when the DTC patients were stratified according to the type of tumor. It must be emphasized that this study include the greater patients group, among the few studies carried out until now determining the role of DNA repair genes in thyroid cancer susceptibility.

  17. The association of XRCC3 Thr241Met genetic variant with risk of ...

    African Journals Online (AJOL)

    Methods: We identified three eligible studies, 499 prostate cancer cases and 571 ... Conclusions: Results from this meta-analysis indicate that the XRCC3 Thr241Met genetic variant is associated with prostate cancer risk. ... Article Metrics.

  18. X线对肺癌细胞株A549 XRCC2和XRCC3表达水平的影响%Effect of X-ray on expression levels of XRCC2 and XRCC3 in lung cancer cell line A549

    Institute of Scientific and Technical Information of China (English)

    史卫林; 李坚; 陈萍; 戴春华

    2009-01-01

    目的:研究X线对肺癌细胞X线修复交叉互补基因2((X-ray repair cross complementing gene 2,XRCC2))与XRCC3表达水平的影响,探讨DNA同源重组修复机制在肺癌放疗过程中的作用.方法:以噻唑蓝还原法(MTT)检测X线对肺腺癌细胞株A549抑制率的影响,实时荧光定量RT-PCR技术检测X线处理肺癌细胞(人肺腺癌细胞株A549)后XRCC2和XRCC3 mR-NA的表达水平.结果:肺癌细胞抑制率多数情况下随X线照射时间的延长及照射剂量的增大,细胞增殖抑制率增加,呈照射时间依赖性(P<0.05)和剂量依赖性(P<0.05),除了16Gy组与32Gy组比较无统计学意义(P=0.211).X线照射后肺癌细胞XRCC2与XRCC3 mRNA的表达水平均先增高后降低,在照射后48 h表达水平达高峰(P<0.05),且随着照射剂量的增大,XRCC2与XR-CC3 mRNA的表达水平也随之增加(P<0.05).结论:X线照射可引起肺癌细胞XRCC2与XRCC3 mRNA表达水平的明显改变,表明DNA同源重组修复机制可能在肺癌放疗耐受中起了重要的作用.%Objective:To study the effect of X-ray on expression levels of X-ray repair cross-complementing gene2(XRCC2)and XRCC3 in lung cancer cells,and explore the effect of DNA homologous recombination repair mechanism in radiotherapy of lung cancer. Methods:Cell inhibition ratio was measured using MTT assay. The expression levels of XRCC2 mRNA and XRCC3 mRNA in lung cancer cell line A549 were measured by RFQ-PCR assay. Results:The rate of proliferation inhibiting of lung cancer cells increased in line with the prolong radiation time of X-ray (P < 0.05) and the increase of radiation dose(P < 0.05) ,but there was no difference between the groups of 16 Gy and 32 Gy (P=0.211). The expression levels of XRCC2 and XRCC3 mRNA in these lung cancer cells increased significantly after treated with X-ray,and then decreased. The expression levels of XRCC2 and XRCC3 mRNA peaked at 48 h after X-ray treatment (P < 0.05). The expression levels of XRCC2 and XRCC3 m

  19. ERCC2/XPD Lys751Gln alter DNA repair efficiency of platinum-induced DNA damage through P53 pathway.

    Science.gov (United States)

    Zhang, Guopei; Guan, Yangyang; Zhao, Yuejiao; van der Straaten, Tahar; Xiao, Sha; Xue, Ping; Zhu, Guolian; Liu, Qiufang; Cai, Yuan; Jin, Cuihong; Yang, Jinghua; Wu, Shengwen; Lu, Xiaobo

    2017-02-01

    Platinum-based treatment causes Pt-DNA adducts which lead to cell death. The platinum-induced DNA damage is recognized and repaired by the nucleotide excision repair (NER) system of which ERCC2/XPD is a critical enzyme. Single nucleotide polymorphisms in ERCC2/XPD have been found to be associated with platinum resistance. The aim of the present study was to investigate whether ERCC2/XPD Lys751Gln (rs13181) polymorphism is causally related to DNA repair capacity of platinum-induced DNA damage. First, cDNA clones expressing different genotypes of the polymorphism was transfected to an ERCC2/XPD defective CHO cell line (UV5). Second, all cells were treated with cisplatin. Cellular survival rate were investigated by MTT growth inhibition assay, DNA damage levels were investigated by comet assay and RAD51 staining. The distribution of cell cycle and the change of apoptosis rates were detected by a flow cytometric method (FCM). Finally, P53mRNA and phospho-P53 protein levels were further investigated in order to explore a possible explanation. As expected, there was a significantly increased in viability of UV5(ERCC2 (AA)) as compared to UV5(ERCC2 (CC)) after cisplatin treatment. The DNA damage level of UV5(ERCC2 (AA)) was significant decreased compared to UV5(ERCC2 (CC)) at 24 h of treatment. Mutation of ERCC2rs13181 AA to CC causes a prolonged S phase in cell cycle. UV5(ERCC2 (AA)) alleviated the apoptosis compared to UV5(ERCC2 (CC)), meanwhile P53mRNA levels in UV(ERCC2 (AA)) was also lower when compared UV5(ERCC2 (CC)). It co-incides with a prolonged high expression of phospho-P53, which is relevant for cell cycle regulation, apoptosis, and the DNA damage response (DDR). We concluded that ERCC2/XPD rs13181 polymorphism is possibly related to the DNA repair capacity of platinum-induced DNA damage. This functional study provides some clues to clarify the relationship between cisplatin resistance and ERCC2/XPDrs13181 polymorphism.

  20. Risk of radiation-induced subcutaneous fibrosis in relation to single nucleotide polymorphisms in TGFB1, SOD2, XRCC1, XRCC3, APEX and ATM--a study based on DNA from formalin fixed paraffin embedded tissue samples

    DEFF Research Database (Denmark)

    Andreassen, C N; Alsner, J; Overgaard, M

    2006-01-01

    accrued from a historical cohort of 319 post-mastectomy radiotherapy patients. All patients received hypo-fractionated radiotherapy. The TGFB1 position--509, codons 10 and 25, XRCC1 codons 194, 280 and 399, XRCC3 codon 241, SOD2 codon 16, ATM codon 1853 and APEX (apurinic/apyrimidinic exonuclease gene...

  1. The expression of XRCC1、XRCC3 and hOGG1 protein in human esophageal carcinoma and some of clinical factors of esophageal carcinoma%食管癌患者XRCC1, XRCC3及hOGG1蛋白的表达与临床因素的相关性研究

    Institute of Scientific and Technical Information of China (English)

    王海峰; 刘敏; 张瑾熔; 杨晓蕾; 帕丽达·阿皮孜; 阿依古丽·哈热

    2010-01-01

    目的 检测人类X射线交错互补修复基因(X-ray repair cross-compplementing gene1,XRCC1)、人类8-羟基鸟嘌呤糖苷酶1(human 8-hydroxyguanine glycosylase 1,hOGG1)基因和人类X射线交错互补修复基因(X-ray repair cross-compplementing gene 3,XRCC3)蛋白在食管癌和癌旁组织中的表达,探讨3种蛋白与食管癌发生及发展的关系.方法 采用蛋白免疫印迹法检测XRCC1、XRCC3及hOGG1蛋白在食管癌与癌旁组织中的表达,应用ECL法显影并以其灰度值来表示蛋白表达的量.结果 XRCC1、XRCC3及hOGG1蛋白在癌组织中的表达高于癌旁组织(P均<0.05).同时XRCC1蛋白在癌组织与癌旁组织中的差异程度与民族有相关性(P<0.05).结论 XRCC1、XRCC3及hOGG1蛋白表达水平与食管癌的发生可能具有相关性,并且XRCC1蛋白还可能参与食管癌的进展.

  2. RAD51-G135C和XRCC3-C241T多态性与伴重现染色体易位急性髓系白血病发生的关系%Relationship between RAD51-G135C/XRCC3-C241T polymorphisms and development of acute myeloid leukemia with recurrent chromosome translocation

    Institute of Scientific and Technical Information of China (English)

    杨琳; 肖志坚; 刘亮; 秘营昌; 李建勇; 马晓瑭; 艾晓非; 秦铁军; 徐泽锋; 王建祥

    2011-01-01

    目的 探讨DNA同源重组修复基因RAD51-G135C和XRCC3-C241T多态性与伴重现染色体易位急性髓系白血病(AML)发生的关系.方法 共收集625例初治原发性AML患者的骨髓、806名患者一级亲属和704名与患者无血缘关系正常人的外周血样本,常规提取基因组DNA.用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法分析RAD51-G135C和XRCC3-C241T基因多态性.选取XRCC3-C241T不同基因型细胞系进行体外照射,用TaqMan实时定量PCR法检测CBFβ-MYH11融合基因mRNA的相对表达量.结果 同正常人和一级亲属比较,XRCC3-C241T变异基因型(C/T+T/T)能明显提高inv(16)/t(16;16)/CBFβ-MYH11(+)AML的发病风险,风险值分别提高了6.22倍(P<0.001)和6.99倍(P<0.001);同正常人和一级亲属比较,RAD51-G135C纯合变异基因型(C/C)亦能明显提高inv(16)/t(16;16)/CBFβ-MYH11(+)AML的发病风险,风险值分别提高了0.87倍(P=0.010)和1.15倍(P=0.001).经照射后,XRCC3-C241T纯合变异型HL-60细胞系CBFβ-MYH11融合基因mRNA表达量是野生型KG1a细胞系的59.49倍.RAD51-G135C和XRCC3-C241T多态性位点基因型与t(15;17)/PML-RARα(+)AML、t(8;21)/AMLI-ETO(+)AML和11q23异常AML发生风险无明显相关性.结论 XRCC3-C241T变异基因型和RAD51-G135C纯合变异基因型可显著增高inv(16)/t(16;16)/CBFβ-MYH11(+)AML发生的风险.%Objective To investigate the relationship between DNA homologous recombination (HR) repair genes RAD51-G135C/XRCC3-C241T polymorphisms and development of acute myeloid leukemia (AML) with recurrent chromosome translocation. Methods Genomic DNA was extracted from bone marrow cells of 625 de novo AML patients and peripheral blood cells of 806 patient family members and 704 unrelated volunteers. Genotypes of RAD51-G135C and XRCC3-C241T were analyzed by PCR-RFLP. Cell lines with genotypes differed from XRCC3-C241T were selected and irradiated in vitro. The CBFβ-MYH11 fusion gene was detected by TaqMan real-time PCR

  3. 转染XRCC3基因的人脑胶质瘤细胞增加烷化剂类抗癌药耐药性%Xrcc- 3 Mediates DNA Crosslinking Agent Drug Resistance in Human Glioma Cells

    Institute of Scientific and Technical Information of China (English)

    王之敏; 左剑玲; 许期年; 王秀云

    2004-01-01

    背景和目的:我们既往的研究表明,在人上皮肿瘤细胞中,XRCC3基因的表达水平同肿瘤细胞对美法仑和顺铂的耐药密切相关,提示XRCC3基因在其中起关键作用.为进一步研究XRCC3基因在脑胶质瘤细胞耐药中的作用,我们选用低水平表达XRCC3基因的人脑胶质瘤细胞SKI-1,将其过度表达XRCC3,研究其耐药性的变化.方法:采用脂质体方法将已插入XRCC3基因的pcDNA3.0表达载体转染人脑胶质瘤细胞SKI-1,G418筛选,得到稳定高表达XRCC3的细胞克隆,转染pcDNA3.1空载体作为对照,用Westernblot方法证实.采用改良的sulforhodamineB(SRB)Colorimetric抗癌药筛选法,对稳定表达XRCC3基因和空载体的SKI-1细胞进行细胞毒试验.结果:XRCC3细胞能稳定地高表达XRCC3蛋白,较MOCK细胞高4倍.XRCC3细胞对顺铂和美法仑的耐药性明显较MOCK细胞增强,分别增加了1.8和2.3倍;对BCNU的耐药性无明显增加.结论:XRCC3基因在人脑胶质瘤细胞对DNA交链剂耐药中起重要作用.

  4. XRCC3 is essential for proper double-strand break repair and homologous recombination in rice meiosis.

    Science.gov (United States)

    Zhang, Bingwei; Wang, Mo; Tang, Ding; Li, Yafei; Xu, Meng; Gu, Minghong; Cheng, Zhukuan; Yu, Hengxiu

    2015-09-01

    RAD51 paralogues play important roles in the assembly and stabilization of RAD51 nucleoprotein filaments, which promote homologous pairing and strand exchange reactions in organisms ranging from yeast to vertebrates. XRCC3, a RAD51 paralogue, has been characterized in budding yeast, mouse, and Arabidopsis. In the present study, XRCC3 in rice was identified and characterized. The rice xrcc3 mutant exhibited normal vegetative growth but complete male and female sterility. Cytological investigations revealed that homologous pairing and synapsis were severely disrupted in the mutant. Meiotic chromosomes were frequently entangled from diplotene to metaphase I, resulting in chromosome fragmentation at anaphase I. The immunostaining signals from γH2AX were regular, implying that double-strand break (DSB) formation was normal in xrcc3 meiocytes. However, COM1 was not detected on early prophase I chromosomes, suggesting that the DSB end-processing system was destroyed in the mutant. Moreover, abnormal chromosome localization of RAD51C, DMC1, ZEP1, ZIP4, and MER3 was observed in xrcc3. Taken together, the results suggest that XRCC3 plays critical roles in both DSB repair and homologous chromosome recombination during rice meiosis. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  5. Acute myeloid leukemia of donor origin after allogeneic stem cell transplantation from a sibling who harbors germline XPD and XRCC3 homozygous polymorphisms

    Directory of Open Access Journals (Sweden)

    da Silva Dayse A

    2011-09-01

    Full Text Available Abstract A 54-year-old woman was diagnosed with infiltrative ductal breast carcinoma. Two years after treatment, the patient developed an acute myeloid leukemia (AML which harbored del(11q23 in 8% of the blast cells. The patient was submitted for allogeneic stem cell transplantation (aSCT from her HLA-compatible sister. Ten months after transplantation, she relapsed with an AML with basophilic maturation characterized by CD45low CD33high, CD117+, CD13-/+, HLA Drhigh, CD123high, and CD203c+ blast cells lacking expression of CD7, CD10, CD34, CD15, CD14, CD56, CD36, CD64, and cytoplasmic tryptase. Karyotype analysis showed the emergence of a new clone with t(2;14 and FISH analysis indicated the presence of MLL gene rearrangement consistent with del(11q23. Interestingly, AML blast cell DNA tested with microsatellite markers showed the same pattern as the donor's, suggesting that this AML emerged from donor cells. Additionally, polymorphisms of the XPA, XPD, XRCC1, XRCC3 and RAD51 DNA repair genes revealed three unfavorable alleles with low DNA repair capacity. In summary, we report the first case of AML involving XPD and XRCC3 polymorphisms from donor origin following allogeneic stem cell transplantation and highlight the potential need for careful analysis of DNA repair gene polymorphisms in selecting candidate donors prior to allogeneic stem cell transplantation.

  6. The effects of XRCC3 codon 241 polymorphism on the levels of aflatoxin B_1-DNA adducts%XRCC3基因多态性对AFB_1-DNA加合物水平的影响

    Institute of Scientific and Technical Information of China (English)

    黄永秩; 龙喜带; 周远峰; 班植副; 姚金光; 曲德英

    2010-01-01

    目的 探讨DNA修复酶基因X线修复交叉补体因子3(x-ray repair cross-complementing group 3,XRCG3)codon 241多态性对黄曲霉毒素B_1(aflatoxin B_1,AFB_1)高污染区广西人群AFB_1-DNA加合物水平的影响.方法 应用竞争性酶联免疫吸附法检测研究对象(966例)AFB_1-DNA加合物水平,而XRCC3基因型分析则通过PCR-RFLP来完成.结果 (1)带有codon 241 Met等位基因的XRCC3基因型(XRCC3-Thr/Met,XRCC3-Met/Met)与高AFB_1-DNA加合物水平相关,其风险值分别为1.43(1.08~1.89)和2.42(1.13~5.22);(2)XRCC3多态性与长时间的AFB_1暴露在AFB_1-DNA加合物形成过程中存在协同作用(OR=11.00,P<0.01).结论 AFB_1在带有易感基因型XRCC3-Thr/Met和XRCC3-Met/Met的人群更易诱导产生DNA损伤(AFB_1-DNA加合物).

  7. Comparison of ERCC2 and MGMT expression in human glioma and relation ERCC2,MGMT and relation that after preparing%人脑胶质瘤耐药基因ERCC2、MGMT表达之间的相关性及其与预后的关系研究

    Institute of Scientific and Technical Information of China (English)

    李登锦; 王如密; 王爱东; 黄强; 徐元宾

    2004-01-01

    目的探讨人脑胶质瘤组织中两种耐药基因ERCC2、MGMT表达之间的相关性及其与预后的关系.方法采用双管RT-PCR方法检测19例人脑胶质瘤组织中ERCC2和MGMT mRNA水平,并分析它们的相关性及其与患者生存时间的关系.结果 ERCC2、MGMT的表达量分别为(1.42±0.93),(2.89±1.82),ERCC2与MGMT之间具有极显著的相关性(P<0.01).与患者的生存时间具有显著的相关性(P<0.05).结论 ERCC2、MGMT基因表达之间具有内在的联系,共同参与细胞对DNA损伤的修复,并形成肿瘤耐药;与肿瘤的预后具有明显的相关性.

  8. XRCC1和XRCC3单核苷酸多态性与晚期非小细胞肺癌铂类药物化疗疗效的相关性%Effect of the XRCC1 and XRCC3 Genetic Polymorphisms on the Efficacy of Platinum-based Chemotherapy in Patients with Advanced Non-small Cell Lung Cancer

    Institute of Scientific and Technical Information of China (English)

    许崇安; 王小杰; 张晔; 李琳

    2011-01-01

    背景与目的 DNA修复基因多态性预测铂类药物化疗敏感性对非小细胞肺癌(non-small cell lung cancer,NSCLC)个体化治疗具有重要意义.本研究旨在探讨X线修复交错互补基因1(X-ray repair cross complementing gene 1,XRCC1)和X线修复交错互补基因3(X-ray repair cross complementing gene 3,XRCC3)单核苷酸多态性与晚期NSCLC患者对铂类药物化疗疗效的关系.方法 采用PCR-RFLP方法检测130例以含铂方案化疗的晚期NSCLC患者外周血DNA中XRCC1 Arg194 Trp、Arg399 Gln和XRCC3 Thr241 Met基因多态性,分析其基因型与化疗疗效的关系.结果 130例晚期NSCLC患者采用含铂方案化疗2个周期后,化疗总有效率为33.8%.XRCC1 194和399基因多态性与铂类药物化疗敏感性相关,而XRCC3 241基因多态性与化疗敏感性无关(P=0.145).携带至少1个XRCC1 194 Trp等位基因者化疗有效率至少是携带Arg/Arg基因型患者的2.5倍(42.1%vs22.2%,OR=2.545,95%CI:1.159-5.590,P=0.020).携带XRCC1399 Arg/Arg基因型者的化疗有效率为45.5%,明显高于携带至少1个Gln等位基因者(21.9%)(OR=0.336,95%CI:0.156-0.722,P=0.005).XRCC1 194和399基因多态性之间存在联合作用,同时携带至少1个XRCC1 194 Trp等位基因和399 Arg/Arg基因型者的化疗有效率明显高于同时携带194 Arg/Arg和399 Arg/Gln基因型者(44.4% vs 18.8%,OR=3.467,95%CI:1.223-9.782,P=0.019).XRCC1和XRCC3基因多态性在化疗敏感性方面存在一定的联合作用,携带至少1个XRCC1 194 Trp等位基因和399 Arg/Arg野生型基因同时又携带XRCC3 241 Thr/Met基因型者的化疗有效率明显高于其它基因型携带者.结论 XRCC1和XRCC3的多态联合可能与晚期NSCLC患者对铂类药物化疗疗效具有相关性.%Background and objective DNA repair gene polymorphisms can be used to predict the sensitivity of platinum-based chemotherapy. Thus, such polymorphisms are important for the individual treatment of non-small cell lung

  9. ERCC2 2251A>C genetic polymorphism was highly correlated with early relapse in high-risk stage II and stage III colorectal cancer patients: A preliminary study

    Directory of Open Access Journals (Sweden)

    Lee Su-Chen

    2008-02-01

    Full Text Available Abstract Background Early relapse in colorectal cancer (CRC patients is attributed mainly to the higher malignant entity (such as an unfavorable genotype, deeper tumor invasion, lymph node metastasis and advance cancer stage and poor response to chemotherapy. Several investigations have demonstrated that genetic polymorphisms in drug-targeted genes, metabolizing enzymes, and DNA-repairing enzymes are all strongly correlated with inter-individual differences in the efficacy and toxicity of many treatment regimens. This preliminary study attempts to identify the correlation between genetic polymorphisms and clinicopathological features of CRC, and evaluates the relationship between genetic polymorphisms and chemotherapeutic susceptibility of Taiwanese CRC patients. To our knowledge, this study discusses, for the first time, early cancer relapse and its indication by multiple genes. Methods Six gene polymorphisms functional in drug-metabolism – GSTP1 Ile105Val, ABCB1 Ile1145Ile, MTHFR Ala222Val, TYMS double (2R or triple (3R tandem repeat – and DNA-repair genesERCC2 Lys751Gln and XRCC1 Arg399Gln – were assessed in 201 CRC patients using a polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP technique and DNA sequencing. Patients were diagnosed as either high-risk stage II (T2 and 3 N0 M0 or III (any T N1 and 2 M0 and were administered adjuvant chemotherapy regimens that included 5-fluorouracil (5FU and leucovorin (LV. The correlations between genetic polymorphisms and patient clinicopathological features and relapses were investigated. Results In this study, the distributions of GSTP1 (P = 0.003, ABCB1 (P = 0.001, TYMS (P ERCC2 (P XRCC1 (P = 0.006 genotypes in the Asian population, with the exception of MTHFR (P = 0.081, differed significantly from their distributions in a Caucasian population. However, the unfavorable genotype ERCC2 2251A>C (P = 0.006, tumor invasion depth (P = 0.025, lymph node metastasis (P = 0

  10. Oxidative stress in mammalian cells impinges on the cysteines redox state of human XRCC3 protein and on its cellular localization.

    Directory of Open Access Journals (Sweden)

    Pierre-Marie Girard

    Full Text Available In vertebrates, XRCC3 is one of the five Rad51 paralogs that plays a central role in homologous recombination (HR, a key pathway for maintaining genomic stability. While investigating the potential role of human XRCC3 (hXRCC3 in the inhibition of DNA replication induced by UVA radiation, we discovered that hXRCC3 cysteine residues are oxidized following photosensitization by UVA. Our in silico prediction of the hXRCC3 structure suggests that 6 out of 8 cysteines are potentially accessible to the solvent and therefore potentially exposed to ROS attack. By non-reducing SDS-PAGE we show that many different oxidants induce hXRCC3 oxidation that is monitored in Chinese hamster ovarian (CHO cells by increased electrophoretic mobility of the protein and in human cells by a slight decrease of its immunodetection. In both cell types, hXRCC3 oxidation was reversed in few minutes by cellular reducing systems. Depletion of intracellular glutathione prevents hXRCC3 oxidation only after UVA exposure though depending on the type of photosensitizer. In addition, we show that hXRCC3 expressed in CHO cells localizes both in the cytoplasm and in the nucleus. Mutating all hXRCC3 cysteines to serines (XR3/S protein does not affect the subcellular localization of the protein even after exposure to camptothecin (CPT, which typically induces DNA damages that require HR to be repaired. However, cells expressing mutated XR3/S protein are sensitive to CPT, thus highlighting a defect of the mutant protein in HR. In marked contrast to CPT treatment, oxidative stress induces relocalization at the chromatin fraction of both wild-type and mutated protein, even though survival is not affected. Collectively, our results demonstrate that the DNA repair protein hXRCC3 is a target of ROS induced by environmental factors and raise the possibility that the redox environment might participate in regulating the HR pathway.

  11. The ERCC2/DNA repair protein is associated with the class II BTF2/TFIIH transcription factor.

    NARCIS (Netherlands)

    L. Schaeffer; V. Moncollin; R. Roy (Richard); A. Staub; M. Mezzina; A. Sarasin; G. Weeda (Geert); J.H.J. Hoeijmakers (Jan); J-M. Egly (Jean-Marc)

    1994-01-01

    textabstractERCC2 is involved in the DNA repair syndrome xeroderma pigmentosum (XP) group D and was found to copurify with the RNA polymerase II (B) transcription factor BTF2/TFIIH that possesses a bidirectional helicase activity. Antibodies directed towards the 89 kDa (ERCC3) or the p62 subunit of

  12. Meta-Analysis of Association between XRCC3 Polymorphism and Lung Cancer%XRCC3多态性与肺癌关联的Meta分析

    Institute of Scientific and Technical Information of China (English)

    黄萌; 蔡琳

    2010-01-01

    目的 综合评价XRCC3 rs861539多态性与肺癌的关联.方法 计算机检索有关数据库,获取16个研究数据信息,结合本研究资料,依据NOS标准对文献进行质量评价,采用多变量Meta分析方法选择遗传模型,应用Stata评价异质性和发表偏倚、计算效应合并OR值及95%CI,Quanto与SPSS分析各研究的把握度及分类间的差异.结果 欧美的研究存在遗传模型异质性, rs861539与中国人群肺癌无显著关联(隐性模型合并OR=1.59,95%CI:0.52~4.87).结论 rs861539变异对中国人群肺癌无明显遗传效应,尚需进一步探讨与环境可能存在的交互作用.

  13. The impact of homologous recombination repair deficiency on depleted uranium clastogenicity in Chinese hamster ovary cells: XRCC3 protects cells from chromosome aberrations, but increases chromosome fragmentation

    Energy Technology Data Exchange (ETDEWEB)

    Holmes, Amie L. [Wise Laboratory of Environmental and Genetic Toxicology, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04104-9300, United States of America (United States); Maine Center for Toxicology and Environmental Health, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04104-9300, United States of America (United States); Department of Applied Medical Science, University of Southern Maine, 96 Falmouth Street, P.O. Box 9300, Portland, ME 04104-9300, United States of America (United States); Joyce, Kellie [Wise Laboratory of Environmental and Genetic Toxicology, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04104-9300, United States of America (United States); Maine Center for Toxicology and Environmental Health, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04104-9300, United States of America (United States); Xie, Hong [Wise Laboratory of Environmental and Genetic Toxicology, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04104-9300, United States of America (United States); Maine Center for Toxicology and Environmental Health, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04104-9300, United States of America (United States); Department of Applied Medical Science, University of Southern Maine, 96 Falmouth Street, P.O. Box 9300, Portland, ME 04104-9300, United States of America (United States); Falank, Carolyne [Wise Laboratory of Environmental and Genetic Toxicology, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04104-9300, United States of America (United States); Maine Center for Toxicology and Environmental Health, University of Southern Maine, 96 Falmouth St., P.O. Box 9300, Portland, ME 04104-9300, United States of America (United States); and others

    2014-04-15

    Highlights: • The role of homologous recombination repair in DU-induced toxicity was examined. • Loss of RAD51D did not affect DU-induced cytotoxicity or genotoxicity. • XRCC3 protects cell from DU-induced chromosome breaks and fusions. • XRCC3 plays a role in DU-induced chromosome fragmentation of the X chromosome. - Abstract: Depleted uranium (DU) is extensively used in both industry and military applications. The potential for civilian and military personnel exposure to DU is rising, but there are limited data on the potential health hazards of DU exposure. Previous laboratory research indicates DU is a potential carcinogen, but epidemiological studies remain inconclusive. DU is genotoxic, inducing DNA double strand breaks, chromosome damage and mutations, but the mechanisms of genotoxicity or repair pathways involved in protecting cells against DU-induced damage remain unknown. The purpose of this study was to investigate the effects of homologous recombination repair deficiency on DU-induced genotoxicity using RAD51D and XRCC3-deficient Chinese hamster ovary (CHO) cell lines. Cells deficient in XRCC3 (irs1SF) exhibited similar cytotoxicity after DU exposure compared to wild-type (AA8) and XRCC3-complemented (1SFwt8) cells, but DU induced more break-type and fusion-type lesions in XRCC3-deficient cells compared to wild-type and XRCC3-complemented cells. Surprisingly, loss of RAD51D did not affect DU-induced cytotoxicity or genotoxicity. DU induced selective X-chromosome fragmentation irrespective of RAD51D status, but loss of XRCC3 nearly eliminated fragmentation observed after DU exposure in wild-type and XRCC3-complemented cells. Thus, XRCC3, but not RAD51D, protects cells from DU-induced breaks and fusions and also plays a role in DU-induced chromosome fragmentation.

  14. XRCC3基因多态与乳头状甲状腺癌的遗传易感性%Genetic polymorphisms of XRCC3 and susceptibility of papillary thyroid carcinoma

    Institute of Scientific and Technical Information of China (English)

    倪红霞; 边建超; 沈强; 汤洪伟; 朱虔兮; 吴毅

    2006-01-01

    目的探讨X-线交错互补修复基因3(XRCC3)多态与乳头状甲状腺癌(PTC)的关系.方法采用以医院为基础的病例对照研究设计,应用PCR-RFLP和PCR-SSP技术检测191例PTC患者和201例对照的XRCC3基因多态.结果在XRCC3基因 A4541G、 A17893G和C18067T多态位点,所有等位基因和基因型在病例组和对照组的分布均无统计学差异.在吸烟、饮酒和经常饮茶者中,4541G/G基因型使PTC的发病风险降低,其OR值分别为0.09(95%CI:0.02-0.51)、0.10(95%CI:0.04-1.00)和0.18(95%CI:0.05-0.68).AAT单倍型在对照组的频率高于病例组,差异有统计学意义(P=0.014);以GAC单倍型为参照,AAT单倍型可使PTC发病风险降低,OR值为0.34(95%CI:0.11-0.92).结论 XRCC3基因A4541G、A17893G和C18067T多态与PTC无关联,但在吸烟、饮酒和常饮茶者中,4541G/G基因型可使PTC发病风险降低,是PTC的保护因素.AAT单倍型亦可降低PTC的发病风险.

  15. Rad51C deficiency destabilizes XRCC3, impairs recombination and radiosensitizes S/G2-phase cells

    Energy Technology Data Exchange (ETDEWEB)

    Lio, Yi-Ching; Schild, David; Brenneman, Mark A.; Redpath, J. Leslie; Chen, David J.

    2004-05-01

    The highly conserved Rad51 protein plays an essential role in repairing DNA damage through homologous recombination. In vertebrates, five Rad51 paralogs (Rad51B, Rad51C, Rad51D, XRCC2, XRCC3) are expressed in mitotically growing cells, and are thought to play mediating roles in homologous recombination, though their precise functions remain unclear. Here we report the use of RNA interference to deplete expression of Rad51C protein in human HT1080 and HeLa cells. In HT1080 cells, depletion of Rad51C by small interfering RNA caused a significant reduction of frequency in homologous recombination. The level of XRCC3 protein was also sharply reduced in Rad51C-depleted HeLa cells, suggesting that XRCC3 is dependent for its stability upon heterodimerization with Rad51C. In addition, Rad51C-depleted HeLa cells showed hypersensitivity to the DNA cross-linking agent mitomycin C, and moderately increased sensitivity to ionizing radiation. Importantly, the radiosensitivity of Rad51C-deficient HeLa cells was evident in S and G{sub 2}/M phases of the cell cycle but not in G{sub 1} phase. Together, these results provide direct cellular evidence for the importance of human Rad51C in homologous recombinational repair.

  16. RAD51-G135C和XRCC3-C241T多态性与inv(16)/t(16;16)/CBFβ-MYH11阳性急性髓系白血病预后的关系%Relationship between RAD51-G135C and XRCC3-C241T polymorphisms and prognosis of inv( 16)/t(16;16) (CBFβ-MYH11) acute myeloid leukemia

    Institute of Scientific and Technical Information of China (English)

    刘亮; 杨琳; 秘营昌; 李建勇; 秦铁军; 徐泽锋; 张悦; 王建祥; 肖志坚

    2011-01-01

    目的 探讨DNA同源重组修复基因RAD51-G135C和XRCC3-C241T多态性与inv(16)/t(16;16)/CBβ-MYH11阳性急性髓系白血病(AML)患者预后之间的关系.方法 对染色体核型可供分析且随访资料完整的103例初治原发性inv(16)/t(16;16)/CBβ-MYH11阳性AML患者进行回顾性分析.用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测患者RAD51-G135C、XRCC3-C241T基因多态性.采用单因素(包括性别、初诊时年龄、白细胞计数、血小板计数、血红蛋白含量、染色体核型、KIT基因突变、RAD51-G135C和XRCC3-C241T基因多态性)和多因素分析方法评估患者完全缓解(CR)率、总体生存(OS)率和无复发生存(RFS)率的影响因素.结果 全部患者中位随访时间为28(1-106)个月,总体CR率为92.2%,预期5年OS率和RFS率分别为43.6%(95%CI 37.7%-49.5%)和26.4%(95%CI 21.1%-31.7%),预期中位OS时间和RFS时间分别为53.0(95%CI 33.4~72.7)个月和27(95%CI 22.9-31.1)个月.多因素分析结果显示:高白细胞计数(P=0.004)和年龄>30岁(P=0.035)是与CR率有关的独立不良预后因素,XRCC3-C241T变异基因型(P=0.007)和高白细胞计数(P=0.009)是与RFS率有关的独立不良预后因素,高白细胞计数(P=0.002)和伴有+8染色体核型异常(P=0.035)是与OS率有关的独立不良预后因素;而RAD51-G135C基因型对此类白血病的预后无明显影响.结论 XRCC3-C241T变异基因型是inv(16)/t(16;16)/CBFβ-MYH11阳性AML一个独立的不良预后因素.%Objective To investigate the impact of polymorphisms of DNA homologous recombination (HR) repair genes RAD51-G135C and XRCC3-C241T on the prognosis of acute myeloid leukemia(AML)with inv(16)/t(16;16)(CBFβ-MYH11).Methods One hundred and three de novo inv( 16)/t(16;16)(CBFβ-MYH11) AML patients were followed-up and retrospectively analyzed.Polymorphisms of RAD51-G135C and XRCC3-C241T were detected by PCR-RFLP.The prognostic factors,including sex, age, white blood cell count

  17. Effects and underlying mechanisms of homologous recombina-tion-associated protein XRCC3 on esophageal squamous-cell carci-noma radiotherapy response%同源重组相关蛋白XRCC3对食管鳞癌细胞放疗敏感性的影响及其分子机制研究

    Institute of Scientific and Technical Information of China (English)

    钱东; 郭艺航; 曾宪亮; 王欢欢; 吴志强; 孟茂斌; 王平; 袁智勇

    2015-01-01

    Objective:To investigate the effects and underlying mechanisms of XRCC3 on esophageal squamous-cell carcinoma (ESCC) radiotherapy response. Methods:Expression levels of XRCC3 were detected by reverse transcription PCR, Western blot, and immunohistochemistry. We knocked down XRCC3 with lentiviral infection in ESCC cells. Cell apoptosis was examined by flow cytom-etry. DNA damage and telomere dysfunction-induced foci were determined by immunofluorescence. Results:The expression levels of XRCC3 in ESCC cells and tissues were higher than those in normal esophageal epithelial cells and corresponding adjacent noncancer-ous esophageal tissues. Knockdown of XRCC3 in ESCC cells substantially increased the therapeutic efficacy of radiation. We demon-strated that the radiation resistance of XRCC3 was attributed to the XRCC3-maintaining telomere stability, which reduced ESCC cell death through radiation-induced apoptosis. Conclusion: Our data suggested that XRCC3 protects ESCC cells from ionizing radia-tion-induced DNA damage and death by enhancing telomere stability. Thus, XRCC3 can be used as a promising therapeutic target for ESCCs.%目的:探讨同源重组相关蛋白XRCC3对食管鳞癌(esophageal squmaous cell carcinoma,ESCC)细胞放疗敏感性的影响及其潜在的分子机制。方法:利用免疫印迹(Western blot),逆转录聚合酶链式反应(reverse transcription PCR,RT-PCR)及免疫组织化学(immunohistochemistry,IHC)分别检测食管鳞癌细胞以及患者石蜡封存组织标本中XRCC3的表达;利用慢病毒感染的方式构建稳定沉默XRCC3表达的食管鳞癌细胞株;运用流式细胞仪通过Annexin V-PI双染检测细胞凋亡;免疫荧光染色法检测细胞DNA损伤以及端粒损伤水平的变化。结果:与正常食管鳞状上皮细胞或组织相比,XRCC3在食管鳞癌细胞及组织中呈高表达;流式及相关实验揭示沉默XRCC3的表达会增加食管鳞癌细胞在放疗的作

  18. Association between Single Nucleotide Polymorphisms in XRCC3 and Radiation-Induced Adverse Effects on Normal Tissue: A Meta-Analysis.

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    Yu-Zhe Song

    Full Text Available The X-ray repair cross-complementing group 3 (XRCC3 protein plays an important role in the repair of DNA double-strand breaks. The relationship between XRCC3 polymorphisms and the risk of radiation-induced adverse effects on normal tissue remains inconclusive. Thus, we performed a meta-analysis to elucidate the association between XRCC3 polymorphisms and radiation-induced adverse effects on normal tissue. All eligible studies up to December 2014 were identified through a search of the PubMed, Embase and Web of Science databases. Seventeen studies involving 656 cases and 2193 controls were ultimately included in this meta-analysis. The pooled odds ratios (ORs with corresponding 95% confidence intervals (CIs were calculated to evaluate the association between XRCC3 polymorphisms and the risk of radiation-induced normal tissue adverse effects. We found that the XRCC3 p.Thr241Met (rs861539 polymorphism was significantly associated with early adverse effects induced by radiotherapy (OR = 1.99, 95%CI: 1.31-3.01, P = 0.001. A positive association lacking statistical significance with late adverse effects was also identified (OR = 1.28, 95%CI: 0.97-1.68, P = 0.08. In addition, the rs861539 polymorphism was significantly correlated with a higher risk of adverse effects induced by head and neck area irradiation (OR = 2.41, 95%CI: 1.49-3.89, p = 0.0003 and breast irradiation (OR = 1.41, 95%CI: 1.02-1.95, p = 0.04, whereas the correlation was not significant for lung irradiation or pelvic irradiation. Furthermore, XRCC3 rs1799794 polymorphism may have a protective effect against late adverse effects induced by radiotherapy (OR = 0.47, 95%CI: 0.26-0.86, P = 0.01. Well-designed large-scale clinical studies are required to further validate our results.

  19. XRCC3 Thr241Met is associated with response to platinum-based chemotherapy but not survival in advanced non-small cell lung cancer.

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    Mantang Qiu

    Full Text Available BACKGROUND: A lot of studies have investigated the correlation between x-ray repair cross-complementing group 3 (XRCC3 Thr241Met polymorphism and clinical outcomes in non-small cell cancer (NSCLC, while the conclusion is still conflicting. MATERIALS AND METHODS: We conducted this meta-analysis to evaluate the predictive value of XRCC3 Thr241Met polymorphism on response and overall survival of patients with NSCLC. Pooled odds ratios (ORs and hazard ratios (HRs and corresponding 95% confidence intervals (95% CIs were used to estimate the association strength. RESULTS: A total of 14 eligible studies with 2828 patients were identified according to our inclusion criteria. Meta-analysis results showed that carriers of the variant 241Met allele were significantly associated with good response, compared with those harboring the wild 241Thr allele (Met vs. Thr, OR = 1.453, 95% CI: 1.116-1.892, Pheterogeneity = 0.968 and ThrMet+MetMet vs. ThrThr, OR = 1.476, 95% CI: 1.087-2.004, Pheterogeneity = 0.696. This significant association was observed in Caucasian population but not in Asian population. On the other hand, there was no significant association of XRCC3 Thr241Met polymorphism with survival (ThrMet+MetMet vs. ThrThr, HR = 1.082, 95% CI: 0.929-1.261, Pheterogeneity = 0.564, and there was no difference between Asian and Caucasian population. CONCLUSIONS: These findings suggest a predictive role of XRCC3 Thr241Met polymorphism on response to platinum-based chemotherapy in patients with advanced NSCLC. Additionally, we first report that the XRCC3 Thr241Met polymorphism is associated with response to platinum-based chemotherapy and highlights the prognostic value of the XRCC3 Thr241Met polymorphism.

  20. XRCC3基因多态性与宫颈癌发病风险的关系

    Institute of Scientific and Technical Information of China (English)

    肖洪玉; 吴文清; 包小梅; 谢红艳

    2010-01-01

    目的:研究X线修复交叉互补基因3(XRCC3)Thr241Met多态性位点在广东人群中的分布,并分析其多态性与宫颈癌发病风险的关系。方法:采用病例-对照研究方法,应用PCR-RFLP检测158例宫颈癌患者及年龄相匹配的164例正常人群XRCC3Thr241Met多态性位点基因型及等位基因,并分析该位点与宫颈癌发病风险的关系。结果:Thr241Met基因型和等位基因频率在病例组和对照组中的分布差异有统计学意义(P〈0.05),等位基因Met可能增加个体患宫颈癌的风险(OR=1.983,95%CI=1.364~2.883,P=0.000),提示Thr241Met多态性可能与个体患宫颈癌风险相关;但Thr241Met多态性与宫颈癌患者临床病理特征无关。结论:Thr241Met多态性可能与宫颈癌风险相关,Met等位基因可增加个体患宫颈癌的风险,但与宫颈癌临床病理特征无关。

  1. XRCC3基因多态性与宫颈癌发病风险的关系

    Institute of Scientific and Technical Information of China (English)

    肖洪玉; 吴文清; 包小梅; 谢红艳

    2010-01-01

    目的:研究X线修复交叉互补基因3(XRCC3)Thr241Met多态性位点在广东人群中的分布,并分析其多态性与宫颈癌发病风险的关系.方法:采用病例-对照研究方法,应用 PCR-RFLP检测158例宫颈癌患者及年龄相匹配的164例正常人群XRCC3 Thr241Met多态性位点基因型及等位基因,并分析该位点与宫颈癌发病风险的关系.结果:Thr241Met基因型和等位基因频率在病例组和对照组中的分布差异有统计学意义(P<0.05),等位基因Met可能增加个体患宫颈癌的风险(OR=1.983,95%CI=1.364~2.883,P=0.000),提示Thr241Met多态性可能与个体患宫颈癌风险相关;但Thr241Met多态性与宫颈癌患者临床病理特征无关.结论:Thr241Met多态性可能与宫颈癌风险相关,Met等位基因可增加个体患宫颈癌的风险,但与宫颈癌临床病理特征无关.

  2. DNA Repair Gene Polymorphisms in Relation to Non-Small Cell Lung Cancer Survival

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    Yuliang Su

    2015-07-01

    Full Text Available Background: Single nucleotide polymorphisms (SNPs in the DNA repair genes are suspected to be related to the survival of lung cancer patients due to their possible influence on DNA repair capacity (DRC. However, the study results are inconsistent. Methods: A follow-up study of 610 non-small cell lung cancer (NSCLC patients was conducted to investigate genetic polymorphisms associated with the DNA repair genes in relation to NSCLC survival; 6 SNPs were genotyped, including XRCC1 (rs25487 G>A, hOGG1 (rs1052133 C>G, MUTYH (rs3219489 G>C, XPA (rs1800975 G>A, ERCC2 (rs1799793 G>A and XRCC3 (rs861539 C>T. Kaplan-Meier survival curve and Cox proportional hazards regression analyses were performed. SNP-SNP interaction was also examined using the survival tree analysis. Results: Advanced disease stage and older age at diagnosis were associated with poor prognosis of NSCLC. Patients with the variant ‘G' allele of hOGG1 rs1052133 had poor overall survival compared with those with the homozygous wild ‘CC' genotype, especially in female patients, adenocarcinoma histology, early stage, light smokers and without family history of cancer. For never smoking female lung cancer patients, individuals carrying homozygous variant ‘AA' genotype of XPA had shorter survival time compared to those with wild ‘G' alleles. Furthermore, females carrying homozygous variant XPA and hOGG1 genotypes simultaneously had 2.78-fold increased risk for death. Among all 6 polymorphisms, the homozygous variant ‘AA' of XPA carriers had poor prognosis compared to the carriers of wild ‘G' alleles of XPA together with other base excision repair (BER polymorphisms. Conclusions: Besides disease stage and age, the study found DNA repair gene polymorphisms were associated with lung cancer survival.

  3. DNA修复基因XRCC1和XRCC3多态性与膀胱癌风险关联研究

    Institute of Scientific and Technical Information of China (English)

    杨庆祥; 陈昆; 韩前河

    2009-01-01

    目的:探讨DNA修复基因多态性与膀胱癌易感性的关系.方法:采用病例-对照研究,以PCR-RFLP技术检测膀胱癌组和对照组的基因多态,比较不同基因型与膀胱癌风险的关系.结果:XRCC1三种基因型在两组间的分布无统计学差异;XRCC3三种基因型在两组之间的分布有统计学差异.结论:XRCC1 Arg194Trp多态与膀胱癌易感性无关;携带XRCC3 241Met基因型的个体患膀胱癌的风险显著增加.

  4. Relationship between RAD51-G135C and XRCC3-C241 T Single Nucleotide Polymorphisms and Onset of Acute Myeloid Leukemia%RAD51-G135C和XRCC3-C241T单核苷酸多态性与急性髓系白血病发病相关性研究

    Institute of Scientific and Technical Information of China (English)

    苗蕾; 钱锡峰; 杨国华; 赵利东

    2015-01-01

    目的:探讨RAD51-G135C和XRCC3-C241T单核苷酸多态性与急性髓系白血病(AML)发病的相关性.方法:研究分为两组:AML患者组(545例AML患者的外周血样本)和对照组(1 034名与患者无血缘关系的正常人的外周血样本),分别抽提2组基因组DNA,通过TaqMan探针实时荧光定量PCR技术分析RAD51-G135C和XRCC3-C241T基因多态性,并分析两者多态性与急性髓系白血病发病相关性.结果:与对照组相比,RAD51-G135C纯合变异型(CC)可显著增加AML患者的发病风险(OR =3.07),而RAD51-G135C杂合变异型(GC)与AML发病无统计学相关性.XRCC3-C241T纯合变异型(TT)与AML发病尚无统计学相关性,而XRCC3-C241T杂合变异型(CT)却可增加AML患者的发病风险(OR =0.66).结论:RAD51-G135C纯合变异型和XRCC3-C241T杂合变异型显著增高AML的发病风险,对AML的发病更有预测价值.

  5. hOGG1、XRCC1、XRCC3单核苷酸多态性与食管癌放射敏感性的相关性研究%Association study on single nucleotide polymorphism in hOGG1, XRCC1,XRCC3 and radiosensitivity in esophageal cancer

    Institute of Scientific and Technical Information of China (English)

    张旭升; 阿合力·那斯肉拉; 张瑾熔; 吕茵; 葛峰

    2010-01-01

    目的 研究hOGG1、XRCC1、XRCC3单核苷酸多态性与食管癌放射敏感性的关系.方法 采用PCR-RFLP法检测94例食管鳞状细胞癌患者外周血hOGG1、XRCC1、XRCC3基因单核苷酸多态性,并分析hOGG1 Ser326Cys、XRCC1 Arg399Gln、XRCC3 Thr241Met单核苷酸多态性在食管癌放射治疗有效组及放射治疗无效组中的分布情况.结果 94例食管鳞癌患者经根治性三维适形或调强放疗,有效率为84.06%, XRCC1 Arg399Gln等位基因频率在食管癌放射治疗有效组及无效组中的分布差异有统计学意义(P=0.001).hOGG1 Ser326Cys及XRCC3 Thr241Met等位基因在两组中的分布差异均无统计学意义(P=0.586、0.152).XRCC1 Arg/Arg、Arg/Gln、Gln/Gln基因型患者放疗有效率分别为91.5%、88.9%和60.0%,3种基因型放疗有效率差异有统计学意义(P=0.009).hOGG1 Ser326Cys及XRCC3 Thr241Met各基因型间放疗有效率差异无统计学意义(P>0.05).结论 XRCC3 Arg399Gln单核苷酸多态性与食管癌放射敏感性存在相关性;hOGG1 Ser326Cys,XRCC1 Thr241Met 基因多态性与食管癌放射敏感性无明显相关性.

  6. Analysis of relationship between protein expression of XRCC3 and HOGG1 and prognosis in patients with esophageal squamous cell carcinoma after radiotherapy%食管鳞癌XRCC3和HOGG1表达与放疗预后相关性分析

    Institute of Scientific and Technical Information of China (English)

    帕丽达·阿皮孜阿吉; 伊斯刊达尔·阿布力米提; 张瑾熔

    2013-01-01

    目的 探讨食管鳞状细胞癌(ESCC)癌组织中X射线修复交叉互补基因3(XRCC3)和人类8-羟基鸟嘌呤糖苷酶1(HOGG1)的蛋白表达与ESCC放疗预后相关性.方法 采用免疫组织化学SP法检测治疗前171例ESCC组织标本中XRCC1、HOGG1蛋白表达.Kaplan-Meier法生存分析并Logrank法检验表达阴、阳性间生存差异,Cox模型多因素预后分析.结果 随访率为87.2%,其中随访时间满1、2、3年者分别为140、136、129例.XRCC3主要表达于细胞核,HOGG1主要表达于细胞核与线粒体,两者符合程度达72.5%(x2=23.94,P=0.000).XRCC3表达阳、阴性的近期疗效相似(x2 =0.98,P=0.614),生存率也相似,中位生存期均为54个月(x2=0.17,P=0.683),HOGG1表达阳、阴性近期疗效相似(x2=0.26,P =0.880),生存率也相似,中位生存期均为49个月(x2=0.08,P =0.780).多因素分析结果显示疗效评价、病变长度与ESCC预后相关(x2=7.99、3.76,P=0.005、0.045).结论 XRCC3、HOGG1的蛋白表达与ESCC放疗预后可能无关.%Objective To investigate the relationship between the protein expression of X-ray repair cross-complementing protein 3 (XRCC3) and human 8-hydroxyguanine glycosylase 1 (HOGG1) in esophageal squamous cell carcinoma (ESCC) tissue and the prognosis in ESCC patients after radiotherapy.Methods Immunohistochemical SP method was used to measure the protein expression of XRCC3 and HOGG1 in 171 ESCC tissue samples before radiotherapy.The Kaplan-Meier method was used for survival analysis,and the logrank test was used for analyzing the survival difference between negative and positive samples.The Cox model was used for multivariate prognostic analysis.Results The follow-up rate was 87.2% ; 140 patients were followed up for at least 1 year,136 patients for at least 2 years,and 129 patients for at least 3 years.XRCC3 was mainly expressed in the nucleus,and HOGG1 was mainly expressed in the nucleus and mitochondria,with a coincidence degree of 72.5% (x2 =23.94,P

  7. XRCC1、XPD、XRCC3、CCND1基因多态性与职业慢性苯中毒发病工龄的关联%Analysis for the association between genetic polymorphisms of XRCC1, XPD, XRCC3, CCND1 and the latency of the occupational chronic benzene poisoning

    Institute of Scientific and Technical Information of China (English)

    许建宁; 黄慧隆; 王全凯; 王雅文; 杨敏; 郑玉新

    2007-01-01

    目的 探讨DNA损伤修复基因XRCC1、XPD、XRCC3基因和细胞周期调控基因CCND1的多态性与慢性苯中毒发病工龄的关系.方法 以确诊的80名慢性苯中毒患者作为研究对象,应用PCR-RFLP分析技术,检测DNA损伤修复基因XRCC1(C26304T、G27466A、G28152A、G36189A位点)、XPD(C22541A、C23591T、A35931C位点)、XRCC3(C18067T位点)和细胞周期调控CCND1基因G870A位点的多态性,比较不同基因型Kaplan-Meier生存曲线,评价慢性苯中毒发病工龄与XRCC1、XPD、XRCC3和CCND1基因多态性的关联.结果 携带XRCC1 27466G/G基因型的个体发生慢性苯中毒的发病工龄比携带27466G/A+A/A变异基因型的个体长6.9年;携带CCND1870G/G基因型的个体比G/A+A/A基因型个体的发病工龄短6.2年.结论 XRCC1和CCND1基因多态性可能影响慢性职业性苯中毒的发病工龄.

  8. Association between XRCC1 and XRCC3 polymorphisms with lung cancer risk: a meta-analysis from case-control studies.

    Directory of Open Access Journals (Sweden)

    Guohua Huang

    Full Text Available Many studies have reported the association of X-ray repair cross-complementing group 1 (XRCC1 Arg399Gln, Arg194Trp, Arg280His, -77T>C, and X-ray repair cross-complementing group 3 (XRCC3 T241M polymorphisms with lung cancer risk, but the results remained controversial. Hence, we performed a meta-analysis to investigate the association between lung cancer risk and XRCC1 Arg399Gln (14,156 cases and 16,667 controls from 41 studies, Arg194Trp (7,426 cases and 9,603 controls from 23 studies, Arg280His (6,211 cases and 6,763 controls from 16 studies, -77T>C (2,487 cases and 2,576 controls from 5 studies, and XRCC3 T241M (8,560 cases and 11,557 controls from 19 studies in different inheritance models. We found that -77T>C polymorphism was associated with increased lung cancer risk (dominant model: odds ration [OR] = 1.45, 95% confidence interval [CI] = 1.27-1.66, recessive model: OR = 1.73, 95% CI = 1.14-2.62, additive model: OR = 1.91, 95% CI = 1.24-1.94 when all the eligible studies were pooled into the meta-analysis. In the stratified and sensitive analyses, significantly decreased lung cancer risk was observed in overall analysis (dominant model: OR = 0.83, 95% CI = 0.78-0.89; recessive model: OR = 0.90, 95% CI = 0.81-1.00; additive model: OR = 0.82, 95% CI = 0.74-0.92, Caucasians (dominant model: OR = 0.82, 95% CI = 0.76-0.87; recessive model: OR = 0.89, 95% CI = 0.80-0.99; additive model: OR = 0.81, 95% CI = 0.73-0.91, and hospital-based controls (dominant model: OR = 0.81, 95% CI = 0.76-0.88; recessive model: OR = 0.89, 95% CI = 0.79-1.00; additive model: OR = 0.80, 95% CI = 0.71-0.90 for XRCC3 T241M. In conclusion, this meta-analysis indicates that XRCC1 -77T>C shows an increased lung cancer risk and XRCC3 T241M polymorphism is associated with decreased lung cancer risk, especially in Caucasians.

  9. XRCC3单核苷酸多态性与肺癌放疗近期疗效的相关性研究

    Institute of Scientific and Technical Information of China (English)

    刘鹏; 苏丹; 王磊; 张毅敏; 邓清华; 倪玲玲; 朱远; 胡巧英; 马胜林

    2006-01-01

    一般认为肿瘤细胞DNA损伤修复能力与放射敏感性密切相关。DNA损伤修复过程中许多基因扮演着重要角色,这些基因的单核苷酸多态性(SNP)可改变蛋白质功能,并改变DNA修复能力,从而为通过检测这些基因SNP来预测机体细胞的放射敏感性指明了方向。笔者采用TaqMan—MGB探针技术和等位基因特异适时荧光PCR技术研究XRCC3第241密码子C/TSNP与肺癌放疗疗效的相关性。

  10. Homologous recombination as a potential target for caffeine radiosensitization in mammalian cells: reduced caffeine radiosensitization in XRCC2 and XRCC3 mutants

    Science.gov (United States)

    Asaad, N. A.; Zeng, Z. C.; Guan, J.; Thacker, J.; Iliakis, G.

    2000-01-01

    The radiosensitizing effect of caffeine has been associated with the disruption of multiple DNA damage-responsive cell cycle checkpoints, but several lines of evidence also implicate inhibition of DNA repair. The role of DNA repair inhibition in caffeine radiosensitization remains uncharacterized, and it is unknown which repair process, or lesion, is affected. We show that a radiosensitive cell line, mutant for the RAD51 homolog XRCC2 and defective in homologous recombination repair (HRR), displays significantly diminished caffeine radiosensitization that can be restored by expression of XRCC2. Despite the reduced radiosensitization, caffeine effectively abrogates checkpoints in S and G2 phases in XRCC2 mutant cells indicating that checkpoint abrogation is not sufficient for radiosensitization. Another radiosensitive line, mutant for XRCC3 and defective in HRR, similarly shows reduced caffeine radiosensitization. On the other hand, a radiosensitive mutant (irs-20) of DNA-PKcs with a defect in non-homologous end-joining (NHEJ) is radiosensitized by caffeine to an extent comparable to wild-type cells. In addition, rejoining of radiation-induced DNA DSBs, that mainly reflects NHEJ, remains unaffected by caffeine in XRCC2 and XRCC3 mutants, or their wild-type counterparts. These observations suggest that caffeine targets steps in HRR but not in NHEJ and that abrogation of checkpoint response is not sufficient to explain radiosensitization. Indeed, immortalized fibroblasts from AT patients show caffeine radiosensitization despite the checkpoint defects associated with ATM mutation. We propose that caffeine radiosensitization is mediated by inhibition of stages in DNA DSB repair requiring HRR and that checkpoint disruption contributes by allowing these DSBs to transit into irreparable states. Thus, checkpoints may contribute to genomic stability by promoting error-free HRR.

  11. Associations of polymorphisms in DNA repair genes and MDR1 gene with chemotherapy response and survival of non-small cell lung cancer.

    Directory of Open Access Journals (Sweden)

    Yan Du

    Full Text Available OBJECTIVES: We aimed to determine the associations of genetic polymorphisms of excision repair cross-complementation group 1 (ERCC1 rs11615, xeroderma pigmentosum group D (XPD/ERCC2 rs13181, X-ray repair cross complementing group 1 (XRCC1 rs25487, XRCC3 rs1799794, and breast cancer susceptibility gene 1 (BRCA1 rs1799966 from the DNA repair pathway and multiple drug resistance 1 (MDR1/ABCB1 rs1045642 with response to chemotherapy and survival of non-small cell lung cancer (NSCLC in a Chinese population. MATERIALS AND METHODS: A total of 352 NSCLC patients were enrolled to evaluate the associations of the six SNPs with response to chemotherapy and overall survival. Logistic regressions were applied to test the associations of genetic polymorphisms with response to chemotherapy in 161 advanced NSCLC patients. Overall survival was analyzed in 161 advanced and 156 early stage NSCLC patients using the Kaplan-Meier method with log-rank test, respectively. Multivariate Cox proportional hazards model was performed to determine the factors independently associated with NSCLC prognosis. RESULTS: BRCA1 rs1799966 minor allele C (TC+CC vs. TT, OR = 0.402, 95% CI = 0.204-0.794, p = 0.008 and MDR1/ABCB1 rs1045642 minor allele A (GA +AA vs. GG, OR = 0.478, 95% CI = 0.244-0.934, p = 0.030 were associated with a better response to chemotherapy in advanced NSCLC patients. Survival analyses indicated that BRCA1 rs1799966 TC+CC genotypes were associated with a decreased risk of death (HR = 0.617, 95% CI = 0.402-0.948, p = 0.028 in advanced NSCLC patients, and the association was still significant after the adjustment for covariates. Multivariate Cox regression analysis showed that ERCC1 rs11615 AA genotype (P = 0.020 and smoking (p = 0.037 were associated with increased risks of death in early stage NSCLC patients after surgery. CONCLUSIONS: Polymorphisms of genes in DNA repair pathway and MDR1 could contribute to chemotherapy response and survival of patients with

  12. XRCC1和XRCC3基因多态性与膀胱癌发病风险的相关性

    Institute of Scientific and Technical Information of China (English)

    李菡; 林夏雯; 陈宇; 立彦

    2016-01-01

    目的:研究 DNA 修复基因 XRCC1(rs25487)和 XRCC3(rs1799796)的单核苷酸多态性与膀胱癌易感性及其病理参数的相关性。方法:采用病例-对照研究方法,收集经病理诊断为膀胱癌患者的279例为病例组,健康体检正常的人群280例为对照组,采用限制性片段长度多态性-聚合酶链式反应(PCR-RFLP)技术检测多态性位点rs25487和rs1799796在病例组和对照组中的基因型分布。采用Logistic 回归模型分析各基因型与膀胱癌发生的关系并比较不同基因型与膀胱癌及其病理参数的关系。结果: XRCC1(rs25487)和XRCC3(rs1799796)位点在病例及对照组中分布无统计学差异(均 P >0.05);rs25487的 AG 基因型在肿瘤分期Ⅰ-Ⅱ期(OR =0.48,95%CI =0.31~0.73)、高分化(OR =0.53,95%CI =0.29~0.97)、低分化(OR=0.56,95%CI =0.33~0.94)、无周围淋巴结转移组(OR =0.53,95% CI =0.34~0.84)、无远端淋巴结转移组(OR =0.56,95%CI =0.37~0.83)中的分布频率低于对照组;rs1799796的GG基因型在中分化(OR =3.68,95%CI =1.62~8.36)、有周围淋巴结转移组(OR =2.36,95%CI =1.23~4.53)及有远端淋巴结转移组(OR =2.51,95%CI =1.08~5.80)中的分布频率高于对照组,使膀胱癌的发病风险增加。结论:本研究发现XRCC1(rs25487)和XRCC3(rs1799796)与膀胱癌的病理进展相关。

  13. hOGG1、XRCC3、ERCC1基因多态性在子宫内膜异位症的表达意义

    Institute of Scientific and Technical Information of China (English)

    王娅菲; 卢霞

    2014-01-01

    目的研究DNA修复基因hOGG1、XRCC3、ERCC多态性与子宫内膜异位症发病风险的关系。方法:采用病例一对照研究的方法,应用PCR-RELP方法检测子宫内膜异位症患者与非子宫内膜异位症妇女hOGG1、XRCC3、ERCC1基因多态性分布。结果:hOGG1Ser326Cys基因多态性在内异症组与对照组未见明显差异(X2=0 172,P=0.678);XRCC3 Thr241Met基因多态性在内异症组与对照组来见明显差异(X2=3.769,P=0.052);ERCClC19007T基因多态性在内异症组与对照组未见明显差异(X2=0.232,P=0.630)。结论:DNA修复基因hOGGI、XRCC3、ERCC1多态性并未增加子宫内膜异位症发生风险。

  14. hOGG1、XRCC3、ERCC1基因多态性在子宫内膜异位症的表达意义

    Institute of Scientific and Technical Information of China (English)

    王娅菲; 卢霞

    2014-01-01

    目的:研究 DNA 修复基因 hOGG1、XRCC3、ERCC 多态性与子宫内膜异位症发病风险的关系。方法:采用病例-对照研究的方法,应用 PCR -RELP 方法检测子宫内膜异位症患者与非子宫内膜异位症妇女 hOGG1、XRCC3、ERCC1基因多态性分布。结果:h0GG1Ser326Cys 基因多态性在内异症组与对照组未见明显差异(X2=0.172,P =0.678);XRCC3 Thr241Met 基因多态性在内异症组与对照组未见明显差异(X2=3.769,P =0.052);ERCC1C19007T 基因多态性在内异症组与对照组未见明显差异(X2=0.232,P =0.630)。结论:DNA 修复基因 hOGG1、XRCC3、ERCC1多态性并未增加子宫内膜异位症发生风险。

  15. Interaction between lifestyle factors and the XRCC1, XPD, and XRCC3 genetic variations modulates the risk for sporadic colorectal cancer

    Directory of Open Access Journals (Sweden)

    Procopciuc Lucia Maria

    2014-03-01

    Full Text Available Introducere: Variațiile genetice, cum ar fi cele care influențează sistemele de reparare a defectelor de replicare a ADN, pot reprezenta factori de susceptibilitate în cancerul colorectal sporadic (CCR ca urmare a interacțiunii cu factori de mediu. Material și metodă: 80 de femei și 70 de bărbați, pacienți diagnosticați cu CCR sporadic în Clinica Chirurgie III Cluj au fost genotipați pentru Arg399Gln-XRCC1, Lys751Gln-XPD și Met241Thr-XRCC3 utilizând metodele PCR-RFLP. Am determinat de asemenea, genotipurile pentru 100 femei și 62 bărbați , care au format grupul de control. Rezultatele au fost analizate din punct de vedere al relației cu factorii de risc de mediu, fumatul și dieta. Rezultate: Bărbații fumători purtători ai variațiilor genetice Arg399Gln, Lys751Gln, Met241Thr au avut un risc semnificativ crescut de 4.09 (95%IC[0.96-19.98],p=0.05, 5.95(95%IC[1.08-43.22],p=0.03 și respectiv 3.73(95%IC[0.86-18.53],p=0.05 de a dezvolta cancer colorectal sporadic. Un risc semnificativ crescut de a dezvolta cancer colorectal sporadic a fost observat în cazul femeilor și bărbaților cu o dietă bogată în carne roșie prăjită purtători ai variațiilor genetice Arg399Gln (OR 2.77 95%IC [1.34-6.82],p=0.015 și OR 8.64 95%IC[2.67-29.14],p<0.001, Lys751Gln (OR 4.12 95%IC[1.37-12.74],p=0.007 și OR 5.06 95%IC[1.4- 19.02],p=0.006, Met241Thr (OR5.92 95%IC[2.21-16.23],p<0.001 și OR 5.64 95%IC[1.52-21.7],p=0.022. Femeile a căror dietă a inclus cantități mari de carne roșie prăjită au avut un risc semnificativ crescut de a dezvolta timpuriu cancer colorectal sporadic dacă au fost purtătoare a variațiilor genetice Arg399Gln-XRCC1 (OR 5.14 95%IC[0.99-28.3],p=0.047, Thr241Met-XRCC3 (OR 6.67 95%IC[1.05-46.67],p=0.025 și Lys751Gln-XPD (OR 4.7 95%IC[0.99-23.32],p=0.034. Concluzii: În cazul populației de origine română, asocierea genotipurilor mutante cu factori de mediu modulează riscul pentru CCR sporadic. La femei

  16. 中国上海及其周边省份汉族人群XRCC3基因Thr241Met多态与脑胶质瘤遗传易感性关联研究%Association between XRCC3 Thr241Met polymorphism and genetic susceptibility to glioma in Chinese Han population living in Shanghai and surrounding provinces in east China

    Institute of Scientific and Technical Information of China (English)

    周可可; 刘艳红; 张海石; 钟逾; 刘宏亮; 卢大儒; 黄峰平; 周良辅

    2007-01-01

    目的:分析上海及其周边省份汉族人群中脑胶质瘤患者X线交叉互补修复基因3(X-ray repair cross-complementing group 3,XRCC3)Thr241Met单核苷酸多态性(single-nucleotide polymorphism,SNP),探讨其与脑胶质瘤遗传易感性的相关性.方法:应用TaqMan技术检测我国上海及其周边省份(江苏、浙江、安徽等)汉族人群中771例脑胶质瘤患者(病例组)和752例非肿瘤对照受试者(对照组)XRCC3基因Thr241Met多态性;应用统计学方法对TaqMan技术成功检测分型结果进行处理,分析该位点多态性与脑胶质瘤遗传易感性的相关性.结果:1 468例受试者(病例组760例,对照组708例)应用TaqMan技术成功进行了目标基因检测及分型,基因分型成功率为96.4%.统计学分析发现:对照组C和T等位基因频率以及TC、TT基因型频率与病例组无显著差异.经年龄和性别因素校正,TC基因型(P=0.909;OR=0.981;95%CI=0.701~1.371)或TT基因型(P=0.642; OR=0.7; 95%CI=0.156~3.146)与CC基因型相比并不增加脑胶质瘤的发生风险.结论:我国上海及其周边省份汉族人群XRCC3基因Thr241Met的变异基因型TC和TT可能不是脑胶质瘤的遗传高危因素.

  17. NQO1C609T,RAD51G135C和XRCC3C241T单核苷酸多态性与急性淋巴细胞白血病发病相关性研究%Relationship between NQO1C609T,RAD51 G135C,XRCC3 C241T Single Nucleotide Polymorphisms and Acute Lymphoblastic Leukemia

    Institute of Scientific and Technical Information of China (English)

    张战强; 杨琳; 张悦; 杨艺红; 聂玲; 李璘; 王建祥; 竺晓凡; 肖志坚

    2009-01-01

    本研究探索NQO1C609T,RAD51 G135C和XRCC3C241T单核苷酸多态性与急性淋巴细胞白血病(ALL)发生的关系.对170例ALL患者和458名与患者无血缘关系的正常人,用聚合酶链反应-限制性内切酶片段长度多态性(PCR-RFLP)方法分析其NQO1C609T,RAD51G135C和XRCC3C241T基因型.结果表明:在单基因水平分析时NQO1C609T,RAD51G135C和XRCC3C241T基因型比例在正常对照和ALL患者之间无统计学差异,提示其单独作用时对ALL发病的影响无统计学意义.当3个基因联合分析时,NQO1C609T和RAD51G135C均为变异型时伴髓系抗原阳性的ALL和伴平衡易位ALL的发病风险增加(OR值分别为5.553和2.618);NQO1C609T纯合变异型时农村儿童ALL的发病风险增加(OR值为2.541).结论:NQ01C609T、RAD51G135C和XRCC3C241T基因型联合作用可能促进ALL的发病,提示多基因联合分析较单基因对ALL的发病分析可能更有预测意义.

  18. 某些同源重组修复基因多态性与慢性苯中毒风险性关系研究%Study on the association of Genetic Polymorphism in XRCC2 c.188 and XRCC3c.241 with the risks of chronic benzene poisoning

    Institute of Scientific and Technical Information of China (English)

    张忠彬; 管继如; 叶榕; 顾寿永; 万俊香; 金锡鹏; 夏昭林

    2004-01-01

    目的 探讨X线修复交叉互补基因2(XRCC2)、X线修复交叉互补基因3(XRCC3)的基因多态性与慢性苯中毒发病风险的关系.方法采用病例对照设计,以152名苯中毒工人为病例组,152名接触苯而没有中毒表现的工人为对照组.应用聚合酶链反应-限制性片段长度多态性分析技术(PCR-RFLP)检测XRCC2c.188和XRCC3c.241位点的多态性.结果未检测到XRCC2c.188的突变基因型,XRCC3c.241基因各基因型在病例组和对照组间的分布差异无显著性.结论 XRCC2c.188和XRCC3c.241位点的多态性与慢性苯中毒的发病风险没有关系,它们其他位点的多态与慢性苯中毒易感性的关系需进一步研究确证.

  19. hOGG1、XRCC1、XRCC3基因单核苷酸多态性与食管癌放疗预后关系的研究

    Institute of Scientific and Technical Information of China (English)

    张瑾熔; 张旭升; 王义海; 阿合力·那斯肉拉; 吕茵; 张国庆

    2011-01-01

    食管癌是世界上最常见的恶性肿瘤之一,其发病率高,预后差,死亡率居癌症第6位[1],其病理类型90%以上为鳞状细胞癌,对射线较敏感,放射治疗在食管癌综合治疗中占重要地位.然而单纯放疗后5年生存率10%~30%,局部复发高达60%~80%.如何通过分子生物学手段达到改善食管癌的疗效及提高食管癌的预后已经成为目前研究的主要方向.hOGG1、XRCC1、XRCC3是DNA损伤修复的重要基因,这些基因的单核苷酸多态性可以改变修复蛋白的功能进一步改变DNA损伤修复能力,在肿瘤的发生、发展及治疗过程中发挥重要作用.本研究采用PCR-RFLP法研究hOGG1、XRCC1、XRCC3基因单核苷酸多态性与食管癌放射治疗预后的关系,旨在为食管癌治疗方案的选择提供参考依据.

  20. Polymorphisms in DNA Repair Genes and Susceptibility to Glioma in a Chinese Population

    Directory of Open Access Journals (Sweden)

    Jun-Hong Guan

    2013-02-01

    Full Text Available The excision repair cross-complementing rodent repair deficiency complementation group 1 (ERCC1, and X-ray repair cross-complementing group 1 (XRCC1 genes appear to protect mammalian cells from the harmful effects of ionizing radiation. We conducted a large case-control study to investigate the association of polymorphisms in ERCC1 C118T, ERCC1 C8092A, XRCC1 A194T, XRCC1 A194T, and XRCC3 C241T, with glioma risk in a Chinese population. Five single nucleotide polymorphisms (SNPs were genotyped, using the MassARRAY IPLEX platform, in 443 glioma cases and 443 controls. Association analyses based on an χ2 test and binary logistic regression were performed to determine the odds ratio (OR and a 95% confidence interval (95% CI for each SNP. For XRCC1 Arg194Trp, the variant genotype T/T was strongly associated with a lower risk of glioma cancer when compared with the wild type C/C (OR = 2.45, 95% CI = 1.43–4.45. Individuals carrying the XRCC1 399A allele had an increased risk of glioma (OR = 1.33, 95% CI = 1.02–1.64. The XRCC3 241T/T genotype was associated with a strong increased glioma risk (OR = 3.78, 95% CI = 1.86–9.06. Further analysis of the interactions of two susceptibility-associated SNPs, XRCC1 Arg194Trp and XRCC3 Thr241Met, showed that the combination of the XRCC1 194T and XRCC3 241T alleles brought a large increase in glioma risk (OR = 2.75, 95% CI = 1.54–4.04. XRCC1 Arg194Trp, XRCC1 Arg399Gln, and XRCC3 C241T, appear to be associated with susceptibility to glioma in a Chinese population.

  1. Correlations between clinical normal tissue radiosensitivity and single nucleotide polymorphisms in ATM, XRCC1, XRCC3, APEX, SOD2, and TGF-B1

    DEFF Research Database (Denmark)

    Alsner, Jan; Andreassen, Christian Nicolaj; Overgaard, Marie

    Cancer patients exhibit large patient-to-patient variability in normal tissue reactions after radiotherapy. Several observations indicate that the variation in normal tissue sensitivity is influenced by genetic factors. However, little is known about the genetic variations underlying inter......-individual differences when unselected cancer patients undergo radiotherapy. To address the genetic basis of variations in radiation-induced normal tissue reactions, different lines of experiments can be pursued. We are using a 'candidate gene approach' where we analyse subsets of genetic variants in genes involved...... in biological pathways suspected to underlie phenotypes of interest. These variants can be either common alterations like single nucleotide polymorphisms, SNPs, or rare variants in potential susceptibility loci like ATM. In parallel, we are using microarray analysis on normal fibroblasts isolated from patients...

  2. ERCC1和XRCC3基因多态性在接受含铂方案化疗NSCLC中的疗效预测作用%Predictive Role of ERCC1 and XRCC3 Gene Polymorphism on Response of Platinum-based Chemotherapy in Advanced NSCLC

    Institute of Scientific and Technical Information of China (English)

    任胜祥; 周彩存; 周崧雯; 张玲; 苏春霞; 张增利; 邓沁芳; 张颉

    2009-01-01

    型C/T或T/T患者的生存时间显著延长(P=0.003).Cox多因素分析显示,ERCC1 118基困型C/T或T/T以及化疗有效患者的生存期显著延长.[结论]DNA修复基冈ERCC1 118基凶型C/T或T/T多态性可以延长NSCLC患者铂类治疗后的生存时间.

  3. DNA repair gene polymorphisms in relation to chromosome aberration frequencies in retired radiation workers

    Energy Technology Data Exchange (ETDEWEB)

    Wilding, Craig S. [Genetics Department, Westlakes Research Institute, Westlakes Science and Technology Park, Moor Row, Cumbria CA24 3JY (United Kingdom)]. E-mail: craig.wilding@westlakes.ac.uk; Relton, Caroline L. [Genetics Department, Westlakes Research Institute, Westlakes Science and Technology Park, Moor Row, Cumbria CA24 3JY (United Kingdom); Paediatric and Lifecourse Epidemiology Research Group, School of Clinical Medical Sciences (Child Health), Newcastle University, Sir James Spence Institute, Royal Victoria Infirmary, Newcastle-upon-Tyne NE1 4LP (United Kingdom); Rees, Gwen S. [Genetics Department, Westlakes Research Institute, Westlakes Science and Technology Park, Moor Row, Cumbria CA24 3JY (United Kingdom); Tarone, Robert E. [International Epidemiology Institute, 1455 Research Boulevard, Suite 550, Rockville, MD 20850 (United States); Whitehouse, Caroline A. [Genetics Department, Westlakes Research Institute, Westlakes Science and Technology Park, Moor Row, Cumbria CA24 3JY (United Kingdom); Tawn, E. Janet [Genetics Department, Westlakes Research Institute, Westlakes Science and Technology Park, Moor Row, Cumbria CA24 3JY (United Kingdom)

    2005-02-15

    Polymorphic variation in DNA repair genes was examined in a group of retired workers from the British Nuclear Fuels plc facility at Sellafield in relation to previously determined translocation frequencies in peripheral blood lymphocytes. Variation at seven polymorphisms in four genes involved in the base excision repair (XRCC1 R194W, R399Q and a [AC]{sub n} microsatellite in the 3' UTR) and double strand break repair (XRCC3 T241M and a [AC]{sub n} microsatellite in intron 3 of XRCC3, XRCC4 I134T, and a GACTAn microsatellite located 120kb 5' of XRCC5) pathways was determined for 291 retired radiation workers who had received cumulative occupational external radiation doses of between 0 and 1873mSv. When the interaction between radiation dose and each DNA repair gene polymorphism was examined in relation to translocation frequency there was no evidence for any of the polymorphisms studied influencing the response to occupational exposure. A positive interaction observed between genotype (individuals with at least one allele >=20 repeat units) at a microsatellite locus in the XRCC3 gene and smoking status should be interpreted cautiously because interactions were investigated for seven polymorphisms and two exposures. Nonetheless, further research is warranted to examine whether this DNA repair gene variant might be associated with a sub-optimal repair response to smoking-induced DNA damage and hence an increased frequency of translocations.

  4. Chromosomal Aberrations and DNA Repair Gene Variants in a Radon-exposed Population

    Energy Technology Data Exchange (ETDEWEB)

    Kiuru, A.; Lindholm, C.; Koivistoinen, A.; Salomaa, S.

    2004-07-01

    Polymorphisms of XRCC1 (X-ray repair cross-complementing group 1), XRCC3 (X-ray repair cross-complementing group 3), and hOGG1 (the human homologue of the yeast OGG1 gene) DNA repair genes have been associated with altered DNA repair capacity and risk of various cancers. In the present study our goal was to clarify the influence of various DNA repair gene variants on the frequency of chromosomal aberrations (CA) in subjects exposed to residential radon. The study group of 84 non-smoking, healthy individuals exposed to domestic radon were analysed using the fluorescence in-situ hybridization (FISH) technique. No association between radon concentration and CA frequencies was observed. However, a significant increase with age was shown as well as a large variability in translocation frequencies between individuals within the same age group. In order to investigate the role of individual susceptibility to this variation genotypes of DNA repair genes XRCC1 (codons 194, 280 and 399), XRCC3 (codon 241) and hOGG1 (codon 326) were determined from leukocyte DNA using methods based on polymerase chain reaction. Multiple regression analysis was applied to evaluate the effect of the polymorphisms and the other confounding factors (age, exposure to randon etc) to the frequency of CA. The preliminary statistical analyses showed that the different gene appeared not to be related to a pronounced increase in chromosome aberration frequencies observed by FISH painting. However, the analysis indicated that the homozygous variant of XRCC3 codon 241 was associated (P<0.05) with two-ways translocations in conjunction with age. Larger studies, both with regard to the cohort and the number of gene variants are needed to elucidate the influence of other DNA repair variants to the yield of chromosomal aberrations. The results indicate that the chromosomal translocations accumulated by age (spontaneous background) may be partly explained by defects in homologous recombination repair. (Author

  5. Risk of radiation-induced subcutaneous fibrosis in relation to single nucleotide polymorphisms in TGFB1, SOD2, XRCC1, XRCC3, APEX and ATM - a study based on DNA from formalin fixed paraffin embedded tissue samples

    DEFF Research Database (Denmark)

    Andreassen, Christian Nicolaj; Alsner, Jan; Overgaard, Marie

    2006-01-01

    -complementing 3 gene), SOD2 (manganese superoxide dismutase gene) and ATM (gene of ataxia telangiectasia mutated). The present study was conducted to seek a confirmation of these findings.Materials and methods: Like the 41 patients previously investigated, the 120 subjects included in the present study were...

  6. Determination of the frequency of polymorphisms in genes related to the genome stability maintenance of the population residing at Monte Alegre, PA (Brazil) municipality; Determinacao da frequencia de polimorfismos em genes relacionados a manutencao da estabilidade do genoma na populacao residente no municipio de Monte Alegre, PA

    Energy Technology Data Exchange (ETDEWEB)

    Hozumi, Cristiny Gomes

    2010-07-01

    The human exposure to ionizing radiation coming from natural sources is an inherent feature of human life on earth, for man and all living things have always been exposed to these sources. Ionizing radiation is a known genotoxic agent which can affect the genomic stability and genes related to DNA repair may play a role when they have committed certain polymorphism. This study aimed to analyze the frequency of polymorphisms (SNPs) in genes of DNA repair and cell cycle control: hOGG1 (Ser326Cys), XRCC3 (Thr241 Met) and p53 (Arg72Pro) in saliva samples from a population located Monte Alegre, state of Para were collected in August 2008 and 40 samples of men and 46 samples of women, adding a total of 86 samples. By RFLP was determined the frequency of homozygous genotypes and / or heterozygous for polymorphic genes. The I)OGG1 gene was 5% of the allele 326Cys, XRCC3 gene found about 21 % of the allele 241 Met and p53 gene showed 40.8% of the 72Pro allele. And the genotype frequencies of individuals for the three genes were 91.04%, 88.06% and 59.7% for homozygous wild genotype, 5.97%, 11.94% and 22.39% for heterozygote genotype and 2,99%, zero and 17:91% for homozygous polymorphic hOGG1 genes respectively, XRCC3, p53. These values are similar to those found in previous studies. The influence of these polymorphisms, which are involved in DNA repair and consequent genotoxicity induced by radiation depends on dose and exposure factors such as smoking, which is statistically a factor in public health surveillance in the region. This study gathered information and molecular epidemiology in Monte Alegre, that help to characterization of local population. (author)

  7. Arabidopsis RAD51C gene is important for homologous recombination in meiosis and mitosis.

    Science.gov (United States)

    Abe, Kiyomi; Osakabe, Keishi; Nakayama, Shigeki; Endo, Masaki; Tagiri, Akemi; Todoriki, Setsuko; Ichikawa, Hiroaki; Toki, Seiichi

    2005-10-01

    Rad51 is a homolog of the bacterial RecA recombinase, and a key factor in homologous recombination in eukaryotes. Rad51 paralogs have been identified from yeast to vertebrates. Rad51 paralogs are thought to play an important role in the assembly or stabilization of Rad51 that promotes homologous pairing and strand exchange reactions. We previously characterized two RAD51 paralogous genes in Arabidopsis (Arabidopsis thaliana) named AtRAD51C and AtXRCC3, which are homologs of human RAD51C and XRCC3, respectively, and described the interaction of their products in a yeast two-hybrid system. Recent studies showed the involvement of AtXrcc3 in DNA repair and functional role in meiosis. To determine the role of RAD51C in meiotic and mitotic recombination in higher plants, we characterized a T-DNA insertion mutant of AtRAD51C. Although the atrad51C mutant grew normally during vegetative developmental stage, the mutant produced aborted siliques, and their anthers did not contain mature pollen grains. Crossing of the mutant with wild-type plants showed defective male and female gametogeneses as evidenced by lack of seed production. Furthermore, meiosis was severely disturbed in the mutant. The atrad51C mutant also showed increased sensitivity to gamma-irradiation and cisplatin, which are known to induce double-strand DNA breaks. The efficiency of homologous recombination in somatic cells in the mutant was markedly reduced relative to that in wild-type plants.

  8. Micronuclei in humans induced by exposure to low level of ionizing radiation: influence of polymorphisms in DNA repair genes

    Energy Technology Data Exchange (ETDEWEB)

    Angelini, Sabrina [Department of Pharmacology, University of Bologna, Via Irnerio 48, Bologna 40126 (Italy) and Department of Biosciences, Karolinska Institute, Novum, Huddinge 141 57 (Sweden)]. E-mail: angelini@biocfarm.unibo.it; Kumar, Rajiv [Department of Biosciences, Karolinska Institute, Novum, Huddinge 141 57 (Sweden); Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg (Germany); Carbone, Fabio [Department of Pharmacology, University of Bologna, Via Irnerio 48, Bologna 40126 (Italy); Maffei, Francesca [Department of Pharmacology, University of Bologna, Via Irnerio 48, Bologna 40126 (Italy); Forti, Giorgio Cantelli [Department of Pharmacology, University of Bologna, Via Irnerio 48, Bologna 40126 (Italy); Violante, Francesco Saverio [Department of Biosciences, Karolinska Institute, Novum, Huddinge 141 57 (Sweden); Occupational Medicine Unit, S. Orsola-Malpighi Hospital, Via Pelagi 9, Bologna 40100 (Italy); Lodi, Vittorio [Department of Biosciences, Karolinska Institute, Novum, Huddinge 141 57 (Sweden); Curti, Stefania [Department of Biosciences, Karolinska Institute, Novum, Huddinge 141 57 (Sweden); Hemminki, Kari [Department of Biosciences, Karolinska Institute, Novum, Huddinge 141 57 (Sweden); Hrelia, Patrizia [Department of Pharmacology, University of Bologna, Via Irnerio 48, Bologna 40126 (Italy)

    2005-02-15

    Understanding the risks deriving from protracted exposure to low doses of ionizing radiation has remarkable societal importance in view of the large number of work settings in which sources of IR are encountered. To address this question, we studied the frequency of micronuclei (MN), which is an indicator of DNA damage, in a population exposed to low levels of ionizing radiation and in matched controls. In both exposed population and controls, the possible influence of single nucleotide polymorphisms in XRCC1, XRCC3 and XPD genes on the frequency of micronuclei was also evaluated. We also considered the effects of confounding factors, like smoking status, age and gender. The results indicated that MN frequency was significantly higher in the exposed workers than in the controls [8.62 {+-} 2.80 versus 6.86 {+-} 2.65; P = 0.019]. Radiological workers with variant alleles for XRCC1 or XRCC3 polymorphisms or wild-type alleles for XPD exon 23 or 10 polymorphisms showed a significantly higher MN frequency than controls with the same genotypes. Smoking status did not affect micronuclei frequency either in exposed workers or controls, while age was associated with increased MN frequency in the exposed only. In the combined population, gender but not age exerted an influence on the yield of MN, being higher in females than in males. Even though there is a limitation in this study due to the small number of subjects, these results suggest that even exposures to low level of ionizing radiation could have genotoxic effects and that XRCC3, XRCC1 and XPD polymorphisms might contribute to the increased genetic damage in susceptible individuals occupationally exposed to chronic low levels of ionizing radiation. For a clear conclusion on the induction of DNA damage caused by protracted exposure to low doses of ionizing radiation and the possible influence of genetic polymorphism in DNA repair genes larger studies are needed.

  9. Haplotype analyses of DNA repair gene polymorphisms and their role in ulcerative colitis.

    Directory of Open Access Journals (Sweden)

    Avinash Bardia

    Full Text Available Ulcerative colitis (UC is a major clinical form of inflammatory bowel disease. UC is characterized by mucosal inflammation limited to the colon, always involving the rectum and a variable extent of the more proximal colon in a continuous manner. Genetic variations in DNA repair genes may influence the extent of repair functions, DNA damage, and thus the manifestations of UC. This study thus evaluated the role of polymorphisms of the genes involved in DNA repair mechanisms. A total of 171 patients and 213 controls were included. Genotyping was carried out by ARMS PCR and PCR-RFLP analyses for RAD51, XRCC3 and hMSH2 gene polymorphisms. Allelic and genotypic frequencies were computed in both control & patient groups and data was analyzed using appropriate statistical tests. The frequency of 'A' allele of hMSH2 in the UC group caused statistically significant increased risk for UC compared to controls (OR 1.64, 95% CI 1.16-2.31, p = 0.004. Similarly, the CT genotype of XRCC3 gene was predominant in the UC group and increased the risk for UC by 1.75 fold compared to controls (OR 1.75, 95% CI 1.15-2.67, p = 0.03, further confirming the risk of 'T' allele in UC. The GC genotype frequency of RAD51 gene was significantly increased (p = 0.02 in the UC group (50.3% compared to controls (38%. The GC genotype significantly increased the risk for UC compared to GG genotype by 1.73 fold (OR 1.73, 95% CI 1.14-2.62, p = 0.02 confirming the strong association of 'C' allele with UC. Among the controls, the SNP loci combination of hMSH2:XRCC3 were in perfect linkage. The GTC and ACC haplotypes were found to be predominant in UC than controls with a 2.28 and 2.93 fold significant increase risk of UC.

  10. DNA Repair Gene Polymorphisms in the Nucleotide Excision Repair Pathway and Lung Cancer Risk: A Meta-analysis

    Institute of Scientific and Technical Information of China (English)

    Chao-rong Mei; Meng Luo; Hong-mei Li; Wen-jun Deng; Qing-hua Zhou

    2011-01-01

    Objective: A number of studies have reported the association of “XPA”, “XPC”, “XPD/ERCC2gene polymorphisms with lung cancer risk. However, the results were conflict. To clarify the impact of polymorphisms of “XPA”, “XPC”; “XPD/ERCC2”, on lung cancer risk, a meta-analysis was performed in this study. Methods: The electronic databases PubMed and Embase were retrieved for studies included in this meta-analysis by “XPA”; “XPC”, “XPD/ERCC2”, “lung”, “cancer/neoplasm/tumor/carcinoma”, “polymorphism” (An upper date limit of October, 31, 2009). A meta-analysis was performed to evaluate the relationship among XPA, XPC and XPD polymorphism and lung cancer risks. Results: A total of 31 publications retrieved from Pubmed and Embase included in this study. XPC A939C CC genotype increased lung cancer risk in total population (recessive genetic model: OR=1.23, 95% Cl:1.05-1.44;homozygote comparison: OR=1.21,95%Cl:1.02-1.43and CC vs. CA contrast: OR=1.25,95%Cl:1.06-1.48), except in Asians. XPD A751C, 751C allele and CC genotype also increased lung cancer risk in total population and in Caucasians (recessive genetic model: Total population: OR=1.20, 95%Cl:1.07-1.35). No significant correlation was found between XPD A751C and lung cancer risk in Asians and African Americans. XPD G312A AA genotype increased lung cancer risk in total population, in Asians and Caucasians(recessive genetic model: Total population: OR=1.20, 95%Cl:1.06-1.36). No significant association was found between XPA G23A, XPC C499T, XPD C156A and lung cancer risk. Conclusion: Our results suggest that the polymorphisms in XPC and XPD involve in lung cancer risks. XPA polymorphisms is less related to lung cancer risk.

  11. Expression analyses of multiple DNA repair genes in glioma by TaqMan low-density array%TaqMan低密度表达芯片检测DNA损伤修复基因在原发胶质瘤中的表达研究

    Institute of Scientific and Technical Information of China (English)

    姜政; 胡锦; 李新钢; 卢大儒; 江玉泉; 周伟

    2007-01-01

    目的 运用低密度表达谱芯片检测人脑原发胶质瘤组织中DNA损伤修复基因的表达情况,进一步分析其表达变化的意义.方法 使用TaqMan低密度表达芯片技术检测27个DNA损伤修复基因在40例不同级别原发胶质瘤组织和10例正常脑组织中的表达情况,并通过统计学分析其在不同级别胶质瘤和正常脑组织中的表达差异.结果 与正常脑组织相比较,有13个DNA损伤修复基因在Ⅱ、Ⅲ、Ⅳ级胶质瘤中均表达下调,包括ERCC1、ERCC2、ERCC3、ERCC4、MGMT、MLH1、MLH3、NTHL1、OGG1、RAD50、SMUG1、XRCC4、XRCC5(P<0.05).MSH2、MSH6、NUDT1和XRCC3只在Ⅱ级和Ⅲ级胶质瘤中表达下调;MRE11A和MUS81只在Ⅲ级和Ⅳ级胶质瘤中表达下调.PMS2、RAD52和XRCC1只在Ⅲ级胶质瘤中表达下调,而UNG只在Ⅱ级中表达下调.结论 TaqMan低密度表达芯片为多个基因的同时定量表达提供了一种准确、快速、有效的多变量检测技术,可用于发现新的肿瘤相关基因.大量的DNA损伤修复基因的表达下调,与胶质瘤的发生密切相关.

  12. Specific targeted gene repair using single-stranded DNA oligonucleotides at an endogenous locus in mammalian cells uses homologous recombination.

    Science.gov (United States)

    McLachlan, Jennifer; Fernandez, Serena; Helleday, Thomas; Bryant, Helen E

    2009-12-03

    The feasibility of introducing point mutations in vivo using single-stranded DNA oligonucleotides (ssON) has been demonstrated but the efficiency and mechanism remain elusive and potential side effects have not been fully evaluated. Understanding the mechanism behind this potential therapy may help its development. Here, we demonstrate the specific repair of an endogenous non-functional hprt gene by a ssON in mammalian cells, and show that the frequency of such an event is enhanced when cells are in S-phase of the cell cycle. A potential barrier in using ssONs as gene therapy could be non-targeted mutations or gene rearrangements triggered by the ssON. Both the non-specific mutation frequencies and the frequency of gene rearrangements were largely unaffected by ssONs. Furthermore, we find that the introduction of a mutation causing the loss of a functional endogenous hprt gene by a ssON occurred at a similarly low but statistically significant frequency in wild type cells and in cells deficient in single strand break repair, nucleotide excision repair and mismatch repair. However, this mutation was not induced in XRCC3 mutant cells deficient in homologous recombination. Thus, our data suggest ssON-mediated targeted gene repair is more efficient in S-phase and involves homologous recombination.

  13. Polymorphisms in human DNA repair genes and head and neck squamous cell carcinoma

    Indian Academy of Sciences (India)

    Rim Khlifi; Ahmed Rebai; Amel Hamza-Chaffai

    2012-12-01

    Genetic polymorphisms in some DNA repair proteins are associated with a number of malignant transformations like head and neck squamous cell carcinoma (HNSCC). Xeroderma pigmentosum group D (XPD) and X-ray repair cross-complementing proteins 1 (XRCC1) and 3 (XRCC3) genes are involved in DNA repair and were found to be associated with HNSCC in numerous studies. To establish our overall understanding of possible relationships between DNA repair gene polymorphisms and development of HNSCC, we surveyed the literature on epidemiological studies that assessed potential associations with HNSCC risk in terms of gene–environment interactions, genotype-induced functional defects in enzyme activity and/or protein expression, and the influence of ethnic origin on these associations.We conclude that large, well-designed studies of common polymorphisms in DNA repair genes are needed. Such studies may benefit from analysis of multiple genes or polymorphisms and from the consideration of relevant exposures that may influence the likelihood of HNSCC when DNA repair capacity is reduced.

  14. Deficiency in nucleotide excision repair family gene activity, especially ERCC3, is associated with non-pigmented hair fiber growth.

    Directory of Open Access Journals (Sweden)

    Mei Yu

    Full Text Available We conducted a microarray study to discover gene expression patterns associated with a lack of melanogenesis in non-pigmented hair follicles (HF by microarray. Pigmented and non-pigmented HFs were collected and micro-dissected into the hair bulb (HB and the upper hair sheaths (HS including the bulge region. In comparison to pigmented HS and HBs, nucleotide excision repair (NER family genes ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, XPA, NTPBP, HCNP, DDB2 and POLH exhibited statistically significantly lower expression in non- pigmented HS and HBs. Quantitative PCR verified microarray data and identified ERCC3 as highly differentially expressed. Immunohistochemistry confirmed ERCC3 expression in HF melanocytes. A reduction in ERCC3 by siRNA interference in human melanocytes in vitro reduced their tyrosinase production ability. Our results suggest that loss of NER gene function is associated with a loss of melanin production capacity. This may be due to reduced gene transcription and/or reduced DNA repair in melanocytes which may eventually lead to cell death. These results provide novel information with regard to melanogenesis and its regulation.

  15. Xeroderma Pigmentosum-Trichothiodystrophy overlap patient with novel XPD/ERCC2 mutation

    DEFF Research Database (Denmark)

    Kralund, Henrik H; Ousager, Lilian; Jaspers, Nicolaas G

    2013-01-01

    outcome from many of these mutations. We demonstrate a patient, believed to represent an overlap between XP and TTD/CS. In addition to other organ dysfunctions, the young man presented with Photosensitivity, Ichthyosis, Brittle hair, Impaired physical and mental development, Decreased fertility and Short...

  16. Gene

    Data.gov (United States)

    U.S. Department of Health & Human Services — Gene integrates information from a wide range of species. A record may include nomenclature, Reference Sequences (RefSeqs), maps, pathways, variations, phenotypes,...

  17. Are SNP-Smoking Association Studies Needed in Controls? DNA Repair Gene Polymorphisms and Smoking Intensity.

    Science.gov (United States)

    Verde, Zoraida; Reinoso, Luis; Chicharro, Luis Miguel; Resano, Pilar; Sánchez-Hernández, Ignacio; Rodríguez González-Moro, Jose Miguel; Bandrés, Fernando; Gómez-Gallego, Félix; Santiago, Catalina

    2015-01-01

    Variations in tobacco-related cancers, incidence and prevalence reflect differences in tobacco consumption in addition to genetic factors. Besides, genes related to lung cancer risk could be related to smoking behavior. Polymorphisms altering DNA repair capacity may lead to synergistic effects with tobacco carcinogen-induced lung cancer risk. Common problems in genetic association studies, such as presence of gene-by-environment (G x E) correlation in the population, may reduce the validity of these designs. The main purpose of this study was to evaluate the independence assumption for selected SNPs and smoking behaviour in a cohort of 320 healthy Spanish smokers. We found an association between the wild type alleles of XRCC3 Thr241Met or KLC3 Lys751Gln and greater smoking intensity (OR = 12.98, 95% CI = 2.86-58.82 and OR=16.90, 95% CI=2.09-142.8; respectively). Although preliminary, the results of our study provide evidence that genetic variations in DNA-repair genes may influence both smoking habits and the development of lung cancer. Population-specific G x E studies should be carried out when genetic and environmental factors interact to cause the disease.

  18. Are SNP-Smoking Association Studies Needed in Controls? DNA Repair Gene Polymorphisms and Smoking Intensity.

    Directory of Open Access Journals (Sweden)

    Zoraida Verde

    Full Text Available Variations in tobacco-related cancers, incidence and prevalence reflect differences in tobacco consumption in addition to genetic factors. Besides, genes related to lung cancer risk could be related to smoking behavior. Polymorphisms altering DNA repair capacity may lead to synergistic effects with tobacco carcinogen-induced lung cancer risk. Common problems in genetic association studies, such as presence of gene-by-environment (G x E correlation in the population, may reduce the validity of these designs. The main purpose of this study was to evaluate the independence assumption for selected SNPs and smoking behaviour in a cohort of 320 healthy Spanish smokers. We found an association between the wild type alleles of XRCC3 Thr241Met or KLC3 Lys751Gln and greater smoking intensity (OR = 12.98, 95% CI = 2.86-58.82 and OR=16.90, 95% CI=2.09-142.8; respectively. Although preliminary, the results of our study provide evidence that genetic variations in DNA-repair genes may influence both smoking habits and the development of lung cancer. Population-specific G x E studies should be carried out when genetic and environmental factors interact to cause the disease.

  19. Polymorphisms in DNA repair genes, smoking, and bladder cancer risk: findings from the International Consortium of Bladder Cancer

    Science.gov (United States)

    Stern, Mariana C.; Lin, Jie; Figueroa, Jonine D.; Kelsey, Karl T.; Kiltie, Anne E.; Yuan, Jian-Min; Matullo, Giuseppe; Fletcher, Tony; Benhamou, Simone; Taylor, Jack A.; Placidi, Donatella; Zhang, Zuo-Feng; Steineck, Gunnar; Rothman, Nathaniel; Kogevinas, Manolis; Silverman, Debra; Malats, Nuria; Chanock, Stephen; Wu, Xifeng; Karagas, Margaret R.; Andrew, Angeline S.; Nelson, Heather H.; Bishop, D. Timothy; Sak, Sei Chung; Choudhury, Ananya; Barrett, Jennifer H; Elliot, Faye; Corral, Román; Joshi, Amit D.; Gago-Dominguez, Manuela; Cortessis, Victoria K.; Xiang, Yong-Bing; Vineis, Paolo; Sacerdote, Carlotta; Guarrera, Simonetta; Polidoro, Silvia; Allione, Alessandra; Gurzau, Eugen; Koppova, Kvetoslava; Kumar, Rajiv; Rudnai, Peter; Porru, Stefano; Carta, Angela; Campagna, Marcello; Arici, Cecilia; Park, SungShim Lani; Garcia-Closas, Montserrat

    2009-01-01

    Tobacco smoking is the most important and well-established bladder cancer risk factor, and a rich source of chemical carcinogens and reactive oxygen species that can induce damage to DNA in urothelial cells. Therefore, common variation in DNA repair genes might modify bladder cancer risk. In this study we present results from meta- and pooled analyses conducted as part of the International Consortium of Bladder Cancer. We included data on 10 single nucleotide polymorphisms corresponding to 7 DNA repair genes from 13 studies. Pooled- and meta-analyses included 5,282 cases and 5,954 controls of non-Latino white origin. We found evidence for weak but consistent associations with ERCC2 D312N (rs1799793) (per allele OR = 1.10; 95% CI = 1.01–1.19; p = 0.021), NBN E185Q (rs1805794) (per allele OR = 1.09; 95% CI = 1.01–1.18; p = 0.028), and XPC A499V (rs2228000) (per allele OR = 1.10; 95% CI = 1.00–1.21, p = 0.044). The association with NBN E185Q was limited to ever smokers (interaction p = 0.002), and was strongest for the highest levels of smoking dose and smoking duration. Overall, our study provides the strongest evidence to date for a role of common variants in DNA repair genes in bladder carcinogenesis. PMID:19706757

  20. Challenges in biotechnology at LLNL: from genes to proteins

    Energy Technology Data Exchange (ETDEWEB)

    Albala, J S

    1999-03-11

    This effort has undertaken the task of developing a link between the genomics, DNA repair and structural biology efforts within the Biology and Biotechnology Research Program at LLNL. Through the advent of the I.M.A.G.E. (Integrated Molecular Analysis of Genomes and their Expression) Consortium, a world-wide effort to catalog the largest public collection of genes, accepted and maintained within BBRP, it is now possible to systematically express the protein complement of these to further elucidate novel gene function and structure. The work has ensued in four phases, outlined as follows: (1) Gene and System selection; (2) Protein expression and purification; (3) Structural analysis; and (4) biological integration. Proteins to be expressed have been those of high programmatic interest. This includes, in particular, proteins involved in the maintenance of genome integrity, particularly those involved in the repair of DNA damage, including ERCC1, ERCC4, XRCC2, XRCC3, XRCC9, HEX1, APN1, p53, RAD51B, RAD51C, and RAD51. Full-length cDNA cognates of selected genes were isolated, and cloned into baculovirus-based expression vectors. The baculoviral expression system for protein over-expression is now well-established in the Albala laboratory. Procedures have been successfully optimized for full-length cDNA clining into expression vectors for protein expression from recombinant constructs. This includes the reagents, cell lines, techniques necessary for expression of recombinant baculoviral constructs in Spodoptera frugiperda (Sf9) cells. The laboratory has also generated a high-throughput baculoviral expression paradigm for large scale expression and purification of human recombinant proteins amenable to automation.

  1. SNPs in DNA repair or oxidative stress genes and late subcutaneous fibrosis in patients following single shot partial breast irradiation

    Directory of Open Access Journals (Sweden)

    Falvo Elisabetta

    2012-01-01

    Full Text Available Abstract Background The aim of this study was to evaluate the potential association between single nucleotide polymorphisms related response to radiotherapy injury, such as genes related to DNA repair or enzymes involved in anti-oxidative activities. The paper aims to identify marker genes able to predict an increased risk of late toxicity studying our group of patients who underwent a Single Shot 3D-CRT PBI (SSPBI after BCS (breast conserving surgery. Methods A total of 57 breast cancer patients who underwent SSPBI were genotyped for SNPs (single nucleotide polymorphisms in XRCC1, XRCC3, GST and RAD51 by Pyrosequencing technology. Univariate analysis (ORs and 95% CI was performed to correlate SNPs with the risk of developing ≥ G2 fibrosis or fat necrosis. Results A higher significant risk of developing ≥ G2 fibrosis or fat necrosis in patients with: polymorphic variant GSTP1 (Ile105Val (OR = 2.9; 95%CI, 0.88-10.14, p = 0.047. Conclusions The presence of some SNPs involved in DNA repair or response to oxidative stress seem to be able to predict late toxicity. Trial Registration ClinicalTrials.gov: NCT01316328

  2. Gene Polymorphisms and Chemotherapy in Non-small Cell Lung Cancer

    Institute of Scientific and Technical Information of China (English)

    Kayo OSAWA

    2009-01-01

    The phamacogenetics is being used to predict whether the selected chemotherapy will be really effective and tolerable to the patient. Irinotecan, oxidized by CYP3A4 to produce inactive compounds, is used for treatment of various cancers including advanced non small cell lung cancer (NSCLC) patients. CYP3A4*16B polymorphism was associated with decreased metabolism ofirrinotecan. Irinotecan is also metabolized by carboxylesterase to its principal active metabolite, SN-38, which is subsequently glucuronidated by UGT1As to form the inactive compound SN-38G. UGT1A1*28 and UGT1A1*6 polymorphisms were useful for predicting severe toxicity with NSCLC patients treated with irinotecan-based chemotherapy. Platinum-based compounds (cisplatin, carboplatin) are being used in combination with new cytotoxic drugs such as gemcitabine, paclitaxel, docetaxel, or vinorelbine in the treatment of advanced NSCLC. Cisplatin activity is mediated through the formation of cisplatin-DNA adducts. Gene polymorphisms of DNA repair factors are therefore obvious candidates for determinants of repair capacity and chemotherapy efficacy. ERCC1, XRCC1 and XRCC3 gene polymorphisms were a useful marker for predicting better survival in advanced NSCLC patients treated with platinum-based chemotherapy. XPA and XPD polymorphisms significantly increased response to platinum-based chemotherapy. These DNA repair gene polymorphisms were useful as a predictor of clinical outcome to the platinum-based chemotherapy. EGFR kinase inhibitors induce dramatic clinical responses in NSCLC patients with advanced disease. EGFR gene polymorphism in intron 1 contains a polymorphic single sequence dinudeotide repeat (CA-SSR) showed a statistically significant correlation with the gefitinib response and was appeared to be a useful predictive marker of the development of clinical outcome containing skin rashes with gefitinib treatment. The other polymorphisms of EGFR were also associated with increased EGFR promoter activity

  3. Gene Polymorphisms and Chemotherapy in Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Kayo OSAWA

    2009-08-01

    Full Text Available The phamacogenetics is being used to predict whether the selected chemotherapy will be really effective and tolerable to the patient. Irinotecan, oxidized by CYP3A4 to produce inactive compounds, is used for treatment of various cancers including advanced non small cell lung cancer (NSCLC patients. CYP3A4*16B polymorphism was associated with decreased metabolism of irrinotecan. Irinotecan is also metabolized by carboxylesterase to its principal active metabolite, SN-38, which is subsequently glucuronidated by UGT1As to form the inactive compound SN-38G. UGT1A1*28 and UGT1A1*6 polymorphisms were useful for predicting severe toxicity with NSCLC patients treated with irinotecan-based chemotherapy. Platinum-based compounds (cisplatin, carboplatin are being used in combination with new cytotoxic drugs such as gemcitabine, paclitaxel, docetaxel, or vinorelbine in the treatment of advanced NSCLC. Cisplatin activity is mediated through the formation of cisplatin-DNA adducts. Gene polymorphisms of DNA repair factors are therefore obvious candidates for determinants of repair capacity and chemotherapy efficacy. ERCC1, XRCC1 and XRCC3 gene polymorphisms were a useful marker for predicting better survival in advanced NSCLC patients treated with platinum-based chemotherapy. XPA and XPD polymorphisms significantly increased response to platinum-based chemotherapy. These DNA repair gene polymorphisms were useful as a predictor of clinical outcome to the platinum-based chemotherapy. EGFR kinase inhibitors induce dramatic clinical responses in NSCLC patients with advanced disease. EGFR gene polymorphism in intron 1 contains a polymorphic single sequence dinucleotide repeat (CA-SSR showed a statistically significant correlation with the gefitinib response and was appeared to be a useful predictive marker of the development of clinical outcome containing skin rashes with gefitinib treatment. The other polymorphisms of EGFR were also associated with increased EGFR

  4. Assessment of single nucleotide polymorphisms in screening 52 DNA repair and cell cycle control genes in Fanconi anemia patients

    Directory of Open Access Journals (Sweden)

    Petrović Sandra

    2015-01-01

    Full Text Available Fanconi anemia (FA is a rare genetically heterogeneous disorder associated with bone marrow failure, birth defects and cancer susceptibility. Apart from the disease- causing mutations in FANC genes, the identification of specific DNA variations, such as single nucleotide polymorphisms (SNPs, in other candidate genes may lead to a better clinical description of this condition enabling individualized treatment with improvement of the prognosis. In this study, we have assessed 95 SNPs located in 52 key genes involved in base excision repair (BER, nucleotide excision repair (NER, mismatch repair (MMR, double strand break (DSB repair and cell cycle control using a DNA repair chip (Asper Biotech, Estonia which includes most of the common variants for the candidate genes. The SNP genotyping was performed in five FA-D2 patients and in one FA-A patient. The polymorphisms studied were synonymous (n=10, nonsynonymous (missense (n=52 and in non-coding regions of the genome (introns and 5 ‘and 3’ untranslated regions (UTR (n=33. Polymorphisms found at the homozygous state are selected for further analysis. Our results have shown a significant inter-individual variability among patients in the type and the frequency of SNPs and also elucidate the need for further studies of polymorphisms located in ATM, APEX APE 1, XRCC1, ERCC2, MSH3, PARP4, NBS1, BARD1, CDKN1B, TP53 and TP53BP1 which may be of great importance for better clinical description of FA. In addition, the present report recommends the use of SNPs as predictive and prognostic genetic markers to individualize therapy of FA patients. [Projekat Ministarstva nauke Republike Srbije, br. 173046

  5. RAD25 (SSL2), the yeast homolog of the human xeroderma pigmentosum group B DNA repair gene, is essential for viability

    Energy Technology Data Exchange (ETDEWEB)

    Park, E.; Prakash, L. (Univ. of Rochester School of Medicine, NY (United States)); Guzder, S.N.; Prakash, S. (Univ. of Rochester, NY (United States)); Koken, M.H.M.; Jaspers-Dekker, I.; Weeda, G.; Hoeijmakers, H.J. (Erasmus Univ., Rotterdam (Netherlands))

    1992-12-01

    Xeroderma pigmentosum (XP) patients are extremely sensitive to ultraviolet (UV) light and suffer from a high incidence of skin cancers, due to a defect in nucleotide excision repair. The disease is genetically heterogeneous, and seven complementation groups, A-G, have been identified. Homologs of human excision repair genes ERCC1, XPDC/ERCC2, and XPAC have been identified in the yeast Saccharomyces cerevisiae. Since no homolog of human XPBC/ERCC3 existed among the known yeast genes, we cloned the yeast homolog by using XPBC cDNA as a hybridization probe. The yeast homolog, RAD25 (SSL2), encodes a protein of 843 amino acids (M[sub r] 95,356). The RAD25 (SSL2)- and XPCX-encoded proteins share 55% identical and 72% conserved amino acid residues, and the two proteins resemble one another in containing the conserved DNA helicase sequence motifs. A nonsense mutation at codon 799 that deletes the 45 C-terminal amino acid residues in RAD25 (SSL2) confers UV sensitivity. This mutation shows epistasis with genes in the excision repair group, whereas a synergistic increase in UN sensitivity occurs when it is combined with mutations in genes in other DNA repair pathways, indicating that RAD25 (SSL2) functions in excision repair but not in other repair pathways. We also show that RAD25 (SSL2) is an essential gene. A mutation of the Lys[sup 392] residue to arginine in the conserved Walker type A nucleotide-binding motif is lethal, suggesting an essential role of the putative RAD 25 (SSL2) ATPase/DNA helicase activity in viability. 40 refs., 3 figs., 1 tab.

  6. Polymorphisms of homologous recombination genes and clinical outcomes of non-small cell lung cancer patients treated with definitive radiotherapy.

    Directory of Open Access Journals (Sweden)

    Ming Yin

    Full Text Available The repair of DNA double-strand breaks (DSBs is the major mechanism to maintain genomic stability in response to irradiation. We hypothesized that genetic polymorphisms in DSB repair genes may affect clinical outcomes among non-small cell lung cancer (NSCLC patients treated with definitive radio(chemotherapy. We genotyped six potentially functional single nucleotide polymorphisms (SNPs (i.e., RAD51 -135G>C/rs1801320 and -172G>T/rs1801321, XRCC2 4234G>C/rs3218384 and R188H/rs3218536 G>A, XRCC3 T241M/rs861539 and NBN E185Q/rs1805794 and estimated their associations with overall survival (OS and radiation pneumonitis (RP in 228 NSCLC patients. We found a predictive role of RAD51 -135G>C SNP in RP development (adjusted hazard ratio [HR] = 0.52, 95% confidence interval [CI], 0.31-0.86, P = 0.010 for CG/CC vs. GG. We also found that RAD51 -135G>C and XRCC2 R188H SNPs were independent prognostic factors for overall survival (adjusted HR = 1.70, 95% CI, 1.14-2.62, P = 0.009 for CG/CC vs. GG; and adjusted HR = 1.70; 95% CI, 1.02-2.85, P = 0.043 for AG vs. GG, respectively and that the SNP-survival association was most pronounced in the presence of RP. Our study suggests that HR genetic polymorphisms, particularly RAD51 -135G>C, may influence overall survival and radiation pneumonitis in NSCLC patients treated with definitive radio(chemotherapy. Large studies are needed to confirm our findings.

  7. The Effect of Polymorphisms in DNA Repair Genes and Carcinogen Metabolizers on Leukocyte Telomere Length: A Cohort of Healthy Spanish Smokers.

    Science.gov (United States)

    Verde, Zoraida; Reinoso-Barbero, Luis; Chicharro, Luis; Resano, Pilar; Sánchez-Hernández, Ignacio; Rodríguez González-Moro, Jose Miguel; Bandrés, Fernando; Gómez-Gallego, Félix; Santiago, Catalina

    2016-04-01

    Smoking implies exposure to carcinogenic agents that causes DNA damage, which could be suspected to enhance telomere attrition. To protect and deal with DNA damage, cells possess mechanisms that repair and neutralize harmful substances. Polymorphisms altering DNA repair capacity or carcinogen metabolism may lead to synergistic effects with tobacco carcinogen-induced shorter telomere length independently of cancer interaction. The aim of this study was to explore the association between leukocyte telomere length (LTL) and several genetic polymorphisms in DNA repair genes and carcinogen metabolizers in a cohort of healthy smokers. We evaluated the effect of six genetic polymorphisms in cytochrome P1A1 (Ile462Val), XRCC1 (Arg399Gln), APEX1 (Asp148Glu), XRCC3 (Thr241Met), and XPD (Asp312Asn; Lys751Gln) on LTL in a cohort of 145 healthy smokers in addition to smoking habits. Logistic regression analysis showed an association between XRCC1 399Gln allele and shorter telomere length (OR = 5.03, 95% CI = 1.08% to 23.36%). There were not association between the rest of polymorphisms analyzed and LTL. Continuous exposure to tobacco could overwhelm the DNA repair machinery, making the effect of the polymorphisms that reduce repair capacity more pronounced. Analyzing the function of smoking-induced DNA-repair genes and LTL is an important goal in order to identify therapeutic targets to treat smoking-induced diseases. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  8. Polymorphisms in DNA-repair genes in a cohort of prostate cancer patients from different areas in Spain: heterogeneity between populations as a confounding factor in association studies.

    Directory of Open Access Journals (Sweden)

    Luis Alberto Henríquez-Hernández

    Full Text Available BACKGROUND: Differences in the distribution of genotypes between individuals of the same ethnicity are an important confounder factor commonly undervalued in typical association studies conducted in radiogenomics. OBJECTIVE: To evaluate the genotypic distribution of SNPs in a wide set of Spanish prostate cancer patients for determine the homogeneity of the population and to disclose potential bias. DESIGN SETTING AND PARTICIPANTS: A total of 601 prostate cancer patients from Andalusia, Basque Country, Canary and Catalonia were genotyped for 10 SNPs located in 6 different genes associated to DNA repair: XRCC1 (rs25487, rs25489, rs1799782, ERCC2 (rs13181, ERCC1 (rs11615, LIG4 (rs1805388, rs1805386, ATM (rs17503908, rs1800057 and P53 (rs1042522. The SNP genotyping was made in a Biotrove OpenArray® NT Cycler. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Comparisons of genotypic and allelic frequencies among populations, as well as haplotype analyses were determined using the web-based environment SNPator. Principal component analysis was made using the SnpMatrix and XSnpMatrix classes and methods implemented as an R package. Non-supervised hierarchical cluster of SNP was made using MultiExperiment Viewer. RESULTS AND LIMITATIONS: We observed that genotype distribution of 4 out 10 SNPs was statistically different among the studied populations, showing the greatest differences between Andalusia and Catalonia. These observations were confirmed in cluster analysis, principal component analysis and in the differential distribution of haplotypes among the populations. Because tumor characteristics have not been taken into account, it is possible that some polymorphisms may influence tumor characteristics in the same way that it may pose a risk factor for other disease characteristics. CONCLUSION: Differences in distribution of genotypes within different populations of the same ethnicity could be an important confounding factor responsible for the lack

  9. Genes and Gene Therapy

    Science.gov (United States)

    ... correctly, a child can have a genetic disorder. Gene therapy is an experimental technique that uses genes to ... or prevent disease. The most common form of gene therapy involves inserting a normal gene to replace an ...

  10. The relationship between seven common polymorphisms from five DNA repair genes and the risk for breast cancer in northern Chinese women.

    Directory of Open Access Journals (Sweden)

    Peijian Ding

    Full Text Available BACKGROUND: Converging evidence supports the central role of DNA damage in progression to breast cancer. We therefore in this study aimed to assess the potential interactions of seven common polymorphisms from five DNA repair genes (XRCC1, XRCC2, XRCC3, XPA and APEX1 in association with breast cancer among Han Chinese women. METHODOLOGY/PRINCIPAL FINDINGS: This was a case-control study involving 606 patients diagnosed with sporadic breast cancer and 633 age- and ethnicity-matched cancer-free controls. The polymerase chain reaction-ligase detection reaction method was used to determine genotypes. All seven polymorphisms were in accordance with Hardy-Weinberg equilibrium in controls. Differences in the genotypes and alleles of XRCC1 gene rs25487 and XPA gene rs1800975 were statistically significant between patients and controls, even after the Bonferroni correction (P<0.05/7. Accordingly, the risk for breast cancer was remarkably increased for rs25487 (OR = 1.28; 95% CI: 1.07-1.51; P = 0.006, but decreased for rs1800975 (OR = 0.77; 95% CI: 0.67-0.90; P = 0.001 under an additive model at a Bonferroni corrected alpha of 0.05/7. Allele combination analysis showed higher frequencies of the most common combination C-G-G-C-G-G-G (alleles in order of rs1799782, rs25487, rs3218536, rs861539, rs1800975, rs1760944 and rs1130409 in controls than in patients (PSim = 0.002. In further interaction analysis, two-locus model including rs1800975 and rs25487 was deemed as the overall best model with the maximal testing accuracy of 0.654 and the cross-validation consistency of 10 out of 10 (P = 0.001. CONCLUSION: Our findings provide clear evidence that XRCC1 gene rs25487 and XPA gene rs1800975 might exert both independent and interactive effects on the development of breast cancer among northern Chinese women.

  11. ATM Heterozygosity and the Development of Radiation-Induced Erectile Dysfunction and Urinary Morbidity Following Radiotherapy for Prostate Cancer

    Science.gov (United States)

    2009-02-01

    Lindgren, H. Hjalgrim, K. Humphreys , C. Schöllkopf, E. T. Chang, G. Roos, L. P. Ryder, K. I. Falk and H. O. Adami, Variation in DNA repair genes ERCC2...candidate genes for blood- pressure homeostasis. Nat Genet 1999;22:239–247. 06. Doris PA. Hypertension genetics, single nucleotide polymor- phisms, and the

  12. AGXT and ERCC2 polymorphisms are associated with clinical outcome in metastatic colorectal cancer patients treated with 5-FU/oxaliplatin

    DEFF Research Database (Denmark)

    Kjersem, J B; Thomsen, M.; Guren, T

    2016-01-01

    The objective of the study was to investigate whether specific single nucleotide polymorphisms (SNPs) with influence on drug transport, biotransformation and repair mechanisms are associated with treatment outcome and toxicity in metastatic colorectal cancer (mCRC). We genotyped blood samples fro...... as markers of clinical outcome in oxaliplatin-treated mCRC patients. If validated in other studies, they could improve the selection of therapy in mCRC.The Pharmacogenomics Journal advance online publication, 11 August 2015; doi:10.1038/tpj.2015.54....

  13. Polymorphism of CYP3A4 and ABCB1 genes increase the risk of neuropathy in breast cancer patients treated with paclitaxel and docetaxel

    Directory of Open Access Journals (Sweden)

    Kus T

    2016-08-01

    Full Text Available Tulay Kus,1 Gokmen Aktas,1 Mehmet Emin Kalender,1 Abdullah Tuncay Demiryurek,2 Mustafa Ulasli,1 Serdar Oztuzcu,3 Alper Sevinc,1 Seval Kul,4 Celaletdin Camci1 1Department of Internal Medicine, Division of Medical Oncology, University of Gaziantep, Gaziantep Oncology Hospital, Gaziantep, Turkey; 2Department of Medical Pharmacology, 3Department of Medical Biology, Faculty of Medicine, University of Gaziantep, Gaziantep, Turkey; 4Department of Biostatistics, Faculty of Medicine, University of Gaziantep, Gaziantep, Turkey Background: Interindividual variability of pharmacogenetics may account for unpredictable neurotoxicities of taxanes. Methods: From March 2011 to June 2015, female patients with operable breast cancer who had received docetaxel- or paclitaxel-containing adjuvant chemotherapy were included in this study. All patients were treated with single-agent paclitaxel intravenously (IV 175 mg/m2 every 3 weeks for four cycles, or IV 80 mg/m2 weekly for 12 cycles, and IV 100 mg/m2 docetaxel for four cycles as adjuvant treatment. We evaluated the relationship between neurotoxicity of taxanes and single-nucleotide polymorphisms of ABCB1, CYP3A4, ERCC1, ERCC2, FGFR4, TP53, ERBB2, and CYP2C8 genes. Taxane-induced neurotoxicity during the treatment was evaluated according to the National Cancer Institute Common Toxicity Criteria version 4.03 prior to each cycle. Chi-squared tests were used to compare the two groups, and multivariate binary logistic regression models were used for determining possible risk factors of neuropathy. Results: Pharmacogenetic analysis was performed in 219 females. ABCB1 3435 TT genotype had significantly higher risk for grade ≥2 neurotoxicity (odds ratio [OR]: 2.759, 95% confidence interval [CI]: 1.172–6.493, P: 0.017 compared to TC and CC genotype, and also CYP3A4 392 AA and AG genotype had significantly higher risk for grade ≥2 neurotoxicity (OR: 2.259, 95% CI: 1.033–4.941, P: 0.038 compared to GG genotype. For

  14. Polymorphism of CYP3A4 and ABCB1 genes increase the risk of neuropathy in breast cancer patients treated with paclitaxel and docetaxel

    Science.gov (United States)

    Kus, Tulay; Aktas, Gokmen; Kalender, Mehmet Emin; Demiryurek, Abdullah Tuncay; Ulasli, Mustafa; Oztuzcu, Serdar; Sevinc, Alper; Kul, Seval; Camci, Celaletdin

    2016-01-01

    Background Interindividual variability of pharmacogenetics may account for unpredictable neurotoxicities of taxanes. Methods From March 2011 to June 2015, female patients with operable breast cancer who had received docetaxel- or paclitaxel-containing adjuvant chemotherapy were included in this study. All patients were treated with single-agent paclitaxel intravenously (IV) 175 mg/m2 every 3 weeks for four cycles, or IV 80 mg/m2 weekly for 12 cycles, and IV 100 mg/m2 docetaxel for four cycles as adjuvant treatment. We evaluated the relationship between neurotoxicity of taxanes and single-nucleotide polymorphisms of ABCB1, CYP3A4, ERCC1, ERCC2, FGFR4, TP53, ERBB2, and CYP2C8 genes. Taxane-induced neurotoxicity during the treatment was evaluated according to the National Cancer Institute Common Toxicity Criteria version 4.03 prior to each cycle. Chi-squared tests were used to compare the two groups, and multivariate binary logistic regression models were used for determining possible risk factors of neuropathy. Results Pharmacogenetic analysis was performed in 219 females. ABCB1 3435 TT genotype had significantly higher risk for grade ≥2 neurotoxicity (odds ratio [OR]: 2.759, 95% confidence interval [CI]: 1.172–6.493, P: 0.017) compared to TC and CC genotype, and also CYP3A4 392 AA and AG genotype had significantly higher risk for grade ≥2 neurotoxicity (OR: 2.259, 95% CI: 1.033–4.941, P: 0.038) compared to GG genotype. For FDGF4 gene with AG and GG genotype, OR was 1.879 (95% CI: 1.001–3.525, P: 0.048) compared to AA genotype with regard to any grade of neuropathy risk. We could not find any other association of other genotypes with neurotoxicity grades. Conclusion ABCB1 3435 TT genotype and CYP3A4 392 AA/AG genotypes may be used as predictors of neurotoxicity during taxane chemotherapy. PMID:27574448

  15. Disease: H00403 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available P); Cockayne syndrome (CS); UV-sensitive syndrome (UVS); Trichothiodystrophy (TTD); Cerebro-oculo-facio-skel...thin photo-sensitive TTD, three TFIIH coding genes (ERCC2, ERCC3, and TTDA/GTF2H5) are implicated. Cerebro...peldoorn E, Kleijer WJ, Garritsen VH, Busch D, Edersheim TG, Jaspers NG Cerebro-o

  16. Studying Genes

    Science.gov (United States)

    ... NIGMS NIGMS Home > Science Education > Studying Genes Studying Genes Tagline (Optional) Middle/Main Content Area Other Fact Sheets What are genes? Genes are segments of DNA that contain instructions ...

  17. Immunoglobulin genes

    Energy Technology Data Exchange (ETDEWEB)

    Honjo, T. (Kyoto Univ. (Japan)); Alt, F.W. (Columbia Univ., Dobbs Ferry, NY (USA). Hudson Labs.); Rabbitts, T.H. (Medical Research Council, Cambridge (UK))

    1989-01-01

    This book reports on the structure, function, and expression of the genes encoding antibodies in normal and neoplastic cells. Topics covered are: B Cells; Organization and rearrangement of immunoglobin genes; Immunoglobin genes in disease; Immunoglobin gene expression; and Immunoglobin-related genes.

  18. Resistance of hypoxic cells to ionizing radiation is influenced by homologous recombination status.

    NARCIS (Netherlands)

    Sprong, D.; Janssen, H.L.K.; Vens, C.; Begg, A.C.

    2006-01-01

    PURPOSE: To determine the role of DNA repair in hypoxic radioresistance. METHODS AND MATERIALS: Chinese hamster cell lines with mutations in homologous recombination (XRCC2, XRCC3, BRAC2, RAD51C) or nonhomologous end-joining (DNA-PKcs) genes were irradiated under normoxic (20% oxygen) and hypoxic (&

  19. Low-intensity red and infrared lasers affect mRNA expression of DNA nucleotide excision repair in skin and muscle tissue.

    Science.gov (United States)

    Sergio, Luiz Philippe S; Campos, Vera Maria A; Vicentini, Solange C; Mencalha, Andre Luiz; de Paoli, Flavia; Fonseca, Adenilson S

    2016-04-01

    Lasers emit light beams with specific characteristics, in which wavelength, frequency, power, fluence, and emission mode properties determine the photophysical, photochemical, and photobiological responses. Low-intensity lasers could induce free radical generation in biological tissues and cause alterations in macromolecules, such as DNA. Thus, the aim of this work was to evaluate excision repair cross-complementing group 1 (ERCC1) and excision repair cross-complementing group 2 (ERCC2) messenger RNA (mRNA) expression in biological tissues exposed to low-intensity lasers. Wistar rat (n = 28, 4 for each group) skin and muscle were exposed to low-intensity red (660 nm) and near-infrared (880 nm) lasers at different fluences (25, 50, and 100 J/cm(2)), and samples of these tissues were withdrawn for RNA extraction, cDNA synthesis, and gene expression evaluation by quantitative polymerase chain reaction. Laser exposure was in continuous wave and power of 100 mW. Data show that ERCC1 and ERCC2 mRNA expressions decrease in skin (p laser, but increase in muscle tissue (p  0.05), but ERCC2 mRNA expression decreases in skin (p laser. Our results show that ERCC1 and ERCC2 mRNA expression is differently altered in skin and muscle tissue exposed to low-intensity lasers depending on wavelengths and fluences used in therapeutic protocols.

  20. Tumor site- and stage-specific associations between allelic variants of glutathione S-transferase and DNA-repair genes and overall survival in colorectal cancer patients receiving 5-fluorouracil-based chemotherapy.

    Directory of Open Access Journals (Sweden)

    Ching-Yu Lai

    Full Text Available INTRODUCTION: Our retrospective cohort study investigated the effect of tumor site and stage on the associations between the allelic variants of glutathione S-transferase (GST and DNA-repair genes and overall survival (OS in CRC patients treated with 5-fluorouracil (5-FU-based adjuvant chemotherapy. MATERIAL AND METHODS: We genotyped GSTM1, GSTT1, GSTP1 Ile105Val, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln in 491 CRC patients between 1995 and 2001. A Cox proportional-hazards model was used to calculate the hazard ratios (HRs and 95% confidence intervals (CIs for the relationships between the allelic variants and OS. Survival analyses were performed for each allelic variant by using the log-rank test and Kaplan-Meier analysis. RESULTS: The CRC patients with the XPD Gln allelic variants had poorer survival than patients with the Lys/Lys genotype (HR  =1.38, 95% CI  =1.02-1.87, and rectal cancer patients had the poorest survival among them (HR  =1.87, 95% CI  =1.18-2.95. A significantly shorter OS was observed among stage II/III colon cancer patients with the XRCC1 Gln allelic variants (HR  =1.69, 95% CI  =1.06-2.71, compared to those with XRCC1 Arg/Arg genotype. In the combined analysis of the XRCC1 and XPD genes patients with stage II/III tumors, the poorest OS occurred in colon cancer patients with the XRCC1 Gln and XPD Gln allelic variants (HR  =2.60, 95% CI  =1.19-5.71 and rectal cancer patients with the XRCC1 Arg/Arg and XPD Gln allelic variants (HR  =2.77, 95% CI  =1.25-6.17. CONCLUSION: The XPD and XRCC1 allelic variants may be prognostic markers for CRC patients receiving 5-FU based chemotherapy. The contributions of the XPD and XRCC1 allelic variants to OS are tumor site- and/or stage-dependent.

  1. Gene therapy

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    2005147 CNHK200-hA-a gene-viral therapeutic system and its antitumor effect on lung cancer. WANG Wei-guo(王伟国),et al. Viral & Gene Ther Center, Eastern Hepatobilli Surg Instit 2nd Milit Univ, Shanghai 200438. Chin J Oncol,2005:27(2):69-72. Objective: To develop a novel vector system, which combines the advantages of the gene therapy,

  2. Trichoderma genes

    Science.gov (United States)

    Foreman, Pamela [Los Altos, CA; Goedegebuur, Frits [Vlaardingen, NL; Van Solingen, Pieter [Naaldwijk, NL; Ward, Michael [San Francisco, CA

    2012-06-19

    Described herein are novel gene sequences isolated from Trichoderma reesei. Two genes encoding proteins comprising a cellulose binding domain, one encoding an arabionfuranosidase and one encoding an acetylxylanesterase are described. The sequences, CIP1 and CIP2, contain a cellulose binding domain. These proteins are especially useful in the textile and detergent industry and in pulp and paper industry.

  3. Gene Therapy.

    Science.gov (United States)

    Thorne, Barb; Takeya, Ryan; Vitelli, Francesca; Swanson, Xin

    2017-03-14

    Gene therapy refers to a rapidly growing field of medicine in which genes are introduced into the body to treat or prevent diseases. Although a variety of methods can be used to deliver the genetic materials into the target cells and tissues, modified viral vectors represent one of the more common delivery routes because of its transduction efficiency for therapeutic genes. Since the introduction of gene therapy concept in the 1970s, the field has advanced considerably with notable clinical successes being demonstrated in many clinical indications in which no standard treatment options are currently available. It is anticipated that the clinical success the field observed in recent years can drive requirements for more scalable, robust, cost effective, and regulatory-compliant manufacturing processes. This review provides a brief overview of the current manufacturing technologies for viral vectors production, drawing attention to the common upstream and downstream production process platform that is applicable across various classes of viral vectors and their unique manufacturing challenges as compared to other biologics. In addition, a case study of an industry-scale cGMP production of an AAV-based gene therapy product performed at 2,000 L-scale is presented. The experience and lessons learned from this largest viral gene therapy vector production run conducted to date as discussed and highlighted in this review should contribute to future development of commercial viable scalable processes for vial gene therapies.

  4. 候选基因单核苷酸多态性与胃癌患者卡培他滨联合紫杉醇化疗后生存期的关系%Relationship between single nucleotide polymorphisms of candidate genes and survival of patients with gastric cancer undergoing chemotherapy with capecitabine and paclitaxel

    Institute of Scientific and Technical Information of China (English)

    郑磊贞; 顾建春; 龚继芳; 李小平; 陈思宇; 章莉; 焦晓栋; 王杰军

    2011-01-01

    目的 探讨热点候选肿瘤相关基因的单核苷酸多态性(SNPs)与胃癌患者卡培他滨联合紫杉醇化疗后生存期的关系.方法 收集93例经病理学检查确诊的胃癌患者,采用卡培他滨联合紫杉醇为主的方案进行化疗.用TaqMan-MGB探针进行原癌基因TP53 rs1042522(G/C)、代谢相关基因GSTPI rs1695(A/G)和CYP11B2 rs1799998(T/C)以及DNA损伤修复相关基因XRCCI rs1799782(C/T)和ERCC2 rs1799793(G/A)的基因分型.比较不同基因型患者化疗后中位生存时间(MST)及各种因素对预后的影响.结果 对93例患者的中位随访时间为29.6个月,MST为34.93个月.TP53 rs1042522(G/C)多态性位点与胃癌患者化疗后的MST相关,携带TP53 rs1042522野生基因型G/G组的MST为51.2个月,而携带变异基因型(G/C+C/C)组的MST为26.6个月,经1og-rank检验两组间差异无统计学差异,但较为接近(P=0.073);其他基因多态性与MST无显著相关性(P>0.05).Cox回归分析显示性别.手术和病理分期是影响胃癌患者化疗预后效果的主要影响因素.结论 TP53(rs1042522G/C)位点基因多态性与用药效果呈临界相关,进一步的验证还需要扩大样本.%Objective To investigate the relationship between single nucleotide polymorphisms of tumor-associated candidate genes and survival of patients with gastric cancer undergoing chemotherapy with capecitabine and paclitaxel.Methods Ninety-three patients pathologically confirmed of gastric cancer were selected, and received chemotherapy with capecitabine and paclitaxel. Genotypes of protooncogene TP53 rs1042522 (G/C), metabolism-associated gene GSTP1 rs1695(A/G) and CYP11B2 rs1799998 (T/C), DNA repair-associated gene XRCC1 rs1799782 (C/T) and ERCC2 rs1799793 (G/A) were determined by TaqMan-MGB methods. The median survival time (MST) after chemotherapy was compared among patients with different genotypes, and influencing factors for prognosis were analysed. Results The median time of follow-up was 29

  5. Gene Therapy

    Science.gov (United States)

    ... or improve your body's ability to fight disease. Gene therapy holds promise for treating a wide range of diseases, such as cancer, cystic fibrosis, heart disease, diabetes, hemophilia and AIDS. Researchers are still studying how and ...

  6. Genes V.

    Energy Technology Data Exchange (ETDEWEB)

    Lewin, B.

    1994-12-31

    This fifth edition book encompasses a wide range of topics covering 1,272 pages. The book is arranged into nine parts with a total of 36 chapters. These nine parts include Introduction; DNA as a Store of Information; Translation; Constructing Cells; Control of Prokaryotypic Gene Expression; Perpetuation of DNA; Organization of the Eukaryotypic Genome; Eukaryotypic Transcription and RNA Processing; The Dynamic Genome; and Genes in Development.

  7. Haplotype frequencies in a sub-region of chromosome 19q13.3, related to risk and prognosis of cancer, differ dramatically between ethnic groups

    DEFF Research Database (Denmark)

    Schierup, M.H.; Mailund, T.; Li, H.

    2009-01-01

    Background: A small region of about 70 kb on human chromosome 19q13.3 encompasses 4 genes of which 3, ERCC1, ERCC2, and PPP1R13L (aka RAI) are related to DNA repair and cell survival, and one, CD3EAP, aka ASE1, may be related to cell proliferation. The whole region seems related to the cellular r...

  8. Haplotype frequencies in a sub-region of chromosome 19q13.3, related to risk and prognosis of cancer, differ dramatically between ethnic groups

    DEFF Research Database (Denmark)

    Schierup, M.H.; Mailund, T.; Li, H.

    2009-01-01

    Background: A small region of about 70 kb on human chromosome 19q13.3 encompasses 4 genes of which 3, ERCC1, ERCC2, and PPP1R13L (aka RAI) are related to DNA repair and cell survival, and one, CD3EAP, aka ASE1, may be related to cell proliferation. The whole region seems related to the cellular r...

  9. DREB genes

    African Journals Online (AJOL)

    Unipar

    2015-03-12

    Mar 12, 2015 ... to AP2/ERF family, dehydration-responsive element-binding protein (DREB) genes, (CitsERF01 to ... Protein sequences of DREB subfamilies belonging to group I, .... position 37, and it was present in consensus in all protein.

  10. Endothelial Genes

    Science.gov (United States)

    2005-06-01

    8217Department of Surgery, Division of Oncology , and 2Department of BRCA-l and BRCA-2 (breast cancer susceptibility genes), Pathology, University of...Suppression subtractive hybridization re- Cancer: principles and practice of oncology . Philadelphia: Lippincott- vealed an RNA sequence (GenBank accession...Lippman ME. Cancer of the breast: molecular biology angiogenesis in sarcomas and carcinomas. Clin Cancer Res 1999;5: of breast cancer. In: DeVita VT

  11. Gene Ontology

    Directory of Open Access Journals (Sweden)

    Gaston K. Mazandu

    2012-01-01

    Full Text Available The wide coverage and biological relevance of the Gene Ontology (GO, confirmed through its successful use in protein function prediction, have led to the growth in its popularity. In order to exploit the extent of biological knowledge that GO offers in describing genes or groups of genes, there is a need for an efficient, scalable similarity measure for GO terms and GO-annotated proteins. While several GO similarity measures exist, none adequately addresses all issues surrounding the design and usage of the ontology. We introduce a new metric for measuring the distance between two GO terms using the intrinsic topology of the GO-DAG, thus enabling the measurement of functional similarities between proteins based on their GO annotations. We assess the performance of this metric using a ROC analysis on human protein-protein interaction datasets and correlation coefficient analysis on the selected set of protein pairs from the CESSM online tool. This metric achieves good performance compared to the existing annotation-based GO measures. We used this new metric to assess functional similarity between orthologues, and show that it is effective at determining whether orthologues are annotated with similar functions and identifying cases where annotation is inconsistent between orthologues.

  12. Gene doping: gene delivery for olympic victory

    OpenAIRE

    2012-01-01

    With one recently recommended gene therapy in Europe and a number of other gene therapy treatments now proving effective in clinical trials it is feasible that the same technologies will soon be adopted in the world of sport by unscrupulous athletes and their trainers in so called ‘gene doping’. In this article an overview of the successful gene therapy clinical trials is provided and the potential targets for gene doping are highlighted. Depending on whether a doping gene product is secreted...

  13. Chromatid Paints: A New Method for Detecting Tumor-Specific Chromosomal Inversions

    Science.gov (United States)

    1999-10-01

    a neomycin resistance marker (NEO) by homologous recombination in the yeast Saccha- have been established and previously described [14]. romyces...irslSF-C7 mutant knockout in DT40 chicken lymphoblastoid cells, line. This implies that, while XRCC2 and XRCC3 shutdown of RAD51 expression resulted in...Morita, H. Yamada, M. Oshimura, Construction of mouse A9 clones containing a single human chromosome tagged with neomycin -resistance gene via mi- [1

  14. GeneEd -- A Genetics Educational Resource

    Science.gov (United States)

    ... Javascript on. Feature: Genetics 101 GeneEd — A Genetics Educational Resource Past Issues / Summer 2013 Table of Contents Science ... The Hereditary Material of Life / GeneEd — A Genetics Educational Resource / Using The Genetics Home Reference Website / Understanding the ...

  15. Special Issue: Gene Conversion in Duplicated Genes

    Directory of Open Access Journals (Sweden)

    Hideki Innan

    2011-06-01

    Full Text Available Gene conversion is an outcome of recombination, causing non-reciprocal transfer of a DNA fragment. Several decades later than the discovery of crossing over, gene conversion was first recognized in fungi when non-Mendelian allelic distortion was observed. Gene conversion occurs when a double-strand break is repaired by using homologous sequences in the genome. In meiosis, there is a strong preference to use the orthologous region (allelic gene conversion, which causes non-Mendelian allelic distortion, but paralogous or duplicated regions can also be used for the repair (inter-locus gene conversion, also referred to as non-allelic and ectopic gene conversion. The focus of this special issue is the latter, interlocus gene conversion; the rate is lower than allelic gene conversion but it has more impact on phenotype because more drastic changes in DNA sequence are involved.

  16. Principles of gene therapy

    OpenAIRE

    Mammen Biju; Ramakrishnan T; Sudhakar Uma; Vijayalakshmi

    2007-01-01

    Genes are specific sequences of bases that encode instructions to make proteins. When genes are altered so that encoded proteins are unable to carry out their normal functions, genetic disorders can result. Gene therapy is designed to introduce genetic material into cells to compensate for abnormal genes or to make a beneficial protein. This article reviews the fundamentals in gene therapy and its various modes of administration with an insight into the role of gene therapy in Periodontics an...

  17. Organization of immunoglobulin genes.

    Science.gov (United States)

    Tonegawa, S; Brack, C; Hozumi, N; Pirrotta, V

    1978-01-01

    The nucleotide-sequence determination of a cloned, embryonic Vlambda gene directly demonstrated that V genes are separate from a corresponding C gene in embryonic cells. Analysis by restriction enzymes of total cellular DNA from various sources strongly suggested that the two separate immunoglobulin genes become continuous during differentiation of B lymphocytes. There seems to be a strict correlation between the joining event and activation of the joined genes. Cloning of more immunoglobulin genes from embryo and plasma cells will not only provide direct demonstration of such a gene-joining event but also help in the elucidation of a possible relationship of the event to gene activation mechanisms.

  18. Gene doping: gene delivery for olympic victory.

    Science.gov (United States)

    Gould, David

    2013-08-01

    With one recently recommended gene therapy in Europe and a number of other gene therapy treatments now proving effective in clinical trials it is feasible that the same technologies will soon be adopted in the world of sport by unscrupulous athletes and their trainers in so called 'gene doping'. In this article an overview of the successful gene therapy clinical trials is provided and the potential targets for gene doping are highlighted. Depending on whether a doping gene product is secreted from the engineered cells or is retained locally to, or inside engineered cells will, to some extent, determine the likelihood of detection. It is clear that effective gene delivery technologies now exist and it is important that detection and prevention plans are in place.

  19. Gene Cluster Statistics with Gene Families

    Science.gov (United States)

    Durand, Dannie

    2009-01-01

    Identifying genomic regions that descended from a common ancestor is important for understanding the function and evolution of genomes. In distantly related genomes, clusters of homologous gene pairs are evidence of candidate homologous regions. Demonstrating the statistical significance of such “gene clusters” is an essential component of comparative genomic analyses. However, currently there are no practical statistical tests for gene clusters that model the influence of the number of homologs in each gene family on cluster significance. In this work, we demonstrate empirically that failure to incorporate gene family size in gene cluster statistics results in overestimation of significance, leading to incorrect conclusions. We further present novel analytical methods for estimating gene cluster significance that take gene family size into account. Our methods do not require complete genome data and are suitable for testing individual clusters found in local regions, such as contigs in an unfinished assembly. We consider pairs of regions drawn from the same genome (paralogous clusters), as well as regions drawn from two different genomes (orthologous clusters). Determining cluster significance under general models of gene family size is computationally intractable. By assuming that all gene families are of equal size, we obtain analytical expressions that allow fast approximation of cluster probabilities. We evaluate the accuracy of this approximation by comparing the resulting gene cluster probabilities with cluster probabilities obtained by simulating a realistic, power-law distributed model of gene family size, with parameters inferred from genomic data. Surprisingly, despite the simplicity of the underlying assumption, our method accurately approximates the true cluster probabilities. It slightly overestimates these probabilities, yielding a conservative test. We present additional simulation results indicating the best choice of parameter values for data

  20. Association between SNPs in defined functional pathways and risk of early or late toxicity as well as individual radiosensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Reuther, Sebastian; Raabe, Annette; Borgmann, Kerstin; Dikomey, Ekkehard [University Medical Center Hamburg-Eppendorf, Laboratory of Radiobiology and Experimental Radiooncology, Department of Radiotherapy and Radiooncology, Hamburg (Germany); Szymczak, Silke [University at Luebeck, Institute of Medical Biometry and Statistics, University Medical Center Schleswig-Holstein (Germany); Christian-Albrechts-University Kiel, Institute of Clinical Molecular Biology, Kiel (Germany); Ziegler, Andreas [University at Luebeck, Institute of Medical Biometry and Statistics, University Medical Center Schleswig-Holstein (Germany); University of Luebeck, Center for Clinical Trials, Luebeck (Germany); Petersen, Cordula [University Medical Center Hamburg-Eppendorf, Clinic of Radiotherapy and Radiooncology, Hamburg (Germany); Hoeller, Ulrike [Charite Universitaetsmedizin Berlin, Department of Radiotherapy, Berlin (Germany)

    2014-08-26

    The aim of this study was to determine the impact of functional single nucleotide polymorphism (SNP) pathways involved in the ROS pathway, DNA repair, or TGFB1 signaling on acute or late normal toxicity as well as individual radiosensitivity. Patients receiving breast-conserving surgery and radiotherapy were examined either for erythema (n = 83), fibrosis (n = 123), or individual radiosensitivity (n = 123). The 17 SNPs analyzed are involved in the ROS pathway (GSTP1, SOD2, NQO1, NOS3, XDH), DNA repair (XRCC1, XRCC3, XRCC6, ERCC2, LIG4, ATM) or TGFB signaling (SKIL, EP300, APC, AXIN1, TGFB1). Associations with biological and clinical endpoints were studied for single SNPs but especially for combinations of SNPs assuming that a SNP is either beneficial or deleterious and needs to be weighted. With one exception, no significant association was seen between a single SNP and the three endpoints studied. No significant associations were also observed when applying a multi-SNP model assuming that each SNP was deleterious. In contrast, significant associations were obtained when SNPs were suggested to be either beneficial or deleterious. These associations increased, when each SNP was weighted individually. Detailed analysis revealed that both erythema and individual radiosensitivity especially depend on SNPs affecting DNA repair and TGFB1 signaling, while SNPs in ROS pathway were of minor importance. Functional pathways of SNPs may be used to form a risk score allowing to predict acute and late radiation-induced toxicity but also to unravel the underlying biological mechanisms. (orig.) [German] Fuer ein SNP-Netzwerk (''single nucleotide polymorphism'', Einzelnukleotidpolymorphismus), welches im ROS-Signalweg, an der DNA-Reparatur und im TGFB1-Signalweg involviert ist, sollen die Bedeutung fuer die akute und spaete Toxizitaet sowie die individuelle Strahlenempfindlichkeit bestimmt werden. Nach Strahlentherapie wurden Brustkrebspatientinnen entweder

  1. Lateral gene transfer, rearrangement, reconciliation

    NARCIS (Netherlands)

    Patterson, M.D.; Szollosi, G.; Daubin, V.; Tannier, E.

    2013-01-01

    Background. Models of ancestral gene order reconstruction have progressively integrated different evolutionary patterns and processes such as unequal gene content, gene duplications, and implicitly sequence evolution via reconciled gene trees. These models have so far ignored lateral gene transfer,

  2. Gene doping in sports.

    Science.gov (United States)

    Unal, Mehmet; Ozer Unal, Durisehvar

    2004-01-01

    Gene or cell doping is defined by the World Anti-Doping Agency (WADA) as "the non-therapeutic use of genes, genetic elements and/or cells that have the capacity to enhance athletic performance". New research in genetics and genomics will be used not only to diagnose and treat disease, but also to attempt to enhance human performance. In recent years, gene therapy has shown progress and positive results that have highlighted the potential misuse of this technology and the debate of 'gene doping'. Gene therapies developed for the treatment of diseases such as anaemia (the gene for erythropoietin), muscular dystrophy (the gene for insulin-like growth factor-1) and peripheral vascular diseases (the gene for vascular endothelial growth factor) are potential doping methods. With progress in gene technology, many other genes with this potential will be discovered. For this reason, it is important to develop timely legal regulations and to research the field of gene doping in order to develop methods of detection. To protect the health of athletes and to ensure equal competitive conditions, the International Olympic Committee, WADA and International Sports Federations have accepted performance-enhancing substances and methods as being doping, and have forbidden them. Nevertheless, the desire to win causes athletes to misuse these drugs and methods. This paper reviews the current status of gene doping and candidate performance enhancement genes, and also the use of gene therapy in sports medicine and ethics of genetic enhancement.

  3. Human Gene Therapy: Genes without Frontiers?

    Science.gov (United States)

    Simon, Eric J.

    2002-01-01

    Describes the latest advancements and setbacks in human gene therapy to provide reference material for biology teachers to use in their science classes. Focuses on basic concepts such as recombinant DNA technology, and provides examples of human gene therapy such as severe combined immunodeficiency syndrome, familial hypercholesterolemia, and…

  4. Reference: 66 [Arabidopsis Phenome Database[Archive

    Lifescience Database Archive (English)

    Full Text Available these, AtXRCC3, the homologue of XRCC3. atxrcc3 plants are sterile, while they have normal vegetative development. Cytological observ...ation shows that the atxrcc3 mutation does not affect homologous chromosome synapsi

  5. Genes and Hearing Loss

    Science.gov (United States)

    ... Find an ENT Doctor Near You Genes and Hearing Loss Genes and Hearing Loss Patient Health Information News media interested in covering ... One of the most common birth defects is hearing loss or deafness (congenital), which can affect as many ...

  6. Essential Bacillus subtilis genes

    DEFF Research Database (Denmark)

    Kobayashi, K.; Ehrlich, S.D.; Albertini, A.

    2003-01-01

    To estimate the minimal gene set required to sustain bacterial life in nutritious conditions, we carried out a systematic inactivation of Bacillus subtilis genes. Among approximate to4,100 genes of the organism, only 192 were shown to be indispensable by this or previous work. Another 79 genes were...... predicted to be essential. The vast majority of essential genes were categorized in relatively few domains of cell metabolism, with about half involved in information processing, one-fifth involved in the synthesis of cell envelope and the determination of cell shape and division, and one-tenth related...... to cell energetics. Only 4% of essential genes encode unknown functions. Most essential genes are present throughout a wide range of Bacteria, and almost 70% can also be found in Archaea and Eucarya. However, essential genes related to cell envelope, shape, division, and respiration tend to be lost from...

  7. Cochlear Gene Therapy

    OpenAIRE

    2012-01-01

    The purpose of this review is to highlight recent advances in cochlear gene therapy over the past several years. Cochlear gene therapy has undergone tremendous advances over the past decade. Beginning with some groundbreaking work in 2005 documenting hair cell regeneration using virallymediated delivery of the mouse atonal 1 gene, gene therapy is now being explored as a possible treatment for a variety of causes of hearing loss.

  8. Discovering genes underlying QTL

    Energy Technology Data Exchange (ETDEWEB)

    Vanavichit, Apichart [Kasetsart University, Kamphaengsaen, Nakorn Pathom (Thailand)

    2002-02-01

    A map-based approach has allowed scientists to discover few genes at a time. In addition, the reproductive barrier between cultivated rice and wild relatives has prevented us from utilizing the germ plasm by a map-based approach. Most genetic traits important to agriculture or human diseases are manifested as observable, quantitative phenotypes called Quantitative Trait Loci (QTL). In many instances, the complexity of the phenotype/genotype interaction and the general lack of clearly identifiable gene products render the direct molecular cloning approach ineffective, thus additional strategies like genome mapping are required to identify the QTL in question. Genome mapping requires no prior knowledge of the gene function, but utilizes statistical methods to identify the most likely gene location. To completely characterize genes of interest, the initially mapped region of a gene location will have to be narrowed down to a size that is suitable for cloning and sequencing. Strategies for gene identification within the critical region have to be applied after the sequencing of a potentially large clone or set of clones that contains this gene(s). Tremendous success of positional cloning has been shown for cloning many genes responsible for human diseases, including cystic fibrosis and muscular dystrophy as well as plant disease resistance genes. Genome and QTL mapping, positional cloning: the pre-genomics era, comparative approaches to gene identification, and positional cloning: the genomics era are discussed in the report. (M. Suetake)

  9. Reading and Generalist Genes

    Science.gov (United States)

    Haworth, Claire M. A.; Meaburn, Emma L.; Harlaar, Nicole; Plomin, Robert

    2007-01-01

    Twin-study research suggests that many (but not all) of the same genes contribute to genetic influence on diverse learning abilities and disabilities, a hypothesis called "generalist genes". This generalist genes hypothesis was tested using a set of 10 DNA markers (single nucleotide polymorphisms [SNPs]) found to be associated with early reading…

  10. Journey from Jumping Genes to Gene Therapy.

    Science.gov (United States)

    Whartenby, Katharine A

    2015-01-01

    Gene therapy for cancer is a still evolving approach that resulted from a long history of studies into genetic modification of organisms. The fascination with manipulating gene products has spanned hundreds if not thousands of years, beginning with observations of the hereditary nature of traits in plants and culminating to date in the alteration of genetic makeup in humans via modern technology. From early discoveries noting the potential for natural mobility of genetic material to the culmination of clinical trials in a variety of disease, gene transfer has had an eventful and sometimes tumultuous course. Within the present review is a brief history of the biology of gene transfer, how it came to be applied to genetic diseases, and its early applications to cancer therapies. Some of the different types of methods used to modify cells, the theories behind the approaches, and some of the limitations encountered along the way are reviewed.

  11. Gene conversion in human rearranged immunoglobulin genes.

    Science.gov (United States)

    Darlow, John M; Stott, David I

    2006-07-01

    Over the past 20 years, many DNA sequences have been published suggesting that all or part of the V(H) segment of a rearranged immunoglobulin gene may be replaced in vivo. Two different mechanisms appear to be operating. One of these is very similar to primary V(D)J recombination, involving the RAG proteins acting upon recombination signal sequences, and this has recently been proven to occur. Other sequences, many of which show partial V(H) replacements with no addition of untemplated nucleotides at the V(H)-V(H) joint, have been proposed to occur by an unusual RAG-mediated recombination with the formation of hybrid (coding-to-signal) joints. These appear to occur in cells already undergoing somatic hypermutation in which, some authors are convinced, RAG genes are silenced. We recently proposed that the latter type of V(H) replacement might occur by homologous recombination initiated by the activity of AID (activation-induced cytidine deaminase), which is essential for somatic hypermutation and gene conversion. The latter has been observed in other species, but not in human Ig genes, so far. In this paper, we present a new analysis of sequences published as examples of the second type of rearrangement. This not only shows that AID recognition motifs occur in recombination regions but also that some sequences show replacement of central sections by a sequence from another gene, similar to gene conversion in the immunoglobulin genes of other species. These observations support the proposal that this type of rearrangement is likely to be AID-mediated rather than RAG-mediated and is consistent with gene conversion.

  12. 多因子降维法在人群散发性结直肠癌交互作用分析中的应用%Application of multifactor dimensionality reduction on the interactions between gene-gene,geneenvironment and the risk sporadic colorectal cancer in Chinese population

    Institute of Scientific and Technical Information of China (English)

    金明娟; 刘冰; 张爽爽; 张勇晶; 徐玫; 马新源; 姚开颜; 陈坤

    2008-01-01

    用分析的可行性.方法 采用自然人群为基础的病例对照研究设计,运用PCR-RFLP方法对206例结直肠癌病例和845例正常对照开展OGG1 Ser326Cys,XRCC1 Arg194Trp、Arg280His和Arg399Gln,XPD Lys751Gln和XRCC3 Thr241Met等DNA修复体系常见单核苷酸多态性(SNP)的检测分型.结果 个体特征与结直肠癌的关联分析表明,年龄与结直肠癌的发病正相关,高年龄组(≥61岁)与低年龄组(≥42岁至<61岁)相比,结直肠癌患病风险增高有统计学意义(校正OR=2.04,95%CI:1.49~2.80);家族肿瘤史同样与结直肠癌的发病存在有统计学意义的正相关关系(校正OR=1.51,95%CI:1.05~2.17).前述各SNP的等位基因和基因型分布频率在正常对照组和病例组间差异均无统计学意义(P>0.05).采用MDR对基因-基因、基因-环境交互作用模型的筛选分析表明,最佳的交互作用模型包含了年龄分布、饮酒史、XRCC1 Arg194Trp和OGG1 Ser326Cys等4个因子(平均检验准确度=0.616,交叉验证一致性=10/10,P=0.011);进一步以筛选出的低风险组合为参照,logistic拟合分析发现高风险组合可以使结直肠癌的患病风险增高并有统计学意义(OR=2.72,95%CI:1.66~4.47).结论 DNA修复基因多态性对中国人散发性结直肠癌风险的遗传影响符合低外显性特征,并与环境因子可能存在着复杂的联合作用.

  13. Gene therapy in periodontics

    Directory of Open Access Journals (Sweden)

    Anirban Chatterjee

    2013-01-01

    Full Text Available GENES are made of DNA - the code of life. They are made up of two types of base pair from different number of hydrogen bonds AT, GC which can be turned into instruction. Everyone inherits genes from their parents and passes them on in turn to their children. Every person′s genes are different, and the changes in sequence determine the inherited differences between each of us. Some changes, usually in a single gene, may cause serious diseases. Gene therapy is ′the use of genes as medicine′. It involves the transfer of a therapeutic or working gene copy into specific cells of an individual in order to repair a faulty gene copy. Thus it may be used to replace a faulty gene, or to introduce a new gene whose function is to cure or to favorably modify the clinical course of a condition. It has a promising era in the field of periodontics. Gene therapy has been used as a mode of tissue engineering in periodontics. The tissue engineering approach reconstructs the natural target tissue by combining four elements namely: Scaffold, signaling molecules, cells and blood supply and thus can help in the reconstruction of damaged periodontium including cementum, gingival, periodontal ligament and bone.

  14. Regulated Gene Therapy.

    Science.gov (United States)

    Breger, Ludivine; Wettergren, Erika Elgstrand; Quintino, Luis; Lundberg, Cecilia

    2016-01-01

    Gene therapy represents a promising approach for the treatment of monogenic and multifactorial neurological disorders. It can be used to replace a missing gene and mutated gene or downregulate a causal gene. Despite the versatility of gene therapy, one of the main limitations lies in the irreversibility of the process: once delivered to target cells, the gene of interest is constitutively expressed and cannot be removed. Therefore, efficient, safe and long-term gene modification requires a system allowing fine control of transgene expression.Different systems have been developed over the past decades to regulate transgene expression after in vivo delivery, either at transcriptional or post-translational levels. The purpose of this chapter is to give an overview on current regulatory system used in the context of gene therapy for neurological disorders. Systems using external regulation of transgenes using antibiotics are commonly used to control either gene expression using tetracycline-controlled transcription or protein levels using destabilizing domain technology. Alternatively, specific promoters of genes that are regulated by disease mechanisms, increasing expression as the disease progresses or decreasing expression as disease regresses, are also examined. Overall, this chapter discusses advantages and drawbacks of current molecular methods for regulated gene therapy in the central nervous system.

  15. Gene therapy: An overview

    Directory of Open Access Journals (Sweden)

    Sudip Indu

    2013-01-01

    Full Text Available Gene therapy "the use of genes as medicine" involves the transfer of a therapeutic or working copy of a gene into specific cells of an individual in order to repair a faulty gene copy. The technique may be used to replace a faulty gene, or to introduce a new gene whose function is to cure or to favorably modify the clinical course of a condition. The objective of gene therapy is to introduce new genetic material into target cells while causing no damage to the surrounding healthy cells and tissues, hence the treatment related morbidity is decreased. The delivery system includes a vector that delivers a therapeutic gene into the patient′s target cell. Functional proteins are created from the therapeutic gene causing the cell to return to a normal stage. The vectors used in gene therapy can be viral and non-viral. Gene therapy, an emerging field of biomedicine, is still at infancy and much research remains to be done before this approach to the treatment of condition will realize its full potential.

  16. Gene therapy in periodontics.

    Science.gov (United States)

    Chatterjee, Anirban; Singh, Nidhi; Saluja, Mini

    2013-03-01

    GENES are made of DNA - the code of life. They are made up of two types of base pair from different number of hydrogen bonds AT, GC which can be turned into instruction. Everyone inherits genes from their parents and passes them on in turn to their children. Every person's genes are different, and the changes in sequence determine the inherited differences between each of us. Some changes, usually in a single gene, may cause serious diseases. Gene therapy is 'the use of genes as medicine'. It involves the transfer of a therapeutic or working gene copy into specific cells of an individual in order to repair a faulty gene copy. Thus it may be used to replace a faulty gene, or to introduce a new gene whose function is to cure or to favorably modify the clinical course of a condition. It has a promising era in the field of periodontics. Gene therapy has been used as a mode of tissue engineering in periodontics. The tissue engineering approach reconstructs the natural target tissue by combining four elements namely: Scaffold, signaling molecules, cells and blood supply and thus can help in the reconstruction of damaged periodontium including cementum, gingival, periodontal ligament and bone.

  17. Cyanobacterial signature genes.

    Science.gov (United States)

    Martin, Kirt A; Siefert, Janet L; Yerrapragada, Sailaja; Lu, Yue; McNeill, Thomas Z; Moreno, Pedro A; Weinstock, George M; Widger, William R; Fox, George E

    2003-01-01

    A comparison of 8 cyanobacterial genomes reveals that there are 181 shared genes that do not have obvious orthologs in other bacteria. These signature genes define aspects of the genotype that are uniquely cyanobacterial. Approximately 25% of these genes have been associated with some function. These signature genes may or may not be involved in photosynthesis but likely they will be in many cases. In addition, several examples of widely conserved gene order involving two or more signature genes were observed. This suggests there may be regulatory processes that have been preserved throughout the long history of the cyanobacterial phenotype. The results presented here will be especially useful because they identify which of the many genes of unassigned function are likely to be of the greatest interest.

  18. The study on polymorphism of DNA repair genes,smoking and DNA damage in a sample of healthy subjects%健康人群吸烟、DNA损伤与DNA修复基因多态研究

    Institute of Scientific and Technical Information of China (English)

    朱守民; 夏昭林

    2003-01-01

    DNA修复基因在防止机体受致癌剂作用中起重要作用,但尚不清楚特定的遗传变异对修复表现型和癌症风险的影响.通过测定308位属于欧洲发展规划组织(EPIC)的意大利人的DNA加合物水平及调查3种DNA损伤修复基因的多态性:XRCCl-Arg399Gln(外显子10),XRCC3-Thr241Met(外显子7)和XPD-Lys751Gln(外显子23).通过用DNA32P一末端标记阵列测DNA加合物水平.用PCR-RFLP测其基因型.XRCC3-241Met基因型与较高的DNA加合物水平显著相关,而XRCCl-399Gln型和XPD-751Gln型仅在从不吸烟者中才与较高的DNA加合物水平相关.XRCC3-241 Met纯合子平均DNA加合物水平为11.44±1.48(±SE),Thr/Met杂合子为7.69±0.88,而Thr/Thr纯合子为6.94±1.11(F=3.026,P=0.042).从不吸烟者XRCCl-399Gln纯合子DNA加合物水平平均为15.60±5.42,与Gln/Arg杂合子的6.16±0.97和Arg/Arg纯合子的6.78±1.10相比(F=5.237,P=0.007).调整几种混杂因素后观察到XPD-751Gln相比从不吸烟的XPD-751 Lys纯合子其比值比有显著性(OR=3.81,95% CI:1.02~14.16)且DNA加合物水平高于平均值.表明所有已分析的多态可导致不同的DNA修复,并提示需进一步探讨存在于基因多态、吸烟和其他风险因素间的交互作用.

  19. DNA damages of liver cells and expressions of DNA damage repair genes in rats exposed to vinyl chloride monomer%氯乙烯致大鼠肝细胞DNA损伤与DNA修复基因表达

    Institute of Scientific and Technical Information of China (English)

    朱守民; 王爱红; 许祖德; 吴建辉; 孙祖越; 夏昭林

    2004-01-01

    目的研究氯乙烯(VCM)对大鼠肝细胞DNA的损伤作用,及对DNA损伤修复酶[O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)、X线修复交叉互补基团1(XRCC1)和X线修复交叉互补基团3(XRCC3)]表达的影响;探索VCM所致DNA损伤的修复机制.方法采用腹腔注射VCM染毒,实验组按不同染毒剂量分为3个剂量组,分别为低剂量5 mg/kg、中剂量10 mg/kg和高剂量20 mg/kg,染毒12周,以单细胞凝胶电泳(彗星试验)测DNA损伤,免疫组化法测DNA损伤修复酶的表达.结果低、中和高剂量组大鼠肝细胞DNA损伤细胞百分率分别为11.75%、12.38%和17.63%,均高于对照组(5.67%),且中、高剂量与对照组比较,差异有显著性(P<0.05,P<0.01).MGMT和XRCC1表达随染毒剂量增加而减少,而XRCC3的表达随染毒剂量的增加而增加.VCM致DNA损伤与XRCC3表达有相关关系(r=0.438,P=0.067).结论 VCM可导致肝细胞DNA发生损伤,且存在剂量-反应关系;DNA损伤修复酶参与修复VCM所致的DNA损伤.

  20. Primetime for Learning Genes

    Science.gov (United States)

    Keifer, Joyce

    2017-01-01

    Learning genes in mature neurons are uniquely suited to respond rapidly to specific environmental stimuli. Expression of individual learning genes, therefore, requires regulatory mechanisms that have the flexibility to respond with transcriptional activation or repression to select appropriate physiological and behavioral responses. Among the mechanisms that equip genes to respond adaptively are bivalent domains. These are specific histone modifications localized to gene promoters that are characteristic of both gene activation and repression, and have been studied primarily for developmental genes in embryonic stem cells. In this review, studies of the epigenetic regulation of learning genes in neurons, particularly the brain-derived neurotrophic factor gene (BDNF), by methylation/demethylation and chromatin modifications in the context of learning and memory will be highlighted. Because of the unique function of learning genes in the mature brain, it is proposed that bivalent domains are a characteristic feature of the chromatin landscape surrounding their promoters. This allows them to be “poised” for rapid response to activate or repress gene expression depending on environmental stimuli. PMID:28208656

  1. Primetime for Learning Genes.

    Science.gov (United States)

    Keifer, Joyce

    2017-02-11

    Learning genes in mature neurons are uniquely suited to respond rapidly to specific environmental stimuli. Expression of individual learning genes, therefore, requires regulatory mechanisms that have the flexibility to respond with transcriptional activation or repression to select appropriate physiological and behavioral responses. Among the mechanisms that equip genes to respond adaptively are bivalent domains. These are specific histone modifications localized to gene promoters that are characteristic of both gene activation and repression, and have been studied primarily for developmental genes in embryonic stem cells. In this review, studies of the epigenetic regulation of learning genes in neurons, particularly the brain-derived neurotrophic factor gene (BDNF), by methylation/demethylation and chromatin modifications in the context of learning and memory will be highlighted. Because of the unique function of learning genes in the mature brain, it is proposed that bivalent domains are a characteristic feature of the chromatin landscape surrounding their promoters. This allows them to be "poised" for rapid response to activate or repress gene expression depending on environmental stimuli.

  2. An Ontology of Gene

    OpenAIRE

    Masuya, Hiroshi; Mizoguchi, Riichiro

    2012-01-01

    The concept of a gene was established in the era of classical genetics and is now essential for life science for elucidating the molecular basis of the coding of genetic information necessary to realize the body of an organism and its biological functions. However, an ontology fully representing multiple aspects of a gene is still not available. In this study, we dissected the biological and ontological definitions of bearers of genetic information, including genes and alleles. Based on this ...

  3. Placental gene therapy

    OpenAIRE

    David, A. L.; Ashcroft, R

    2009-01-01

    Gene therapy uses genetic material as a drug delivery vehicle to express therapeutic proteins. Placental gene therapy may be useful for correction of two important obstetric conditions, foetal growth restriction and pre-eclampsia in which there is a failure of the physiological trophoblast remodelling of the uterine spiral arteries in early pregnancy. The patient in this scenario is the foetus. Placental gene therapy might be justifiable when: there is reasonable certainty that the foetus wil...

  4. Antisense gene silencing

    DEFF Research Database (Denmark)

    Nielsen, Troels T; Nielsen, Jørgen E

    2013-01-01

    Since the first reports that double-stranded RNAs can efficiently silence gene expression in C. elegans, the technology of RNA interference (RNAi) has been intensively exploited as an experimental tool to study gene function. With the subsequent discovery that RNAi could also be applied to mammal......Since the first reports that double-stranded RNAs can efficiently silence gene expression in C. elegans, the technology of RNA interference (RNAi) has been intensively exploited as an experimental tool to study gene function. With the subsequent discovery that RNAi could also be applied...

  5. History of gene therapy.

    Science.gov (United States)

    Wirth, Thomas; Parker, Nigel; Ylä-Herttuala, Seppo

    2013-08-10

    Two decades after the initial gene therapy trials and more than 1700 approved clinical trials worldwide we not only have gained much new information and knowledge regarding gene therapy in general, but also learned to understand the concern that has persisted in society. Despite the setbacks gene therapy has faced, success stories have increasingly emerged. Examples for these are the positive recommendation for a gene therapy product (Glybera) by the EMA for approval in the European Union and the positive trials for the treatment of ADA deficiency, SCID-X1 and adrenoleukodystrophy. Nevertheless, our knowledge continues to grow and during the course of time more safety data has become available that helps us to develop better gene therapy approaches. Also, with the increased understanding of molecular medicine, we have been able to develop more specific and efficient gene transfer vectors which are now producing clinical results. In this review, we will take a historical view and highlight some of the milestones that had an important impact on the development of gene therapy. We will also discuss briefly the safety and ethical aspects of gene therapy and address some concerns that have been connected with gene therapy as an important therapeutic modality.

  6. Delivery Systems in Gene Therapy

    Institute of Scientific and Technical Information of China (English)

    Liu Hu; Anas El-Aneed; Cui Guohui

    2005-01-01

    1 Gene therapy Gene therapy includes the treatment of both genetically based and infectious diseases by introducing genetic materials which have therapeutic effects[1~3]. In its simplest terms, a wild type gene (which is non-functional in the cell leading to disease development) is introduced into the somatic cell lacking this gene to restore the normal gene function in this cell. Many gene therapy strategies, however, utilize genes to destroy specific cells.

  7. Gene promoters dictate histone occupancy within genes.

    Science.gov (United States)

    Perales, Roberto; Erickson, Benjamin; Zhang, Lian; Kim, Hyunmin; Valiquett, Elan; Bentley, David

    2013-10-01

    Spt6 is a transcriptional elongation factor and histone chaperone that reassembles transcribed chromatin. Genome-wide H3 mapping showed that Spt6 preferentially maintains nucleosomes within the first 500 bases of genes and helps define nucleosome-depleted regions in 5' and 3' flanking sequences. In Spt6-depleted cells, H3 loss at 5' ends correlates with reduced pol II density suggesting enhanced transcription elongation. Consistent with its 'Suppressor of Ty' (Spt) phenotype, Spt6 inactivation caused localized H3 eviction over 1-2 nucleosomes at 5' ends of Ty elements. H3 displacement differed between genes driven by promoters with 'open'/DPN and 'closed'/OPN chromatin conformations with similar pol II densities. More eviction occurred on genes with 'closed' promoters, associated with 'noisy' transcription. Moreover, swapping of 'open' and 'closed' promoters showed that they can specify distinct downstream patterns of histone eviction/deposition. These observations suggest a novel function for promoters in dictating histone dynamics within genes possibly through effects on transcriptional bursting or elongation rate.

  8. Smart Genes, Stupid Science.

    Science.gov (United States)

    Randerson, Sherman; Mahadeva, Madhu N.

    1983-01-01

    Because many people still believe that specific, identifiable genes dictate the level of human intelligence and that the number/quality of these genes can be evaluated, presents evidence from human genetics (related to nervous system development) to counter this view. Also disputes erroneous assumptions made in "heritability studies" of human…

  9. XLMR genes: update 2000.

    NARCIS (Netherlands)

    Chiurazzi, P.; Hamel, B.C.J.; Neri, G.

    2001-01-01

    This is the sixth edition of the catalogue of XLMR genes, ie X-linked genes whose malfunctioning causes mental retardation. The cloning era is not yet concluded, actually much remains to be done to account for the 202 XLMR conditions listed in this update. Many of these may eventually prove to be du

  10. Glaucoma Genes and Mechanisms.

    Science.gov (United States)

    Wiggs, Janey L

    2015-01-01

    Genetic studies have yielded important genes contributing to both early-onset and adult-onset forms of glaucoma. The proteins encoded by the current collection of glaucoma genes participate in a broad range of cellular processes and biological systems. Approximately half the glaucoma-related genes function in the extracellular matrix, however proteins involved in cytokine signaling, lipid metabolism, membrane biology, regulation of cell division, autophagy, and ocular development also contribute to the disease pathogenesis. While the function of these proteins in health and disease are not completely understood, recent studies are providing insight into underlying disease mechanisms, a critical step toward the development of gene-based therapies. In this review, genes known to cause early-onset glaucoma or contribute to adult-onset glaucoma are organized according to the cell processes or biological systems that are impacted by the function of the disease-related protein product.

  11. Gene therapy for hemophilia.

    Science.gov (United States)

    Chuah, M K; Evens, H; VandenDriessche, T

    2013-06-01

    Hemophilia A and B are X-linked monogenic disorders resulting from deficiencies of factor VIII and FIX, respectively. Purified clotting factor concentrates are currently intravenously administered to treat hemophilia, but this treatment is non-curative. Therefore, gene-based therapies for hemophilia have been developed to achieve sustained high levels of clotting factor expression to correct the clinical phenotype. Over the past two decades, different types of viral and non-viral gene delivery systems have been explored for hemophilia gene therapy research with a variety of target cells, particularly hepatocytes, hematopoietic stem cells, skeletal muscle cells, and endothelial cells. Lentiviral and adeno-associated virus (AAV)-based vectors are among the most promising vectors for hemophilia gene therapy. In preclinical hemophilia A and B animal models, the bleeding phenotype was corrected with these vectors. Some of these promising preclinical results prompted clinical translation to patients suffering from a severe hemophilic phenotype. These patients receiving gene therapy with AAV vectors showed long-term expression of therapeutic FIX levels, which is a major step forwards in this field. Nevertheless, the levels were insufficient to prevent trauma or injury-induced bleeding episodes. Another challenge that remains is the possible immune destruction of gene-modified cells by effector T cells, which are directed against the AAV vector antigens. It is therefore important to continuously improve the current gene therapy approaches to ultimately establish a real cure for hemophilia. © 2013 International Society on Thrombosis and Haemostasis.

  12. Gene amplification in carcinogenesis

    Directory of Open Access Journals (Sweden)

    Lucimari Bizari

    2006-01-01

    Full Text Available Gene amplification increases the number of genes in a genome and can give rise to karyotype abnormalities called double minutes (DM and homogeneously staining regions (HSR, both of which have been widely observed in human tumors but are also known to play a major role during embryonic development due to the fact that they are responsible for the programmed increase of gene expression. The etiology of gene amplification during carcinogenesis is not yet completely understood but can be considered a result of genetic instability. Gene amplification leads to an increase in protein expression and provides a selective advantage during cell growth. Oncogenes such as CCND1, c-MET, c-MYC, ERBB2, EGFR and MDM2 are amplified in human tumors and can be associated with increased expression of their respective proteins or not. In general, gene amplification is associated with more aggressive tumors, metastases, resistance to chemotherapy and a decrease in the period during which the patient stays free of the disease. This review discusses the major role of gene amplification in the progression of carcinomas, formation of genetic markers and as possible therapeutic targets for the development of drugs for the treatment of some types of tumors.

  13. Antisense gene silencing

    DEFF Research Database (Denmark)

    Nielsen, Troels T; Nielsen, Jørgen E

    2013-01-01

    Since the first reports that double-stranded RNAs can efficiently silence gene expression in C. elegans, the technology of RNA interference (RNAi) has been intensively exploited as an experimental tool to study gene function. With the subsequent discovery that RNAi could also be applied...... to mammalian cells, the technology of RNAi expanded from being a valuable experimental tool to being an applicable method for gene-specific therapeutic regulation, and much effort has been put into further refinement of the technique. This review will focus on how RNAi has developed over the years and how...

  14. Gene Therapy of Cancerous Diseases

    OpenAIRE

    Valenčáková, A.; Dziaková, A.; Hatalová, E.

    2015-01-01

    Gene therapy of cancerous diseases provides new means of curing patients with oncologic illnesses. There are several approaches in treating cancer by gene therapy. Most commonly used methods are: cancer immunogene therapy, suicide gene therapy, application of tumor-suppressor genes, antiangiogenic therapy, mesenchymal stem cells used as vectors, gene directed enzyme/prodrug therapy and bacteria used as anti-cancer agents. Cancer gene immunotherapy uses several immunologic agents for the purp...

  15. "Bad genes" & criminal responsibility.

    Science.gov (United States)

    González-Tapia, María Isabel; Obsuth, Ingrid

    2015-01-01

    The genetics of the accused is trying to break into the courts. To date several candidate genes have been put forward and their links to antisocial behavior have been examined and documented with some consistency. In this paper, we focus on the so called "warrior gene", or the low-activity allele of the MAOA gene, which has been most consistently related to human behavior and specifically to violence and antisocial behavior. In preparing this paper we had two objectives. First, to summarize and analyze the current scientific evidence, in order to gain an in depth understanding of the state of the issue and determine whether a dominant line of generally accepted scientific knowledge in this field can be asserted. Second, to derive conclusions and put forward recommendations related to the use of genetic information, specifically the presence of the low-activity genotype of the MAOA gene, in modulation of criminal responsibility in European and US courts.

  16. Gene Expression Omnibus (GEO)

    Data.gov (United States)

    U.S. Department of Health & Human Services — Gene Expression Omnibus is a public functional genomics data repository supporting MIAME-compliant submissions of array- and sequence-based data. Tools are provided...

  17. Gene therapy in ophthalmology.

    Science.gov (United States)

    Uthra, Satagopan; Kumaramanickavel, Govindasamy

    2009-09-01

    It has been more than a year since ophthalmologists and scientists under Dr. Robin Ali's team at the Moorsfield Eye Hospital and the Institute of Ophthalmology, University College London, successfully treated patients with a severely blinding disease, Leber's congenital amaurosis (LCA) using gene therapy. This success does not look to be transient, and this achievement in gene replacement therapy clinical trial for LCA has instilled hope in numerous families with patients suffering from this and similar retinal degenerative diseases, for whom restoration of lost vision has remained a distant dream so far. The encouragement that this success has given is expected to also lead to start of clinical trials for other blinding ocular diseases for which gene therapy experiments at the laboratory and animal levels have been successful. This article reviews the various studies that have led to the understanding of gene therapy outcomes in human ocular diseases and attempts to provide a brief sketch of successful clinical trials.

  18. Gene therapy for hemophilia.

    Science.gov (United States)

    Hortelano, G; Chang, P L

    2000-01-01

    Hemophilia A and B are X-linked genetic disorders caused by deficiency of the coagulation factors VIII and IX, respectively. Because of the health hazards and costs of current product replacement therapy, much effort is devoted to the development of gene therapy for these disorders. Approaches to gene therapy for the hemophilias include: ex vivo gene therapy in which cells from the intended recipients are explanted, genetically modified to secrete Factor VIII or IX, and reimplanted into the donor; in vivo gene therapy in which Factor VIII or IX encoding vectors are directly injected into the recipient; and non-autologous gene therapy in which universal cell lines engineered to secrete Factor VIII or IX are enclosed in immuno-protective devices before implantation into recipients. Research into these approaches is aided by the many murine and canine models available. While problems of achieving high and sustained levels of factor delivery, and issues related to efficacy, safety and cost are still to be resolved, progress in gene therapy for the hemophilias has been encouraging and is likely to reach human clinical trial in the foreseeable future.

  19. Evidence for homosexuality gene

    Energy Technology Data Exchange (ETDEWEB)

    Pool, R.

    1993-07-16

    A genetic analysis of 40 pairs of homosexual brothers has uncovered a region on the X chromosome that appears to contain a gene or genes for homosexuality. When analyzing the pedigrees of homosexual males, the researcheres found evidence that the trait has a higher likelihood of being passed through maternal genes. This led them to search the X chromosome for genes predisposing to homosexuality. The researchers examined the X chromosomes of pairs of homosexual brothers for regions of DNA that most or all had in common. Of the 40 sets of brothers, 33 shared a set of five markers in the q28 region of the long arm of the X chromosome. The linkage has a LOD score of 4.0, which translates into a 99.5% certainty that there is a gene or genes in this area that predispose males to homosexuality. The chief researcher warns, however, that this one site cannot explain all instances of homosexuality, since there were some cases where the trait seemed to be passed paternally. And even among those brothers where there was no evidence that the trait was passed paternally, seven sets of brothers did not share the Xq28 markers. It seems likely that homosexuality arises from a variety of causes.

  20. Gene-gene, gene-environment, gene-nutrient interactionsand single nucleotide polymorphisms of inflammatorycytokines

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Inflammation plays a significant role in the etiologyof type 2 diabetes mellitus (T2DM). The rise in thepro-inflammatory cytokines is the essential step inglucotoxicity and lipotoxicity induced mitochondrialinjury, oxidative stress and beta cell apoptosis inT2DM. Among the recognized markers are interleukin(IL)-6, IL-1, IL-10, IL-18, tissue necrosis factor-alpha(TNF-α), C-reactive protein, resistin, adiponectin, tissueplasminogen activator, fibrinogen and heptoglobins.Diabetes mellitus has firm genetic and very strongenvironmental influence; exhibiting a polygenic modeof inheritance. Many single nucleotide polymorphisms(SNPs) in various genes including those of pro and antiinflammatorycytokines have been reported as a riskfor T2DM. Not all the SNPs have been confirmed byunifying results in different studies and wide variationshave been reported in various ethnic groups. Theinter-ethnic variations can be explained by the factthat gene expression may be regulated by gene-gene,gene-environment and gene-nutrient interactions. Thisreview highlights the impact of these interactions ondetermining the role of single nucleotide polymorphismof IL-6, TNF-α, resistin and adiponectin in pathogenesisof T2DM.

  1. Identification of four soybean reference genes for gene expression normalization

    Science.gov (United States)

    Gene expression analysis requires the use of reference genes stably expressed independently of specific tissues or environmental conditions. Housekeeping genes (e.g., actin, tubulin, ribosomal, polyubiquitin and elongation factor 1-alpha) are commonly used as reference genes with the assumption tha...

  2. The Mycoplasma hominis vaa gene displays a mosaic gene structure

    DEFF Research Database (Denmark)

    Boesen, Thomas; Emmersen, Jeppe M. G.; Jensen, Lise T.;

    1998-01-01

    Mycoplasma hominis contains a variable adherence-associated (vaa) gene. To classify variants of the vaa genes, we examined 42 M. hominis isolated by PCR, DNA sequencing and immunoblotting. This uncovered the existence of five gene categories. Comparison of the gene types revealed a modular compos...

  3. Hox genes and study of Hox genes in crustacean

    Institute of Scientific and Technical Information of China (English)

    HOU Lin; CHEN Zhijuan; XU Mingyu; LIN Shengguo; WANG Lu

    2004-01-01

    Homeobox genes have been discovered in many species. These genes are known to play a major role in specifying regional identity along the anterior-posterior axis of animals from a wide range of phyla.The products of the homeotic genes are a set of evolutionarily conserved transcription factors that control elaborate developmental processes and specify cell fates in metazoans. Crustacean, presenting a variety of body plans not encountered in any other class or phylum of the Metazoa, has been shown to possess a single set of homologous Hox genes like insect. The ancestral crustacean Hox gene complex comprised ten genes: eight homologous to the hometic Hox genes and two related to nonhomeotic genes presented within the insect Hox complexes. The crustacean in particular exhibits an abundant diversity segment specialization and tagmosis. This morphological diversity relates to the Hox genes. In crustacean body plan, different Hox genes control different segments and tagmosis.

  4. Entrez Gene: gene-centered information at NCBI

    OpenAIRE

    Maglott, Donna; Ostell, Jim; Pruitt, Kim D; Tatusova, Tatiana

    2006-01-01

    Entrez Gene () is NCBI's database for gene-specific information. Entrez Gene includes records from genomes that have been completely sequenced, that have an active research community to contribute gene-specific information or that are scheduled for intense sequence analysis. The content of Entrez Gene represents the result of both curation and automated integration of data from NCBI's Reference Sequence project (RefSeq), from collaborating model organism databases and from other databases wit...

  5. Gene therapy for brain tumors.

    Science.gov (United States)

    Bansal, K; Engelhard, H H

    2000-09-01

    "Gene therapy" can be defined as the transfer of genetic material into a patient's cells for therapeutic purposes. To date, a diverse and creative assortment of treatment strategies utilizing gene therapy have been devised, including gene transfer for modulating the immune system, enzyme prodrug ("suicide gene") therapy, oncolytic therapy, replacement/therapeutic gene transfer, and antisense therapy. For malignant glioma, gene-directed prodrug therapy using the herpes simplex virus thymidine kinase gene was the first gene therapy attempted clinically. A variety of different strategies have now been pursued experimentally and in clinical trials. Although, to date, gene therapy for brain tumors has been found to be reasonably safe, concerns still exist regarding issues related to viral delivery, transduction efficiency, potential pathologic response of the brain, and treatment efficacy. Improved viral vectors are being sought, and potential use of gene therapy in combination with other treatments is being investigated.

  6. Introns in higher plant genes

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    The intron is an important component of eukaryotic gene. Extensive studies have been conducted to get a better understanding of its structure and function. This paper presents a brief review of the structure and function of introns in higher plant genes. It is shown that higher plant introns possess structural properties shared by all eukaryotic introns, however, they also exhibit a striking degree of diversity. The process of intron splicing in higher plant genes involves interaction between multiple cis-acting elements and trans-acting factors, such as 5′ splicing site, 3′ splicing site and many protein factors. The process of intron splicing is an important level at which gene expression is regulated. Especially alternative splicing of intron can regulate time and space of gene expression. In addition, some introns in higher plant genes also regulate gene expression by affecting the pattern of gene expression, enhancing the level of gene expression and driving the gene expression.

  7. Gene therapy prospects--intranasal delivery of therapeutic genes.

    Science.gov (United States)

    Podolska, Karolina; Stachurska, Anna; Hajdukiewicz, Karolina; Małecki, Maciej

    2012-01-01

    Gene therapy is recognized to be a novel method for the treatment of various disorders. Gene therapy strategies involve gene manipulation on broad biological processes responsible for the spreading of diseases. Cancer, monogenic diseases, vascular and infectious diseases are the main targets of gene therapy. In order to obtain valuable experimental and clinical results, sufficient gene transfer methods are required. Therapeutic genes can be administered into target tissues via gene carriers commonly defined as vectors. The retroviral, adenoviral and adeno-associated virus based vectors are most frequently used in the clinic. So far, gene preparations may be administered directly into target organs or by intravenous, intramuscular, intratumor or intranasal injections. It is common knowledge that the number of gene therapy clinical trials has rapidly increased. However, some limitations such as transfection efficiency and stable and long-term gene expression are still not resolved. Consequently, great effort is focused on the evaluation of new strategies of gene delivery. There are many expectations associated with intranasal delivery of gene preparations for the treatment of diseases. Intranasal delivery of therapeutic genes is regarded as one of the most promising forms of pulmonary gene therapy research. Gene therapy based on inhalation of gene preparations offers an alternative way for the treatment of patients suffering from such lung diseases as cystic fibrosis, alpha-1-antitrypsin defect, or cancer. Experimental and first clinical trials based on plasmid vectors or recombinant viruses have revealed that gene preparations can effectively deliver therapeutic or marker genes to the cells of the respiratory tract. The noninvasive intranasal delivery of gene preparations or conventional drugs seems to be very encouraging, although basic scientific research still has to continue.

  8. FunGene: the Functional Gene Pipeline and Repository

    Directory of Open Access Journals (Sweden)

    Jordan A. Fish

    2013-10-01

    Full Text Available Ribosomal RNA genes have become the standard molecular markers for microbial community analysis for good reasons, including universal occurrence in cellular organisms, availability of large databases, and ease of rRNA gene region amplification and analysis. As markers, however, rRNA genes have some significant limitations. The rRNA genes are often present in multiple copies, unlike most protein-coding genes. The slow rate of change in rRNA genes means that multiple species sometimes share identical 16S rRNA gene sequences, while many more species share identical sequences in the short 16S rRNA regions commonly analyzed. In addition, the genes involved in many important processes are not distributed in a phylogenetically coherent manner, potentially due to gene loss or horizontal gene transfer.While rRNA genes remain the most commonly used markers, key genes in ecologically important pathways, e.g., those involved in carbon and nitrogen cycling, can provide important insights into community composition and function not obtainable through rRNA analysis. However, working with ecofunctional gene data requires some tools beyond those required for rRNA analysis. To address this, our Functional Gene Pipeline and Repository (FunGene; http://fungene.cme.msu.edu/ offers databases of many common ecofunctional genes and proteins, as well as integrated tools that allow researchers to browse these collections and choose subsets for further analysis, build phylogenetic trees, test primers and probes for coverage, and download aligned sequences. Additional FunGene tools are specialized to process coding gene amplicon data. For example, FrameBot produces frameshift-corrected protein and DNA sequences from raw reads while finding the most closely related protein reference sequence. These tools can help provide better insight into microbial communities by directly studying key genes involved in important ecological processes.

  9. Gene decay in archaea

    Directory of Open Access Journals (Sweden)

    M. W. J. van Passel

    2007-01-01

    Full Text Available The gene-dense chromosomes of archaea and bacteria were long thought to be devoid of pseudogenes, but with the massive increase in available genome sequences, whole genome comparisons between closely related species have identified mutations that have rendered numerous genes inactive. Comparative analyses of sequenced archaeal genomes revealed numerous pseudogenes, which can constitute up to 8.6% of the annotated coding sequences in some genomes. The largest proportion of pseudogenes is created by gene truncations, followed by frameshift mutations. Within archaeal genomes, large numbers of pseudogenes contain more than one inactivating mutation, suggesting that pseudogenes are deleted from the genome more slowly in archaea than in bacteria. Although archaea seem to retain pseudogenes longer than do bacteria, most archaeal genomes have unique repertoires of pseudogenes.

  10. A review on microcephaly genes

    Directory of Open Access Journals (Sweden)

    Irshad S.

    2012-06-01

    Full Text Available This review aims to summarize the recent findings regarding microcephaly genes. We have discussed the molecular genetics studies of microcephaly genes including a comprehensive appraisal of the seven mapped loci (MCPH1–MCPH7, their corresponding genes and protein products of the genes, their likely role in normal brain development and the details of the mutations reported in these genes.

  11. Gene therapy for skin diseases.

    Science.gov (United States)

    Gorell, Emily; Nguyen, Ngon; Lane, Alfred; Siprashvili, Zurab

    2014-04-01

    The skin possesses qualities that make it desirable for gene therapy, and studies have focused on gene therapy for multiple cutaneous diseases. Gene therapy uses a vector to introduce genetic material into cells to alter gene expression, negating a pathological process. This can be accomplished with a variety of viral vectors or nonviral administrations. Although results are promising, there are several potential pitfalls that must be addressed to improve the safety profile to make gene therapy widely available clinically.

  12. Gene Therapy for Skin Diseases

    OpenAIRE

    2014-01-01

    The skin possesses qualities that make it desirable for gene therapy, and studies have focused on gene therapy for multiple cutaneous diseases. Gene therapy uses a vector to introduce genetic material into cells to alter gene expression, negating a pathological process. This can be accomplished with a variety of viral vectors or nonviral administrations. Although results are promising, there are several potential pitfalls that must be addressed to improve the safety profile to make gene thera...

  13. Correlating Expression Data with Gene Function Using Gene Ontology

    Institute of Scientific and Technical Information of China (English)

    LIU,Qi; DENG,Yong; WANG,Chuan; SHI,Tie-Liu; LI,Yi-Xue

    2006-01-01

    Clustering is perhaps one of the most widely used tools for microarray data analysis. Proposed roles for genes of unknown function are inferred from clusters of genes similarity expressed across many biological conditions.However, whether function annotation by similarity metrics is reliable or not and to what extent the similarity in gene expression patterns is useful for annotation of gene functions, has not been evaluated. This paper made a comprehensive research on the correlation between the similarity of expression data and of gene functions using Gene Ontology. It has been found that although the similarity in expression patterns and the similarity in gene functions are significantly dependent on each other, this association is rather weak. In addition, among the three categories of Gene Ontology, the similarity of expression data is more useful for cellular component annotation than for biological process and molecular function. The results presented are interesting for the gene functions prediction research area.

  14. The gene tree delusion.

    Science.gov (United States)

    Springer, Mark S; Gatesy, John

    2016-01-01

    Higher-level relationships among placental mammals are mostly resolved, but several polytomies remain contentious. Song et al. (2012) claimed to have resolved three of these using shortcut coalescence methods (MP-EST, STAR) and further concluded that these methods, which assume no within-locus recombination, are required to unravel deep-level phylogenetic problems that have stymied concatenation. Here, we reanalyze Song et al.'s (2012) data and leverage these re-analyses to explore key issues in systematics including the recombination ratchet, gene tree stoichiometry, the proportion of gene tree incongruence that results from deep coalescence versus other factors, and simulations that compare the performance of coalescence and concatenation methods in species tree estimation. Song et al. (2012) reported an average locus length of 3.1 kb for the 447 protein-coding genes in their phylogenomic dataset, but the true mean length of these loci (start codon to stop codon) is 139.6 kb. Empirical estimates of recombination breakpoints in primates, coupled with consideration of the recombination ratchet, suggest that individual coalescence genes (c-genes) approach ∼12 bp or less for Song et al.'s (2012) dataset, three to four orders of magnitude shorter than the c-genes reported by these authors. This result has general implications for the application of coalescence methods in species tree estimation. We contend that it is illogical to apply coalescence methods to complete protein-coding sequences. Such analyses amalgamate c-genes with different evolutionary histories (i.e., exons separated by >100,000 bp), distort true gene tree stoichiometry that is required for accurate species tree inference, and contradict the central rationale for applying coalescence methods to difficult phylogenetic problems. In addition, Song et al.'s (2012) dataset of 447 genes includes 21 loci with switched taxonomic names, eight duplicated loci, 26 loci with non-homologous sequences that are

  15. Neighboring Genes Show Correlated Evolution in Gene Expression

    Science.gov (United States)

    Ghanbarian, Avazeh T.; Hurst, Laurence D.

    2015-01-01

    When considering the evolution of a gene’s expression profile, we commonly assume that this is unaffected by its genomic neighborhood. This is, however, in contrast to what we know about the lack of autonomy between neighboring genes in gene expression profiles in extant taxa. Indeed, in all eukaryotic genomes genes of similar expression-profile tend to cluster, reflecting chromatin level dynamics. Does it follow that if a gene increases expression in a particular lineage then the genomic neighbors will also increase in their expression or is gene expression evolution autonomous? To address this here we consider evolution of human gene expression since the human-chimp common ancestor, allowing for both variation in estimation of current expression level and error in Bayesian estimation of the ancestral state. We find that in all tissues and both sexes, the change in gene expression of a focal gene on average predicts the change in gene expression of neighbors. The effect is highly pronounced in the immediate vicinity (genes increasing their expression in humans tend to avoid nuclear lamina domains and be enriched for the gene activator 5-hydroxymethylcytosine, we conclude that, most probably owing to chromatin level control of gene expression, a change in gene expression of one gene likely affects the expression evolution of neighbors, what we term expression piggybacking, an analog of hitchhiking. PMID:25743543

  16. Gene interaction of gene polymorphism on lung cancer risk%基因多态性在肺癌发生中交互作用

    Institute of Scientific and Technical Information of China (English)

    梁戈玉; 浦跃朴; 尹立红

    2007-01-01

    目的 探讨代谢酶基因与修复酶基因多态性在肺癌发生中的交互作用.方法 采用1:1配对病例-对照研究,收集原发性肺癌患者227例和相应非肿瘤对照227例,对CYP1BI、CYP2C19、CYP2D6、CYP2E1、GSTM1、GSTT1、GSTP1、mEH、NQO1、XRCC1、XRCC3、hOGG1、NAT2、XPD基因多态性进行检测,应用Logistic回归对基因-基因交互作用进行分析.结果 CYP2C19突变基因型与NQO1突变基因型,mEH-exon3突变基因型与NQO1突变基因型之间对肺癌的发生存在交互作用,可导致肺癌易感性的增高.未见其他代谢酶基因与修复酶基因在汉族人群肺癌发生中存在交互作用.结论 对基因多态性的联合检测更有利于筛选易感人群.今后应加大样本含量,进行多基因之间的联合作用分析.

  17. Searching for speciation genes

    DEFF Research Database (Denmark)

    Holt, Benjamin George; Côté, Isabelle M; Emerson, Brent C

    2011-01-01

    Closely related species that show clear phenotypic divergence, but without obvious geographic barriers, can provide opportunities to study how diversification can occur when opportunities for allopatric speciation are limited. We examined genetic divergence in the coral reef fish genus Hypoplectr...... evidence for genes that may be associated with colour morphotype in the genus Hypoplectrus....

  18. Gene therapy in ophthalmology

    Directory of Open Access Journals (Sweden)

    Satagopan Uthra

    2009-01-01

    Full Text Available It has been more than a year since ophthalmologists and scientists under Dr. Robin Ali′s team at the Moorsfield Eye Hospital and the Institute of Ophthalmology, University College London, successfully treated patients with a severely blinding disease, Leber′s congenital amaurosis (LCA using gene therapy. This success does not look to be transient, and this achievement in gene replacement therapy clinical trial for LCA has instilled hope in numerous families with patients suffering from this and similar retinal degenerative diseases, for whom restoration of lost vision has remained a distant dream so far. The encouragement that this success has given is expected to also lead to start of clinical trials for other blinding ocular diseases for which gene therapy experiments at the laboratory and animal levels have been successful. This article reviews the various studies that have led to the understanding of gene therapy outcomes in human ocular diseases and attempts to provide a brief sketch of successful clinical trials.

  19. Old genes experience stronger translational selection than young genes.

    Science.gov (United States)

    Yin, Hongyan; Ma, Lina; Wang, Guangyu; Li, Mengwei; Zhang, Zhang

    2016-09-15

    Selection on synonymous codon usage for translation efficiency and/or accuracy has been identified as a widespread mechanism in many living organisms. However, it remains unknown whether translational selection associates closely with gene age and acts differentially on genes with different evolutionary ages. To address this issue, here we investigate the strength of translational selection acting on different aged genes in human. Our results show that old genes present stronger translational selection than young genes, demonstrating that translational selection correlates positively with gene age. We further explore the difference of translational selection in duplicates vs. singletons and in housekeeping vs. tissue-specific genes. We find that translational selection acts comparably in old singletons and old duplicates and stronger translational selection in old genes is contributed primarily by housekeeping genes. For young genes, contrastingly, singletons experience stronger translational selection than duplicates, presumably due to redundant function of duplicated genes during their early evolutionary stage. Taken together, our results indicate that translational selection acting on a gene would not be constant during all stages of evolution, associating closely with gene age. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Genes2FANs: connecting genes through functional association networks

    Directory of Open Access Journals (Sweden)

    Dannenfelser Ruth

    2012-07-01

    Full Text Available Abstract Background Protein-protein, cell signaling, metabolic, and transcriptional interaction networks are useful for identifying connections between lists of experimentally identified genes/proteins. However, besides physical or co-expression interactions there are many ways in which pairs of genes, or their protein products, can be associated. By systematically incorporating knowledge on shared properties of genes from diverse sources to build functional association networks (FANs, researchers may be able to identify additional functional interactions between groups of genes that are not readily apparent. Results Genes2FANs is a web based tool and a database that utilizes 14 carefully constructed FANs and a large-scale protein-protein interaction (PPI network to build subnetworks that connect lists of human and mouse genes. The FANs are created from mammalian gene set libraries where mouse genes are converted to their human orthologs. The tool takes as input a list of human or mouse Entrez gene symbols to produce a subnetwork and a ranked list of intermediate genes that are used to connect the query input list. In addition, users can enter any PubMed search term and then the system automatically converts the returned results to gene lists using GeneRIF. This gene list is then used as input to generate a subnetwork from the user’s PubMed query. As a case study, we applied Genes2FANs to connect disease genes from 90 well-studied disorders. We find an inverse correlation between the counts of links connecting disease genes through PPI and links connecting diseases genes through FANs, separating diseases into two categories. Conclusions Genes2FANs is a useful tool for interpreting the relationships between gene/protein lists in the context of their various functions and networks. Combining functional association interactions with physical PPIs can be useful for revealing new biology and help form hypotheses for further experimentation. Our

  1. Industrial scale gene synthesis.

    Science.gov (United States)

    Notka, Frank; Liss, Michael; Wagner, Ralf

    2011-01-01

    The most recent developments in the area of deep DNA sequencing and downstream quantitative and functional analysis are rapidly adding a new dimension to understanding biochemical pathways and metabolic interdependencies. These increasing insights pave the way to designing new strategies that address public needs, including environmental applications and therapeutic inventions, or novel cell factories for sustainable and reconcilable energy or chemicals sources. Adding yet another level is building upon nonnaturally occurring networks and pathways. Recent developments in synthetic biology have created economic and reliable options for designing and synthesizing genes, operons, and eventually complete genomes. Meanwhile, high-throughput design and synthesis of extremely comprehensive DNA sequences have evolved into an enabling technology already indispensable in various life science sectors today. Here, we describe the industrial perspective of modern gene synthesis and its relationship with synthetic biology. Gene synthesis contributed significantly to the emergence of synthetic biology by not only providing the genetic material in high quality and quantity but also enabling its assembly, according to engineering design principles, in a standardized format. Synthetic biology on the other hand, added the need for assembling complex circuits and large complexes, thus fostering the development of appropriate methods and expanding the scope of applications. Synthetic biology has also stimulated interdisciplinary collaboration as well as integration of the broader public by addressing socioeconomic, philosophical, ethical, political, and legal opportunities and concerns. The demand-driven technological achievements of gene synthesis and the implemented processes are exemplified by an industrial setting of large-scale gene synthesis, describing production from order to delivery.

  2. Endovascular Gene Delivery from a Stent Platform: Gene- Eluting Stents.

    Science.gov (United States)

    Fishbein, Ilia; Chorny, Michael; Adamo, Richard F; Forbes, Scott P; Corrales, Ricardo A; Alferiev, Ivan S; Levy, Robert J

    A synergistic impact of research in the fields of post-angioplasty restenosis, drug-eluting stents and vascular gene therapy over the past 15 years has shaped the concept of gene-eluting stents. Gene-eluting stents hold promise of overcoming some biological and technical problems inherent to drug-eluting stent technology. As the field of gene-eluting stents matures it becomes evident that all three main design modules of a gene-eluting stent: a therapeutic transgene, a vector and a delivery system are equally important for accomplishing sustained inhibition of neointimal formation in arteries treated with gene delivery stents. This review summarizes prior work on stent-based gene delivery and discusses the main optimization strategies required to move the field of gene-eluting stents to clinical translation.

  3. Tumor-specific gene expression patterns with gene expression profiles

    Institute of Scientific and Technical Information of China (English)

    RUAN Xiaogang; LI Yingxin; LI Jiangeng; GONG Daoxiong; WANG Jinlian

    2006-01-01

    Gene expression profiles of 14 common tumors and their counterpart normal tissues were analyzed with machine learning methods to address the problem of selection of tumor-specific genes and analysis of their differential expressions in tumor tissues. First, a variation of the Relief algorithm, "RFE_Relief algorithm" was proposed to learn the relations between genes and tissue types. Then, a support vector machine was employed to find the gene subset with the best classification performance for distinguishing cancerous tissues and their counterparts. After tissue-specific genes were removed, cross validation experiments were employed to demonstrate the common deregulated expressions of the selected gene in tumor tissues. The results indicate the existence of a specific expression fingerprint of these genes that is shared in different tumor tissues, and the hallmarks of the expression patterns of these genes in cancerous tissues are summarized at the end of this paper.

  4. Entrez Gene: gene-centered information at NCBI.

    Science.gov (United States)

    Maglott, Donna; Ostell, Jim; Pruitt, Kim D; Tatusova, Tatiana

    2011-01-01

    Entrez Gene (http://www.ncbi.nlm.nih.gov/gene) is National Center for Biotechnology Information (NCBI)'s database for gene-specific information. Entrez Gene maintains records from genomes which have been completely sequenced, which have an active research community to submit gene-specific information, or which are scheduled for intense sequence analysis. The content represents the integration of curation and automated processing from NCBI's Reference Sequence project (RefSeq), collaborating model organism databases, consortia such as Gene Ontology and other databases within NCBI. Records in Entrez Gene are assigned unique, stable and tracked integers as identifiers. The content (nomenclature, genomic location, gene products and their attributes, markers, phenotypes and links to citations, sequences, variation details, maps, expression, homologs, protein domains and external databases) is available via interactive browsing through NCBI's Entrez system, via NCBI's Entrez programming utilities (E-Utilities) and for bulk transfer by FTP.

  5. Effects of PCB153 on DNA damage and DNA repair-related genes expressions induced by PBDE-47 in human neuroblastoma cells in vitro%PCB153对PBDE-47致SH-SY5Y细胞DNA损伤和修复基因表达的影响

    Institute of Scientific and Technical Information of China (English)

    高萍; 何卫红; 何平; 徐八一; 徐志霞; 王爱国; 陈学敏

    2008-01-01

    目的 探讨PCB153和PBDE-47单独及联合染毒对SH-SY5Y细胞DNA损伤及其修复基因表达的影响.方法 设DMSO溶剂对照组,1、5、10μmol/L PBDE-47(低、中、高)单独染毒组和与5μmol/L PCB153联合染毒组及相应的抗氧化剂组(N-乙酰-L-半胱氨酸NAC 100μmol/L),分别对SH-SY5Y细胞染毒24h.用单细胞凝胶电泳试验测定DNA损伤情况,用Real Time PCR检测DNA损伤修复酶XRCCI及XRCC3 mRNA表达情况.结果 中、高剂量单独染毒组和中、高剂量联合染毒组细胞尾部DNA百分率、Olive尾距均显著高于对照组(P<0.05),且呈现明显的剂量.效应关系,中、高联合染毒组细胞尾部DNA百分率、Olive尾距均显著高于相应的PBDE-47或PCB153单独染毒组(P<0.05),加入抗氧化剂后其细胞尾部DNA百分率及Olive尾距均明显下降(P<0.05),高剂量联合组对细胞DNA损伤具有交互作用(F=23.74,P<0.01);高剂量染毒组及中、高剂量联合染毒组XRCC1 mRNA表达与对照组相比均明显下降(P<0.05),加入抗氧化剂后其XRCCI mRNA表达上升(P<0.05);高剂量单独和联合染毒组XRCC3 mRNA表达与对照组相比均明显上升(P<0.05),加入抗氧化剂后可使XRCC3 mRNA表达明显下降(P<0.05).相关分析结果表明,细胞DNA损伤与XRCC1mRNA的表达呈负相关,与XRCC3 mRNA的表达呈正相关(r分别为0.74,0.76,P<0.05).结论 一定剂量的PBDE-47可导致DNA损伤和影响DNA损伤修复基因的表达,PCB153可增强PBDE-47对细胞DNA的损伤作用,氧化应激可能在PBDE-47致DNA损伤过程中发挥了重要作用.

  6. Gene set analysis for longitudinal gene expression data

    Directory of Open Access Journals (Sweden)

    Piepho Hans-Peter

    2011-07-01

    Full Text Available Abstract Background Gene set analysis (GSA has become a successful tool to interpret gene expression profiles in terms of biological functions, molecular pathways, or genomic locations. GSA performs statistical tests for independent microarray samples at the level of gene sets rather than individual genes. Nowadays, an increasing number of microarray studies are conducted to explore the dynamic changes of gene expression in a variety of species and biological scenarios. In these longitudinal studies, gene expression is repeatedly measured over time such that a GSA needs to take into account the within-gene correlations in addition to possible between-gene correlations. Results We provide a robust nonparametric approach to compare the expressions of longitudinally measured sets of genes under multiple treatments or experimental conditions. The limiting distributions of our statistics are derived when the number of genes goes to infinity while the number of replications can be small. When the number of genes in a gene set is small, we recommend permutation tests based on our nonparametric test statistics to achieve reliable type I error and better power while incorporating unknown correlations between and within-genes. Simulation results demonstrate that the proposed method has a greater power than other methods for various data distributions and heteroscedastic correlation structures. This method was used for an IL-2 stimulation study and significantly altered gene sets were identified. Conclusions The simulation study and the real data application showed that the proposed gene set analysis provides a promising tool for longitudinal microarray analysis. R scripts for simulating longitudinal data and calculating the nonparametric statistics are posted on the North Dakota INBRE website http://ndinbre.org/programs/bioinformatics.php. Raw microarray data is available in Gene Expression Omnibus (National Center for Biotechnology Information with

  7. Optimal Reference Genes for Gene Expression Normalization in Trichomonas vaginalis.

    Science.gov (United States)

    dos Santos, Odelta; de Vargas Rigo, Graziela; Frasson, Amanda Piccoli; Macedo, Alexandre José; Tasca, Tiana

    2015-01-01

    Trichomonas vaginalis is the etiologic agent of trichomonosis, the most common non-viral sexually transmitted disease worldwide. This infection is associated with several health consequences, including cervical and prostate cancers and HIV acquisition. Gene expression analysis has been facilitated because of available genome sequences and large-scale transcriptomes in T. vaginalis, particularly using quantitative real-time polymerase chain reaction (qRT-PCR), one of the most used methods for molecular studies. Reference genes for normalization are crucial to ensure the accuracy of this method. However, to the best of our knowledge, a systematic validation of reference genes has not been performed for T. vaginalis. In this study, the transcripts of nine candidate reference genes were quantified using qRT-PCR under different cultivation conditions, and the stability of these genes was compared using the geNorm and NormFinder algorithms. The most stable reference genes were α-tubulin, actin and DNATopII, and, conversely, the widely used T. vaginalis reference genes GAPDH and β-tubulin were less stable. The PFOR gene was used to validate the reliability of the use of these candidate reference genes. As expected, the PFOR gene was upregulated when the trophozoites were cultivated with ferrous ammonium sulfate when the DNATopII, α-tubulin and actin genes were used as normalizing gene. By contrast, the PFOR gene was downregulated when the GAPDH gene was used as an internal control, leading to misinterpretation of the data. These results provide an important starting point for reference gene selection and gene expression analysis with qRT-PCR studies of T. vaginalis.

  8. Dominance from the perspective of gene-gene and gene-chemical interactions.

    Science.gov (United States)

    Gladki, Arkadiusz; Zielenkiewicz, Piotr; Kaczanowski, Szymon

    2016-02-01

    In this study, we used genetic interaction (GI) and gene-chemical interaction (GCI) data to compare mutations with different dominance phenotypes. Our analysis focused primarily on Saccharomyces cerevisiae, where haploinsufficient genes (HI; genes with dominant loss-of-function mutations) were found to be participating in gene expression processes, namely, the translation and regulation of gene transcription. Non-ribosomal HI genes (mainly regulators of gene transcription) were found to have more GIs and GCIs than haplosufficient (HS) genes. Several properties seem to lead to the enrichment of interactions, most notably, the following: importance, pleiotropy, gene expression level and gene expression variation. Importantly, after these properties were appropriately considered in the analysis, the correlation between dominance and GI/GCI degrees was still observed. Strikingly, for the GCIs of heterozygous strains, haploinsufficiency was the only property significantly correlated with the number of GCIs. We found ribosomal HI genes to be depleted in GIs/GCIs. This finding can be explained by their high variation in gene expression under different genetic backgrounds and environmental conditions. We observed the same distributions of GIs among non-ribosomal HI, ribosomal HI and HS genes in three other species: Schizosaccharomyces pombe, Drosophila melanogaster and Homo sapiens. One potentially interesting exception was the lack of significant differences in the degree of GIs between non-ribosomal HI and HS genes in Schizosaccharomyces pombe.

  9. Gene-gene interaction between tuberculosis candidate genes in a South African population.

    Science.gov (United States)

    de Wit, Erika; van der Merwe, Lize; van Helden, Paul D; Hoal, Eileen G

    2011-02-01

    In a complex disease such as tuberculosis (TB) it is increasingly evident that gene-gene interactions play a far more important role in an individual's susceptibility to develop the disease than single polymorphisms on their own, as one gene can enhance or hinder the expression of another gene. Gene-gene interaction analysis is a new approach to elucidate susceptibility to TB. The possibility of gene-gene interactions was assessed, focusing on 11 polymorphisms in nine genes (DC-SIGN, IFN-γ, IFNGR1, IL-8, IL-1Ra, MBL, NRAMP1, RANTES, and SP-D) that have been associated with TB, some repeatedly. An optimal model, which best describes and predicts TB case-control status, was constructed. Significant interactions were detected between eight pairs of variants. The models fitted the observed data extremely well, with p activation is greatly enhanced by IFN-γ and IFN-γ response elements that are present in the human NRAMP1 promoter region, providing further evidence for their interaction. This study enabled us to test the theory that disease outcome may be due to interaction of several gene effects. With eight instances of statistically significant gene-gene interactions, the importance of epistasis is clearly identifiable in this study. Methods for studying gene-gene interactions are based on a multilocus and multigene approach, consistent with the nature of complex-trait diseases, and may provide the paradigm for future genetic studies of TB.

  10. Gene doping in modern sport.

    Directory of Open Access Journals (Sweden)

    MAREK SAWCZUK

    2009-01-01

    Full Text Available Background: The subject of this paper is gene doping, which should be understood as "he non-therapeutic use of cells, genes, genetic elements, or of the modulation of gene expression, having the capacity to improve athletic performance". The authors of this work, based on the review of literature and previous research, make an attempt at wider characterization of gene doping and the discussion of related potential threats.Methods: This is a comprehensive survey of literature on the latest applications of molecular biology in medicine. The analysis involves a dozen scientific databases examined in order to find genes used in gene therapy and potentially useful in gene doping. Results: The obtained results enable better recognition of gene doping and indicate genes used in medicine that could be used in gene doping. This paper describes potential effects of their use and associated risk, and predicts the possible developments of gene doping in the future. Conclusion: Gene doping is undoubtedly a part of modern sport. Although WADA included gene doping on the list of banned methods as early as 2004, as previously stated above, it has not managed to develop efficient methods of detection.

  11. [Gene pool and gene geography of the USSR population].

    Science.gov (United States)

    Rychkov, Iu G; Balanovskaia, E V

    1992-01-01

    Gene pool and gene geography are discussed from the point of view of their conceptual history beginning from the original concept of A.S. Serebrovskiĭ (1928). Difference between the present-day gene geography and gene geography of gene pool is accentuated: the former only represents a portion of the latter. Historical and territorial integrity of the USSR population gene pool, in conjunction with its huge diversity, is the main problem being analysed by various means of computerized genetic cartography. Coupled with the gene frequency mapping, following methods were also used: mapping of average heterozygosity, of interpopulation differentiation, of principal component scores and mapping of geographical trend for each mapped genetic parameter. The work is based on 100 allelic genes and haplotypes from 30 independent loci studied on the average in 225 local populations. Statistical analysis of gene geographical maps is based on 3975 nodes of regular cartographic net for the USSR territory. The wind rose of systematic changes in the USSR gene pool has three main geographic orientations: W-E, SW-NE and S-N. At the same time, there are only two main systematic forces of gene pool evolution: the force of social history with predominant W-E orientation and the force of natural history with predominant S-N orientation of their actions. The heterozygosity level of gene pool declines strictly in accordance with the resultant in the SW-NE direction.

  12. Immunotherapy and gene therapy.

    Science.gov (United States)

    Simpson, Elizabeth

    2004-02-01

    The Immunotherapy and Gene Therapy meeting of the Academy of Medical Sciences reviewed the state-of-the-art and translational prospects for therapeutic interventions aimed at killing tumor cells, correcting genetic defects and developing vaccines for chronic infections. Crucial basic science concepts and information about dendritic cells, the structure and function of T-cell receptors, and manipulation of the immune response by cytokine antagonists and peptides were presented. This information underpins vaccine design and delivery, as well as attempts to immunomodulate autoimmune disease. Results from studies using anticancer DNA vaccines, which include appropriate signals for both the innate and adaptive immune response, were presented in several talks. The vaccines incorporated helper epitopes and cancer target epitopes such as immunoglobulin idiotypes (for lymphomas and myelomas), melanoma-associated antigens (for melanoma and other solid tumors) and minor histocompatibility antigens (for leukemia). The results of using vaccines employing similar principles and designed to reduce viral load in HIV/AIDS patients were also presented. The introduction of suicide genes incorporating the bacterial enzyme nitroreductase gene (ntr) targeted at tumor cells prior to administration of the prodrug CB-1954, converted by ntr into a toxic alkylating agent, was discussed against the background of clinical trials and improved suicide gene design. The introduction into hematopoietic stem cells of missing genes for the common gamma-chain, deficiency of which causes severe combined immunodeficiency (SCID), used similar retroviral transduction. The outcome of treating six SCID patients in the UK, and ten in France was successful immune reconstitution in the majority of patients, but in two of the French cases a complication of lymphoproliferative disease due to insertional mutagenesis was observed. The adoptive transfer of T-cells specific for minor histocompatibility antigens (for

  13. SOX genes: architects of development.

    Science.gov (United States)

    Prior, H M; Walter, M A

    1996-07-01

    Development in higher organisms involves complex genetic regulation at the molecular level. The emerging picture of development control includes several families of master regulatory genes which can affect the expression of down-stream target genes in developmental cascade pathways. One new family of such development regulators is the SOX gene family. The SOX genes are named for a shared motif called the SRY box a region homologous to the DNA-binding domain of SRY, the mammalian sex determining gene. Like SRY, SOX genes play important roles in chordate development. At least a dozen human SOX genes have been identified and partially characterized (Tables 1 and 2). Mutations in SOX9 have recently been linked to campomelic dysplasia and autosomal sex reversal, and other SOX genes may also be associated with human disease.

  14. Brains, genes, and primates.

    Science.gov (United States)

    Izpisua Belmonte, Juan Carlos; Callaway, Edward M; Caddick, Sarah J; Churchland, Patricia; Feng, Guoping; Homanics, Gregg E; Lee, Kuo-Fen; Leopold, David A; Miller, Cory T; Mitchell, Jude F; Mitalipov, Shoukhrat; Moutri, Alysson R; Movshon, J Anthony; Okano, Hideyuki; Reynolds, John H; Ringach, Dario; Sejnowski, Terrence J; Silva, Afonso C; Strick, Peter L; Wu, Jun; Zhang, Feng

    2015-05-06

    One of the great strengths of the mouse model is the wide array of genetic tools that have been developed. Striking examples include methods for directed modification of the genome, and for regulated expression or inactivation of genes. Within neuroscience, it is now routine to express reporter genes, neuronal activity indicators, and opsins in specific neuronal types in the mouse. However, there are considerable anatomical, physiological, cognitive, and behavioral differences between the mouse and the human that, in some areas of inquiry, limit the degree to which insights derived from the mouse can be applied to understanding human neurobiology. Several recent advances have now brought into reach the goal of applying these tools to understanding the primate brain. Here we describe these advances, consider their potential to advance our understanding of the human brain and brain disorders, discuss bioethical considerations, and describe what will be needed to move forward.

  15. Alphaviruses in Gene Therapy

    Directory of Open Access Journals (Sweden)

    Kenneth Lundstrom

    2009-04-01

    Full Text Available Alphaviruses are enveloped single stranded RNA viruses, which as gene therapy vectors provide high-level transient gene expression. Semliki Forest virus (SFV, Sindbis virus (SIN and Venezuelan Equine Encephalitis (VEE virus have been engineered as efficient replication-deficient and -competent expression vectors. Alphavirus vectors have frequently been used as vehicles for tumor vaccine generation. Moreover, SFV and SIN vectors have been applied for intratumoral injections in animals implanted with tumor xenografts. SIN vectors have demonstrated natural tumor targeting, which might permit systemic vector administration. Another approach for systemic delivery of SFV has been to encapsulate replication-deficient viral particles in liposomes, which can provide passive targeting to tumors and allow repeated administration without host immune responses. This approach has demonstrated safe delivery of encapsulated SFV particles to melanoma and kidney carcinoma patients in a phase I trial. Finally, the prominent neurotropism of alphaviruses make them attractive for the treatment of CNS-related diseases.

  16. Gene Disease Diagnostic System

    Institute of Scientific and Technical Information of China (English)

    黄国亮; 张腾飞; 程京; 周玉祥; 刘诚迅; 金国藩; 邬敏贤; 严瑛白; 杨蓉

    2002-01-01

    Binary optics, where the optical element can be fabricated on a thin glass plate with micro-ion-etching film layer, has been widely applied in recent years. A novel optical scanning system for gene disease diagnostics described in this paper has four kinds of optical devices, including beam splitters, an array lens, an array filter and detection arrays. A software was developed to design the binary optics system using an iterative method. Two beam splitters were designed and fabricated, which can divide a beam into a 9×9 array or into a 13×13 array. The beam splitters have good diffraction efficiencies (>70%) and an even energy distribution. The gene disease diagnostic system is a portable biochip and binary optics technology. The binary optical devices in the non-confocal scanning system can raise the fluorescence detection sensitivity of the micro-array hybrid biochip.

  17. Gene therapy for mucopolysaccharidosis

    Science.gov (United States)

    Ponder, Katherine P; Haskins, Mark E

    2012-01-01

    Mucopolysaccharidoses (MPS) are due to deficiencies in activities of lysosomal enzymes that degrade glycosaminoglycans. Some attempts at gene therapy for MPS in animal models have involved intravenous injection of vectors derived from an adeno-associated virus (AAV), adenovirus, retrovirus or a plasmid, which primarily results in expression in liver and secretion of the relevant enzyme into blood. Most vectors can correct disease in liver and spleen, although correction in other organs including the brain requires high enzyme activity in the blood. Alternative approaches are to transduce hematopoietic stem cells, or to inject a vector locally into difficult-to-reach sites such as the brain. Gene therapy holds great promise for providing a long-lasting therapeutic effect for MPS if safety issues can be resolved. PMID:17727324

  18. 基因多态性与肺癌易感性关系研究进展%Research advances of relationship between genetic polymorphisms and lung cancer susceptibility

    Institute of Scientific and Technical Information of China (English)

    杜国波

    2009-01-01

    There is relationship between the polymorphisms of phase Ⅰ, Ⅱ metabolizing enzymes genes as well as DNA repair genes and lung cancer susceptibility. More researches of the relation-ship between lung cancer and some suscepti-ble genes,such as CYP1A1 ,CYP2D6,GSTM1 ,GSTT1 ,XRCC1 ,hOGG1 ,XPD,XPA,XRCC3 are reported.%研究表明基因多态性与机体患肺癌的风险存在一定关系,研究较多的是Ⅰ、Ⅱ相代谢酶基因及DNA修复基因多态性与肺癌易感性关系.本文重点阐述CYP1A1、CYP2D6、GSTM1、GSTT1、XRCC1、hOGG1、XPD、XPA和XRCC3等基因与肺癌易感性关系.

  19. Gene Porter Bridwell

    Science.gov (United States)

    1994-01-01

    Gene Porter Bridwell served as the director of the Marshall Space Flight Center from January 6, 1994 until February 3, 1996, when he retired from NASA after thirty-four years service. Bridwell, a Marshall employee since 1962, had been Marshall's Space Shuttle Projects Office Director and Space Station Redesign Team deputy manager. Under Bridwell, Marshall worked to develop its role as a Center of Excellence for propulsion and for providing access to space.

  20. Gene Porter Bridwell

    Science.gov (United States)

    1994-01-01

    Gene Porter Bridwell served as the director of the Marshall Space Flight Center from January 6, 1994 until February 3, 1996, when he retired from NASA after thirty-four years service. Bridwell, a Marshall employee since 1962, had been Marshall's Space Shuttle Projects Office Director and Space Station Redesign Team deputy manager. Under Bridwell, Marshall worked to develop its role as a Center of Excellence for propulsion and for providing access to space.

  1. Epigenetics: beyond genes

    CSIR Research Space (South Africa)

    Fossey, A

    2009-06-01

    Full Text Available to neighbouring euchromatic genes, known as position effect variegation and can be transmitted through mitosis, forming the basis of epigenetic inheritance from one cell generation to another; creating cellular memory (Brzeski and Jerzmanowski, 2004... life form, supports meiosis that produces haploid male and female spores and initiates the gametophytic generation. Gametogenesis and subsequent fertilisation take place when gametophytic and sporophytic structures interact. The product...

  2. PRRT2 gene mutations

    Science.gov (United States)

    Gardiner, Alice R.; Bhatia, Kailash P.; Stamelou, Maria; Dale, Russell C.; Kurian, Manju A.; Schneider, Susanne A.; Wali, G.M.; Counihan, Tim; Schapira, Anthony H.; Spacey, Sian D.; Valente, Enza-Maria; Silveira-Moriyama, Laura; Teive, Hélio A.G.; Raskin, Salmo; Sander, Josemir W.; Lees, Andrew; Warner, Tom; Kullmann, Dimitri M.; Wood, Nicholas W.; Hanna, Michael

    2012-01-01

    ABSTRACT Objective: The proline-rich transmembrane protein (PRRT2) gene was recently identified using exome sequencing as the cause of autosomal dominant paroxysmal kinesigenic dyskinesia (PKD) with or without infantile convulsions (IC) (PKD/IC syndrome). Episodic neurologic disorders, such as epilepsy, migraine, and paroxysmal movement disorders, often coexist and are thought to have a shared channel-related etiology. To investigate further the frequency, spectrum, and phenotype of PRRT2 mutations, we analyzed this gene in 3 large series of episodic neurologic disorders with PKD/IC, episodic ataxia (EA), and hemiplegic migraine (HM). Methods: The PRRT2 gene was sequenced in 58 family probands/sporadic individuals with PKD/IC, 182 with EA, 128 with HM, and 475 UK and 96 Asian controls. Results: PRRT2 genetic mutations were identified in 28 out of 58 individuals with PKD/IC (48%), 1/182 individuals with EA, and 1/128 individuals with HM. A number of loss-of-function and coding missense mutations were identified; the most common mutation found was the p.R217Pfs*8 insertion. Males were more frequently affected than females (ratio 52:32). There was a high proportion of PRRT2 mutations found in families and sporadic cases with PKD associated with migraine or HM (10 out of 28). One family had EA with HM and another large family had typical HM alone. Conclusions: This work expands the phenotype of mutations in the PRRT2 gene to include the frequent occurrence of migraine and HM with PKD/IC, and the association of mutations with EA and HM and with familial HM alone. We have also extended the PRRT2 mutation type and frequency in PKD and other episodic neurologic disorders. PMID:23077024

  3. Gene therapy in gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Xu Chang-tai; Guo Xue-gang; Pan Bo-rong

    2003-01-01

    @@ 1 Introduction We have reviewed the gene therapy in gastrointestinal diseases[1]. Gastric cancer is common in China[2~20] ,and its early diagnosis andtreatment are still difficult up to now[13~36]. The expression of anexogenous gene introduced by gene therapy into patients with gliomascan be monitored non- invasively by positron- emission tomography[4]. In recent years, gene study in cancer is a hotspot, and great progress hasbeen achieved[33~41].

  4. Gene therapy for gastric diseases.

    OpenAIRE

    Fumoto, Shintaro; Nishi, Junya; Nakamura, Junzo; Nishida, Koyo

    2008-01-01

    Gene therapy for gastric cancer and gastric ulcer is a rationalized strategy since various genes correlate with these diseases. Since gene expressions in non-target tissues/cells cause side effects, a selective gene delivery system targeted to the stomach and/or cancer must be developed. The route of vector transfer (direct injection, systemic, intraperitoneal, gastric serosal surface and oral administration) is an important issue which can determine efficacy and safety. Strategies for cancer...

  5. Genealogy and gene trees.

    Science.gov (United States)

    Rasmuson, Marianne

    2008-02-01

    Heredity can be followed in persons or in genes. Persons can be identified only a few generations back, but simplified models indicate that universal ancestors to all now living persons have occurred in the past. Genetic variability can be characterized as variants of DNA sequences. Data are available only from living persons, but from the pattern of variation gene trees can be inferred by means of coalescence models. The merging of lines backwards in time leads to a MRCA (most recent common ancestor). The time and place of living for this inferred person can give insights in human evolutionary history. Demographic processes are incorporated in the model, but since culture and customs are known to influence demography the models used ought to be tested against available genealogy. The Icelandic data base offers a possibility to do so and points to some discrepancies. Mitochondrial DNA and Y chromosome patterns give a rather consistent view of human evolutionary history during the latest 100 000 years but the earlier epochs of human evolution demand gene trees with longer branches. The results of such studies reveal as yet unsolved problems about the sources of our genome.

  6. Gene-gene and gene-environmental interactions of childhood asthma: a multifactor dimension reduction approach.

    Directory of Open Access Journals (Sweden)

    Ming-Wei Su

    Full Text Available BACKGROUND: The importance of gene-gene and gene-environment interactions on asthma is well documented in literature, but a systematic analysis on the interaction between various genetic and environmental factors is still lacking. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a population-based, case-control study comprised of seventh-grade children from 14 Taiwanese communities. A total of 235 asthmatic cases and 1,310 non-asthmatic controls were selected for DNA collection and genotyping. We examined the gene-gene and gene-environment interactions between 17 single-nucleotide polymorphisms in antioxidative, inflammatory and obesity-related genes, and childhood asthma. Environmental exposures and disease status were obtained from parental questionnaires. The model-free and non-parametrical multifactor dimensionality reduction (MDR method was used for the analysis. A three-way gene-gene interaction was elucidated between the gene coding glutathione S-transferase P (GSTP1, the gene coding interleukin-4 receptor alpha chain (IL4Ra and the gene coding insulin induced gene 2 (INSIG2 on the risk of lifetime asthma. The testing-balanced accuracy on asthma was 57.83% with a cross-validation consistency of 10 out of 10. The interaction of preterm birth and indoor dampness had the highest training-balanced accuracy at 59.09%. Indoor dampness also interacted with many genes, including IL13, beta-2 adrenergic receptor (ADRB2, signal transducer and activator of transcription 6 (STAT6. We also used likelihood ratio tests for interaction and chi-square tests to validate our results and all tests showed statistical significance. CONCLUSIONS/SIGNIFICANCE: The results of this study suggest that GSTP1, INSIG2 and IL4Ra may influence the lifetime asthma susceptibility through gene-gene interactions in schoolchildren. Home dampness combined with each one of the genes STAT6, IL13 and ADRB2 could raise the asthma risk.

  7. Gene therapy of cancer and development of therapeutic target gene

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Chang Min; Kwon, Hee Chung

    1998-04-01

    We applied HSV-tk/GCV strategy to orthotopic rat hepatoma model and showed anticancer effects of hepatoma. The increased expression of Lac Z gene after adenovirus-mediated gene delivery throughout hepatic artery was thought that is increased the possibility of gene therapy for curing hepatoma. With the construction of kGLP-laboratory, it is possible to produce a good quantity and quality of adenovirus in lage-scale production and purification of adenovirus vector. Also, the analysis of hepatoma related genes by PCR-LOH could be used for the diagnosis of patients and the development of therapeutic gene.

  8. Independent Gene Discovery and Testing

    Science.gov (United States)

    Palsule, Vrushalee; Coric, Dijana; Delancy, Russell; Dunham, Heather; Melancon, Caleb; Thompson, Dennis; Toms, Jamie; White, Ashley; Shultz, Jeffry

    2010-01-01

    A clear understanding of basic gene structure is critical when teaching molecular genetics, the central dogma and the biological sciences. We sought to create a gene-based teaching project to improve students' understanding of gene structure and to integrate this into a research project that can be implemented by instructors at the secondary level…

  9. Compositional gradients in Gramineae genes

    DEFF Research Database (Denmark)

    Wong, Gane Ka-Shu; Wang, Jun; Tao, Lin

    2002-01-01

    In this study, we describe a property of Gramineae genes, and perhaps all monocot genes, that is not observed in eudicot genes. Along the direction of transcription, beginning at the junction of the 5'-UTR and the coding region, there are gradients in GC content, codon usage, and amino-acid usage...

  10. Decationized polyplexes for gene delivery

    NARCIS (Netherlands)

    Novo, L.; Mastrobattista, E.; Nostrum, van C.F.; Lammers, T.G.G.M.; Hennink, W.E.

    2015-01-01

    Gene therapy has received much attention in the field of drug delivery. Synthetic, nonviral gene delivery systems have gained increasing attention as vectors for gene therapy mainly due to a favorable immunogenicity profile and ease of manufacturing as compared to viral vectors. The great majority o

  11. Ascidian gene-expression profiles

    OpenAIRE

    Jeffery, William R.

    2002-01-01

    With the advent of gene-expression profiling, a large number of genes can now be investigated simultaneously during critical stages of development. This approach will be particularly informative in studies of ascidians, basal chordates whose genomes and embryology are uniquely suited for mapping developmental gene networks.

  12. Gene electrotransfer in clinical trials

    DEFF Research Database (Denmark)

    Gehl, Julie

    2014-01-01

    Electroporation is increasingly being used for delivery of chemotherapy to tumors. Likewise, gene delivery by electroporation is rapidly gaining momentum for both vaccination purposes and for delivery of genes coding for other therapeutic molecules, such as chronic diseases or cancer. This chapte...... describes how gene therapy may be performed using electric pulses to enhance uptake and expression.......Electroporation is increasingly being used for delivery of chemotherapy to tumors. Likewise, gene delivery by electroporation is rapidly gaining momentum for both vaccination purposes and for delivery of genes coding for other therapeutic molecules, such as chronic diseases or cancer. This chapter...

  13. Gene therapy of liver cancer

    Institute of Scientific and Technical Information of China (English)

    Ruben Hernandez-Alcoceba; Bruno Sangro; Jesus Prieto

    2006-01-01

    The application of gene transfer technologies to the treatment of cancer has led to the development of new experimental approaches like gene directed enzyme/prodrug therapy (GDEPT), inhibition of oncogenes and restoration of tumor-suppressor genes. In addition,gene therapy has a big impact on other fields like cancer immunotherapy, anti-angiogenic therapy and virotherapy.These strategies are being evaluated for the treatment of primary and metastatic liver cancer and some of them have reached clinical phases. We present a review on the basis and the actual status of gene therapy approaches applied to liver cancer.

  14. Classifying genes to the correct Gene Ontology Slim term in Saccharomyces cerevisiae using neighbouring genes with classification learning

    OpenAIRE

    Tsatsoulis Costas; Amthauer Heather A

    2010-01-01

    Abstract Background There is increasing evidence that gene location and surrounding genes influence the functionality of genes in the eukaryotic genome. Knowing the Gene Ontology Slim terms associated with a gene gives us insight into a gene's functionality by informing us how its gene product behaves in a cellular context using three different ontologies: molecular function, biological process, and cellular component. In this study, we analyzed if we could classify a gene in Saccharomyces ce...

  15. Gene finding in novel genomes

    Directory of Open Access Journals (Sweden)

    Korf Ian

    2004-05-01

    Full Text Available Abstract Background Computational gene prediction continues to be an important problem, especially for genomes with little experimental data. Results I introduce the SNAP gene finder which has been designed to be easily adaptable to a variety of genomes. In novel genomes without an appropriate gene finder, I demonstrate that employing a foreign gene finder can produce highly inaccurate results, and that the most compatible parameters may not come from the nearest phylogenetic neighbor. I find that foreign gene finders are more usefully employed to bootstrap parameter estimation and that the resulting parameters can be highly accurate. Conclusion Since gene prediction is sensitive to species-specific parameters, every genome needs a dedicated gene finder.

  16. GeneDistiller--distilling candidate genes from linkage intervals.

    Directory of Open Access Journals (Sweden)

    Dominik Seelow

    Full Text Available BACKGROUND: Linkage studies often yield intervals containing several hundred positional candidate genes. Different manual or automatic approaches exist for the determination of the gene most likely to cause the disease. While the manual search is very flexible and takes advantage of the researchers' background knowledge and intuition, it may be very cumbersome to collect and study the relevant data. Automatic solutions on the other hand usually focus on certain models, remain "black boxes" and do not offer the same degree of flexibility. METHODOLOGY: We have developed a web-based application that combines the advantages of both approaches. Information from various data sources such as gene-phenotype associations, gene expression patterns and protein-protein interactions was integrated into a central database. Researchers can select which information for the genes within a candidate interval or for single genes shall be displayed. Genes can also interactively be filtered, sorted and prioritised according to criteria derived from the background knowledge and preconception of the disease under scrutiny. CONCLUSIONS: GeneDistiller provides knowledge-driven, fully interactive and intuitive access to multiple data sources. It displays maximum relevant information, while saving the user from drowning in the flood of data. A typical query takes less than two seconds, thus allowing an interactive and explorative approach to the hunt for the candidate gene. ACCESS: GeneDistiller can be freely accessed at http://www.genedistiller.org.

  17. RANGE: Gene Transfer of Reversibly Controlled Polycistronic Genes

    Directory of Open Access Journals (Sweden)

    Yiwei Chen

    2013-01-01

    Full Text Available We developed a single vector recombinant adeno-associated viral (rAAV expression system for spatial and reversible control of polycistronic gene expression. Our approach (i integrates the advantages of the tetracycline (Tet-controlled transcriptional silencer tTSKid and the self-cleaving 2A peptide bridge, (ii combines essential regulatory components as an autoregulatory loop, (iii simplifies the gene delivery scheme, and (iv regulates multiple genes in a synchronized manner. Controlled by an upstream Tet-responsive element (TRE, both the ubiquitous chicken β-actin promoter (CAG and the neuron-specific synapsin-1 promoter (Syn could regulate expression of tTSKid together with two 2A-linked reporter genes. Transduction in vitro exhibited maximally 50-fold regulation by doxycycline (Dox. Determined by gene delivery method as well as promoter, highly specific tissues were transduced in vivo. Bioluminescence imaging (BLI visualized reversible “ON/OFF” gene switches over repeated “Doxy-Cycling” in living mice. Thus, the reversible rAAV-mediated N-cistronic gene expression system, termed RANGE, may serve as a versatile tool to achieve reversible polycistronic gene regulation for the study of gene function as well as gene therapy.

  18. RANGE: Gene Transfer of Reversibly Controlled Polycistronic Genes.

    Science.gov (United States)

    Chen, Yiwei; Cao, Liji; Luo, Chonglin; Ditzel, Désirée Aw; Peter, Jörg; Sprengel, Rolf

    2013-04-09

    We developed a single vector recombinant adeno-associated viral (rAAV) expression system for spatial and reversible control of polycistronic gene expression. Our approach (i) integrates the advantages of the tetracycline (Tet)-controlled transcriptional silencer tTS(Kid) and the self-cleaving 2A peptide bridge, (ii) combines essential regulatory components as an autoregulatory loop, (iii) simplifies the gene delivery scheme, and (iv) regulates multiple genes in a synchronized manner. Controlled by an upstream Tet-responsive element (TRE), both the ubiquitous chicken β-actin promoter (CAG) and the neuron-specific synapsin-1 promoter (Syn) could regulate expression of tTS(Kid) together with two 2A-linked reporter genes. Transduction in vitro exhibited maximally 50-fold regulation by doxycycline (Dox). Determined by gene delivery method as well as promoter, highly specific tissues were transduced in vivo. Bioluminescence imaging (BLI) visualized reversible "ON/OFF" gene switches over repeated "Doxy-Cycling" in living mice. Thus, the reversible rAAV-mediated N-cistronic gene expression system, termed RANGE, may serve as a versatile tool to achieve reversible polycistronic gene regulation for the study of gene function as well as gene therapy.Molecular Therapy - Nucleic Acids (2013) 2, e85; doi:10.1038/mtna.2013.15; published online 9 April 2013.

  19. Genes, Children and Pediatricians

    Directory of Open Access Journals (Sweden)

    Joana Correia

    2017-01-01

    Full Text Available A male newborn, presenting hipotonia and posterior parietal bossing, developed, in the first 12 hours of life, refusal to feed and hypoglycaemia. A cranial ultrasound, skull X-ray and CT scan revealed an occipital and parietal fracture with an underlying haematoma and extensive extracranial soft-tissue swelling. He was submitted to surgical drainage. After 24 hours: new intracerebral bleeding. At the age of two-months he presented abnormal skin and sparse kinky hair. Serum copper and caeruloplasmin levels were below the normal range. Molecular diagnosis of Menkes disease was made by the identification of a new mutation in ATP7A gene.

  20. MUTATIONS IN CALMODULIN GENES

    DEFF Research Database (Denmark)

    2013-01-01

    The present invention relates to an isolated polynucleotide encoding at least a part of calmodulin and an isolated polypeptide comprising at least a part of a calmodulin protein, wherein the polynucleotide and the polypeptide comprise at least one mutation associated with a cardiac disorder. The ...... the binding of calmodulin to ryanodine receptor 2 and use of such compound in a treatment of an individual having a cardiac disorder. The invention further provides a kit that can be used to detect specific mutations in calmodulin encoding genes....

  1. MUTATIONS IN CALMODULIN GENES

    DEFF Research Database (Denmark)

    2013-01-01

    The present invention relates to an isolated polynucleotide encoding at least a part of calmodulin and an isolated polypeptide comprising at least a part of a calmodulin protein, wherein the polynucleotide and the polypeptide comprise at least one mutation associated with a cardiac disorder...... the binding of calmodulin to ryanodine receptor 2 and use of such compound in a treatment of an individual having a cardiac disorder. The invention further provides a kit that can be used to detect specific mutations in calmodulin encoding genes....

  2. Genes and Disease: Prader-Willi Syndrome

    Science.gov (United States)

    ... MD): National Center for Biotechnology Information (US); 1998-. Genes and Disease [Internet]. Show details National Center for ... 45K) PDF version of this title (3.8M) Gene sequence Genome view see gene locations Entrez Gene ...

  3. Association between RAD 51 rs1801320 and susceptibility to glioblastoma.

    Science.gov (United States)

    Franceschi, S; Tomei, S; Mazzanti, C M; Lessi, F; Aretini, P; La Ferla, M; De Gregorio, V; Pasqualetti, F; Zavaglia, K; Bevilacqua, G; Naccarato, A G

    2016-01-01

    Glioblastoma is the most common and aggressive malignant primary brain tumor. Despite decades of research and the advent of new therapies, patients with glioblastoma continue to have a very poor prognosis. Radiation therapy has a major role as adjuvant treatment for glioblastoma following surgical resection. Many studies have shown that polymorphisms of genes involved in pathways of DNA repair may affect the sensitivity of the cells to treatment. Although the role of these polymorphisms has been investigated in relation to response to radiotherapy, their role as predisposing factors to glioblastoma has not been clarified yet. In the present study, we evaluated the association between polymorphisms in DNA repair genes, namely: XRCC1 rs25487, XRCC3 rs861539 and RAD51 rs1801320, with the susceptibility to develop glioblastoma. Eighty-five glioblastoma patients and 70 matched controls were recruited for this study. Data from the 1000 Genomes Project (98 Tuscans) were also downloaded and used for the association analysis. Subjects carrying RAD51 rs1801320 GC genotype showed an increased risk of glioblastoma (GC vs GG, χ(2) = 10.75; OR 3.0087; p = 0.0010). The C allele was also significantly associated to glioblastoma (χ(2) = 8.66; OR 2.5674; p = 0.0032). Moreover, RAD51 rs1801320 C allele increased the risk to develop glioblastoma also when combined to XRCC1 rs25487 G allele and XRCC3 rs861539 C allele (χ(2) = 6.558; p = 0.0053).

  4. Alcoholism: genes and mechanisms.

    Science.gov (United States)

    Oroszi, Gabor; Goldman, David

    2004-12-01

    Alcoholism is a chronic relapsing/remitting disease that is frequently unrecognized and untreated, in part because of the partial efficacy of treatment. Only approximately one-third of patients remain abstinent and one-third have fully relapsed 1 year after withdrawal from alcohol, with treated patients doing substantially better than untreated [1]. The partial effectiveness of strategies for prevention and treatment, and variation in clinical course and side effects, represent a challenge and an opportunity to better understand the neurobiology of addiction. The strong heritability of alcoholism suggests the existence of inherited functional variants of genes that alter the metabolism of alcohol and variants of other genes that alter the neurobiologies of reward, executive cognitive function, anxiety/dysphoria, and neuronal plasticity. Each of these neurobiologies has been identified as a critical domain in the addictions. Functional alleles that alter alcoholism-related intermediate phenotypes include common alcohol dehydrogenase 1B and aldehyde dehydrogenase 2 variants that cause the aversive flushing reaction; catechol-O-methyltransferase (COMT) Val158Met leading to differences in three aspects of neurobiology: executive cognitive function, stress/anxiety response, and opioid function; opioid receptor micro1 (OPRM1) Asn40Asp, which may serve as a gatekeeper molecule in the action of naltrexone, a drug used in alcoholism treatment; and HTTLPR, which alters serotonin transporter function and appears to affect stress response and anxiety/dysphoria, which are factors relevant to initial vulnerability, the process of addiction, and relapse.

  5. Tetraspanin genes in plants.

    Science.gov (United States)

    Wang, Feng; Vandepoele, Klaas; Van Lijsebettens, Mieke

    2012-07-01

    Tetraspanins represent a four-transmembrane protein superfamily with a conserved structure and amino acid residues that are present in mammals, insects, fungi and plants. Tetraspanins interact with each other or with other membrane proteins to form tetraspanin-enriched microdomains that play important roles in development, pathogenesis and immune responses via facilitating cell-cell adhesion and fusion, ligand binding and intracellular trafficking. Here, we emphasize evolutionary aspects within the plant kingdom based on genomic sequence information. A phylogenetic tree based on 155 tetraspanin genes of 11 plant species revealed ancient and fast evolving clades. Tetraspanins were only present in multicellular plants, were often duplicated in the plant genomes and predicted by the electronic Fluorescent Pictograph for gene expression analysis to be either functionally redundant or divergent. Tetraspanins contain a large extracellular loop with conserved cysteines that provide the binding sites for the interactions. The Arabidopsis thaliana TETRASPANIN1/TORNADO2/EKEKO has a function in leaf and root patterning and TETRASPANIN3 was identified in the plasmodesmatal proteome, suggesting a role in cell-cell communication during plant development.

  6. Improvements to cardiovascular gene ontology.

    Science.gov (United States)

    Lovering, Ruth C; Dimmer, Emily C; Talmud, Philippa J

    2009-07-01

    Gene Ontology (GO) provides a controlled vocabulary to describe the attributes of genes and gene products in any organism. Although one might initially wonder what relevance a 'controlled vocabulary' might have for cardiovascular science, such a resource is proving highly useful for researchers investigating complex cardiovascular disease phenotypes as well as those interpreting results from high-throughput methodologies. GO enables the current functional knowledge of individual genes to be used to annotate genomic or proteomic datasets. In this way, the GO data provides a very effective way of linking biological knowledge with the analysis of the large datasets of post-genomics research. Consequently, users of high-throughput methodologies such as expression arrays or proteomics will be the main beneficiaries of such annotation sets. However, as GO annotations increase in quality and quantity, groups using small-scale approaches will gradually begin to benefit too. For example, genome wide association scans for coronary heart disease are identifying novel genes, with previously unknown connections to cardiovascular processes, and the comprehensive annotation of these novel genes might provide clues to their cardiovascular link. At least 4000 genes, to date, have been implicated in cardiovascular processes and an initiative is underway to focus on annotating these genes for the benefit of the cardiovascular community. In this article we review the current uses of Gene Ontology annotation to highlight why Gene Ontology should be of interest to all those involved in cardiovascular research.

  7. Chromatin analysis of occluded genes

    Science.gov (United States)

    Lee, Jae Hyun; Gaetz, Jedidiah; Bugarija, Branimir; Fernandes, Croydon J.; Snyder, Gregory E.; Bush, Eliot C.; Lahn, Bruce T.

    2009-01-01

    We recently described two opposing states of transcriptional competency. One is termed ‘competent’ whereby a gene is capable of responding to trans-acting transcription factors of the cell, such that it is active if appropriate transcriptional activators are present, though it can also be silent if activators are absent or repressors are present. The other is termed ‘occluded’ whereby a gene is silenced by cis-acting, chromatin-based mechanisms in a manner that blocks it from responding to trans-acting factors, such that it is silent even when activators are present in the cellular milieu. We proposed that gene occlusion is a mechanism by which differentiated cells stably maintain their phenotypic identities. Here, we describe chromatin analysis of occluded genes. We found that DNA methylation plays a causal role in maintaining occlusion for a subset of occluded genes. We further examined a variety of other chromatin marks typically associated with transcriptional silencing, including histone variants, covalent histone modifications and chromatin-associated proteins. Surprisingly, we found that although many of these marks are robustly linked to silent genes (which include both occluded genes and genes that are competent but silent), none is linked specifically to occluded genes. Although the observation does not rule out a possible causal role of these chromatin marks in occlusion, it does suggest that these marks might be secondary effect rather than primary cause of the silent state in many genes. PMID:19380460

  8. Identification of genes and gene products necessary for bacterial bioluminescence.

    OpenAIRE

    Engebrecht, J; Silverman, M.

    1984-01-01

    Expression of luminescence in Escherichia coli was recently achieved by cloning genes from the marine bacterium Vibrio fischeri. One DNA fragment on a hybrid plasmid encoded regulatory functions and enzymatic activities necessary for light production. We report the results of a genetic analysis to identify the luminescence genes (lux) that reside on this recombinant plasmid. lux gene mutations were generated by hydroxylamine treatment, and these mutations were ordered on a linear map by compl...

  9. GENE MUTATIONS, GENETIC DISEASE AND PHARMACOGENETIC GENES DISORDER

    OpenAIRE

    Ishak

    2010-01-01

    Somatic cell mutation is able to create genetic variance in a cell population and can induce cancer and tumor when gene mutations took place at repressor gene in controlling cell cycles such as p53 gene. Whereas germline cell mutation can cause genetic disease such as sickle cell anemia, breast cancer, thalassemia, parkinson’s as well as defect of biochemical pathway that influence drug-receptor interaction, which has negative effect and lead to hospitalized of patient. Most of reports mentio...

  10. PROAPOPTOTIC FUNCTION OF FHIT GENE

    Institute of Scientific and Technical Information of China (English)

    QIU Zhe-fu; HAN De-min; ZHANG Luo; ZHANG Wei

    2006-01-01

    Tumor suppressor gene plays an important role in maintaining the homeostasis between cell loss and growth. Fragile in maintaining the homeostasis between cell loss and growth. Fragile histidine triad (FHIT) gene found recently was studied in a deep going way; it becomes the focus as a result of its roleof ep going way; it becomes the focus as a result of its roleof anti-tumor in human various type of tissue. Due to the high efficiency of FHIT gene benefiting the anti-tumor, it is proposed gh efficiency of FHIT gene benefiting the anti-tumor, it is proposed as a candidate of tumor suppressor gene though there are several opposite opinions.several opposite opinions. We stress the summary of some properties of FHIT gene on proapoptosis according to the published data which showed gene on proapoptosis according to the published data which showed the stronger proapoptotic function of FHIT gene; the apoptosis induced by FHIT depends on the expression level and status of ene; the apoptosis induced by FHIT depends on the expression level and status of FHIT; and FHIT gene can alternate the cell cycling properties and reduce the tumorigenic potential; the apoptotic process e can alternate the cell cycling properties and reduce the tumorigenic potential; the apoptotic process induced by FHIT has no relation to p53 gene. In a ward, in consideration of its multiple functions against malignancies, FHIT in consideration of its multiple functions against malignancies, FHIT gene deserves attention and exploration as a selective target for searching the mechanism of tumorigenesis and clinical et for searching the mechanism of tumorigenesis and clinical therapeutic applications in further.le histidine triad (FHIT) gene; Apoptosis; Tumorigenesis; Tumor suppressor gene deserves attention and exploration as a selective target for searching the mechanism of tumorigenesis and clinical therapeutic applications in further.

  11. Regulation of gene expression by Goodwin's loop with many genes

    Science.gov (United States)

    Sielewiesiuk, Jan; Łopaciuk, Agata

    2012-01-01

    The paper presents a simple analysis of a long Goodwin's loop containing many genes. The genes form a closed series. The rate of transcription of any gene is up or down regulated by theprotein product of the preceding gene. We describe the loop with a system of ordinary differential equations of order s. Oscillatory solutions of the system are possible at the odd number of repressions and any number of inductions if the product of all Hill's coefficients, related to both repressions and inductions, is larger than:

  12. Gene: a gene-centered information resource at NCBI.

    Science.gov (United States)

    Brown, Garth R; Hem, Vichet; Katz, Kenneth S; Ovetsky, Michael; Wallin, Craig; Ermolaeva, Olga; Tolstoy, Igor; Tatusova, Tatiana; Pruitt, Kim D; Maglott, Donna R; Murphy, Terence D

    2015-01-01

    The National Center for Biotechnology Information's (NCBI) Gene database (www.ncbi.nlm.nih.gov/gene) integrates gene-specific information from multiple data sources. NCBI Reference Sequence (RefSeq) genomes for viruses, prokaryotes and eukaryotes are the primary foundation for Gene records in that they form the critical association between sequence and a tracked gene upon which additional functional and descriptive content is anchored. Additional content is integrated based on the genomic location and RefSeq transcript and protein sequence data. The content of a Gene record represents the integration of curation and automated processing from RefSeq, collaborating model organism databases, consortia such as Gene Ontology, and other databases within NCBI. Records in Gene are assigned unique, tracked integers as identifiers. The content (citations, nomenclature, genomic location, gene products and their attributes, phenotypes, sequences, interactions, variation details, maps, expression, homologs, protein domains and external databases) is available via interactive browsing through NCBI's Entrez system, via NCBI's Entrez programming utilities (E-Utilities and Entrez Direct) and for bulk transfer by FTP.

  13. Gene expression analysis identifies global gene dosage sensitivity in cancer

    DEFF Research Database (Denmark)

    Fehrmann, Rudolf S. N.; Karjalainen, Juha M.; Krajewska, Malgorzata;

    2015-01-01

    expression. We reanalyzed 77,840 expression profiles and observed a limited set of 'transcriptional components' that describe well-known biology, explain the vast majority of variation in gene expression and enable us to predict the biological function of genes. On correcting expression profiles...... for these components, we observed that the residual expression levels (in 'functional genomic mRNA' profiling) correlated strongly with copy number. DNA copy number correlated positively with expression levels for 99% of all abundantly expressed human genes, indicating global gene dosage sensitivity. By applying...

  14. PDMAEMA based gene delivery materials

    Directory of Open Access Journals (Sweden)

    Seema Agarwal

    2012-09-01

    Full Text Available Gene transfection is the transfer of genetic material like DNA into cells. Cationic polymers which form nanocomplexes with DNA, so-called non-viral gene vectors, are a highly promising platform for efficient gene transfection. Despite intensive research efforts and some of the on-going clinical trials on gene transfection, none of the existing cationic polymer systems are generally acceptable for human gene therapy. Since the process of gene transfection is complex and puts different challenges and demands on the delivery system, there is a strong requirement for the design and development of a multifunctional system in a simple way. This review will discuss recent efforts in design, synthesis, and performance of poly(2-dimethylaminoethyl methacrylate (PDMAEMA nanocomplexes with DNA.

  15. Gene targeting with retroviral vectors

    Energy Technology Data Exchange (ETDEWEB)

    Ellis, J.; Bernstein, A. (Toronto Univ., ON (Canada))

    1989-04-01

    The authors have designed and constructed integration-defective retroviral vectors to explore their potential for gene targeting in mammalian cells. Two nonoverlapping deletion mutants of the bacterial neomycin resistance (neo) gene were used to detect homologous recombination events between viral and chromosomal sequences. Stable neo gene correction events were selected at a frequency of approximately 1 G418/sup r/ cell per 3 x 10/sup 6/ infected cells. Analysis of the functional neo gene in independent targeted cell clones indicated that unintegrated retroviral linear DNA recombined with the target by gene conversion for variable distances into regions of nonhomology. In addition, transient neo gene correction events which were associated with the complete loss of the chromosomal target sequences were observed. These results demonstrated that retroviral vectors can recombine with homologous chromosomal sequences in rodent and human cells.

  16. Brief isoflurane anaesthesia affects differential gene expression, gene ontology and gene networks in rat brain.

    Science.gov (United States)

    Lowes, Damon A; Galley, Helen F; Moura, Alessandro P S; Webster, Nigel R

    2017-01-15

    Much is still unknown about the mechanisms of effects of even brief anaesthesia on the brain and previous studies have simply compared differential expression profiles with and without anaesthesia. We hypothesised that network analysis, in addition to the traditional differential gene expression and ontology analysis, would enable identification of the effects of anaesthesia on interactions between genes. Rats (n=10 per group) were randomised to anaesthesia with isoflurane in oxygen or oxygen only for 15min, and 6h later brains were removed. Differential gene expression and gene ontology analysis of microarray data was performed. Standard clustering techniques and principal component analysis with Bayesian rules were used along with social network analysis methods, to quantitatively model and describe the gene networks. Anaesthesia had marked effects on genes in the brain with differential regulation of 416 probe sets by at least 2 fold. Gene ontology analysis showed 23 genes were functionally related to the anaesthesia and of these, 12 were involved with neurotransmitter release, transport and secretion. Gene network analysis revealed much greater connectivity in genes from brains from anaesthetised rats compared to controls. Other importance measures were also altered after anaesthesia; median [range] closeness centrality (shortest path) was lower in anaesthetized animals (0.07 [0-0.30]) than controls (0.39 [0.30-0.53], pgenes after anaesthesia and suggests future targets for investigation. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. How eukaryotic genes are transcribed

    OpenAIRE

    Venters, Bryan J; Pugh, B. Franklin

    2009-01-01

    Regulation of eukaryotic gene expression is far more complex than one might have imagined thirty years ago. However, progress towards understanding gene regulatory mechanisms has been rapid and comprehensive, which has made the integration of detailed observations into broadly connected concepts a challenge. This review attempts to integrate the following concepts: 1) a well-defined organization of nucleosomes and modification states at most genes, 2) regulatory networks of sequence-specific ...

  18. Gene set analysis for GWAS

    DEFF Research Database (Denmark)

    Debrabant, Birgit; Soerensen, Mette

    2014-01-01

    Abstract We discuss the use of modified Kolmogorov-Smirnov (KS) statistics in the context of gene set analysis and review corresponding null and alternative hypotheses. Especially, we show that, when enhancing the impact of highly significant genes in the calculation of the test statistic...... parameter and the genesis and distribution of the gene-level statistics, and illustrate the effects of differential weighting in a real-life example....

  19. Gene and genome parameters of mammalian liver circadian genes (LCGs.

    Directory of Open Access Journals (Sweden)

    Gang Wu

    Full Text Available The mammalian circadian system controls various physiology processes and behavior responses by regulating thousands of circadian genes with rhythmic expressions. In this study, we redefined circadian-regulated genes based on published results in the mouse liver and compared them with other gene groups defined relative to circadian regulations, especially the non-circadian-regulated genes expressed in liver at multiple molecular levels from gene position to protein expression based on integrative analyses of different datasets from the literature. Based on the intra-tissue analysis, the liver circadian genes or LCGs show unique features when compared to other gene groups. First, LCGs in general have less neighboring genes and larger in both genomic and 3'-UTR lengths but shorter in CDS (coding sequence lengths. Second, LCGs have higher mRNA and protein abundance, higher temporal expression variations, and shorter mRNA half-life. Third, more than 60% of LCGs form major co-expression clusters centered in four temporal windows: dawn, day, dusk, and night. In addition, larger and smaller LCGs are found mainly expressed in the day and night temporal windows, respectively, and we believe that LCGs are well-partitioned into the gene expression regulatory network that takes advantage of gene size, expression constraint, and chromosomal architecture. Based on inter-tissue analysis, more than half of LCGs are ubiquitously expressed in multiple tissues but only show rhythmical expression in one or limited number of tissues. LCGs show at least three-fold lower expression variations across the temporal windows than those among different tissues, and this observation suggests that temporal expression variations regulated by the circadian system is relatively subtle as compared with the tissue expression variations formed during development. Taken together, we suggest that the circadian system selects gene parameters in a cost effective way to improve tissue

  20. Testing for gene-gene interaction with AMMI models.

    Science.gov (United States)

    Barhdadi, Amina; Dubé, Marie-Pierre

    2010-01-01

    Studies have shown that many common diseases are influenced by multiple genes and their interactions. There is currently a strong interest in testing for association between combinations of these genes and disease, in particular because genes that affect the risk of disease only in the presence of another genetic variant may not be detected in marginal analysis. In this paper we propose the use of additive main effect and multiplicative interaction (AMMI) models to detect and to quantify gene-gene interaction effects for a quantitative trait. The objective of the present research is to demonstrate the practical advantages of these models to describe complex interaction between two unlinked loci. Although gene-gene interactions have often been defined as a deviance from additive genetic effects, the residual term has generally not been appropriately treated. The AMMI models allow for the analysis of a two way factorial data structure and combine the analysis of variance of the two main genotype effects with a principal component analysis of the residual multiplicative interaction. The AMMI models for gene-gene interaction presented here allow for the testing of non additivity between the two loci, and also describe how their interaction structure fits the existing non-additivity. Moreover, these models can be used to identify the specific two genotypes combinations that contribute to the significant gene-gene interaction. We describe the use of the biplot to display the structure of the interaction and evaluate the performance of the AMMI and the special cases of the AMMI previously described by Tukey and Mandel with simulated data sets. Our simulated study showed that the AMMI model is as powerful as general linear models when the interaction is not modeled in the presence of marginal effects. However, in the presence of pure epitasis, i.e. in the absence of marginal effects, the AMMI method was not found to be superior to other tested regression methods.

  1. Introduction: Cancer Gene Networks.

    Science.gov (United States)

    Clarke, Robert

    2017-01-01

    Constructing, evaluating, and interpreting gene networks generally sits within the broader field of systems biology, which continues to emerge rapidly, particular with respect to its application to understanding the complexity of signaling in the context of cancer biology. For the purposes of this volume, we take a broad definition of systems biology. Considering an organism or disease within an organism as a system, systems biology is the study of the integrated and coordinated interactions of the network(s) of genes, their variants both natural and mutated (e.g., polymorphisms, rearrangements, alternate splicing, mutations), their proteins and isoforms, and the organic and inorganic molecules with which they interact, to execute the biochemical reactions (e.g., as enzymes, substrates, products) that reflect the function of that system. Central to systems biology, and perhaps the only approach that can effectively manage the complexity of such systems, is the building of quantitative multiscale predictive models. The predictions of the models can vary substantially depending on the nature of the model and its inputoutput relationships. For example, a model may predict the outcome of a specific molecular reaction(s), a cellular phenotype (e.g., alive, dead, growth arrest, proliferation, and motility), a change in the respective prevalence of cell or subpopulations, a patient or patient subgroup outcome(s). Such models necessarily require computers. Computational modeling can be thought of as using machine learning and related tools to integrate the very high dimensional data generated from modern, high throughput omics technologies including genomics (next generation sequencing), transcriptomics (gene expression microarrays; RNAseq), metabolomics and proteomics (ultra high performance liquid chromatography, mass spectrometry), and "subomic" technologies to study the kinome, methylome, and others. Mathematical modeling can be thought of as the use of ordinary

  2. Genes, evolution and intelligence.

    Science.gov (United States)

    Bouchard, Thomas J

    2014-11-01

    I argue that the g factor meets the fundamental criteria of a scientific construct more fully than any other conception of intelligence. I briefly discuss the evidence regarding the relationship of brain size to intelligence. A review of a large body of evidence demonstrates that there is a g factor in a wide range of species and that, in the species studied, it relates to brain size and is heritable. These findings suggest that many species have evolved a general-purpose mechanism (a general biological intelligence) for dealing with the environments in which they evolved. In spite of numerous studies with considerable statistical power, we know of very few genes that influence g and the effects are very small. Nevertheless, g appears to be highly polygenic. Given the complexity of the human brain, it is not surprising that that one of its primary faculties-intelligence-is best explained by the near infinitesimal model of quantitative genetics.

  3. Gene-environment interaction.

    Science.gov (United States)

    Manuck, Stephen B; McCaffery, Jeanne M

    2014-01-01

    With the advent of increasingly accessible technologies for typing genetic variation, studies of gene-environment (G×E) interactions have proliferated in psychological research. Among the aims of such studies are testing developmental hypotheses and models of the etiology of behavioral disorders, defining boundaries of genetic and environmental influences, and identifying individuals most susceptible to risk exposures or most amenable to preventive and therapeutic interventions. This research also coincides with the emergence of unanticipated difficulties in detecting genetic variants of direct association with behavioral traits and disorders, which may be obscured if genetic effects are expressed only in predisposing environments. In this essay we consider these and other rationales for positing G×E interactions, review conceptual models meant to inform G×E interpretations from a psychological perspective, discuss points of common critique to which G×E research is vulnerable, and address the role of the environment in G×E interactions.

  4. Angiogenin gene polymorphism

    Institute of Scientific and Technical Information of China (English)

    Hongli Wang; Dongsheng Fan; Yingshuang Zhang

    2013-01-01

    Angiogenin is associated with the pathogenesis of diabetic peripheral neuropathy. Here, we se-quenced the coding region of the angiogenin gene in genomic DNA from 207 patients with type 2 diabetes mel itus (129 diabetic peripheral neuropathy patients and 78 diabetic non-neuropathy pa-tients) and 268 healthy controls. Al subjects were from the Han population of northern China. No mutations were found. We then compared the genotype and allele frequencies of the angiogenin synonymous single nucleotide polymorphism rs11701 between the diabetic peripheral neuropathy patients and controls, and between the diabetic neuropathy and non-neuropathy patients, using a case-control design. We detected no statistical y significant genetic associations. Angiogenin may not be associated with genetic susceptibility to diabetic peripheral neuropathy in the Han population of northern China.

  5. Gene therapy in the cornea.

    Science.gov (United States)

    Mohan, Rajiv R; Sharma, Ajay; Netto, Marcelo V; Sinha, Sunilima; Wilson, Steven E

    2005-09-01

    Technological advances in the field of gene therapy has prompted more than three hundred phase I and phase II gene-based clinical trials for the treatment of cancer, AIDS, macular degeneration, cardiovascular, and other monogenic diseases. Besides treating diseases, gene transfer technology has been utilized for the development of preventive and therapeutic vaccines for malaria, tuberculosis, hepatitis A, B and C viruses, AIDS, and influenza. The potential therapeutic applications of gene transfer technology are enormous. The cornea is an excellent candidate for gene therapy because of its accessibility and immune-privileged nature. In the last two decades, various viral vectors, such as adeno, adeno-associated, retro, lenti, and herpes simplex, as well as non-viral methods, were examined for introducing DNA into corneal cells in vitro, in vivo and ex vivo. Most of these studies used fluorescent or non-fluorescent marker genes to track the level and duration of transgene expression in corneal cells. However, limited studies were directed to evaluate prospects of gene-based interventions for corneal diseases or disorders such as allograft rejection, laser-induced post-operative haze, herpes simplex keratitis, and wound healing in animal models. We will review the successes and obstacles impeding gene therapy approaches used for delivering genes into the cornea.

  6. Are TMEM genes potential candidate genes for panic disorder?

    DEFF Research Database (Denmark)

    Gregersen, Noomi O; Buttenschøn, Henriette Nørmølle; Hedemand, Anne

    2014-01-01

    We analysed single nucleotide polymorphisms in two transmembrane genes (TMEM98 and TMEM132E) in panic disorder (PD) patients and control individuals from the Faroe Islands, Denmark and Germany. The genes encode single-pass membrane proteins and are located within chromosome 17q11.2-q12...

  7. Gene-gene Interaction Analyses for Atrial Fibrillation

    NARCIS (Netherlands)

    Lin, Honghuang; Mueller-Nurasyid, Martina; Smith, Albert V; Arking, Dan E; Barnard, John; Bartz, Traci M; Lunetta, Kathryn L; Lohman, Kurt; Kleber, Marcus E; Lubitz, Steven A; Geelhoed, Bastiaan; Trompet, Stella; Niemeijer, Maartje N; Kacprowski, Tim; Chasman, Daniel I; Klarin, Derek; Sinner, Moritz F; Waldenberger, Melanie; Meitinger, Thomas; Harris, Tamara B; Launer, Lenore J; Soliman, Elsayed Z; Chen, Lin Y; Smith, Jonathan D; Van Wagoner, David R; Rotter, Jerome I; Psaty, Bruce M; Xie, Zhijun; Hendricks, Audrey E; Ding, Jingzhong; Delgado, Graciela E; Verweij, Niek; van der Harst, Pim; Macfarlane, Peter W; Ford, Ian; Hofman, Albert; Uitterlinden, André; Heeringa, Jan; Franco, Oscar H; Kors, Jan A; Weiss, Stefan; Völzke, Henry; Rose, Lynda M; Natarajan, Pradeep; Kathiresan, Sekar; Kääb, Stefan; Gudnason, Vilmundur; Alonso, Alvaro; Chung, Mina K; Heckbert, Susan R; Benjamin, Emelia J; Liu, Yongmei; März, Winfried; Rienstra, Michiel; Jukema, J Wouter; Stricker, Bruno H; Dörr, Marcus; Albert, Christine M; Ellinor, Patrick T

    2016-01-01

    Atrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The objective of our study is to examine the effect of gene-gene interaction on AF susceptibility. We performed

  8. Gene-gene Interaction Analyses for Atrial Fibrillation

    NARCIS (Netherlands)

    H. Lin (Honghuang); M. Mueller-Nurasyid; A.V. Smith (Albert Vernon); D.E. Arking (Dan); J. Barnard (John); T.M. Bartz (Traci M.); K.L. Lunetta (Kathryn); K. Lohman (Kurt); M.E. Kleber (Marcus); S.A. Lubitz (Steven); Geelhoed, B. (Bastiaan); S. Trompet (Stella); M.N. Niemeijer (Maartje); T. Kacprowski (Tim); D.I. Chasman (Daniel); Klarin, D. (Derek); M.F. Sinner (Moritz); M. Waldenberger (Melanie); T. Meitinger (Thomas); T.B. Harris (Tamara); Launer, L.J. (Lenore J.); E.Z. Soliman (Elsayed Z.); L. Chen (Lin); J.D. Smith (Jonathan); D.R. van Wagoner (David); Rotter, J.I. (Jerome I.); B.M. Psaty (Bruce); Xie, Z. (Zhijun); A.E. Hendricks (Audrey E.); Ding, J. (Jingzhong); G.E. Delgado (Graciela E.); N. Verweij (Niek); P. van der Harst (Pim); P.W. MacFarlane (Peter); I. Ford (Ian); A. Hofman (Albert); A.G. Uitterlinden (André); J. Heeringa (Jan); O.H. Franco (Oscar); J.A. Kors (Jan); Weiss, S. (Stefan); H. Völzke (Henry); L.M. Rose (Lynda); Natarajan, P. (Pradeep); S. Kathiresan (Sekar); S. Kääb (Stefan); V. Gudnason (Vilmundur); A. Alonso (Alvaro); M.K. Chung (Mina); S.R. Heckbert (Susan); E.J. Benjamin (Emelia); Y. Liu (Yongmei); W. März (Winfried); S.A. Rienstra; J.W. Jukema (Jan Wouter); B.H.Ch. Stricker (Bruno); M. Dörr (Marcus); C.M. Albert (Christine); P.T. Ellinor (Patrick)

    2016-01-01

    textabstractAtrial fibrillation (AF) is a heritable disease that affects more than thirty million individuals worldwide. Extensive efforts have been devoted to the study of genetic determinants of AF. The objective of our study is to examine the effect of gene-gene interaction on AF susceptibility.

  9. Classifying genes to the correct Gene Ontology Slim term in Saccharomyces cerevisiae using neighbouring genes with classification learning

    Directory of Open Access Journals (Sweden)

    Tsatsoulis Costas

    2010-05-01

    Full Text Available Abstract Background There is increasing evidence that gene location and surrounding genes influence the functionality of genes in the eukaryotic genome. Knowing the Gene Ontology Slim terms associated with a gene gives us insight into a gene's functionality by informing us how its gene product behaves in a cellular context using three different ontologies: molecular function, biological process, and cellular component. In this study, we analyzed if we could classify a gene in Saccharomyces cerevisiae to its correct Gene Ontology Slim term using information about its location in the genome and information from its nearest-neighbouring genes using classification learning. Results We performed experiments to establish that the MultiBoostAB algorithm using the J48 classifier could correctly classify Gene Ontology Slim terms of a gene given information regarding the gene's location and information from its nearest-neighbouring genes for training. Different neighbourhood sizes were examined to determine how many nearest neighbours should be included around each gene to provide better classification rules. Our results show that by just incorporating neighbour information from each gene's two-nearest neighbours, the percentage of correctly classified genes to their correct Gene Ontology Slim term for each ontology reaches over 80% with high accuracy (reflected in F-measures over 0.80 of the classification rules produced. Conclusions We confirmed that in classifying genes to their correct Gene Ontology Slim term, the inclusion of neighbour information from those genes is beneficial. Knowing the location of a gene and the Gene Ontology Slim information from neighbouring genes gives us insight into that gene's functionality. This benefit is seen by just including information from a gene's two-nearest neighbouring genes.

  10. Classifying genes to the correct Gene Ontology Slim term in Saccharomyces cerevisiae using neighbouring genes with classification learning.

    Science.gov (United States)

    Amthauer, Heather A; Tsatsoulis, Costas

    2010-05-28

    There is increasing evidence that gene location and surrounding genes influence the functionality of genes in the eukaryotic genome. Knowing the Gene Ontology Slim terms associated with a gene gives us insight into a gene's functionality by informing us how its gene product behaves in a cellular context using three different ontologies: molecular function, biological process, and cellular component. In this study, we analyzed if we could classify a gene in Saccharomyces cerevisiae to its correct Gene Ontology Slim term using information about its location in the genome and information from its nearest-neighbouring genes using classification learning. We performed experiments to establish that the MultiBoostAB algorithm using the J48 classifier could correctly classify Gene Ontology Slim terms of a gene given information regarding the gene's location and information from its nearest-neighbouring genes for training. Different neighbourhood sizes were examined to determine how many nearest neighbours should be included around each gene to provide better classification rules. Our results show that by just incorporating neighbour information from each gene's two-nearest neighbours, the percentage of correctly classified genes to their correct Gene Ontology Slim term for each ontology reaches over 80% with high accuracy (reflected in F-measures over 0.80) of the classification rules produced. We confirmed that in classifying genes to their correct Gene Ontology Slim term, the inclusion of neighbour information from those genes is beneficial. Knowing the location of a gene and the Gene Ontology Slim information from neighbouring genes gives us insight into that gene's functionality. This benefit is seen by just including information from a gene's two-nearest neighbouring genes.

  11. Correlations between clinical normal tissue radiosensitivity and single nucleotide polymorphisms in ATM, XRCC1, XRCC3, APEX, SOD2, and TGF-B1

    DEFF Research Database (Denmark)

    Alsner, Jan; Andreassen, Christian Nicolaj; Overgaard, Marie

    in biological pathways suspected to underlie phenotypes of interest. These variants can be either common alterations like single nucleotide polymorphisms, SNPs, or rare variants in potential susceptibility loci like ATM. In parallel, we are using microarray analysis on normal fibroblasts isolated from patients...

  12. On meme--gene coevolution.

    Science.gov (United States)

    Bull, L; Holland, O; Blackmore, S

    2000-01-01

    In this article we examine the effects of the emergence of a new replicator, memes, on the evolution of a pre-existing replicator, genes. Using a version of the NKCS model we examine the effects of increasing the rate of meme evolution in relation to the rate of gene evolution, for various degrees of interdependence between the two replicators. That is, the effects of memes' (suggested) more rapid rate of evolution in comparison to that of genes is investigated using a tunable model of coevolution. It is found that, for almost any degree of interdependence between the two replicators, as the rate of meme evolution increases, a phase transition-like dynamic occurs under which memes have a significantly detrimental effect on the evolution of genes, quickly resulting in the cessation of effective gene evolution. Conversely, the memes experience a sharp increase in benefit from increasing their rate of evolution. We then examine the effects of enabling genes to reduce the percentage of gene-detrimental evolutionary steps taken by memes. Here a critical region emerges as the comparative rate of meme evolution increases, such that if genes cannot effectively select memes a high percentage of the time, they suffer from meme evolution as if they had almost no selective capability.

  13. Susceptibility Genes in Thyroid Autoimmunity

    Directory of Open Access Journals (Sweden)

    Yoshiyuki Ban

    2005-01-01

    Full Text Available The autoimmune thyroid diseases (AITD are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions that are linked with AITD, and in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD and Hashimoto's thyroiditis (HT and some are common to both the diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4 and thyroid specific genes (e.g. TSHR, Tg. Most likely, these loci interact and their interactions may influence disease phenotype and severity.

  14. The flow of gene expression.

    Science.gov (United States)

    Misteli, Tom

    2004-03-01

    Gene expression is a highly interconnected multistep process. A recent meeting in Iguazu Falls, Argentina, highlighted the need to uncover both the molecular details of each single step as well as the mechanisms of coordination among processes in order to fully understand the expression of genes.

  15. Phytochrome-regulated Gene Expression

    Institute of Scientific and Technical Information of China (English)

    Peter H. Quail

    2007-01-01

    Identification of all genes involved in the phytochrome (phy)-mediated responses of plants to their light environment is an important goal in providing an overall understanding of light-regulated growth and development. This article highlights and integrates the central findings of two recent comprehensive studies in Arabidopsis that have identified the genome-wide set of phy-regulated genes that respond rapidly to red-light signals upon first exposure of dark-grown seedlings, and have tested the functional relevance to normal seedling photomorphogenesis of an initial subset of these genes. The data: (a) reveal considerable complexity in the channeling of the light signals through the different phy-family members (phyA to phyE) to responsive genes; (b) identify a diversity of transcription-factor-encoding genes as major early, if not primary, targets of phy signaling, and, therefore, as potentially important regulators in the transcriptional-network hierarchy; and (c) identify auxin-related genes as the dominant class among rapidly-regulated, hormone-related genes. However, reverse-genetic functional profiling of a selected subset of these genes reveals that only a limited fraction are necessary for optimal phy-induced seedling deetiolation.

  16. Candidate genes for behavioural ecology

    NARCIS (Netherlands)

    Fitzpatrick, M.J.; Ben-Sahar, Y.; Smid, H.M.; Vet, L.E.M.; Robinson, G.E.; Sokolowski, M.B.

    2005-01-01

    In spite of millions of years of evolutionary divergence, the conservation of gene function is common across distant lineages. As such, genes that are known to influence behaviour in one organism are likely to influence similar behaviours in other organisms. Recent studies of the evolution of behavi

  17. Candidate gene prioritization with Endeavour.

    Science.gov (United States)

    Tranchevent, Léon-Charles; Ardeshirdavani, Amin; ElShal, Sarah; Alcaide, Daniel; Aerts, Jan; Auboeuf, Didier; Moreau, Yves

    2016-07-08

    Genomic studies and high-throughput experiments often produce large lists of candidate genes among which only a small fraction are truly relevant to the disease, phenotype or biological process of interest. Gene prioritization tackles this problem by ranking candidate genes by profiling candidates across multiple genomic data sources and integrating this heterogeneous information into a global ranking. We describe an extended version of our gene prioritization method, Endeavour, now available for six species and integrating 75 data sources. The performance (Area Under the Curve) of Endeavour on cross-validation benchmarks using 'gold standard' gene sets varies from 88% (for human phenotypes) to 95% (for worm gene function). In addition, we have also validated our approach using a time-stamped benchmark derived from the Human Phenotype Ontology, which provides a setting close to prospective validation. With this benchmark, using 3854 novel gene-phenotype associations, we observe a performance of 82%. Altogether, our results indicate that this extended version of Endeavour efficiently prioritizes candidate genes. The Endeavour web server is freely available at https://endeavour.esat.kuleuven.be/.

  18. Determining Semantically Related Significant Genes.

    Science.gov (United States)

    Taha, Kamal

    2014-01-01

    GO relation embodies some aspects of existence dependency. If GO term xis existence-dependent on GO term y, the presence of y implies the presence of x. Therefore, the genes annotated with the function of the GO term y are usually functionally and semantically related to the genes annotated with the function of the GO term x. A large number of gene set enrichment analysis methods have been developed in recent years for analyzing gene sets enrichment. However, most of these methods overlook the structural dependencies between GO terms in GO graph by not considering the concept of existence dependency. We propose in this paper a biological search engine called RSGSearch that identifies enriched sets of genes annotated with different functions using the concept of existence dependency. We observe that GO term xcannot be existence-dependent on GO term y, if x- and y- have the same specificity (biological characteristics). After encoding into a numeric format the contributions of GO terms annotating target genes to the semantics of their lowest common ancestors (LCAs), RSGSearch uses microarray experiment to identify the most significant LCA that annotates the result genes. We evaluated RSGSearch experimentally and compared it with five gene set enrichment systems. Results showed marked improvement.

  19. Nonviral Vectors for Gene Delivery

    Science.gov (United States)

    Baoum, Abdulgader Ahmed

    2011-12-01

    The development of nonviral vectors for safe and efficient gene delivery has been gaining considerable attention recently. An ideal nonviral vector must protect the gene against degradation by nuclease in the extracellular matrix, internalize the plasma membrane, escape from the endosomal compartment, unpackage the gene at some point and have no detrimental effects. In comparison to viruses, nonviral vectors are relatively easy to synthesize, less immunogenic, low in cost, and have no limitation in the size of a gene that can be delivered. Significant progress has been made in the basic science and applications of various nonviral gene delivery vectors; however, the majority of nonviral approaches are still inefficient and often toxic. To this end, two nonviral gene delivery systems using either biodegradable poly(D,L-lactide- co-glycolide) (PLG) nanoparticles or cell penetrating peptide (CPP) complexes have been designed and studied using A549 human lung epithelial cells. PLG nanoparticles were optimized for gene delivery by varying particle surface chemistry using different coating materials that adsorb to the particle surface during formation. A variety of cationic coating materials were studied and compared to more conventional surfactants used for PLG nanoparticle fabrication. Nanoparticles (˜200 nm) efficiently encapsulated plasmids encoding for luciferase (80-90%) and slowly released the same for two weeks. After a delay, moderate levels of gene expression appeared at day 5 for certain positively charged PLG particles and gene expression was maintained for at least two weeks. In contrast, gene expression mediated by polyethyleneimine (PEI) ended at day 5. PLG particles were also significantly less cytotoxic than PEI suggesting the use of these vehicles for localized, sustained gene delivery to the pulmonary epithelium. On the other hand, a more simple method to synthesize 50-200 nm complexes capable of high transfection efficiency or high gene knockdown was

  20. Delivery systems for gene therapy

    Directory of Open Access Journals (Sweden)

    Shrikant Mali

    2013-01-01

    Full Text Available The structure of DNA was unraveled by Watson and Crick in 1953, and two decades later Arber, Nathans and Smith discovered DNA restriction enzymes, which led to the rapid growth in the field of recombinant DNA technology. From expressing cloned genes in bacteria to expressing foreign DNA in transgenic animals, DNA is now slated to be used as a therapeutic agent to replace defective genes in patients suffering from genetic disorders or to kill tumor cells in cancer patients. Gene therapy provides modern medicine with new perspectives that were unthinkable two decades ago. Progress in molecular biology and especially, molecular medicine is now changing the basics of clinical medicine. A variety of viral and non-viral possibilities are available for basic and clinical research. This review summarizes the delivery routes and methods for gene transfer used in gene therapy.

  1. Function analysis of unknown genes

    DEFF Research Database (Denmark)

    Rogowska-Wrzesinska, A.

    2002-01-01

      This thesis entitled "Function analysis of unknown genes" presents the use of proteome analysis for the characterisation of yeast (Saccharomyces cerevisiae) genes and their products (proteins especially those of unknown function). This study illustrates that proteome analysis can be used...... to describe different aspects of molecular biology of the cell, to study changes that occur in the cell due to overexpression or deletion of a gene and to identify various protein modifications. The biological questions and the results of the described studies show the diversity of the information that can...... genes and proteins. It reports the first global proteome database collecting 36 yeast single gene deletion mutants and selecting over 650 differences between analysed mutants and the wild type strain. The obtained results show that two-dimensional gel electrophoresis and mass spectrometry based proteome...

  2. Nanoparticles for retinal gene therapy.

    Science.gov (United States)

    Conley, Shannon M; Naash, Muna I

    2010-09-01

    Ocular gene therapy is becoming a well-established field. Viral gene therapies for the treatment of Leber's congentinal amaurosis (LCA) are in clinical trials, and many other gene therapy approaches are being rapidly developed for application to diverse ophthalmic pathologies. Of late, development of non-viral gene therapies has been an area of intense focus and one technology, polymer-compacted DNA nanoparticles, is especially promising. However, development of pharmaceutically and clinically viable therapeutics depends not only on having an effective and safe vector but also on a practical treatment strategy. Inherited retinal pathologies are caused by mutations in over 220 genes, some of which contain over 200 individual disease-causing mutations, which are individually very rare. This review will focus on both the progress and future of nanoparticles and also on what will be required to make them relevant ocular pharmaceutics. Copyright 2010 Elsevier Ltd. All rights reserved.

  3. Gene targeting in malaria parasites.

    Science.gov (United States)

    Ménard, R; Janse, C

    1997-10-01

    Gene targeting, which permits alteration of a chosen gene in a predetermined way by homologous recombination, is an emerging technology in malaria research. Soon after the development of techniques for stable transformation of red blood cell stages of Plasmodium falciparum and Plasmodium berghei, genes of interest were disrupted in the two species. The main limitations of gene targeting in malaria parasites result from the intracellular growth and slow replication of these parasites. On the other hand, the technology is facilitated by the very high rate of homologous recombination following transformation with targeting constructs (approximately 100%). Here, we describe (i) the vector design and the type of mutation that may be generated in a target locus, (ii) the selection and screening strategies that can be used to identify clones with the desired modification, and (iii) the protocol that was used for disrupting the circumsporozoite protein (CS) and thrombospondin-related anonymous protein (TRAP) genes of P. berghei.

  4. The epistatic relationship between BRCA2 and the other RAD51 mediators in homologous recombination.

    Directory of Open Access Journals (Sweden)

    Yong Qing

    2011-07-01

    Full Text Available RAD51 recombinase polymerizes at the site of double-strand breaks (DSBs where it performs DSB repair. The loss of RAD51 causes extensive chromosomal breaks, leading to apoptosis. The polymerization of RAD51 is regulated by a number of RAD51 mediators, such as BRCA1, BRCA2, RAD52, SFR1, SWS1, and the five RAD51 paralogs, including XRCC3. We here show that brca2-null mutant cells were able to proliferate, indicating that RAD51 can perform DSB repair in the absence of BRCA2. We disrupted the BRCA1, RAD52, SFR1, SWS1, and XRCC3 genes in the brca2-null cells. All the resulting double-mutant cells displayed a phenotype that was very similar to that of the brca2-null cells. We suggest that BRCA2 might thus serve as a platform to recruit various RAD51 mediators at the appropriate position at the DNA-damage site.

  5. Gene expression profiling: can we identify the right target genes?

    Directory of Open Access Journals (Sweden)

    J. E. Loyd

    2008-12-01

    Full Text Available Gene expression profiling allows the simultaneous monitoring of the transcriptional behaviour of thousands of genes, which may potentially be involved in disease development. Several studies have been performed in idiopathic pulmonary fibrosis (IPF, which aim to define genetic links to the disease in an attempt to improve the current understanding of the underlying pathogenesis of the disease and target pathways for intervention. Expression profiling has shown a clear difference in gene expression between IPF and normal lung tissue, and has identified a wide range of candidate genes, including those known to encode for proteins involved in extracellular matrix formation and degradation, growth factors and chemokines. Recently, familial pulmonary fibrosis cohorts have been examined in an attempt to detect specific genetic mutations associated with IPF. To date, these studies have identified families in which IPF is associated with mutations in the gene encoding surfactant protein C, or with mutations in genes encoding components of telomerase. Although rare and clearly not responsible for the disease in all individuals, the nature of these mutations highlight the importance of the alveolar epithelium in disease pathogenesis and demonstrate the potential for gene expression profiling in helping to advance the current understanding of idiopathic pulmonary fibrosis.

  6. Genes, Economics, and Happiness *

    Science.gov (United States)

    De Neve, Jan-Emmanuel; Christakis, Nicholas A.; Fowler, James H.; Frey, Bruno S.

    2012-01-01

    We explore the influence of genetic variation on subjective well-being by employing a twin design and genetic association study. In a nationally-representative twin sample, we first show that about 33% of the variation in life satisfaction is explained by genetic variation. Although previous studies have shown that baseline happiness is significantly heritable, little research has considered molecular genetic associations with subjective well-being. We study the relationship between a functional polymorphism on the serotonin transporter gene (5-HTTLPR) and life satisfaction. We initially find that individuals with the longer, transcriptionally more efficient variant of this genotype report greater life satisfaction (n=2,545, p=0.012). However, our replication attempts on independent samples produce mixed results indicating that more work needs to be done to better understand the relationship between this genotype and subjective well-being. This work has implications for how economists think about the determinants of utility, and the extent to which exogenous shocks might affect individual well-being. PMID:24349601

  7. Genes, Economics, and Happiness.

    Science.gov (United States)

    De Neve, Jan-Emmanuel; Christakis, Nicholas A; Fowler, James H; Frey, Bruno S

    2012-11-01

    We explore the influence of genetic variation on subjective well-being by employing a twin design and genetic association study. In a nationally-representative twin sample, we first show that about 33% of the variation in life satisfaction is explained by genetic variation. Although previous studies have shown that baseline happiness is significantly heritable, little research has considered molecular genetic associations with subjective well-being. We study the relationship between a functional polymorphism on the serotonin transporter gene (5-HTTLPR) and life satisfaction. We initially find that individuals with the longer, transcriptionally more efficient variant of this genotype report greater life satisfaction (n=2,545, p=0.012). However, our replication attempts on independent samples produce mixed results indicating that more work needs to be done to better understand the relationship between this genotype and subjective well-being. This work has implications for how economists think about the determinants of utility, and the extent to which exogenous shocks might affect individual well-being.

  8. Gene Prediction Using Multinomial Probit Regression with Bayesian Gene Selection

    Directory of Open Access Journals (Sweden)

    Xiaodong Wang

    2004-01-01

    Full Text Available A critical issue for the construction of genetic regulatory networks is the identification of network topology from data. In the context of deterministic and probabilistic Boolean networks, as well as their extension to multilevel quantization, this issue is related to the more general problem of expression prediction in which we want to find small subsets of genes to be used as predictors of target genes. Given some maximum number of predictors to be used, a full search of all possible predictor sets is combinatorially prohibitive except for small predictors sets, and even then, may require supercomputing. Hence, suboptimal approaches to finding predictor sets and network topologies are desirable. This paper considers Bayesian variable selection for prediction using a multinomial probit regression model with data augmentation to turn the multinomial problem into a sequence of smoothing problems. There are multiple regression equations and we want to select the same strongest genes for all regression equations to constitute a target predictor set or, in the context of a genetic network, the dependency set for the target. The probit regressor is approximated as a linear combination of the genes and a Gibbs sampler is employed to find the strongest genes. Numerical techniques to speed up the computation are discussed. After finding the strongest genes, we predict the target gene based on the strongest genes, with the coefficient of determination being used to measure predictor accuracy. Using malignant melanoma microarray data, we compare two predictor models, the estimated probit regressors themselves and the optimal full-logic predictor based on the selected strongest genes, and we compare these to optimal prediction without feature selection.

  9. Therapeutic genes for anti-HIV/AIDS gene therapy.

    Science.gov (United States)

    Bovolenta, Chiara; Porcellini, Simona; Alberici, Luca

    2013-01-01

    The multiple therapeutic approaches developed so far to cope HIV-1 infection, such as anti-retroviral drugs, germicides and several attempts of therapeutic vaccination have provided significant amelioration in terms of life-quality and survival rate of AIDS patients. Nevertheless, no approach has demonstrated efficacy in eradicating this lethal, if untreated, infection. The curative power of gene therapy has been proven for the treatment of monogenic immunodeficiensies, where permanent gene modification of host cells is sufficient to correct the defect for life-time. No doubt, a similar concept is not applicable for gene therapy of infectious immunodeficiensies as AIDS, where there is not a single gene to be corrected; rather engineered cells must gain immunotherapeutic or antiviral features to grant either short- or long-term efficacy mostly by acquisition of antiviral genes or payloads. Anti-HIV/AIDS gene therapy is one of the most promising strategy, although challenging, to eradicate HIV-1 infection. In fact, genetic modification of hematopoietic stem cells with one or multiple therapeutic genes is expected to originate blood cell progenies resistant to viral infection and thereby able to prevail on infected unprotected cells. Ultimately, protected cells will re-establish a functional immune system able to control HIV-1 replication. More than hundred gene therapy clinical trials against AIDS employing different viral vectors and transgenes have been approved or are currently ongoing worldwide. This review will overview anti-HIV-1 infection gene therapy field evaluating strength and weakness of the transgenes and payloads used in the past and of those potentially exploitable in the future.

  10. Progress of gene targeting in mouse

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Gene targeting is a powerful approach of study- ing the genefunction in vivo. Specific genetic modifications, including simple gene disruption, point mutations, large chromosomal deletions and rearrangements, targeted incor- poration of foreign genes, could be introduced into the mouse genome by gene targeting. Recent studies make it possible to do the gene targeting with temporal and spatial control.

  11. Human Lacrimal Gland Gene Expression

    Science.gov (United States)

    Aakalu, Vinay Kumar; Parameswaran, Sowmya; Maienschein-Cline, Mark; Bahroos, Neil; Shah, Dhara; Ali, Marwan; Krishnakumar, Subramanian

    2017-01-01

    Background The study of human lacrimal gland biology and development is limited. Lacrimal gland tissue is damaged or poorly functional in a number of disease states including dry eye disease. Development of cell based therapies for lacrimal gland diseases requires a better understanding of the gene expression and signaling pathways in lacrimal gland. Differential gene expression analysis between lacrimal gland and other embryologically similar tissues may be helpful in furthering our understanding of lacrimal gland development. Methods We performed global gene expression analysis of human lacrimal gland tissue using Affymetrix ® gene expression arrays. Primary data from our laboratory was compared with datasets available in the NLM GEO database for other surface ectodermal tissues including salivary gland, skin, conjunctiva and corneal epithelium. Results The analysis revealed statistically significant difference in the gene expression of lacrimal gland tissue compared to other ectodermal tissues. The lacrimal gland specific, cell surface secretory protein encoding genes and critical signaling pathways which distinguish lacrimal gland from other ectodermal tissues are described. Conclusions Differential gene expression in human lacrimal gland compared with other ectodermal tissue types revealed interesting patterns which may serve as the basis for future studies in directed differentiation among other areas. PMID:28081151

  12. Comprehensive resource: Skeletal gene database.

    Science.gov (United States)

    Jia, L; Ho, N C; Park, S S; Powell, J; Francomano, C A

    2001-01-01

    The Skeletal Gene Database (SGD) is an integrated resource that provides comprehensive information about bone-related genes, mRNA, and proteins expressed in human and mouse, with rich links to numerous other electronic tools. SGD contains expressed sequence tag (EST) data from all the skeletal-related cDNA libraries that are available to the public. It supplies the query/data access analytic tools for users to search and compare each gene expressed in skeletal tissue(s). The results derived from EST tissue expression profiling will allow users to get the data on the mRNA copy numbers of each gene expressed in each tissue and its normalized value. From the SGD, researchers can obtain information regarding the name, symbol, size, exon/intron number, chromosomal location, LocusLink, and related disease (if any is known) of each gene. This electronic compendium also furnishes information on the protein of the corresponding gene including the protein size (amino acid number and molecular weight). It provides swift and ready access to other useful databases including OMIM, UniGene and PUBMED. The data will be updated regularly in step with current and future research, thereby providing what we hope will serve as a highly useful source of information and a powerful analytic tool to the scientific community.

  13. GENES IN SPORT AND DOPING

    Directory of Open Access Journals (Sweden)

    Andrzej Pokrywka

    2013-06-01

    Full Text Available Genes control biological processes such as muscle production of energy, mitochondria biogenesis, bone formation erythropoiesis, angiogenesis, vasodilation, neurogenesis, etc. DNA profiling for athletes reveals genetic variations that may be associated with endurance ability, muscle performance and power exercise, tendon susceptibility to injuries and psychological aptitude. Already, over 200 genes relating to physical performance have been identified by several research groups. Athletes’ genotyping is developing as a tool for the formulation of personalized training and nutritional programmes to optimize sport training as well as for the prediction of exercise-related injuries. On the other hand, development of molecular technology and gene therapy creates a risk of non-therapeutic use of cells, genes and genetic elements to improve athletic performance. Therefore, the World Anti-Doping Agency decided to include prohibition of gene doping within their World Anti-Doping Code in 2003. In this review article, we will provide a current overview of genes for use in athletes’ genotyping and gene doping possibilities, including their development and detection techniques.

  14. Approaches for skeletal gene therapy.

    Science.gov (United States)

    Niyibizi, Christopher; Wallach, Corey J; Mi, Zhibao; Robbins, Paul D

    2002-01-01

    The role of gene therapy in the treatment of musculoskeletal disorders continues to be an active area of research. As the etiology of many musculoskeletal diseases becomes increasingly understood, advances in cellular and gene therapy maybe applied to their potential treatment This review focuses on current investigational strategies to treat osteogenesis imperfecta (OI). OI is a varied group of genetic disorders that result in the diminished integrity of connective tissues as a result of alterations in the genes that encode for either the pro alpha1 or pro alpha2 component of type I collagen. Because most forms of OI result from dominant negative mutations, isolated gene replacement therapy is not a logical treatment option. The combined use of genetic manipulation and cellular transplantation, however, may provide a means to overcome this obstacle. This article describes the recent laboratory and clinical advances in cell therapy, highlights potential techniques being investigated to suppress the expression of the mutant allele with antisense gene therapy, and attempts to deliver collagen genes to bone cells. The challenges that the investigators face in their quest for the skeletal gene therapy are also discussed.

  15. Linking Genes to Cardiovascular Diseases: Gene Action and Gene-Environment Interactions.

    Science.gov (United States)

    Pasipoularides, Ares

    2015-12-01

    A unique myocardial characteristic is its ability to grow/remodel in order to adapt; this is determined partly by genes and partly by the environment and the milieu intérieur. In the "post-genomic" era, a need is emerging to elucidate the physiologic functions of myocardial genes, as well as potential adaptive and maladaptive modulations induced by environmental/epigenetic factors. Genome sequencing and analysis advances have become exponential lately, with escalation of our knowledge concerning sometimes controversial genetic underpinnings of cardiovascular diseases. Current technologies can identify candidate genes variously involved in diverse normal/abnormal morphomechanical phenotypes, and offer insights into multiple genetic factors implicated in complex cardiovascular syndromes. The expression profiles of thousands of genes are regularly ascertained under diverse conditions. Global analyses of gene expression levels are useful for cataloging genes and correlated phenotypes, and for elucidating the role of genes in maladies. Comparative expression of gene networks coupled to complex disorders can contribute insights as to how "modifier genes" influence the expressed phenotypes. Increasingly, a more comprehensive and detailed systematic understanding of genetic abnormalities underlying, for example, various genetic cardiomyopathies is emerging. Implementing genomic findings in cardiology practice may well lead directly to better diagnosing and therapeutics. There is currently evolving a strong appreciation for the value of studying gene anomalies, and doing so in a non-disjointed, cohesive manner. However, it is challenging for many-practitioners and investigators-to comprehend, interpret, and utilize the clinically increasingly accessible and affordable cardiovascular genomics studies. This survey addresses the need for fundamental understanding in this vital area.

  16. Viral vectors for gene transfer: current status of gene therapeutics.

    Science.gov (United States)

    Heilbronn, Regine; Weger, Stefan

    2010-01-01

    Gene therapy for the correction of inherited or acquired disease has gained increasing importance in recent years. Successful treatment of children suffering from severe combined immunodeficiency (SCID) was achieved using retrovirus vectors for gene transfer. Encouraging improvements of vision were reported in a genetic eye disorder (LCA) leading to early childhood blindness. Adeno-associated virus (AAV) vectors were used for gene transfer in these trials. This chapter gives an overview of the design and delivery of viral vectors for the transport of a therapeutic gene into a target cell or tissue. The construction and production of retrovirus, lentivirus, and AAV vectors are covered. The focus is on production methods suitable for biopharmaceutical upscaling and for downstream processing. Quality control measures and biological safety considerations for the use of vectors in clinical trials are discussed.

  17. [Pathogenicity and pneumococcal capsular genes].

    Science.gov (United States)

    García, E; García, P; López, R

    1994-01-01

    Pneumococci remain to be one of the most prominent human pathogens. Increasing efforts are being dedicated to the development of improved vaccines with wider specificity. Since a clear understanding of the genetics of capsular types in Streptococcus pneumoniae is missing, our efforts are oriented to characterize, at the molecular level, the genes involved in capsular polysaccharide biosynthesis. We have cloned and sequenced a chromosomal DNA fragment of a clinical isolate of type 3 pneumococcus and showed that it contains a type 3 specific gene as well as genes common to other serotypes.

  18. Panspermia and horizontal gene transfer

    Science.gov (United States)

    Klyce, Brig

    2009-08-01

    Evidence that extremophiles are hardy and ubiquitous is helping to make panspermia a respectable theory. But even if life on Earth originally came from space, biologists assume that the subsequent evolution of life is still governed by the darwinian paradigm. In this review we show how panspermia could amend darwinism and point to a cosmic source for, not only extremophiles but, all of life. This version of panspermia can be called "strong panspermia." To support this theory we will discuss recent evidence pertaining to horizontal gene transfer, viruses, genes apparently older than the Earthly evolution of the features they encode, and primate-specific genes without identifiable precursors.

  19. Meta Analysis on DNA Repair Gene XRCC1- 26304C>T Single Neucleotide Polymorphisms and Oral Cancer Susceptibility%DNA修复基因XRCC1-26304C>T多态性与口腔癌易感性关系的meta分析

    Institute of Scientific and Technical Information of China (English)

    姚红磊; 陈涌; 纳应坤; 骆奇; 刘华

    2012-01-01

    Objictive: To evaluate the relationship between X-ray cross-complementing group KXRCCDgene single neucleotide polymorphisms and oral cancer susceptibility. Methods: By searching Medline, EMBSE, CBM and CNKI et al, we collect studies about DNA X -ray cross -complementing group KXRCC1) gene polymorphisms and oral cancer susceptibility. The odds ratios COR) of variant allele of XRCC3-26304OT was calculated by using statistic software RevievMan5. 0 and STATA11. 0. Results: 7 case-control studies were identified for the meta-analysis, a total of 1155 cases and 2036 controls were included. In the (T/T)VS(C/C) group the odds ratio was I. 46(0. 93-2. 28 ); For the recessive genetic model, in the (T/T)VS(C/C) + (C/T) group the odds ratio was 1.30 (0.84 - 2.00)s For the dominint genetic model, in the (T/T) + (C/T)VS(C/C) group the odds ratio was OR = 1.34(1.02-1.76). Conclusion: In the dominant genetic mode, carrying XRCC1 gene mutations (TT + CT) of Asians may be susceptible of oral cancer, but more researches are needed to confirm.%目的:采用系统评价的方法综合分析DNA修复基因(X-ray cross-complementing group 1,XRCC1)26304C>T位点单核苷酸多态性与口腔癌易感性的关系.方法:检索PubMed(1966~2011.4)、EMBASE( 1974~2011.4)、中国生物医学文献数据库CBM(1978~2011.3)、中国期刊全文数据库CNKI(1994~2011.3)等数据库收录的XRCC1-26304C>T单核苷酸多态性与口腔癌易感性的研究.以病例组和对照组等位基因分布的比值比(odds ratio OR)为效应指标,根据异质性检验结果,选择固定效应模型或随机效应模型对OR进行合并.结果:本次meta分析共纳入文献7篇,病例组1155例,对照组2036例.分析结果显示:突变纯合子(T/T)患口腔癌的风险与野生型纯合子(C/C)相比OR=1.46 (0.93~2.28);隐性模式下,突变纯合子(T/T)患口腔癌的风险与野生型(纯合子+杂合子)(C/C)+(C/T)相比OR=1.30 (0.84~2.00);显性模式下,突变个体(突变

  20. The Gene Ontology (GO) project in 2006

    National Research Council Canada - National Science Library

    2006-01-01

    The Gene Ontology (GO) project (http://www.geneontology.org) develops and uses a set of structured, controlled vocabularies for community use in annotating genes, gene products and sequences (also see http://song.sourceforge.net...

  1. The Gene Ontology project in 2008

    National Research Council Canada - National Science Library

    The Gene Ontology (GO) project (http://www.geneontology.org/) provides a set of structured, controlled vocabularies for community use in annotating genes, gene products and sequences (also see http://www.sequenceontology.org...

  2. Integrating Gene Ontology and Blast to predict gene functions

    Institute of Scientific and Technical Information of China (English)

    WANG Cheng-gang; MO Zhi-hong

    2007-01-01

    A GoBlast system was built to predict gene function by integrating Blast search and Gene Ontology (GO) annotations together. The operation system was based on Debian Linux 3.1, with Apache as the web server and Mysql database as the data storage system. FASTA files with GO annotations were taken as the sequence source for blast alignment, which were formatted by wu-formatdb program. The GoBlast system includes three Bioperl modules in Perl: a data input module, a data process module and a data output module. A GoBlast query starts with an amino acid or nucleotide sequence. It ends with an output in an html page, presenting high scoring gene products which are of a high homology to the queried sequence and listing associated GO terms beside respective gene poducts. A simple click on a GO term leads to the detailed explanation of the specific gene function. This avails gene function prediction by Blast. GoBlast can be a very useful tool for functional genome research and is available for free at http://bioq.org/goblast.

  3. Gene function prediction based on the Gene Ontology hierarchical structure.

    Science.gov (United States)

    Cheng, Liangxi; Lin, Hongfei; Hu, Yuncui; Wang, Jian; Yang, Zhihao

    2014-01-01

    The information of the Gene Ontology annotation is helpful in the explanation of life science phenomena, and can provide great support for the research of the biomedical field. The use of the Gene Ontology is gradually affecting the way people store and understand bioinformatic data. To facilitate the prediction of gene functions with the aid of text mining methods and existing resources, we transform it into a multi-label top-down classification problem and develop a method that uses the hierarchical relationships in the Gene Ontology structure to relieve the quantitative imbalance of positive and negative training samples. Meanwhile the method enhances the discriminating ability of classifiers by retaining and highlighting the key training samples. Additionally, the top-down classifier based on a tree structure takes the relationship of target classes into consideration and thus solves the incompatibility between the classification results and the Gene Ontology structure. Our experiment on the Gene Ontology annotation corpus achieves an F-value performance of 50.7% (precision: 52.7% recall: 48.9%). The experimental results demonstrate that when the size of training set is small, it can be expanded via topological propagation of associated documents between the parent and child nodes in the tree structure. The top-down classification model applies to the set of texts in an ontology structure or with a hierarchical relationship.

  4. Role of recA/RAD51 family proteins in mammals.

    Directory of Open Access Journals (Sweden)

    Kawabata,Masahiro

    2005-02-01

    Full Text Available

    DNA damage causes chromosomal instability leading to oncogenesis, apoptosis, and severe failure of cell functions. The DNA repair system includes base excision repair, nucleotide excision repair, mismatch repair, translesion replication, non-homologous end-joining, and recombinational repair. Homologous recombination performs the recombinational repair. The RAD51 gene is an ortholog of Esherichia coli recA, and the gene product Rad51 protein plays a central role in the homologous recombination. In mammals, 7 recA-like genes have been identified: RAD51, RAD51L1/B, RAD51L2/C, RAD51L3/D, XRCC2, XRCC3, and DMC1. These genes, with the exception of meiosis-specific DMC1, are essential for development in mammals. Disruption of the RAD51 gene leads to cell death, whereas RAD51L1/B, RAD51L2/C, RAD51L3/D, XRCC2, and XRCC3 genes (RAD51 paralogs are not essential for viability of cells, but these gene-deficient cells exhibit a similar defective phenotype. Yeast two-hybrid analysis, co-immunoprecipitation, mutation analysis, and domain mapping of Rad51 and Rad51 paralogs have revealed protein-protein interactions among these gene products. Recent investigations have shown that Rad51 paralogs play a role not only in an early step, but also in a late step of homologous recombination. In addition, identification of alternative transcripts of some RAD51 paralogs may reflect the complexity of the homologous recombination system.

  5. How eukaryotic genes are transcribed.

    Science.gov (United States)

    Venters, Bryan J; Pugh, B Franklin

    2009-06-01

    Regulation of eukaryotic gene expression is far more complex than one might have imagined 30 years ago. However, progress towards understanding gene regulatory mechanisms has been rapid and comprehensive, which has made the integration of detailed observations into broadly connected concepts a challenge. This review attempts to integrate the following concepts: (1) a well-defined organization of nucleosomes and modification states at most genes; (2) regulatory networks of sequence-specific transcription factors; (3) chromatin remodeling coupled to promoter assembly of the general transcription factors and RNA polymerase II; and (4) phosphorylation states of RNA polymerase II coupled to chromatin modification states during transcription. The wealth of new insights arising from the tools of biochemistry, genomics, cell biology, and genetics is providing a remarkable view into the mechanics of gene regulation.

  6. Gene Variants Reduce Opioid Risks

    Science.gov (United States)

    ... Opioids Prescription Drugs & Cold Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine ... variant of the gene for the μ-opioid receptor (OPRM1) with a decreased risk for addiction to ...

  7. Gene therapy in ocular diseases

    Directory of Open Access Journals (Sweden)

    Singh Vijay

    2002-01-01

    Full Text Available Gene therapy is a novel form of drug delivery that enlists the synthetic machinery of the patient′s cells to produce a therapeutic agent. Genes may be delivered into cells in vitro or in vivo utilising viral or non-viral vectors. Recent technical advances have led to the demonstration of the molecular basis of various ocular diseases. Ocular disorders with the greatest potential for benefit of gene therapy include hereditary diseases such as retinitis pigmentosa, tumours such as retinoblastoma or melanoma, and acquired proliferative and neovascular retinal disorders. Gene transfer into ocular tissues has been demonstrated with growing functional success and may develop into a new therapeutic tool for clinical ophthalmology in future.

  8. Plant gene technology: social considerations

    African Journals Online (AJOL)

    Administrator

    African Journal of Biotechnology Vol. 3 (3), pp. 156-158 ... The genetic modification of plants by gene technology is of immense potential benefits, but there may ... this modern age. ... advantages over the current rate of food production and.

  9. Genes That Influence Blood Pressure

    Science.gov (United States)

    ... Influence Blood Pressure Gene Linked to Optimism and Self-Esteem Designing New Diabetes Drugs Connect with Us Subscribe to get NIH Research Matters by email RSS Feed Facebook Email us Mailing Address: NIH Research Matters Bldg. ...

  10. MADS-box gene evolution - structure and transcription patterns

    DEFF Research Database (Denmark)

    Johansen, Bo; Pedersen, Louise Buchholt; Skipper, Martin;

    2002-01-01

    Mads-box genes, ABC model, Evolution, Phylogeny, Transcription patterns, Gene structure, Conserved motifs......Mads-box genes, ABC model, Evolution, Phylogeny, Transcription patterns, Gene structure, Conserved motifs...

  11. The evolution of resistance gene in plants

    Institute of Scientific and Technical Information of China (English)

    BEN Haiyan; LIU Xuemin; LI Lijun; LIU Li

    2007-01-01

    Resistance genes enable plants to fight against plant pathogens. Plant resistance genes (R gene) are organized complexly in genome. Some resistance gene sequence data enable an insight into R gene structure and gene evolution. Some sites like Leucine-Rich Repeat (LRR) are of specific interest since homologous recombination can happen. Crossing over, transposon insertion and excision and mutation can produce new specificity. Three models explaining R gene evolution were discussed. More information needed for dissection of R gene evolution though some step can be inferred from genetic and sequence analysis.

  12. The Insect SNMP Gene Family

    Science.gov (United States)

    2009-01-01

    B 1 ( b o v ) Clade 3 - SNMPs Clade 2 Clade 1 CD36 Insect (Holometabola) CD36 Gene family Holometabola Phylogeny (11 Orders) Tribolium castaneum...melanogaster genes (see Nichols and Vogt, 2008). Bootstrap support (1000 replicates) is indicated for the major clades. B. Phylogeny of holometabolous...A. aegypti eggs were graciously provided by Mark Brown (University of Georgia, Department of Entomology) and raised on a larval diet (pond fish food

  13. Rice's Salt Tolerance Gene Cloned

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    @@ In cooperation with US colleagues, CAS researchers have made significant progress in their studies into functional genes for key agronomic traits by cloning SKC1, a salt-tolerant functional gene of rice and making clear its biological functions and mechanisms. This pioneering work,which was reported in the Oct. issue of Nature Genetics (37:1141-1146), is believed to hold promise to increase the output of the crop plant in this country.

  14. Genes de defensa en plantas

    OpenAIRE

    Carbonero Zalduegui, Pilar; García Olmedo, Francisco

    1994-01-01

    Se revisan los avances realizados en la caracterización de los genes que codifican para ciertas familias de proteínas vegetales que son tóxicas o inhibitorias frente a insectos, hongos y bacterias. La caracterización incluye el estudio in vitro de las propiedades de las proteínas purificadas y la experimentación in vivo con plantas transgénicas que expresan los genes correspondientes.

  15. Gene mutations in hepatocellular adenomas

    DEFF Research Database (Denmark)

    Raft, Marie B; Jørgensen, Ernö N; Vainer, Ben

    2015-01-01

    is associated with bi-allelic mutations in the TCF1 gene and morphologically has marked steatosis. β-catenin activating HCA has increased activity of the Wnt/β-catenin pathway and is associated with possible malignant transformation. Inflammatory HCA is characterized by an oncogene-induced inflammation due....... This review offers an overview of the reported gene mutations associated with hepatocellular adenomas together with a discussion of the diagnostic and prognostic value....

  16. Immunoglobulin genes of the turtles.

    Science.gov (United States)

    Magadán-Mompó, Susana; Sánchez-Espinel, Christian; Gambón-Deza, Francisco

    2013-03-01

    The availability of reptile genomes for the use of the scientific community is an exceptional opportunity to study the evolution of immunoglobulin genes. The genome of Chrysemys picta bellii and Pelodiscus sinensis is the first one that has been reported for turtles. The scanning for immunoglobulin genes resulted in the presence of a complex locus for the immunoglobulin heavy chain (IGH). This IGH locus in both turtles contains genes for 13 isotypes in C. picta bellii and 17 in P. sinensis. These correspond with one immunoglobulin M, one immunoglobulin D, several immunoglobulins Y (six in C. picta bellii and eight in P. sinensis), and several immunoglobulins that are similar to immunoglobulin D2 (five in C. picta belli and seven in P. sinensis) that was previously described in Eublepharis macularius. It is worthy to note that IGHD2 are placed in an inverted transcriptional orientation and present sequences for two immunoglobulin domains that are similar to bird IgA domains. Furthermore, its phylogenetic analysis allows us to consider about the presence of IGHA gene in a primitive reptile, so we would be dealing with the memory of the gene that originated from the bird IGHA. In summary, we provide a clear picture of the immunoglobulins present in a turtle, whose analysis supports the idea that turtles emerged from the evolutionary line from the differentiation of birds and the presence of the IGHA gene present in a common ancestor.

  17. Gene expression in colorectal cancer

    DEFF Research Database (Denmark)

    Birkenkamp-Demtroder, Karin; Christensen, Lise Lotte; Olesen, Sanne Harder

    2002-01-01

    Understanding molecular alterations in colorectal cancer (CRC) is needed to define new biomarkers and treatment targets. We used oligonucleotide microarrays to monitor gene expression of about 6,800 known genes and 35,000 expressed sequence tags (ESTs) on five pools (four to six samples in each p...... with a high frequency of loss of heterozygosity. The genes and ESTs presented in this study encode new potential tumor markers as well as potential novel therapeutic targets for prevention or therapy of CRC.......Understanding molecular alterations in colorectal cancer (CRC) is needed to define new biomarkers and treatment targets. We used oligonucleotide microarrays to monitor gene expression of about 6,800 known genes and 35,000 expressed sequence tags (ESTs) on five pools (four to six samples in each...... pool) of total RNA from left-sided sporadic colorectal carcinomas. We compared normal tissue to carcinoma tissue from Dukes' stages A-D (noninvasive to distant metastasis) and identified 908 known genes and 4,155 ESTs that changed remarkably from normal to tumor tissue. Based on intensive filtering 226...

  18. Gene Polymorphisms in Chronic Periodontitis

    Directory of Open Access Journals (Sweden)

    Marja L. Laine

    2010-01-01

    Full Text Available We aimed to conduct a review of the literature for gene polymorphisms associated with chronic periodontitis (CP susceptibility. A comprehensive search of the literature in English was performed using the keywords: periodontitis, periodontal disease, combined with the words genes, mutation, or polymorphism. Candidate gene polymorphism studies with a case-control design and reported genotype frequencies in CP patients were searched and reviewed. There is growing evidence that polymorphisms in the IL1, IL6, IL10, vitamin D receptor, and CD14 genes may be associated with CP in certain populations. However, carriage rates of the rare (-allele of any polymorphism varied considerably among studies and most of the studies appeared under-powered and did not correct for other risk factors. Larger cohorts, well-defined phenotypes, control for other risk factors, and analysis of multiple genes and polymorphisms within the same pathway are needed to get a more comprehensive insight into the contribution of gene polymorphisms in CP.

  19. Homologous gene replacement in Physarum

    Energy Technology Data Exchange (ETDEWEB)

    Burland, T.G. [Univ. of Wisconsin, Madison, WI (United States); Pallotta, D. [Laval Univ., Quebec (Canada)

    1995-01-01

    The protist Physarum polycephalum is useful for analysis of several aspects of cellular and developmental biology. To expand the opportunities for experimental analysis of this organism, we have developed a method for gene replacement. We transformed Physarum amoebae with plasmid DNA carrying a mutant allele, ardD{Delta}1, of the ardD actin gene; ardD{Delta}1 mutates the critical carboxy-terminal region of the gene product. Because ardD is not expressed in the amoeba, replacement of ardD{sup +} with ardD{Delta}1 should not be lethal for this cell type. Transformants were obtained only when linear plasmid DNA was used. Most transformants carried one copy of ardD{Delta}1 in addition to ardD{sup +}, but in two (5%), ardD{sup +} was replaced by a single copy of ardD{Delta}1. This is the first example of homologous gene replacement in Physarum. ardD{Delta}1 was stably maintained in the genome through growth, development and meiosis. We found no effect of ardD{Delta}l on viability, growth, or development of any of the various cell types of Physarum. Thus, the carboxy-terminal region of the ardD product appears not to perform a unique essential role in growth or development. Nevertheless, this method for homologous gene replacement can be applied to analyze the function of any cloned gene. 38 refs., 6 figs., 1 tab.

  20. Cationic Bolaamphiphiles for Gene Delivery

    Science.gov (United States)

    Tan, Amelia Li Min; Lim, Alisa Xue Ling; Zhu, Yiting; Yang, Yi Yan; Khan, Majad

    2014-05-01

    Advances in medical research have shed light on the genetic cause of many human diseases. Gene therapy is a promising approach which can be used to deliver therapeutic genes to treat genetic diseases at its most fundamental level. In general, nonviral vectors are preferred due to reduced risk of immune response, but they are also commonly associated with low transfection efficiency and high cytotoxicity. In contrast to viral vectors, nonviral vectors do not have a natural mechanism to overcome extra- and intracellular barriers when delivering the therapeutic gene into cell. Hence, its design has been increasingly complex to meet challenges faced in targeting of, penetration of and expression in a specific host cell in achieving more satisfactory transfection efficiency. Flexibility in design of the vector is desirable, to enable a careful and controlled manipulation of its properties and functions. This can be met by the use of bolaamphiphile, a special class of lipid. Unlike conventional lipids, bolaamphiphiles can form asymmetric complexes with the therapeutic gene. The advantage of having an asymmetric complex lies in the different purposes served by the interior and exterior of the complex. More effective gene encapsulation within the interior of the complex can be achieved without triggering greater aggregation of serum proteins with the exterior, potentially overcoming one of the great hurdles faced by conventional single-head cationic lipids. In this review, we will look into the physiochemical considerations as well as the biological aspects of a bolaamphiphile-based gene delivery system.

  1. Genetic polymorphisms in the nucleotide excision repair pathway and lung cancer risk: A meta-analysis

    Directory of Open Access Journals (Sweden)

    Chikako Kiyohara, Kouichi Yoshimasu

    2007-01-01

    Full Text Available Various DNA alterations can be caused by exposure to environmental and endogenous carcinogens. Most of these alterations, if not repaired, can result in genetic instability, mutagenesis and cell death. DNA repair mechanisms are important for maintaining DNA integrity and preventing carcinogenesis. Recent lung cancer studies have focused on identifying the effects of single nucleotide polymorphisms (SNPs in candidate genes, among which DNA repair genes are increasingly being studied. Genetic variations in DNA repair genes are thought to modulate DNA repair capacity and are suggested to be related to lung cancer risk. We identified a sufficient number of epidemiologic studies on lung cancer to conduct a meta-analysis for genetic polymorphisms in nucleotide excision repair pathway genes, focusing on xeroderma pigmentosum group A (XPA, excision repair cross complementing group 1 (ERCC1, ERCC2/XPD, ERCC4/XPF and ERCC5/XPG. We found an increased risk of lung cancer among subjects carrying the ERCC2 751Gln/Gln genotype (odds ratio (OR = 1.30, 95% confidence interval (CI = 1.14 - 1.49. We found a protective effect of the XPA 23G/G genotype (OR = 0.75, 95% CI = 0.59 - 0.95. Considering the data available, it can be conjectured that if there is any risk association between a single SNP and lung cancer, the risk fluctuation will probably be minimal. Advances in the identification of new polymorphisms and in high-throughput genotyping techniques will facilitate the analysis of multiple genes in multiple DNA repair pathways. Therefore, it is likely that the defining feature of future epidemiologic studies will be the simultaneous analysis of large samples.

  2. Origin and evolution of new genes

    Institute of Scientific and Technical Information of China (English)

    LI Xin; YANG Shuang; PENG Lixin; CHEN Hong; WANG Wen

    2004-01-01

    Organisms have variable genome sizes andcontain different numbers of genes. This difference demonstrates that new gene origination is a fundamental process in evolutionary biology. Though the study of the origination of new genes dated back more than half a century ago, it is not until the 1990s when the first young genejingwei was found that empirical investigation of the molecular mechanisms of origination of new genes became possible. In the recent years,several young genes were identified and the studies on these genes have greatly enriched the knowledge of this field. Yet more details in a general picture of new genes origination are to be clarified. We have developed a systematic approach to searching for young genes at the genomic level, in the hope to summarize a general pattern of the origination and evolution of new genes, such as the rate of new gene appearance, impact of new genes on their host genomes, etc.

  3. Head and neck squamous-cell cancer and its association with polymorphic enzymes of xenobiotic metabolism and repair.

    Science.gov (United States)

    Harth, Volker; Schafer, Martin; Abel, Josef; Maintz, Laura; Neuhaus, Thomas; Besuden, Mette; Primke, Robert; Wilkesmann, Anja; Thier, Ricarda; Vetter, Hans; Ko, Yon-Dschun; Bruning, Thomas; Bolt, Hermann M; Ickstadt, Katja

    2008-01-01

    Tobacco smoking, alcohol drinking, and occupational exposures to polycyclic aromatic hydrocarbons are the major proven risk factors for human head and neck squamous-cell cancer (HNSCC). Major research focus on gene-environment interactions concerning HNSCC has been on genes encoding enzymes of metabolism for tobacco smoke constituents and repair enzymes. To investigate the role of genetically determined individual predispositions in enzymes of xenobiotic metabolism and in repair enzymes under the exogenous risk factor tobacco smoke in the carcinogenesis of HNSCC, we conducted a case-control study on 312 cases and 300 noncancer controls. We focused on the impact of 22 sequence variations in CYP1A1, CYP1B1, CYP2E1, ERCC2/XPD, GSTM1, GSTP1, GSTT1, NAT2, NQO1, and XRCC1. To assess relevant main and interactive effects of polymorphic genes on the susceptibility to HNSCC we used statistical models such as logic regression and a Bayesian version of logic regression. In subgroup analysis of nonsmokers, main effects in ERCC2 (Lys751Gln) C/C genotype and combined ERCC2 (Arg156Arg) C/A and A/A genotypes were predominant. When stratifying for smokers, the data revealed main effects on combined CYP1B1 (Leu432Val) C/G and G/G genotypes, followed by CYP1B1 (Leu432Val) G/G genotype and CYP2E1 (-70G>T) G/T genotype. When fitting logistic regression models including relevant main effects and interactions in smokers, we found relevant associations of CYP1B1 (Leu432Val) C/G genotype and CYP2E1 (-70G>T) G/T genotype (OR, 10.84; 95% CI, 1.64-71.53) as well as CYP1B1 (Leu432Val) G/G genotype and GSTM1 null/null genotype (OR, 11.79; 95% CI, 2.18-63.77) with HNSCC. The findings underline the relevance of genotypes of polymorphic CYP1B1 combined with exposures to tobacco smoke.

  4. Aphids acquired symbiotic genes via lateral gene transfer

    Directory of Open Access Journals (Sweden)

    Nakabachi Atsushi

    2009-03-01

    Full Text Available Abstract Background Aphids possess bacteriocytes, which are cells specifically differentiated to harbour the obligate mutualist Buchnera aphidicola (γ-Proteobacteria. Buchnera has lost many of the genes that appear to be essential for bacterial life. From the bacteriocyte of the pea aphid Acyrthosiphon pisum, we previously identified two clusters of expressed sequence tags that display similarity only to bacterial genes. Southern blot analysis demonstrated that they are encoded in the aphid genome. In this study, in order to assess the possibility of lateral gene transfer, we determined the full-length sequences of these transcripts, and performed detailed structural and phylogenetic analyses. We further examined their expression levels in the bacteriocyte using real-time quantitative RT-PCR. Results Sequence similarity searches demonstrated that these fully sequenced transcripts are significantly similar to the bacterial genes ldcA (product, LD-carboxypeptidase and rlpA (product, rare lipoprotein A, respectively. Buchnera lacks these genes, whereas many other bacteria, including Escherichia coli, a close relative of Buchnera, possess both ldcA and rlpA. Molecular phylogenetic analysis clearly demonstrated that the aphid ldcA was derived from a rickettsial bacterium closely related to the extant Wolbachia spp. (α-Proteobacteria, Rickettsiales, which are intracellular symbionts of various lineages of arthropods. The evolutionary origin of rlpA was not fully resolved, but it was clearly demonstrated that its double-ψ β-barrel domain is of bacterial origin. Real-time quantitative RT-PCR demonstrated that ldcA and rlpA are expressed 11.6 and 154-fold higher in the bacteriocyte than in the whole body, respectively. LdcA is an enzyme required for recycling murein (peptidoglycan, which is a component of the bacterial cell wall. As Buchnera possesses a cell wall composed of murein but lacks ldcA, a high level of expression of the aphid ldcA in the

  5. Newer Gene Editing Technologies toward HIV Gene Therapy

    Directory of Open Access Journals (Sweden)

    Premlata Shankar

    2013-11-01

    Full Text Available Despite the great success of highly active antiretroviral therapy (HAART in ameliorating the course of HIV infection, alternative therapeutic approaches are being pursued because of practical problems associated with life-long therapy. The eradication of HIV in the so-called “Berlin patient” who received a bone marrow transplant from a CCR5-negative donor has rekindled interest in genome engineering strategies to achieve the same effect. Precise gene editing within the cells is now a realistic possibility with recent advances in understanding the DNA repair mechanisms, DNA interaction with transcription factors and bacterial defense mechanisms. Within the past few years, four novel technologies have emerged that can be engineered for recognition of specific DNA target sequences to enable site-specific gene editing: Homing Endonuclease, ZFN, TALEN, and CRISPR/Cas9 system. The most recent CRISPR/Cas9 system uses a short stretch of complementary RNA bound to Cas9 nuclease to recognize and cleave target DNA, as opposed to the previous technologies that use DNA binding motifs of either zinc finger proteins or transcription activator-like effector molecules fused to an endonuclease to mediate sequence-specific DNA cleavage. Unlike RNA interference, which requires the continued presence of effector moieties to maintain gene silencing, the newer technologies allow permanent disruption of the targeted gene after a single treatment. Here, we review the applications, limitations and future prospects of novel gene-editing strategies for use as HIV therapy.

  6. Sequencing and Gene Expression Analysis of Leishmania tropica LACK Gene.

    Directory of Open Access Journals (Sweden)

    Nour Hammoudeh

    2014-12-01

    Full Text Available Leishmania Homologue of receptors for Activated C Kinase (LACK antigen is a 36-kDa protein, which provokes a very early immune response against Leishmania infection. There are several reports on the expression of LACK through different life-cycle stages of genus Leishmania, but only a few of them have focused on L.tropica.The present study provides details of the cloning, DNA sequencing and gene expression of LACK in this parasite species. First, several local isolates of Leishmania parasites were typed in our laboratory using PCR technique to verify of Leishmania parasite species. After that, LACK gene was amplified and cloned into a vector for sequencing. Finally, the expression of this molecule in logarithmic and stationary growth phase promastigotes, as well as in amastigotes, was evaluated by Reverse Transcription-PCR (RT-PCR technique.The typing result confirmed that all our local isolates belong to L.tropica. LACK gene sequence was determined and high similarity was observed with the sequences of other Leishmania species. Furthermore, the expression of LACK gene in both promastigotes and amastigotes forms was confirmed.Overall, the data set the stage for future studies of the properties and immune role of LACK gene products.

  7. The biology of novel animal genes: Mouse APEX gene knockout

    Energy Technology Data Exchange (ETDEWEB)

    MacInnes, M.; Altherr, M.R.; Ludwig, D. [Los Alamos National Lab., NM (United States); Pedersen, R.; Mold, C. [Univ. of California, San Francisco, CA (United States)

    1997-07-01

    This is the final report of a one-year, Laboratory Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). The controlled breeding of novel genes into mice, including the gene knockout (KO), or conversely by adding back transgenes provide powerful genetic technologies that together suffice to determine in large part the biological role(s) of novel genes. Inbred mouse remains the best understood and most useful mammalian experimental system available for tackling the biology of novel genes. The major mammalian apurinic/apyrimidinic (AP) endonuclease (APE), is involved in a key step in the repair of spontaneous and induced AP sites in DNA. Efficient repair of these lesions is imperative to prevent the stable incorporation of mutations into the cellular genome which may lead to cell death or transformation. Loss or modulation of base excison repair activity in vivo may elevate the spontaneous mutation rate in cells, and may lead to a substantial increase in the incidence of cancer. Despite extensive biochemical analysis, however, the significance of these individual APE functions in vivo has not been elucidated. Mouse embryonic stem (ES) cells heterozygous for a deletion mutation in APE have been generated and whole animals containing the APE mutation have been derived from these ES cells. Animals homozygous for the APE null mutation die early in gestation, underscoring the biological significance of this DNA repair gene.

  8. Newer gene editing technologies toward HIV gene therapy.

    Science.gov (United States)

    Manjunath, N; Yi, Guohua; Dang, Ying; Shankar, Premlata

    2013-11-14

    Despite the great success of highly active antiretroviral therapy (HAART) in ameliorating the course of HIV infection, alternative therapeutic approaches are being pursued because of practical problems associated with life-long therapy. The eradication of HIV in the so-called "Berlin patient" who received a bone marrow transplant from a CCR5-negative donor has rekindled interest in genome engineering strategies to achieve the same effect. Precise gene editing within the cells is now a realistic possibility with recent advances in understanding the DNA repair mechanisms, DNA interaction with transcription factors and bacterial defense mechanisms. Within the past few years, four novel technologies have emerged that can be engineered for recognition of specific DNA target sequences to enable site-specific gene editing: Homing Endonuclease, ZFN, TALEN, and CRISPR/Cas9 system. The most recent CRISPR/Cas9 system uses a short stretch of complementary RNA bound to Cas9 nuclease to recognize and cleave target DNA, as opposed to the previous technologies that use DNA binding motifs of either zinc finger proteins or transcription activator-like effector molecules fused to an endonuclease to mediate sequence-specific DNA cleavage. Unlike RNA interference, which requires the continued presence of effector moieties to maintain gene silencing, the newer technologies allow permanent disruption of the targeted gene after a single treatment. Here, we review the applications, limitations and future prospects of novel gene-editing strategies for use as HIV therapy.

  9. [Developments in gene delivery vectors for ocular gene therapy].

    Science.gov (United States)

    Khabou, Hanen; Dalkara, Deniz

    2015-05-01

    Gene therapy is quickly becoming a reality applicable in the clinic for inherited retinal diseases. Its remarkable success in safety and efficacy, in clinical trials for Leber's congenital amaurosis (LCA) type II generated significant interest and opened up possibilities for a new era of retinal gene therapies. Success in these clinical trials was mainly due to the favorable characteristics of the retina as a target organ. The eye offers several advantages as it is readily accessible and has some degree of immune privilege making it suitable for application of viral vectors. The viral vectors most frequently used for retinal gene delivery are lentivirus, adenovirus and adeno-associated virus (AAV). Here we will discuss the use of these viral vectors in retinal gene delivery with a strong focus on favorable properties of AAV. Thanks to its small size, AAV diffuses well in the inter-neural matrix making it suitable for applications in neural retina. Building on this initial clinical success with LCA II, we have now many opportunities to extend this proof-of-concept to other retinal diseases using AAV as a vector. This article will discuss what are some of the most imminent cellular targets for such therapies and the AAV toolkit that has been built to target these cells successfully. We will also discuss some of the challenges that we face in translating AAV-based gene therapies to the clinic. © 2015 médecine/sciences – Inserm.

  10. Reduced rates of gene loss, gene silencing, and gene mutation in Dnmt1-deficient embryonic stem cells

    NARCIS (Netherlands)

    Chan, M.F.; van Amerongen, R.; Nijjar, T.; Cuppen, E.; Jones, P.A.; Laird, P.W.

    2001-01-01

    Tumor suppressor gene inactivation is a crucial event in oncogenesis. Gene inactivation mechanisms include events resulting in loss of heterozygosity (LOH), gene mutation, and transcriptional silencing. The contribution of each of these different pathways varies among tumor suppressor genes and by c

  11. Characterizing gene-gene interactions in a statistical epistasis network of twelve candidate genes for obesity.

    Science.gov (United States)

    De, Rishika; Hu, Ting; Moore, Jason H; Gilbert-Diamond, Diane

    2015-01-01

    Recent findings have reemphasized the importance of epistasis, or gene-gene interactions, as a contributing factor to the unexplained heritability of obesity. Network-based methods such as statistical epistasis networks (SEN), present an intuitive framework to address the computational challenge of studying pairwise interactions between thousands of genetic variants. In this study, we aimed to analyze pairwise interactions that are associated with Body Mass Index (BMI) between SNPs from twelve genes robustly associated with obesity (BDNF, ETV5, FAIM2, FTO, GNPDA2, KCTD15, MC4R, MTCH2, NEGR1, SEC16B, SH2B1, and TMEM18). We used information gain measures to identify all SNP-SNP interactions among and between these genes that were related to obesity (BMI > 30 kg/m(2)) within the Framingham Heart Study Cohort; interactions exceeding a certain threshold were used to build an SEN. We also quantified whether interactions tend to occur more between SNPs from the same gene (dyadicity) or between SNPs from different genes (heterophilicity). We identified a highly connected SEN of 709 SNPs and 1241 SNP-SNP interactions. Combining the SEN framework with dyadicity and heterophilicity analyses, we found 1 dyadic gene (TMEM18, P-value = 0.047) and 3 heterophilic genes (KCTD15, P-value = 0.045; SH2B1, P-value = 0.003; and TMEM18, P-value = 0.001). We also identified a lncRNA SNP (rs4358154) as a key node within the SEN using multiple network measures. This study presents an analytical framework to characterize the global landscape of genetic interactions from genome-wide arrays and also to discover nodes of potential biological significance within the identified network.

  12. Combining Hierarchical and Associative Gene Ontology Relations with Textual Evidence in Estimating Gene and Gene Product Similarity

    Energy Technology Data Exchange (ETDEWEB)

    Sanfilippo, Antonio P.; Posse, Christian; Gopalan, Banu; Riensche, Roderick M.; Beagley, Nathaniel; Baddeley, Bob L.; Tratz, Stephen C.; Gregory, Michelle L.

    2007-03-01

    Gene and gene product similarity is a fundamental diagnostic measure in analyzing biological data and constructing predictive models for functional genomics. With the rising influence of the Gene Ontology, two complementary approaches have emerged where the similarity between two genes or gene products is obtained by comparing Gene Ontology (GO) annotations associated with the genes or gene products. One approach captures GO-based similarity in terms of hierarchical relations within each gene subontology. The other approach identifies GO-based similarity in terms of associative relations across the three gene subontologies. We propose a novel methodology where the two approaches can be merged with ensuing benefits in coverage and accuracy, and demonstrate that further improvements can be obtained by integrating textual evidence extracted from relevant biomedical literature.

  13. Gene expression profiles in skeletal muscle after gene electrotransfer

    DEFF Research Database (Denmark)

    Hojman, Pernille; Zibert, John R; Gissel, Hanne;

    2007-01-01

    with the control muscles. Most interestingly, no changes in the expression of proteins involved in inflammatory responses or muscle regeneration was detected, indicating limited muscle damage and regeneration. Histological analysis revealed structural changes with loss of cell integrity and striation pattern......BACKGROUND: Gene transfer by electroporation (DNA electrotransfer) to muscle results in high level long term transgenic expression, showing great promise for treatment of e.g. protein deficiency syndromes. However little is known about the effects of DNA electrotransfer on muscle fibres. We have......) followed by a long low voltage pulse (LV, 100 V/cm, 400 ms); a pulse combination optimised for efficient and safe gene transfer. Muscles were transfected with green fluorescent protein (GFP) and excised at 4 hours, 48 hours or 3 weeks after treatment. RESULTS: Differentially expressed genes were...

  14. Imaging reporter gene for monitoring gene therapy; Imagerie par gene rapporteur: un atout pour la therapie genique

    Energy Technology Data Exchange (ETDEWEB)

    Beco, V. de; Baillet, G.; Tamgac, F.; Tofighi, M.; Weinmann, P.; Vergote, J.; Moretti, J.L. [Centre Hospitalier Universitaire Avicenne, Service Central de Medecine Nucleaire et Biophysique, UPRES 2360, 93 - Bobigny (France); Tamgac, G. [Univetsite d' Uludag, Service de Medecine Nucleaire, Bursa (Turkey)

    2002-06-01

    Scintigraphic images can be obtained to document gene function at cellular level. This approach is presented here and the use of a reporter gene to monitor gene therapy is described. Two main ways are presented: either the use of a reporter gene coding for an enzyme the action of which will be monitored by radiolabeled pro-drug, or a cellular receptor gene, the action of which is documented by a radio labeled cognate receptor ligand. (author)

  15. COGNATE: comparative gene annotation characterizer.

    Science.gov (United States)

    Wilbrandt, Jeanne; Misof, Bernhard; Niehuis, Oliver

    2017-07-17

    The comparison of gene and genome structures across species has the potential to reveal major trends of genome evolution. However, such a comparative approach is currently hampered by a lack of standardization (e.g., Elliott TA, Gregory TR, Philos Trans Royal Soc B: Biol Sci 370:20140331, 2015). For example, testing the hypothesis that the total amount of coding sequences is a reliable measure of potential proteome diversity (Wang M, Kurland CG, Caetano-Anollés G, PNAS 108:11954, 2011) requires the application of standardized definitions of coding sequence and genes to create both comparable and comprehensive data sets and corresponding summary statistics. However, such standard definitions either do not exist or are not consistently applied. These circumstances call for a standard at the descriptive level using a minimum of parameters as well as an undeviating use of standardized terms, and for software that infers the required data under these strict definitions. The acquisition of a comprehensive, descriptive, and standardized set of parameters and summary statistics for genome publications and further analyses can thus greatly benefit from the availability of an easy to use standard tool. We developed a new open-source command-line tool, COGNATE (Comparative Gene Annotation Characterizer), which uses a given genome assembly and its annotation of protein-coding genes for a detailed description of the respective gene and genome structure parameters. Additionally, we revised the standard definitions of gene and genome structures and provide the definitions used by COGNATE as a working draft suggestion for further reference. Complete parameter lists and summary statistics are inferred using this set of definitions to allow down-stream analyses and to provide an overview of the genome and gene repertoire characteristics. COGNATE is written in Perl and freely available at the ZFMK homepage ( https://www.zfmk.de/en/COGNATE ) and on github ( https

  16. Analysis of Duplicate Genes in Soybean

    Institute of Scientific and Technical Information of China (English)

    C.M. Cai; K.J. Van; M.Y. Kim; S.H. Lee

    2007-01-01

    @@ Gene duplication is a major determinant of the size and gene complement of eukaryotic genomes (Lockton and Gaut, 2005). There are a number of different ways in which duplicate genes can arise (Sankoff, 2001), but the most spectacular method of gene duplication may be whole genome duplication via polyploidization.

  17. Synthetic promoter libraries- tuning of gene expression

    DEFF Research Database (Denmark)

    Hammer, Karin; Mijakovic, Ivan; Jensen, Peter Ruhdal

    2006-01-01

    The study of gene function often requires changing the expression of a gene and evaluating the consequences. In principle, the expression of any given gene can be modulated in a quasi-continuum of discrete expression levels but the traditional approaches are usually limited to two extremes: gene ...

  18. Deregulated genes in sporadic vestibular schwannomas

    DEFF Research Database (Denmark)

    Cayé-Thomasen, Per; Helweg-Larsen, Rehannah Holga Andrea; Stangerup, Sven-Eric;

    2010-01-01

    In search of genes associated with vestibular schwannoma tumorigenesis, this study examines the gene expression in human vestibular nerve versus vestibular schwannoma tissue samples using microarray technology.......In search of genes associated with vestibular schwannoma tumorigenesis, this study examines the gene expression in human vestibular nerve versus vestibular schwannoma tissue samples using microarray technology....

  19. Deregulated genes in sporadic vestibular schwannomas

    DEFF Research Database (Denmark)

    Cayé-Thomasen, Per; Helweg-Larsen, Rehannah Holga Andrea; Stangerup, Sven-Eric

    2010-01-01

    In search of genes associated with vestibular schwannoma tumorigenesis, this study examines the gene expression in human vestibular nerve versus vestibular schwannoma tissue samples using microarray technology.......In search of genes associated with vestibular schwannoma tumorigenesis, this study examines the gene expression in human vestibular nerve versus vestibular schwannoma tissue samples using microarray technology....

  20. Gene Therapy Applications in Gastroenterology and Hepatology

    Directory of Open Access Journals (Sweden)

    Catherine H Wu

    2000-01-01

    Full Text Available Advantages and disadvantages of viral vectors and nonviral vectors for gene delivery to digestive organs are reviewed. Advances in systems for the introduction of new gene expression are described, including self-deleting retroviral transfer vectors, chimeric viruses and chimeric oligonucleotides. Systems for inhibition of gene expression are discussed, including antisense oligonucleotides, ribozymes and dominant-negative genes.

  1. Using GenePattern for Gene Expression Analysis

    Science.gov (United States)

    Kuehn, Heidi; Liberzon, Arthur; Reich, Michael; Mesirov, Jill P.

    2013-01-01

    The abundance of genomic data now available in biomedical research has stimulated the development of sophisticated statistical methods for interpreting the data, and of special visualization tools for displaying the results in a concise and meaningful manner. However, biologists often find these methods and tools difficult to understand and use correctly. GenePattern is a freely available software package that addresses this issue by providing more than 100 analysis and visualization tools for genomic research in a comprehensive user-friendly environment for users at all levels of computational experience and sophistication. This unit demonstrates how to prepare and analyze microarray data in GenePattern. PMID:18551415

  2. The KCNE genes in hypertrophic cardiomyopathy: a candidate gene study

    DEFF Research Database (Denmark)

    Hedley, Paula L; Haundrup, Ole; Andersen, Paal S

    2011-01-01

    The gene family KCNE1-5, which encode modulating β-subunits of several repolarising K+-ion channels, has been associated with genetic cardiac diseases such as long QT syndrome, atrial fibrillation and Brugada syndrome. The minK peptide, encoded by KCNE1, is attached to the Z-disc of the sarcomere...... as well as the T-tubules of the sarcolemma. It has been suggested that minK forms part of an "electro-mechanical feed-back" which links cardiomyocyte stretching to changes in ion channel function. We examined whether mutations in KCNE genes were associated with hypertrophic cardiomyopathy (HCM), a genetic...

  3. Gene replacement in Penicillium roqueforti.

    Science.gov (United States)

    Goarin, Anne; Silar, Philippe; Malagnac, Fabienne

    2015-05-01

    Most cheese-making filamentous fungi lack suitable molecular tools to improve their biotechnology potential. Penicillium roqueforti, a species of high industrial importance, would benefit from functional data yielded by molecular genetic approaches. This work provides the first example of gene replacement by homologous recombination in P. roqueforti, demonstrating that knockout experiments can be performed in this fungus. To do so, we improved the existing transformation method to integrate transgenes into P. roqueforti genome. In the meantime, we cloned the PrNiaD gene, which encodes a NADPH-dependent nitrate reductase that reduces nitrate to nitrite. Then, we performed a deletion of the PrNiaD gene from P. roqueforti strain AGO. The ΔPrNiaD mutant strain is more resistant to chlorate-containing medium than the wild-type strain, but did not grow on nitrate-containing medium. Because genomic data are now available, we believe that generating selective deletions of candidate genes will be a key step to open the way for a comprehensive exploration of gene function in P. roqueforti.

  4. Gene Ontology Consortium: going forward.

    Science.gov (United States)

    2015-01-01

    The Gene Ontology (GO; http://www.geneontology.org) is a community-based bioinformatics resource that supplies information about gene product function using ontologies to represent biological knowledge. Here we describe improvements and expansions to several branches of the ontology, as well as updates that have allowed us to more efficiently disseminate the GO and capture feedback from the research community. The Gene Ontology Consortium (GOC) has expanded areas of the ontology such as cilia-related terms, cell-cycle terms and multicellular organism processes. We have also implemented new tools for generating ontology terms based on a set of logical rules making use of templates, and we have made efforts to increase our use of logical definitions. The GOC has a new and improved web site summarizing new developments and documentation, serving as a portal to GO data. Users can perform GO enrichment analysis, and search the GO for terms, annotations to gene products, and associated metadata across multiple species using the all-new AmiGO 2 browser. We encourage and welcome the input of the research community in all biological areas in our continued effort to improve the Gene Ontology. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  5. Gene Ontology Consortium: going forward

    Science.gov (United States)

    2015-01-01

    The Gene Ontology (GO; http://www.geneontology.org) is a community-based bioinformatics resource that supplies information about gene product function using ontologies to represent biological knowledge. Here we describe improvements and expansions to several branches of the ontology, as well as updates that have allowed us to more efficiently disseminate the GO and capture feedback from the research community. The Gene Ontology Consortium (GOC) has expanded areas of the ontology such as cilia-related terms, cell-cycle terms and multicellular organism processes. We have also implemented new tools for generating ontology terms based on a set of logical rules making use of templates, and we have made efforts to increase our use of logical definitions. The GOC has a new and improved web site summarizing new developments and documentation, serving as a portal to GO data. Users can perform GO enrichment analysis, and search the GO for terms, annotations to gene products, and associated metadata across multiple species using the all-new AmiGO 2 browser. We encourage and welcome the input of the research community in all biological areas in our continued effort to improve the Gene Ontology. PMID:25428369

  6. Clock Genes in Glia Cells

    Science.gov (United States)

    Chi-Castañeda, Donají

    2016-01-01

    Circadian rhythms are periodic patterns in biological processes that allow the organisms to anticipate changes in the environment. These rhythms are driven by the suprachiasmatic nucleus (SCN), the master circadian clock in vertebrates. At a molecular level, circadian rhythms are regulated by the so-called clock genes, which oscillate in a periodic manner. The protein products of clock genes are transcription factors that control their own and other genes’ transcription, collectively known as “clock-controlled genes.” Several brain regions other than the SCN express circadian rhythms of clock genes, including the amygdala, the olfactory bulb, the retina, and the cerebellum. Glia cells in these structures are expected to participate in rhythmicity. However, only certain types of glia cells may be called “glial clocks,” since they express PER-based circadian oscillators, which depend of the SCN for their synchronization. This contribution summarizes the current information about clock genes in glia cells, their plausible role as oscillators and their medical implications. PMID:27666286

  7. Melatonin Receptor Genes in Vertebrates

    Directory of Open Access Journals (Sweden)

    Hua Dong Yin

    2013-05-01

    Full Text Available Melatonin receptors are members of the G protein-coupled receptor (GPCR family. Three genes for melatonin receptors have been cloned. The MT1 (or Mel1a or MTNR1A and MT2 (or Mel1b or MTNR1B receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype, Mel1c (or MTNR1C, has been identified in fish, amphibians and birds. Another melatonin related orphan receptor, GPR50, which does not bind melatonin, is found exclusively in mammals. The hormone melatonin is secreted primarily by the pineal gland, with highest levels occurring during the dark period of a circadian cycle. This hormone acts systemically in numerous organs. In the brain, it is involved in the regulation of various neural and endocrine processes, and it readjusts the circadian pacemaker, the suprachiasmatic nucleus. This article reviews recent studies of gene organization, expression, evolution and mutations of melatonin receptor genes of vertebrates. Gene polymorphisms reveal that numerous mutations are associated with diseases and disorders. The phylogenetic analysis of receptor genes indicates that GPR50 is an outgroup to all other melatonin receptor sequences. GPR50 may have separated from a melatonin receptor ancestor before the split between MTNR1C and the MTNR1A/B ancestor.

  8. An encyclopedia of mouse genes.

    Science.gov (United States)

    Marra, M; Hillier, L; Kucaba, T; Allen, M; Barstead, R; Beck, C; Blistain, A; Bonaldo, M; Bowers, Y; Bowles, L; Cardenas, M; Chamberlain, A; Chappell, J; Clifton, S; Favello, A; Geisel, S; Gibbons, M; Harvey, N; Hill, F; Jackson, Y; Kohn, S; Lennon, G; Mardis, E; Martin, J; Mila, L; McCann, R; Morales, R; Pape, D; Person, B; Prange, C; Ritter, E; Soares, M; Schurk, R; Shin, T; Steptoe, M; Swaller, T; Theising, B; Underwood, K; Wylie, T; Yount, T; Wilson, R; Waterston, R

    1999-02-01

    The laboratory mouse is the premier model system for studies of mammalian development due to the powerful classical genetic analysis possible (see also the Jackson Laboratory web site, http://www.jax.org/) and the ever-expanding collection of molecular tools. To enhance the utility of the mouse system, we initiated a program to generate a large database of expressed sequence tags (ESTs) that can provide rapid access to genes. Of particular significance was the possibility that cDNA libraries could be prepared from very early stages of development, a situation unrealized in human EST projects. We report here the development of a comprehensive database of ESTs for the mouse. The project, initiated in March 1996, has focused on 5' end sequences from directionally cloned, oligo-dT primed cDNA libraries. As of 23 October 1998, 352,040 sequences had been generated, annotated and deposited in dbEST, where they comprised 93% of the total ESTs available for mouse. EST data are versatile and have been applied to gene identification, comparative sequence analysis, comparative gene mapping and candidate disease gene identification, genome sequence annotation, microarray development and the development of gene-based map resources.

  9. Molecular Studies on Preproinsulin Gene

    Directory of Open Access Journals (Sweden)

    Sabir Sarah

    2016-01-01

    Full Text Available Insulin plays an important role in maintaining the blood glucose level of the body. The β-cells of pancreas produce insulin in the form of precursor that is preproinsulin. The gene of preproinsulin provides an interesting system for addressing question related to molecular evolution. Recombinant DNA technology has made it possible to isolate and sequence the chromosomal genes coding for unique protein products. Although preproinsulin of various organism has been isolated and cloned, but there is no report from buffalo (Bubalus bubalis that is our major livestock. The genomic DNA of buffalo was isolated using Laura-Lee-Boodram method. The part of preproinsulin gene (596bp and 520bp using BPPI-UPS and bpiful_F as forward and BC1-C as reverse primer was amplified. Cloning of amplified fragments of gene were performed in pCR 2.1 vector. Positive clones were screened on the basis of blue white selection. The band obtained on 596bp and 520bp after colony PCR confirmed the successful cloning of preproinsulin gene in pCR 2.1 vector.

  10. Comparative genomic analysis of eutherian kallikrein genes

    Directory of Open Access Journals (Sweden)

    Marko Premzl

    2017-03-01

    Full Text Available The present study made attempts to update and revise eutherian kallikrein genes implicated in major physiological and pathological processes and in medical molecular diagnostics. Using eutherian comparative genomic analysis protocol and free available genomic sequence assemblies, the tests of reliability of eutherian public genomic sequences annotated most comprehensive curated third party data gene data set of eutherian kallikrein genes including 121 complete coding sequences among 335 potential coding sequences. The present analysis first described 13 major gene clusters of eutherian kallikrein genes, and explained their differential gene expansion patterns. One updated classification and nomenclature of eutherian kallikrein genes was proposed, as new framework of future experiments.

  11. Advancement and prospects of tumor gene therapy

    Institute of Scientific and Technical Information of China (English)

    Chao Zhang; Qing-Tao Wang; He Liu; Zhen-Zhu Zhang; Wen-Lin Huang

    2011-01-01

    Gene therapy is one of the most attractive fields in tumor therapy. In past decades, significant progress has been achieved. Various approaches, such as viral and non-viral vectors and physical methods, have been developed to make gene delivery safer and more efficient. Several therapeutic strategies have evolved, including gene-based (tumor suppressor genes, suicide genes, antiangiogenic genes, cytokine and oxidative stress-based genes) and RNA-based (antisense oligonucieotides and RNA interference) approaches. In addition, immune response-based strategies (dendritic cell- and T cell-based therapy) are also under investigation in tumor gene therapy. This review highlights the progress and recent developments in gene delivery systems, therapeutic strategies, and possible clinical directions for gene therapy.

  12. Novel genes in LDL metabolism

    DEFF Research Database (Denmark)

    Christoffersen, Mette; Tybjærg-Hansen, Anne

    2015-01-01

    -exome sequencing and 'exome chip' studies have additionally suggested several novel genes in LDL metabolism including insulin-induced gene 2, signal transducing adaptor family member 1, lysosomal acid lipase A, patatin-like phospholipase domain-containing protein 5 and transmembrane 6 superfamily member 2. Most......PURPOSE OF REVIEW: To summarize recent findings from genome-wide association studies (GWAS), whole-exome sequencing of patients with familial hypercholesterolemia and 'exome chip' studies pointing to novel genes in LDL metabolism. RECENT FINDINGS: The genetic loci for ATP-binding cassette...... transporters G5 and G8, Niemann-Pick C1-Like protein 1, sortilin-1, ABO blood-group glycosyltransferases, myosin regulatory light chain-interacting protein and cholesterol 7α-hydroxylase have all consistently been associated with LDL cholesterol levels and/or coronary artery disease in GWAS. Whole...

  13. Gene Therapy for Bone Engineering

    Directory of Open Access Journals (Sweden)

    Elizabeth eRosado Balmayor

    2015-02-01

    Full Text Available Bone has an intrinsic healing capacity that may be exceeded when the fracture gap is too big or unstable. In that moment, osteogenic measures needs to be taken by physicians. It is important to combine cells, scaffolds and growth factors and the correct mechanical conditions. Growth factors are clinically administered as recombinant proteins. They are, however, expensive and needed in high supraphysiological doses. Moreover, their half-life is short when administered to the fracture. Therefore, gene therapy may be an alternative. Cells can constantly produce the protein of interest in the correct folding, with the physiological glycosylation and in the needed amounts. Genes can be delivered in vivo or ex vivo by viral or non-viral methods. Adenovirus is mostly used. For the non-viral methods, hydrogels and recently sonoporation seem to be promising means. This review will give an overview of recent advancements in gene therapy approaches for bone regeneration strategies.

  14. The plant ADH gene family.

    Science.gov (United States)

    Strommer, Judith

    2011-04-01

    The structures, evolution and functions of alcohol dehydrogenase gene families and their products have been scrutinized for half a century. Our understanding of the enzyme structure and catalytic activity of plant alcohol dehydrogenase (ADH-P) is based on the vast amount of information available for its animal counterpart. The probable origins of the enzyme from a simple β-coil and eventual emergence from a glutathione-dependent formaldehyde dehydrogenase have been well described. There is compelling evidence that the small ADH gene families found in plants today are the survivors of multiple rounds of gene expansion and contraction. To the probable original function of their products in the terminal reaction of anaerobic fermentation have been added roles in yeast-like aerobic fermentation and the production of characteristic scents that act to attract animals that serve as pollinators or agents of seed dispersal and to protect against herbivores.

  15. Candidate genes in panic disorder

    DEFF Research Database (Denmark)

    Howe, A. S.; Buttenschön, Henriette N; Bani-Fatemi, A.

    2016-01-01

    The utilization of molecular genetics approaches in examination of panic disorder (PD) has implicated several variants as potential susceptibility factors for panicogenesis. However, the identification of robust PD susceptibility genes has been complicated by phenotypic diversity, underpowered...... association studies and ancestry-specific effects. In the present study, we performed a succinct review of case-control association studies published prior to April 2015. Meta-analyses were performed for candidate gene variants examined in at least three studies using the Cochrane Mantel-Haenszel fixed......-effect model. Secondary analyses were also performed to assess the influences of sex, agoraphobia co-morbidity and ancestry-specific effects on panicogenesis. Meta-analyses were performed on 23 variants in 20 PD candidate genes. Significant associations after correction for multiple testing were observed...

  16. Simplifying gene trees for easier comprehension

    OpenAIRE

    Mundry Marvin; Lott Paul-Ludwig; Sassenberg Christoph; Lorkowski Stefan; Fuellen Georg

    2006-01-01

    Abstract Background In the genomic age, gene trees may contain large amounts of data making them hard to read and understand. Therefore, an automated simplification is important. Results We present a simplification tool for gene trees called TreeSimplifier. Based on species tree information and HUGO gene names, it summarizes "monophyla". These monophyla correspond to subtrees of the gene tree where the evolution of a gene follows species phylogeny, and they are simplified to single leaves in ...

  17. Genes Contributing to the Development of Alcoholism

    OpenAIRE

    Edenberg, Howard J.

    2012-01-01

    Genetic factors (i.e., variations in specific genes) account for a substantial portion of the risk for alcoholism. However, identifying those genes and the specific variations involved is challenging. Researchers have used both case–control and family studies to identify genes related to alcoholism risk. In addition, different strategies such as candidate gene analyses and genome-wide association studies have been used. The strongest effects have been found for specific variants of genes that...

  18. Activities of Human Gene Nomenclature Committee

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2002-07-16

    The objective of this project, shared between NIH and DOE, has been and remains to enable the medical genetics communities to use common names for genes that are discovered by different gene hunting groups, in different species. This effort provides consistent gene nomenclature and approved gene symbols to the community at large. This contributes to a uniform and consistent understanding of genomes, particularly the human as well as functional genomics based on comparisons between homologous genes in related species (human and mice).

  19. Electroporation-mediated gene delivery.

    Science.gov (United States)

    Young, Jennifer L; Dean, David A

    2015-01-01

    Electroporation has been used extensively to transfer DNA to bacteria, yeast, and mammalian cells in culture for the past 30 years. Over this time, numerous advances have been made, from using fields to facilitate cell fusion, delivery of chemotherapeutic drugs to cells and tissues, and most importantly, gene and drug delivery in living tissues from rodents to man. Electroporation uses electrical fields to transiently destabilize the membrane allowing the entry of normally impermeable macromolecules into the cytoplasm. Surprisingly, at the appropriate field strengths, the application of these fields to tissues results in little, if any, damage or trauma. Indeed, electroporation has even been used successfully in human trials for gene delivery for the treatment of tumors and for vaccine development. Electroporation can lead to between 100 and 1000-fold increases in gene delivery and expression and can also increase both the distribution of cells taking up and expressing the DNA as well as the absolute amount of gene product per cell (likely due to increased delivery of plasmids into each cell). Effective electroporation depends on electric field parameters, electrode design, the tissues and cells being targeted, and the plasmids that are being transferred themselves. Most importantly, there is no single combination of these variables that leads to greatest efficacy in every situation; optimization is required in every new setting. Electroporation-mediated in vivo gene delivery has proven highly effective in vaccine production, transgene expression, enzyme replacement, and control of a variety of cancers. Almost any tissue can be targeted with electroporation, including muscle, skin, heart, liver, lung, and vasculature. This chapter will provide an overview of the theory of electroporation for the delivery of DNA both in individual cells and in tissues and its application for in vivo gene delivery in a number of animal models.

  20. Study on the relationship between chromosomal damage and polymorphisms of DNA repair gene among workers exposed to 1,3-butadiene%DNA修复基因多态性对1,3-丁二烯作业工人染色体损伤的影响

    Institute of Scientific and Technical Information of China (English)

    刘楠; 李斌; 关维俊; 李云; 郑国颖; 程娟; 崔涛; 孟会林

    2014-01-01

    目的 研究DNA修复酶基因XRCC1、XRCC2、ERCC1、ERCC2和RAD52单核苷酸多态性在1,3-丁二烯(BD)致外周血淋巴细胞染色体损伤遗传易感性中的作用.方法 选取187名BD作业工人和60名行政人员作为研究对象,采用胞质分裂阻滞微核试验(CBMN)评价个体外周血淋巴细胞染色体损伤水平,聚合酶链反应-限制性片段长度多态性方法分析XRCC1、XRCC2、ERCC1、ERCC2和RAD52基因多态性.结果 在校正年龄、性别、吸烟、饮酒影响因素后,BD作业工人CBMN率为7.19‰±5.43‰显著高于对照组3.18‰±2.77‰,P<0.01;使用协方差分析,发现暴露组具有XRCC1 C26304T位点CT基因型个体CBMN率显著高于CC基因型个体(8.73‰±6.20‰,6.16‰±4.92‰,P<0.05);XRCC1 G28152A位点GG基因型个体CBMN率显著高于AA基因型个体(6.97‰ ±5.0‰,3.69‰±3.66‰,P<0.05);RCC1 C19007T位点TT基因型个体CBMN率显著低于CC基因型个体(3.88‰±3.58‰,7.62‰±5.63‰,P<0.05).结论 XRCC1 C26304T、G28152A和ERCC1 C19007T位点的多态性可能影响BD作业工人染色体损伤的易感性.

  1. The frustrated gene: origins of eukaryotic gene expression

    OpenAIRE

    Madhani, Hiten D.

    2013-01-01

    Eukarytotic gene expression is frustrated by a series of steps that are generally not observed in prokaryotes and are therefore not essential for the basic chemistry of transcription and translation. Their evolution may have been driven by the need to defend against parasitic nucleic acids.

  2. Candidate Gene Identification of Flowering Time Genes in Cotton

    Directory of Open Access Journals (Sweden)

    Corrinne E. Grover

    2015-07-01

    Full Text Available Flowering time control is critically important to all sexually reproducing angiosperms in both natural ecological and agronomic settings. Accordingly, there is much interest in defining the genes involved in the complex flowering-time network and how these respond to natural and artificial selection, the latter often entailing transitions in day-length responses. Here we describe a candidate gene analysis in the cotton genus , which uses homologs from the well-described flowering network to bioinformatically and phylogenetically identify orthologs in the published genome sequence from Ulbr., one of the two model diploid progenitors of the commercially important allopolyploid cottons, L. and L. Presence and patterns of expression were evaluated from 13 aboveground tissues related to flowering for each of the candidate genes using allopolyploid as a model. Furthermore, we use a comparative context to determine copy number variability of each key gene family across 10 published angiosperm genomes. Data suggest a pattern of repeated loss of duplicates following ancient whole-genome doubling events in diverse lineages. The data presented here provide a foundation for understanding both the parallel evolution of day-length neutrality in domesticated cottons and the flowering-time network, in general, in this important crop plant.

  3. The KCNE genes in hypertrophic cardiomyopathy: a candidate gene study

    Directory of Open Access Journals (Sweden)

    Moolman-Smook Johanna C

    2011-10-01

    Full Text Available Abstract Background The gene family KCNE1-5, which encode modulating β-subunits of several repolarising K+-ion channels, has been associated with genetic cardiac diseases such as long QT syndrome, atrial fibrillation and Brugada syndrome. The minK peptide, encoded by KCNE1, is attached to the Z-disc of the sarcomere as well as the T-tubules of the sarcolemma. It has been suggested that minK forms part of an "electro-mechanical feed-back" which links cardiomyocyte stretching to changes in ion channel function. We examined whether mutations in KCNE genes were associated with hypertrophic cardiomyopathy (HCM, a genetic disease associated with an improper hypertrophic response. Results The coding regions of KCNE1, KCNE2, KCNE3, KCNE4, and KCNE5 were examined, by direct DNA sequencing, in a cohort of 93 unrelated HCM probands and 188 blood donor controls. Fifteen genetic variants, four previously unknown, were identified in the HCM probands. Eight variants were non-synonymous and one was located in the 3'UTR-region of KCNE4. No disease-causing mutations were found and no significant difference in the frequency of genetic variants was found between HCM probands and controls. Two variants of likely functional significance were found in controls only. Conclusions Mutations in KCNE genes are not a common cause of HCM and polymorphisms in these genes do not seem to be associated with a propensity to develop arrhythmia

  4. From gene to disease; hypophosphataemic rickets and the PHEX gene

    NARCIS (Netherlands)

    Jansen, M; van Dael, C.M.L.; Verrijn Stuart, A.A.; van der Hout, A.H.; Rump, P.

    2006-01-01

    X-linked hypophosphataemic rickets is associated with mutations in the PHEX gene on the short arm of the X chromosome, encoding a membrane-bound endoprotease which is predominantly expressed in osteoblasts. Defective PHEX function leaves phosphaturic peptides such as FGF23 uncleaved, enabling these

  5. Genomics of local adaptation with gene flow.

    Science.gov (United States)

    Tigano, Anna; Friesen, Vicki L

    2016-05-01

    Gene flow is a fundamental evolutionary force in adaptation that is especially important to understand as humans are rapidly changing both the natural environment and natural levels of gene flow. Theory proposes a multifaceted role for gene flow in adaptation, but it focuses mainly on the disruptive effect that gene flow has on adaptation when selection is not strong enough to prevent the loss of locally adapted alleles. The role of gene flow in adaptation is now better understood due to the recent development of both genomic models of adaptive evolution and genomic techniques, which both point to the importance of genetic architecture in the origin and maintenance of adaptation with gene flow. In this review, we discuss three main topics on the genomics of adaptation with gene flow. First, we investigate selection on migration and gene flow. Second, we discuss the three potential sources of adaptive variation in relation to the role of gene flow in the origin of adaptation. Third, we explain how local adaptation is maintained despite gene flow: we provide a synthesis of recent genomic models of adaptation, discuss the genomic mechanisms and review empirical studies on the genomics of adaptation with gene flow. Despite predictions on the disruptive effect of gene flow in adaptation, an increasing number of studies show that gene flow can promote adaptation, that local adaptations can be maintained despite high gene flow, and that genetic architecture plays a fundamental role in the origin and maintenance of local adaptation with gene flow.

  6. Gene expression throughout a vertebrate's embryogenesis

    Directory of Open Access Journals (Sweden)

    Hinton David E

    2011-02-01

    Full Text Available Abstract Background Describing the patterns of gene expression during embryonic development has broadened our understanding of the processes and patterns that define morphogenesis. Yet gene expression patterns have not been described throughout vertebrate embryogenesis. This study presents statistical analyses of gene expression during all 40 developmental stages in the teleost Fundulus heteroclitus using four biological replicates per stage. Results Patterns of gene expression for 7,000 genes appear to be important as they recapitulate developmental timing. Among the 45% of genes with significant expression differences between pairs of temporally adjacent stages, significant differences in gene expression vary from as few as five to more than 660. Five adjacent stages have disproportionately more significant changes in gene expression (> 200 genes relative to other stages: four to eight and eight to sixteen cell stages, onset of circulation, pre and post-hatch, and during complete yolk absorption. The fewest differences among adjacent stages occur during gastrulation. Yet, at stage 16, (pre-mid-gastrulation the largest number of genes has peak expression. This stage has an over representation of genes in oxidative respiration and protein expression (ribosomes, translational genes and proteases. Unexpectedly, among all ribosomal genes, both strong positive and negative correlations occur. Similar correlated patterns of expression occur among all significant genes. Conclusions These data provide statistical support for the temporal dynamics of developmental gene expression during all stages of vertebrate development.

  7. Gene therapy: Myth or reality?

    Science.gov (United States)

    Fischer, Alain

    2016-01-01

    Gene therapy has become a reality, although still a fragile one. Clinical benefit has been achieved over the last 17years in a limited number of medical conditions for which pathophysiological studies determined that they were favorable settings. They include inherited disorders of the immune system, leukodystrophies, possibly hemoglobinopathies, hemophilia B, and retinal dystrophies. Advances in the treatment of B-cell leukemias and lymphomas have also been achieved. Advances in vector development and possible usage of gene editing may lead to significant advances over the next years. Copyright © 2016. Published by Elsevier SAS.

  8. JavaGenes Molecular Evolution

    Science.gov (United States)

    Lohn, Jason; Smith, David; Frank, Jeremy; Globus, Al; Crawford, James

    2007-01-01

    JavaGenes is a general-purpose, evolutionary software system written in Java. It implements several versions of a genetic algorithm, simulated annealing, stochastic hill climbing, and other search techniques. This software has been used to evolve molecules, atomic force field parameters, digital circuits, Earth Observing Satellite schedules, and antennas. This version differs from version 0.7.28 in that it includes the molecule evolution code and other improvements. Except for the antenna code, JaveGenes is available for NASA Open Source distribution.

  9. Zipf's Law in Gene Expression

    CERN Document Server

    Furusawa, C; Furusawa, Chikara; Kaneko, Kunihiko

    2002-01-01

    Using data from gene expression databases on various organisms and tissues, including yeast, nematodes, human normal and cancer tissues, and embryonic stem cells, we found that the abundances of expressed genes exhibit a power-law distribution with an exponent close to -1, i.e., they obey Zipf's law. Furthermore, by simulations of a simple model with an intra-cellular reaction network, we found that Zipf's law of chemical abundance is a universal feature of cells where such a network optimizes the efficiency and faithfulness of self-reproduction. These findings provide novel insights into the nature of the organization of reaction dynamics in living cells.

  10. Zipf's Law in Gene Expression

    Science.gov (United States)

    Furusawa, Chikara; Kaneko, Kunihiko

    2003-02-01

    Using data from gene expression databases on various organisms and tissues, including yeast, nematodes, human normal and cancer tissues, and embryonic stem cells, we found that the abundances of expressed genes exhibit a power-law distribution with an exponent close to -1; i.e., they obey Zipf’s law. Furthermore, by simulations of a simple model with an intracellular reaction network, we found that Zipf’s law of chemical abundance is a universal feature of cells where such a network optimizes the efficiency and faithfulness of self-reproduction. These findings provide novel insights into the nature of the organization of reaction dynamics in living cells.

  11. FunGeneClusterS

    DEFF Research Database (Denmark)

    Vesth, Tammi Camilla; Brandl, Julian; Andersen, Mikael Rørdam

    2016-01-01

    and industrial biotechnology applications. We have previously published a method for accurate prediction of clusters from genome and transcriptome data, which could also suggest cross-chemistry, however, this method was limited both in the number of parameters which could be adjusted as well as in user......Secondary metabolites of fungi are receiving an increasing amount of interest due to their prolific bioactivities and the fact that fungal biosynthesis of secondary metabolites often occurs from co-regulated and co-located gene clusters. This makes the gene clusters attractive for synthetic biology...

  12. Correction of gene expression data

    DEFF Research Database (Denmark)

    Darbani Shirvanehdeh, Behrooz; Stewart, C. Neal, Jr.; Noeparvar, Shahin;

    2014-01-01

    This report investigates for the first time the potential inter-treatment bias source of cell number for gene expression studies. Cell-number bias can affect gene expression analysis when comparing samples with unequal total cellular RNA content or with different RNA extraction efficiencies...... an analytical approach to examine the suitability of correction methods by considering the inter-treatment bias as well as the inter-replicate variance, which allows use of the best correction method with minimum residual bias. Analyses of RNA sequencing and microarray data showed that the efficiencies...

  13. Clock genes, chronotypes and diseases

    Directory of Open Access Journals (Sweden)

    Bogdan I. Voinescu

    2009-08-01

    Full Text Available Many common diseases in humans (such as cancer, heart disease, diabetes mellitus orpsychiatric disorders, such as depression seem to be linked to disruptions of circadian cycles and toclock genes variation. It is unlikely that such diseases to be caused by a genetic variation within a singlegene. They must be influenced by complex interactions among multiple genes, as well as environmentaland lifestyle factors. Therefore, it is important to understand how the resulting perturbations in ourcircadian biology could affect our physiological processes and susceptibility to disease. Associationsbetween the polymorphisms of the main components of the circadian molecular clock, circadian type(also known as diurnal preference or chronotype and diseases are presented.

  14. Detecting Sequence Homology at the Gene Cluster Level with MultiGeneBlast

    NARCIS (Netherlands)

    Medema, Marnix H.; Takano, Eriko; Breitling, Rainer; Nowick, Katja

    2013-01-01

    The genes encoding many biomolecular systems and pathways are genomically organized in operons or gene clusters. With MultiGeneBlast, we provide a user-friendly and effective tool to perform homology searches with operons or gene clusters as basic units, instead of single genes. The contextualizatio

  15. Detecting Sequence Homology at the Gene Cluster Level with MultiGeneBlast

    NARCIS (Netherlands)

    Medema, Marnix H.; Takano, Eriko; Breitling, Rainer; Nowick, Katja

    The genes encoding many biomolecular systems and pathways are genomically organized in operons or gene clusters. With MultiGeneBlast, we provide a user-friendly and effective tool to perform homology searches with operons or gene clusters as basic units, instead of single genes. The

  16. A gene-based information gain method for detecting gene-gene interactions in case-control studies.

    Science.gov (United States)

    Li, Jin; Huang, Dongli; Guo, Maozu; Liu, Xiaoyan; Wang, Chunyu; Teng, Zhixia; Zhang, Ruijie; Jiang, Yongshuai; Lv, Hongchao; Wang, Limei

    2015-11-01

    Currently, most methods for detecting gene-gene interactions (GGIs) in genome-wide association studies are divided into SNP-based methods and gene-based methods. Generally, the gene-based methods can be more powerful than SNP-based methods. Some gene-based entropy methods can only capture the linear relationship between genes. We therefore proposed a nonparametric gene-based information gain method (GBIGM) that can capture both linear relationship and nonlinear correlation between genes. Through simulation with different odds ratio, sample size and prevalence rate, GBIGM was shown to be valid and more powerful than classic KCCU method and SNP-based entropy method. In the analysis of data from 17 genes on rheumatoid arthritis, GBIGM was more effective than the other two methods as it obtains fewer significant results, which was important for biological verification. Therefore, GBIGM is a suitable and powerful tool for detecting GGIs in case-control studies.

  17. Integrones: los coleccionistas de genes Integrons: gene collectors

    Directory of Open Access Journals (Sweden)

    J. A. Di Conza

    2010-02-01

    Full Text Available Los integrones son estructuras genéticas que han despertado gran interés, debido a que algunos de ellos vehiculizan genes de resistencia a los antimicrobianos. Están formados por un fragmento que codifica una integrasa (intI y, a continuación, una secuencia attI a la que se unen los genes en casetes que codifican diferentes mecanismos de resistencia. Dentro de intI, en su extremo 3´, hay una secuencia promotora Pc a partir de la cual se transcriben los casetes de resistencia integrados, ya que estos genes carecen de promotor. Sin embargo, estos casetes presentan una secuencia específica denominada attC, la cual es reconocida por la integrasa que se une, por recombinación, a la secuencia attI del integrón en la orientación adecuada para su expresión. Los integrones se han clasificado según la secuencia de su integrasa, pero en la actualidad se prefiere clasificarlos según su localización. Se habla, en general, de "integrones móviles" para referirse a aquellos asociados a secuencias de inserción, transposones y/o plásmidos conjugativos, los que en su mayoría median mecanismos de resistencia, y de "superintegrones", de localización cromosómica y con grandes arreglos de genes en casetes. Los integrones móviles de clase 1 son los más abundantes en aislamientos clínicos y suelen estar asociados a transposones del subgrupo Tn21, seguidos por los de clase 2, derivados principalmente de Tn7. Estos elementos no son móviles por sí mismos, pero su asociación con elementos que sí lo son facilita su transferencia horizontal, lo que explica su amplia difusión entre las bacterias. Esta revisión intenta recopilar la información disponible acerca de los integrones móviles descritos en Argentina hasta la fecha.Integrons gained great interest due to their participation in resistance gene recruitment and expression. Their basic structure includes a fragment that encodes an integrase (intI followed by a recognition sequence (attI into

  18. Gene therapy on demand: site specific regulation of gene therapy.

    Science.gov (United States)

    Jazwa, Agnieszka; Florczyk, Urszula; Jozkowicz, Alicja; Dulak, Jozef

    2013-08-10

    Since 1990 when the first clinical gene therapy trial was conducted, much attention and considerable promise have been given to this form of treatment. Gene therapy has been used with success in patients suffering from severe combined immunodeficiency syndromes (X-SCID and ADA-deficiency), Leber's congenital amaurosis, hemophilia, β-thalassemia and adrenoleukodystrophy. Last year, the first therapeutic vector (Glybera) for treatment of lipoprotein lipase deficiency has been registered in the European Union. Nevertheless, there are still several numerous issues that need to be improved to make this technique more safe, effective and easily accessible for patients. Introduction of the therapeutic gene to the given cells should provide the level of expression which will restore the production of therapeutic protein to normal values or will provide therapeutic efficacy despite not fully physiological expression. However, in numerous diseases the expression of therapeutic genes has to be kept at certain level for some time, and then might be required to be switched off to be activated again when worsening of the symptoms may aggravate the risk of disease relapse. In such cases the promoters which are regulated by local conditions may be more required. In this article the special emphasis is to discuss the strategies of regulation of gene expression by endogenous stimuli. Particularly, the hypoxia- or miRNA-regulated vectors offer the possibilities of tight but, at the same time, condition-dependent and cell-specific expression. Such means have been already tested in certain pathophysiological conditions. This creates the chance for the translational approaches required for development of effective treatments of so far incurable diseases.

  19. State-of-the-art human gene therapy: part I. Gene delivery technologies.

    Science.gov (United States)

    Wang, Dan; Gao, Guangping

    2014-01-01

    Safe and effective gene delivery is a prerequisite for successful gene therapy. In the early age of human gene therapy, setbacks due to problematic gene delivery vehicles plagued the exciting therapeutic outcome. However, gene delivery technologies rapidly evolved ever since. With the advancement of gene delivery techniques, gene therapy clinical trials surged during the past decade. As the first gene therapy product (Glybera) has obtained regulatory approval and reached clinic, human gene therapy finally realized the promise that genes can be medicines. The diverse gene delivery techniques available today have laid the foundation for gene therapy applications in treating a wide range of human diseases. Some of the most urgent unmet medical needs, such as cancer and pandemic infectious diseases, have been tackled by gene therapy strategies with promising results. Furthermore, combining gene transfer with other breakthroughs in biomedical research and novel biotechnologies opened new avenues for gene therapy. Such innovative therapeutic strategies are unthinkable until now, and are expected to be revolutionary. In part I of this review, we introduced recent development of non-viral and viral gene delivery technology platforms. As cell-based gene therapy blossomed, we also summarized the diverse types of cells and vectors employed in ex vivo gene transfer. Finally, challenges in current gene delivery technologies for human use were discussed.

  20. Gene Expression in Trypanosomatid Parasites

    Directory of Open Access Journals (Sweden)

    Santiago Martínez-Calvillo

    2010-01-01

    Full Text Available The parasites Leishmania spp., Trypanosoma brucei, and Trypanosoma cruzi are the trypanosomatid protozoa that cause the deadly human diseases leishmaniasis, African sleeping sickness, and Chagas disease, respectively. These organisms possess unique mechanisms for gene expression such as constitutive polycistronic transcription of protein-coding genes and trans-splicing. Little is known about either the DNA sequences or the proteins that are involved in the initiation and termination of transcription in trypanosomatids. In silico analyses of the genome databases of these parasites led to the identification of a small number of proteins involved in gene expression. However, functional studies have revealed that trypanosomatids have more general transcription factors than originally estimated. Many posttranslational histone modifications, histone variants, and chromatin modifying enzymes have been identified in trypanosomatids, and recent genome-wide studies showed that epigenetic regulation might play a very important role in gene expression in this group of parasites. Here, we review and comment on the most recent findings related to transcription initiation and termination in trypanosomatid protozoa.

  1. Ethics of Gene Therapy Debated.

    Science.gov (United States)

    Borman, Stu

    1991-01-01

    Presented are the highlights of a press conference featuring biomedical ethicist LeRoy Walters of Georgetown University and attorney Andrew Kimbrell of the Foundation on Economic Trends. The opposing points of view of these two speakers serve to outline the pros and cons of the gene therapy issue. (CW)

  2. Patching genes to fight disease

    Energy Technology Data Exchange (ETDEWEB)

    Holzman, D.

    1990-09-03

    The National Institutes of Health has approved the first gene therapy experiments, one of which will try to cure cancer by bolstering the immune system. The applications of such therapy are limited, but the potential aid to people with genetic diseases is great.

  3. Codon Adaptation of Plastid Genes

    Science.gov (United States)

    Suzuki, Haruo; Morton, Brian R.

    2016-01-01

    Codon adaptation is codon usage bias that results from selective pressure to increase the translation efficiency of a gene. Codon adaptation has been studied across a wide range of genomes and some early analyses of plastids have shown evidence for codon adaptation in a limited set of highly expressed plastid genes. Here we study codon usage bias across all fully sequenced plastid genomes which includes representatives of the Rhodophyta, Alveolata, Cryptophyta, Euglenozoa, Glaucocystophyceae, Rhizaria, Stramenopiles and numerous lineages within the Viridiplantae, including Chlorophyta and Embryophyta. We show evidence that codon adaptation occurs in all genomes except for two, Theileria parva and Heicosporidium sp., both of which have highly reduced gene contents and no photosynthesis genes. We also show evidence that selection for codon adaptation increases the representation of the same set of codons, which we refer to as the adaptive codons, across this wide range of taxa, which is probably due to common features descended from the initial endosymbiont. We use various measures to estimate the relative strength of selection in the different lineages and show that it appears to be fairly strong in certain Stramenopiles and Chlorophyta lineages but relatively weak in many members of the Rhodophyta, Euglenozoa and Embryophyta. Given these results we propose that codon adaptation in plastids is widespread and displays the same general features as adaptation in eubacterial genomes. PMID:27196606

  4. Codon Adaptation of Plastid Genes.

    Directory of Open Access Journals (Sweden)

    Haruo Suzuki

    Full Text Available Codon adaptation is codon usage bias that results from selective pressure to increase the translation efficiency of a gene. Codon adaptation has been studied across a wide range of genomes and some early analyses of plastids have shown evidence for codon adaptation in a limited set of highly expressed plastid genes. Here we study codon usage bias across all fully sequenced plastid genomes which includes representatives of the Rhodophyta, Alveolata, Cryptophyta, Euglenozoa, Glaucocystophyceae, Rhizaria, Stramenopiles and numerous lineages within the Viridiplantae, including Chlorophyta and Embryophyta. We show evidence that codon adaptation occurs in all genomes except for two, Theileria parva and Heicosporidium sp., both of which have highly reduced gene contents and no photosynthesis genes. We also show evidence that selection for codon adaptation increases the representation of the same set of codons, which we refer to as the adaptive codons, across this wide range of taxa, which is probably due to common features descended from the initial endosymbiont. We use various measures to estimate the relative strength of selection in the different lineages and show that it appears to be fairly strong in certain Stramenopiles and Chlorophyta lineages but relatively weak in many members of the Rhodophyta, Euglenozoa and Embryophyta. Given these results we propose that codon adaptation in plastids is widespread and displays the same general features as adaptation in eubacterial genomes.

  5. Homeobox gene expression in Brachiopoda

    DEFF Research Database (Denmark)

    Altenburger, Andreas; Martinez, Pedro; Wanninger, Andreas

    2011-01-01

    The molecular control that underlies brachiopod ontogeny is largely unknown. In order to contribute to this issue we analyzed the expression pattern of two homeobox containing genes, Not and Cdx, during development of the rhynchonelliform (i.e., articulate) brachiopod Terebratalia transversa. Not...

  6. Positional cloning of deafness genes

    NARCIS (Netherlands)

    Kremer, H.; Cremers, F.P.M.

    2009-01-01

    The identification of the majority of the known causative genes involved in nonsyndromic sensorineural hearing loss (NSHL) started with linkage analysis as part of a positional cloning procedure. The human and mouse genome projects in combination with technical developments on genotyping, transcript

  7. [From gene to disease: cystinosis

    NARCIS (Netherlands)

    Levtchenko, E.N.; Wilmer, M.J.G.; Graaf-Hess, A.C. de; Heuvel, L.P.W.J. van den; Blom, H.J.; Monnens, L.A.H.

    2004-01-01

    Cystinosis is an autosomal recessive disorder caused by an impaired transport of cystine out of lysosomes. The most severe infantile form of cystinosis starts with Fanconi syndrome at the age of 3-6 months. Untreated patients develop renal failure before the age of 10. The cystinosis gene (CTNS) map

  8. Gene expression studies using microarrays

    NARCIS (Netherlands)

    Burgess, Janette

    2001-01-01

    1. The rapid progression of the collaborative sequencing programmes that are unravelling the complete genome sequences of many organisms are opening pathways for new approaches to gene analysis. As the sequence data become available, the bottleneck in biological research will shift to understanding

  9. Gene Testing for Hereditary Ataxia

    Science.gov (United States)

    ... should be reviewed. • Psychological assessment/Counseling – prior to testing, psychological evaluation is recommended to ensure the person being tested is as prepared as possible to receive the test results, and to ... Before gene testing is ordered, the coordinating physician may choose to ...

  10. Gene therapy and respiratory neuroplasticity.

    Science.gov (United States)

    Mantilla, Carlos B

    2017-01-01

    Breathing is a life-sustaining behavior that in mammals is accomplished by activation of dedicated muscles responsible for inspiratory and expiratory forces acting on the lung and chest wall. Motor control is exerted by specialized pools of motoneurons in the medulla and spinal cord innervated by projections from multiple centers primarily in the brainstem that act in concert to generate both the rhythm and pattern of ventilation. Perturbations that prevent the accomplishment of the full range of motor behaviors by respiratory muscles commonly result in significant morbidity and increased mortality. Recent developments in gene therapy and novel targeting strategies have contributed to deeper understanding of the organization of respiratory motor systems. Gene therapy has received widespread attention and substantial progress has been made in recent years with the advent of improved tools for vector design. Genes can be delivered via a variety of plasmids, synthetic or viral vectors and cell therapies. In recent years, adeno-associated viruses (AAV) have become one of the most commonly used vector systems, primarily because of the extensive characterization conducted to date and the versatility in targeting strategies. Recent studies highlight the power of using AAV to selectively and effectively transduce respiratory motoneurons and muscle fibers with promising therapeutic effects. This brief review summarizes current evidence for the use of gene therapy in respiratory disorders with a primary focus on interventions that address motor control and neuroplasticity, including regeneration, in the respiratory system.

  11. Homeobox genes and melatonin synthesis

    DEFF Research Database (Denmark)

    Rohde, Kristian; Møller, Morten; Rath, Martin Fredensborg

    2014-01-01

    ) transcription factor is believed to control pineal-specific Aanat expression. Based on recent advances in our understanding of Crx in the rodent pineal gland, we here suggest that homeobox genes play a role in adult pineal physiology both by ensuring pineal-specific Aanat expression and by facilitating cAMP...

  12. Gene therapy for heart failure.

    Science.gov (United States)

    Greenberg, Barry

    2017-04-01

    Novel strategies are needed to treat the growing population of heart failure patients. While new drug and device based therapies have improved outcomes over the past several decades, heart failure patients continue to experience amongst the lowest quality of life of any chronic disease, high likelihood of being hospitalized and marked reduction in survival. Better understanding of many of the basic mechanisms involved in the development of heart failure has helped identify abnormalities that could potentially be targeted by gene transfer. Despite success in experimental animal models, translating gene transfer strategies from the laboratory to the clinic remains at an early stage. This review provides an introduction to gene transfer as a therapy for treating heart failure, describes some of the many factors that need to be addressed in order for it to be successful and discusses some of the recent studies that have been carried out in heart failure patients. Insights from these studies highlight both the enormous promise of gene transfer and the obstacles that still need to be overcome for this treatment approach to be successful. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Amplification of kinetic oscillations in gene expression

    Science.gov (United States)

    Zhdanov, V. P.

    2008-10-01

    Because of the feedbacks between the DNA transcription and mRNA translation, the gene expression in cells may exhibit bistability and oscillations. The deterministic and stochastic calculations presented illustrate how the bistable kinetics of expression of one gene in a cell can be influenced by the kinetic oscillations in the expression of another gene. Due to stability of the states of the bistable kinetics of gene 1 and the relatively small difference between the maximum and minimum protein amounts during the oscillations of gene 2, the induced oscillations of gene 1 are found to typically be related either to the low-or high-reactive state of this gene. The quality of the induced oscillations may be appreciably better than that of the inducing oscillations. This means that gene 1 can serve as an amplifier of the kinetic oscillations of gene 2.

  14. Genome-wide Analysis of Gene Regulation

    DEFF Research Database (Denmark)

    Chen, Yun

    cells are capable of regulating their gene expression, so that each cell can only express a particular set of genes yielding limited numbers of proteins with specialized functions. Therefore a rigid control of differential gene expression is necessary for cellular diversity. On the other hand, aberrant...... gene regulation will disrupt the cell’s fundamental processes, which in turn can cause disease. Hence, understanding gene regulation is essential for deciphering the code of life. Along with the development of high throughput sequencing (HTS) technology and the subsequent large-scale data analysis......, genome-wide assays have increased our understanding of gene regulation significantly. This thesis describes the integration and analysis of HTS data across different important aspects of gene regulation. Gene expression can be regulated at different stages when the genetic information is passed from gene...

  15. DNA双链断裂修复基因遗传多态性与非小细胞肺癌预后的相关性%Association between DNA Double-strand Break Repair Gene Polymorphisms and Prognosis of Non-small Cell Lung Cancer Patients

    Institute of Scientific and Technical Information of China (English)

    李晓玉; 何斐; 叶超; 蔡琳

    2014-01-01

    目的 探讨DNA双链断裂修复(DSBR)基因遗传多态性与非小细胞肺癌(NSCLC)预后的关联.方法 应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)和TaqMan探针技术检测679例NSCLC新发病例的DSBR 10个SNP(rs6869366、rs1056503、rs3734091、rs861539、rs861537、rs1799794、rs16942、rs144848、rs 1805794、rs2735383)的基因分型,应用Kaplan-Meier、Log rank检验和Cox回归模型进行预后分析.结果 患者总体5年生存率为29.8%(95%CI:26.1%~33.5%).化疗患者携带XRCC3 rs861539 CT+TT基因型的死亡风险低于携带CC基因型患者(MST:32月vs.60月HR=0.629,95%CI:0.411~0.962,P=0.032; aHR=0.623,95%CI:0.399~0.973,P=0.038);鳞癌患者携带BRCA1 rs16942 AG+GG等位基因型比携带AA基因型的预后差(MST:24月vs.31月;aHR=1.622,95%CI:1.139~2.310,P=0.007);非吸烟女性腺癌患者携带NBS1 rs2735383GC+CC基因型较携带GG基因型的死亡风险低(MST:41月vs.32月;aHR=0.420,95%CI:0.247~0.714,P=0.001); 携带XRCC3rs861539CT+TT基因型的临床早期病例较携带CC基因型的死亡风险降低(aHR=0.444,95%CI:0.192~1.025,P=0.057);男性吸烟的早期患者携带NBS1 rs1805794CG+GG基因型比CC基因型的死亡风险高(aHR=2.768,95%CI:1.273~6.017,P=0.010);携带XRCC3 rs861537 AA基因型的临床晚期病例较携带GG基因型的死亡风险增加(aHR=1.750,95%CI:1.021~3.001,P=0.042).联合分析发现,患者携带4个或5个不利基因型比携带≤3个不利基因型的死亡风险增加(aHR=1.153,95%CI:1.005~1.322,Ptrend=0.042).结论 DSBR基因遗传多态性可作为NSCLC患者预后评价的参考.

  16. Evidence based selection of housekeeping genes.

    Directory of Open Access Journals (Sweden)

    Hendrik J M de Jonge

    Full Text Available For accurate and reliable gene expression analysis, normalization of gene expression data against housekeeping genes (reference or internal control genes is required. It is known that commonly used housekeeping genes (e.g. ACTB, GAPDH, HPRT1, and B2M vary considerably under different experimental conditions and therefore their use for normalization is limited. We performed a meta-analysis of 13,629 human gene array samples in order to identify the most stable expressed genes. Here we show novel candidate housekeeping genes (e.g. RPS13, RPL27, RPS20 and OAZ1 with enhanced stability among a multitude of different cell types and varying experimental conditions. None of the commonly used housekeeping genes were present in the top 50 of the most stable expressed genes. In addition, using 2,543 diverse mouse gene array samples we were able to confirm the enhanced stability of the candidate novel housekeeping genes in another mammalian species. Therefore, the identified novel candidate housekeeping genes seem to be the most appropriate choice for normalizing gene expression data.

  17. Incorporating Single-nucleotide Polymorphisms Into the Lyman Model to Improve Prediction of Radiation Pneumonitis

    Energy Technology Data Exchange (ETDEWEB)

    Tucker, Susan L., E-mail: sltucker@mdanderson.org [Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Li Minghuan [Department of Radiation Oncology, Shandong Cancer Hospital, Jinan, Shandong (China); Xu Ting; Gomez, Daniel [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Yuan Xianglin [Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Yu Jinming [Department of Radiation Oncology, Shandong Cancer Hospital, Jinan, Shandong (China); Liu Zhensheng; Yin Ming; Guan Xiaoxiang; Wang Lie; Wei Qingyi [Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Mohan, Radhe [Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Vinogradskiy, Yevgeniy [University of Colorado School of Medicine, Aurora, Colorado (United States); Martel, Mary [Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Liao Zhongxing [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

    2013-01-01

    Purpose: To determine whether single-nucleotide polymorphisms (SNPs) in genes associated with DNA repair, cell cycle, transforming growth factor-{beta}, tumor necrosis factor and receptor, folic acid metabolism, and angiogenesis can significantly improve the fit of the Lyman-Kutcher-Burman (LKB) normal-tissue complication probability (NTCP) model of radiation pneumonitis (RP) risk among patients with non-small cell lung cancer (NSCLC). Methods and Materials: Sixteen SNPs from 10 different genes (XRCC1, XRCC3, APEX1, MDM2, TGF{beta}, TNF{alpha}, TNFR, MTHFR, MTRR, and VEGF) were genotyped in 141 NSCLC patients treated with definitive radiation therapy, with or without chemotherapy. The LKB model was used to estimate the risk of severe (grade {>=}3) RP as a function of mean lung dose (MLD), with SNPs and patient smoking status incorporated into the model as dose-modifying factors. Multivariate analyses were performed by adding significant factors to the MLD model in a forward stepwise procedure, with significance assessed using the likelihood-ratio test. Bootstrap analyses were used to assess the reproducibility of results under variations in the data. Results: Five SNPs were selected for inclusion in the multivariate NTCP model based on MLD alone. SNPs associated with an increased risk of severe RP were in genes for TGF{beta}, VEGF, TNF{alpha}, XRCC1 and APEX1. With smoking status included in the multivariate model, the SNPs significantly associated with increased risk of RP were in genes for TGF{beta}, VEGF, and XRCC3. Bootstrap analyses selected a median of 4 SNPs per model fit, with the 6 genes listed above selected most often. Conclusions: This study provides evidence that SNPs can significantly improve the predictive ability of the Lyman MLD model. With a small number of SNPs, it was possible to distinguish cohorts with >50% risk vs <10% risk of RP when they were exposed to high MLDs.

  18. Evolution of the chicken Toll-like receptor gene family: A story of gene gain and gene loss

    Directory of Open Access Journals (Sweden)

    Paton Ian R

    2008-02-01

    Full Text Available Abstract Background Toll-like receptors (TLRs perform a vital role in disease resistance through their recognition of pathogen associated molecular patterns (PAMPs. Recent advances in genomics allow comparison of TLR genes within and between many species. This study takes advantage of the recently sequenced chicken genome to determine the complete chicken TLR repertoire and place it in context of vertebrate genomic evolution. Results The chicken TLR repertoire consists of ten genes. Phylogenetic analyses show that six of these genes have orthologs in mammals and fish, while one is only shared by fish and three appear to be unique to birds. Furthermore the phylogeny shows that TLR1-like genes arose independently in fish, birds and mammals from an ancestral gene also shared by TLR6 and TLR10. All other TLRs were already present prior to the divergence of major vertebrate lineages 550 Mya (million years ago and have since been lost in certain lineages. Phylogenetic analysis shows the absence of TLRs 8 and 9 in chicken to be the result of gene loss. The notable exception to the tendency of gene loss in TLR evolution is found in chicken TLRs 1 and 2, each of which underwent gene duplication about 147 and 65 Mya, respectively. Conclusion Comparative phylogenetic analysis of vertebrate TLR genes provides insight into their patterns and processes of gene evolution, with examples of both gene gain and gene loss. In addition, these comparisons clarify the nomenclature of TLR genes in vertebrates.

  19. Gene transfer therapy in vascular diseases.

    Science.gov (United States)

    McKay, M J; Gaballa, M A

    2001-01-01

    Somatic gene therapy of vascular diseases is a promising new field in modern medicine. Recent advancements in gene transfer technology have greatly evolved our understanding of the pathophysiologic role of candidate disease genes. With this knowledge, the expression of selective gene products provides the means to test the therapeutic use of gene therapy in a multitude of medical conditions. In addition, with the completion of genome sequencing programs, gene transfer can be used also to study the biologic function of novel genes in vivo. Novel genes are delivered to targeted tissue via several different vehicles. These vectors include adenoviruses, retroviruses, plasmids, plasmid/liposomes, and oligonucleotides. However, each one of these vectors has inherent limitations. Further investigations into developing delivery systems that not only allow for efficient, targeted gene transfer, but also are stable and nonimmunogenic, will optimize the clinical application of gene therapy in vascular diseases. This review further discusses the available mode of gene delivery and examines six major areas in vascular gene therapy, namely prevention of restenosis, thrombosis, hypertension, atherosclerosis, peripheral vascular disease in congestive heart failure, and ischemia. Although we highlight some of the recent advances in the use of gene therapy in treating vascular disease discovered primarily during the past two years, many excellent studies published during that period are not included in this review due to space limitations. The following is a selective review of practical uses of gene transfer therapy in vascular diseases. This review primarily covers work performed in the last 2 years. For earlier work, the reader may refer to several excellent review articles. For instance, Belalcazer et al. (6) reviewed general aspects of somatic gene therapy and the different vehicles used for the delivery of therapeutic genes. Gene therapy in restenosis and stimulation of

  20. Empirical study of supervised gene screening

    Directory of Open Access Journals (Sweden)

    Ma Shuangge

    2006-12-01

    Full Text Available Abstract Background Microarray studies provide a way of linking variations of phenotypes with their genetic causations. Constructing predictive models using high dimensional microarray measurements usually consists of three steps: (1 unsupervised gene screening; (2 supervised gene screening; and (3 statistical model building. Supervised gene screening based on marginal gene ranking is commonly used to reduce the number of genes in the model building. Various simple statistics, such as t-statistic or signal to noise ratio, have been used to rank genes in the supervised screening. Despite of its extensive usage, statistical study of supervised gene screening remains scarce. Our study is partly motivated by the differences in gene discovery results caused by using different supervised gene screening methods. Results We investigate concordance and reproducibility of supervised gene screening based on eight commonly used marginal statistics. Concordance is assessed by the relative fractions of overlaps between top ranked genes screened using different marginal statistics. We propose a Bootstrap Reproducibility Index, which measures reproducibility of individual genes under the supervised screening. Empirical studies are based on four public microarray data. We consider the cases where the top 20%, 40% and 60% genes are screened. Conclusion From a gene discovery point of view, the effect of supervised gene screening based on different marginal statistics cannot be ignored. Empirical studies show that (1 genes passed different supervised screenings may be considerably different; (2 concordance may vary, depending on the underlying data structure and percentage of selected genes; (3 evaluated with the Bootstrap Reproducibility Index, genes passed supervised screenings are only moderately reproducible; and (4 concordance cannot be improved by supervised screening based on reproducibility.

  1. Gene functional similarity search tool (GFSST

    Directory of Open Access Journals (Sweden)

    Russo James J

    2006-03-01

    Full Text Available Abstract Background With the completion of the genome sequences of human, mouse, and other species and the advent of high throughput functional genomic research technologies such as biomicroarray chips, more and more genes and their products have been discovered and their functions have begun to be understood. Increasing amounts of data about genes, gene products and their functions have been stored in databases. To facilitate selection of candidate genes for gene-disease research, genetic association studies, biomarker and drug target selection, and animal models of human diseases, it is essential to have search engines that can retrieve genes by their functions from proteome databases. In recent years, the development of Gene Ontology (GO has established structured, controlled vocabularies describing gene functions, which makes it possible to develop novel tools to search genes by functional similarity. Results By using a statistical model to measure the functional similarity of genes based on the Gene Ontology directed acyclic graph, we developed a novel Gene Functional Similarity Search Tool (GFSST to identify genes with related functions from annotated proteome databases. This search engine lets users design their search targets by gene functions. Conclusion An implementation of GFSST which works on the UniProt (Universal Protein Resource for the human and mouse proteomes is available at GFSST Web Server. GFSST provides functions not only for similar gene retrieval but also for gene search by one or more GO terms. This represents a powerful new approach for selecting similar genes and gene products from proteome databases according to their functions.

  2. Vascular Gene Expression: A Hypothesis

    Directory of Open Access Journals (Sweden)

    Angélica Concepción eMartínez-Navarro

    2013-07-01

    Full Text Available The phloem is the conduit through which photoassimilates are distributed from autotrophic to heterotrophic tissues and is involved in the distribution of signaling molecules that coordinate plant growth and responses to the environment. Phloem function depends on the coordinate expression of a large array of genes. We have previously identified conserved motifs in upstream regions of the Arabidopsis genes, encoding the homologs of pumpkin phloem sap mRNAs, displaying expression in vascular tissues. This tissue-specific expression in Arabidopsis is predicted by the overrepresentation of GA/CT-rich motifs in gene promoters. In this work we have searched for common motifs in upstream regions of the homologous genes from plants considered to possess a primitive vascular tissue (a lycophyte, as well as from others that lack a true vascular tissue (a bryophyte, and finally from chlorophytes. Both lycophyte and bryophyte display motifs similar to those found in Arabidopsis with a significantly low E-value, while the chlorophytes showed either a different conserved motif or no conserved motif at all. These results suggest that these same genes are expressed coordinately in non- vascular plants; this coordinate expression may have been one of the prerequisites for the development of conducting tissues in plants. We have also analyzed the phylogeny of conserved proteins that may be involved in phloem function and development. The presence of CmPP16, APL, FT and YDA in chlorophytes suggests the recruitment of ancient regulatory networks for the development of the vascular tissue during evolution while OPS is a novel protein specific to vascular plants.

  3. STATE-OF-THE-ART HUMAN GENE THERAPY: PART II. GENE THERAPY STRATEGIES AND APPLICATIONS

    OpenAIRE

    2014-01-01

    In Part I of this Review, we introduced recent advances in gene delivery technologies and explained how they have powered some of the current human gene therapy applications. In Part II, we expand the discussion on gene therapy applications, focusing on some of the most exciting clinical uses. To help readers to grasp the essence and to better organize the diverse applications, we categorize them under four gene therapy strategies: (1) gene replacement therapy for monogenic diseases, (2) gene...

  4. Gene doping: the hype and the harm.

    Science.gov (United States)

    McKanna, Trudy A; Toriello, Helga V

    2010-06-01

    "Gene doping" is the term used to describe the potential abuse of gene therapy as a performance-enhancing agent. Gene doping would apply the techniques used in gene therapy to provide altered expression of genes that would promote physical superiority. For example, insulin-like growth factor 1 (IGF-1) is a primary target for growth hormone; overexpression of IGF-1 can lead to increased muscle mass and power. Although gene doping is still largely theoretical, its implications for sports, health, ethics, and medical genetics are significant.

  5. Msx homeobox gene family and craniofacial development

    Institute of Scientific and Technical Information of China (English)

    SYLVIA ALAPPAT; ZUN YI ZHANG; YI PING CHEN

    2003-01-01

    Vertebrate Msx genes are unlinked,homeobox-containing genes that bear homology to the Drosophila muscle segment homeobox gene.These genes are expressed at multiple sites of tissue-tissue interactions during vertebrate embryonic development.Inductive interactions mediated by the Msx genes are essential for normal craniofacial,limb and ectodermal organ morphogenesis,and are also essential to survival in mice,as manifested by the phenotypic abnormalities shown in knockout mice and in humans.This review summarizes studies on the expression,regulation,and functional analysis of Msx genes that bear relevance to craniofacial development in humans and mice.

  6. Reshaping of global gene expression networks and sex‐biased gene expression by integration of a young gene

    National Research Council Canada - National Science Library

    Chen, Sidi; Ni, Xiaochun; Krinsky, Benjamin H; Zhang, Yong E; Vibranovski, Maria D; White, Kevin P; Long, Manyuan

    2012-01-01

    ...‐biased gene expression in Drosophila . This 4–6 million‐year‐old factor, named Zeus for its role in male fecundity, originated through retroposition of a highly conserved housekeeping gene, Caf40...

  7. GenePRIMP: A GENE PRediction IMprovement Pipeline for Prokaryotic genomes

    Energy Technology Data Exchange (ETDEWEB)

    Pati, Amrita; Ivanova, Natalia N.; Mikhailova, Natalia; Ovchinnikova, Galina; Hooper, Sean D.; Lykidis, Athanasios; Kyrpides, Nikos C.

    2010-04-01

    We present 'gene prediction improvement pipeline' (GenePRIMP; http://geneprimp.jgi-psf.org/), a computational process that performs evidence-based evaluation of gene models in prokaryotic genomes and reports anomalies including inconsistent start sites, missed genes and split genes. We found that manual curation of gene models using the anomaly reports generated by GenePRIMP improved their quality, and demonstrate the applicability of GenePRIMP in improving finishing quality and comparing different genome-sequencing and annotation technologies.

  8. Genes from scratch – the evolutionary fate of de novo genes

    Science.gov (United States)

    Schlötterer, Christian

    2015-01-01

    Although considered an extremely unlikely event, many genes emerge from previously noncoding genomic regions. This review covers the entire life cycle of such de novo genes. Two competing hypotheses about the process of de novo gene birth are discussed as well as the high death rate of de novo genes. Despite the high death rate, some de novo genes are retained and remain functional, even in distantly related species, through their integration into gene networks. Further studies combining gene expression with ribosome profiling in multiple populations across different species will be instrumental for an improved understanding of the evolutionary processes operating on de novo genes. PMID:25773713

  9. Detection of gene x gene interactions in genome-wide association studies of human population data

    National Research Council Canada - National Science Library

    Musani, Solomon K; Shriner, Daniel; Liu, Nianjun; Feng, Rui; Coffey, Christopher S; Yi, Nengjun; Tiwari, Hemant K; Allison, David B

    2007-01-01

    Empirical evidence supporting the commonality of gene x gene interactions, coupled with frequent failure to replicate results from previous association studies, has prompted statisticians to develop...

  10. Detection of gene expression pattern in the early stage after spinal cord injury by gene chip

    Institute of Scientific and Technical Information of China (English)

    刘成龙; 靳安民; 童斌辉

    2003-01-01

    Objective: To study the changes of the gene expression pattern of spinal cord tissues in the early stage after injury by DNA microarray (gene chip). Methods: The contusion model of rat spinal cord was established according to Allen's falling strike method and the gene expression patterns of normal and injured spinal cord tissues were studied by gene chip. Results: The expression of 45 genes was significantly changed in the early stage after spinal cord injury, in which 22 genes up-regulated and 23 genes down-regulated. Conclusions: The expression of some genes changes significantly in the early stage after spinal cord injury, which indicates the complexity of secondary spinal cord injury.

  11. Genes from scratch--the evolutionary fate of de novo genes.

    Science.gov (United States)

    Schlötterer, Christian

    2015-04-01

    Although considered an extremely unlikely event, many genes emerge from previously noncoding genomic regions. This review covers the entire life cycle of such de novo genes. Two competing hypotheses about the process of de novo gene birth are discussed as well as the high death rate of de novo genes. Despite the high death rate, some de novo genes are retained and remain functional, even in distantly related species, through their integration into gene networks. Further studies combining gene expression with ribosome profiling in multiple populations across different species will be instrumental for an improved understanding of the evolutionary processes operating on de novo genes.

  12. The relationship among gene expression, the evolution of gene dosage, and the rate of protein evolution.

    Directory of Open Access Journals (Sweden)

    Jean-François Gout

    2010-05-01

    Full Text Available The understanding of selective constraints affecting genes is a major issue in biology. It is well established that gene expression level is a major determinant of the rate of protein evolution, but the reasons for this relationship remain highly debated. Here we demonstrate that gene expression is also a major determinant of the evolution of gene dosage: the rate of gene losses after whole genome duplications in the Paramecium lineage is negatively correlated to the level of gene expression, and this relationship is not a byproduct of other factors known to affect the fate of gene duplicates. This indicates that changes in gene dosage are generally more deleterious for highly expressed genes. This rule also holds for other taxa: in yeast, we find a clear relationship between gene expression level and the fitness impact of reduction in gene dosage. To explain these observations, we propose a model based on the fact that the optimal expression level of a gene corresponds to a trade-off between the benefit and cost of its expression. This COSTEX model predicts that selective pressure against mutations changing gene expression level or affecting the encoded protein should on average be stronger in highly expressed genes and hence that both the frequency of gene loss and the rate of protein evolution should correlate negatively with gene expression. Thus, the COSTEX model provides a simple and common explanation for the general relationship observed between the level of gene expression and the different facets of gene evolution.

  13. Genome-wide analysis of homeobox genes from Mesobuthus martensii reveals Hox gene duplication in scorpions.

    Science.gov (United States)

    Di, Zhiyong; Yu, Yao; Wu, Yingliang; Hao, Pei; He, Yawen; Zhao, Huabin; Li, Yixue; Zhao, Guoping; Li, Xuan; Li, Wenxin; Cao, Zhijian

    2015-06-01

    Homeobox genes belong to a large gene group, which encodes the famous DNA-binding homeodomain that plays a key role in development and cellular differentiation during embryogenesis in animals. Here, one hundred forty-nine homeobox genes were identified from the Asian scorpion, Mesobuthus martensii (Chelicerata: Arachnida: Scorpiones: Buthidae) based on our newly assembled genome sequence with approximately 248 × coverage. The identified homeobox genes were categorized into eight classes including 82 families: 67 ANTP class genes, 33 PRD genes, 11 LIM genes, five POU genes, six SINE genes, 14 TALE genes, five CUT genes, two ZF genes and six unclassified genes. Transcriptome data confirmed that more than half of the genes were expressed in adults. The homeobox gene diversity of the eight classes is similar to the previously analyzed Mandibulata arthropods. Interestingly, it is hypothesized that the scorpion M. martensii may have two Hox clusters. The first complete genome-wide analysis of homeobox genes in Chelicerata not only reveals the repertoire of scorpion, arachnid and chelicerate homeobox genes, but also shows some insights into the evolution of arthropod homeobox genes.

  14. Newer Gene Editing Technologies toward HIV Gene Therapy

    OpenAIRE

    2013-01-01

    Despite the great success of highly active antiretroviral therapy (HAART) in ameliorating the course of HIV infection, alternative therapeutic approaches are being pursued because of practical problems associated with life-long therapy. The eradication of HIV in the so-called “Berlin patient” who received a bone marrow transplant from a CCR5-negative donor has rekindled interest in genome engineering strategies to achieve the same effect. Precise gene editing within the cells is now a realist...

  15. Database for exchangeable gene trap clones: pathway and gene ontology analysis of exchangeable gene trap clone mouse lines.

    Science.gov (United States)

    Araki, Masatake; Nakahara, Mai; Muta, Mayumi; Itou, Miharu; Yanai, Chika; Yamazoe, Fumika; Miyake, Mikiko; Morita, Ayaka; Araki, Miyuki; Okamoto, Yoshiyuki; Nakagata, Naomi; Yoshinobu, Kumiko; Yamamura, Ken-ichi; Araki, Kimi

    2014-02-01

    Gene trapping in embryonic stem (ES) cells is a proven method for large-scale random insertional mutagenesis in the mouse genome. We have established an exchangeable gene trap system, in which a reporter gene can be exchanged for any other DNA of interest through Cre/mutant lox-mediated recombination. We isolated trap clones, analyzed trapped genes, and constructed the database for Exchangeable Gene Trap Clones (EGTC) [http://egtc.jp]. The number of registered ES cell lines was 1162 on 31 August 2013. We also established 454 mouse lines from trap ES clones and deposited them in the mouse embryo bank at the Center for Animal Resources and Development, Kumamoto University, Japan. The EGTC database is the most extensive academic resource for gene-trap mouse lines. Because we used a promoter-trap strategy, all trapped genes were expressed in ES cells. To understand the general characteristics of the trapped genes in the EGTC library, we used Kyoto Encyclopedia of Genes and Genomes (KEGG) for pathway analysis and found that the EGTC ES clones covered a broad range of pathways. We also used Gene Ontology (GO) classification data provided by Mouse Genome Informatics (MGI) to compare the functional distribution of genes in each GO term between trapped genes in the EGTC mouse lines and total genes annotated in MGI. We found the functional distributions for the trapped genes in the EGTC mouse lines and for the RefSeq genes for the whole mouse genome were similar, indicating that the EGTC mouse lines had trapped a wide range of mouse genes. © 2014 The Authors Development, Growth & Differentiation © 2014 Japanese Society of Developmental Biologists.

  16. cis sequence effects on gene expression

    Directory of Open Access Journals (Sweden)

    Jacobs Kevin

    2007-08-01

    Full Text Available Abstract Background Sequence and transcriptional variability within and between individuals are typically studied independently. The joint analysis of sequence and gene expression variation (genetical genomics provides insight into the role of linked sequence variation in the regulation of gene expression. We investigated the role of sequence variation in cis on gene expression (cis sequence effects in a group of genes commonly studied in cancer research in lymphoblastoid cell lines. We estimated the proportion of genes exhibiting cis sequence effects and the proportion of gene expression variation explained by cis sequence effects using three different analytical approaches, and compared our results to the literature. Results We generated gene expression profiling data at N = 697 candidate genes from N = 30 lymphoblastoid cell lines for this study and used available candidate gene resequencing data at N = 552 candidate genes to identify N = 30 candidate genes with sufficient variance in both datasets for the investigation of cis sequence effects. We used two additive models and the haplotype phylogeny scanning approach of Templeton (Tree Scanning to evaluate association between individual SNPs, all SNPs at a gene, and diplotypes, with log-transformed gene expression. SNPs and diplotypes at eight candidate genes exhibited statistically significant (p cis sequence effects in our study, respectively. Conclusion Based on analysis of our results and the extant literature, one in four genes exhibits significant cis sequence effects, and for these genes, about 30% of gene expression variation is accounted for by cis sequence variation. Despite diverse experimental approaches, the presence or absence of significant cis sequence effects is largely supported by previously published studies.

  17. Gene set analysis using variance component tests

    Science.gov (United States)

    2013-01-01

    Background Gene set analyses have become increasingly important in genomic research, as many complex diseases are contributed jointly by alterations of numerous genes. Genes often coordinate together as a functional repertoire, e.g., a biological pathway/network and are highly correlated. However, most of the existing gene set analysis methods do not fully account for the correlation among the genes. Here we propose to tackle this important feature of a gene set to improve statistical power in gene set analyses. Results We propose to model the effects of an independent variable, e.g., exposure/biological status (yes/no), on multiple gene expression values in a gene set using a multivariate linear regression model, where the correlation among the genes is explicitly modeled using a working covariance matrix. We develop TEGS (Test for the Effect of a Gene Set), a variance component test for the gene set effects by assuming a common distribution for regression coefficients in multivariate linear regression models, and calculate the p-values using permutation and a scaled chi-square approximation. We show using simulations that type I error is protected under different choices of working covariance matrices and power is improved as the working covariance approaches the true covariance. The global test is a special case of TEGS when correlation among genes in a gene set is ignored. Using both simulation data and a published diabetes dataset, we show that our test outperforms the commonly used approaches, the global test and gene set enrichment analysis (GSEA). Conclusion We develop a gene set analyses method (TEGS) under the multivariate regression framework, which directly models the interdependence of the expression values in a gene set using a working covariance. TEGS outperforms two widely used methods, GSEA and global test in both simulation and a diabetes microarray data. PMID:23806107

  18. Gene Therapy and Gene Editing for the Corneal Dystrophies.

    Science.gov (United States)

    Williams, Keryn A; Irani, Yazad D

    2016-01-01

    Despite ever-increasing understanding of the genetic underpinnings of many corneal dystrophies, gene therapy designed to ameliorate disease has not yet been reported in any human patient. In this review, we explore the likely reasons for this apparent failure of translation. We identify the requirements for success: the genetic defect involved must have been identified and mapped, vision in the affected patient must be significantly impaired or likely to be impaired, no better or equivalently effective treatment must be available, the treatment must be capable of modulating corneal pathology, and delivery of the construct to the appropriate cell must be practicable. We consider which of the corneal dystrophies might be amenable to treatment by genetic manipulations, summarize existing therapeutic options for treatment, and explore gene editing using clustered regularly interspaced short palindromic repeat/Cas and other similar transformative technologies as the way of the future. We then summarize recent laboratory-based advances in gene delivery and the development of in vitro and in vivo models of the corneal dystrophies. Finally, we review recent experimental work that has increased our knowledge of the pathobiology of these conditions.

  19. Sequence and gene expression evolution of paralogous genes in willows.

    Science.gov (United States)

    Harikrishnan, Srilakshmy L; Pucholt, Pascal; Berlin, Sofia

    2015-12-22

    Whole genome duplications (WGD) have had strong impacts on species diversification by triggering evolutionary novelties, however, relatively little is known about the balance between gene loss and forces involved in the retention of duplicated genes originating from a WGD. We analyzed putative Salicoid duplicates in willows, originating from the Salicoid WGD, which took place more than 45 Mya. Contigs were constructed by de novo assembly of RNA-seq data derived from leaves and roots from two genotypes. Among the 48,508 contigs, 3,778 pairs were, based on fourfold synonymous third-codon transversion rates and syntenic positions, predicted to be Salicoid duplicates. Both copies were in most cases expressed in both tissues and 74% were significantly differentially expressed. Mean Ka/Ks was 0.23, suggesting that the Salicoid duplicates are evolving by purifying selection. Gene Ontology enrichment analyses showed that functions related to DNA- and nucleic acid binding were over-represented among the non-differentially expressed Salicoid duplicates, while functions related to biosynthesis and metabolism were over-represented among the differentially expressed Salicoid duplicates. We propose that the differentially expressed Salicoid duplicates are regulatory neo- and/or subfunctionalized, while the non-differentially expressed are dose sensitive, hence, functionally conserved. Multiple evolutionary processes, thus drive the retention of Salicoid duplicates in willows.

  20. Gene based therapies for kidney regeneration.

    Science.gov (United States)

    Janssen, Manoe J; Arcolino, Fanny O; Schoor, Perry; Kok, Robbert Jan; Mastrobattista, Enrico

    2016-11-05

    In this review we provide an overview of the expanding molecular toolbox that is available for gene based therapies and how these therapies can be used for a large variety of kidney diseases. Gene based therapies range from restoring gene function in genetic kidney diseases to steering complex molecular pathways in chronic kidney disorders, and can provide a treatment or cure for diseases that otherwise may not be targeted. This approach involves the delivery of recombinant DNA sequences harboring therapeutic genes to improve cell function and thereby promote kidney regeneration. Depending on the therapy, the recombinant DNA will express a gene that directly plays a role in the function of the cell (gene addition), that regulates the expression of an endogenous gene (gene regulation), or that even changes the DNA sequence of endogenous genes (gene editing). Some interventions involve permanent changes in the genome whereas others are only temporary and leave no trace. Efficient and safe delivery are important steps for all gene based therapies and also depend on the mode of action of the therapeutic gene. Here we provide examples on how the different methods can be used to treat various diseases, which technologies are now emerging (such as gene repair through CRISPR/Cas9) and what the opportunities, perspectives, potential and the limitations of these therapies are for the treatment of kidney diseases.

  1. Genomic evidence for adaptation by gene duplication.

    Science.gov (United States)

    Qian, Wenfeng; Zhang, Jianzhi

    2014-08-01

    Gene duplication is widely believed to facilitate adaptation, but unambiguous evidence for this hypothesis has been found in only a small number of cases. Although gene duplication may increase the fitness of the involved organisms by doubling gene dosage or neofunctionalization, it may also result in a simple division of ancestral functions into daughter genes, which need not promote adaptation. Hence, the general validity of the adaptation by gene duplication hypothesis remains uncertain. Indeed, a genome-scale experiment found similar fitness effects of deleting pairs of duplicate genes and deleting individual singleton genes from the yeast genome, leading to the conclusion that duplication rarely results in adaptation. Here we contend that the above comparison is unfair because of a known duplication bias among genes with different fitness contributions. To rectify this problem, we compare homologous genes from the budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe. We discover that simultaneously deleting a duplicate gene pair in S. cerevisiae reduces fitness significantly more than deleting their singleton counterpart in S. pombe, revealing post-duplication adaptation. The duplicates-singleton difference in fitness effect is not attributable to a potential increase in gene dose after duplication, suggesting that the adaptation is owing to neofunctionalization, which we find to be explicable by acquisitions of binary protein-protein interactions rather than gene expression changes. These results provide genomic evidence for the role of gene duplication in organismal adaptation and are important for understanding the genetic mechanisms of evolutionary innovation.

  2. Thesaurus-based disambiguation of gene symbols

    Directory of Open Access Journals (Sweden)

    Wain Hester M

    2005-06-01

    Full Text Available Abstract Background Massive text mining of the biological literature holds great promise of relating disparate information and discovering new knowledge. However, disambiguation of gene symbols is a major bottleneck. Results We developed a simple thesaurus-based disambiguation algorithm that can operate with very little training data. The thesaurus comprises the information from five human genetic databases and MeSH. The extent of the homonym problem for human gene symbols is shown to be substantial (33% of the genes in our combined thesaurus had one or more ambiguous symbols, not only because one symbol can refer to multiple genes, but also because a gene symbol can have many non-gene meanings. A test set of 52,529 Medline abstracts, containing 690 ambiguous human gene symbols taken from OMIM, was automatically generated. Overall accuracy of the disambiguation algorithm was up to 92.7% on the test set. Conclusion The ambiguity of human gene symbols is substantial, not only because one symbol may denote multiple genes but particularly because many symbols have other, non-gene meanings. The proposed disambiguation approach resolves most ambiguities in our test set with high accuracy, including the important gene/not a gene decisions. The algorithm is fast and scalable, enabling gene-symbol disambiguation in massive text mining applications.

  3. Genes2GO: A web application for querying gene sets for specific GO terms.

    Science.gov (United States)

    Chawla, Konika; Kuiper, Martin

    2016-01-01

    Gene ontology annotations have become an essential resource for biological interpretations of experimental findings. The process of gathering basic annotation information in tables that link gene sets with specific gene ontology terms can be cumbersome, in particular if it requires above average computer skills or bioinformatics expertise. We have therefore developed Genes2GO, an intuitive R-based web application. Genes2GO uses the biomaRt package of Bioconductor in order to retrieve custom sets of gene ontology annotations for any list of genes from organisms covered by the Ensembl database. Genes2GO produces a binary matrix file, indicating for each gene the presence or absence of specific annotations for a gene. It should be noted that other GO tools do not offer this user-friendly access to annotations. Genes2GO is freely available and listed under http://www.semantic-systems-biology.org/tools/externaltools/.

  4. Progress in Chimeric Vector and Chimeric Gene Based Cardiovascular Gene Therapy

    Institute of Scientific and Technical Information of China (English)

    HU Chun-Song; YOON Young-sup; ISNER Jeffrey M.; LOSORDO Douglas W.

    2003-01-01

    Gene therapy for cardiovascular diseases has developed from preliminary animal experiments to clinical trials. However, vectors and target genes used currently in gene therapy are mainly focused on viral, nonviral vector and single target gene or monogene. Each vector system has a series of advantages and limitations. Chimeric vectors which combine the advantages of viral and nonviral vector,chimeric target genes which combine two or more target genes and novel gene delivery modes are being developed. In this article, we summarized the progress in chimeric vectors and chimeric genes based cardiovascular gene therapy, which including proliferative or occlusive vascular diseases such as atheroslerosis and restenosis, hypertonic vascular disease such as hypertension and cardiac diseases such as myocardium ischemia, dilated cardiomyopathy and heart failure, even heart transplantation. The development of chimeric vector, chimeric gene and their cardiovascular gene therapy is promising.

  5. Gene therapy for stroke: 2006 overview.

    Science.gov (United States)

    Chu, Yi; Miller, Jordan D; Heistad, Donald D

    2007-03-01

    Gene therapy is a promising approach for treatment of stroke and other cerebrovascular diseases, although it may take many years to realize. Gene therapy could occur prior to a stroke (eg, to stabilize atherosclerotic plaques) and/or following a stroke (eg, to prevent vasospasm after subarachnoid hemorrhage or reduce injury to neurons by ischemic insult). We have transferred the gene coding for vasoactive calcitonin gene-related peptide via cerebrospinal fluid, and demonstrated attenuation of vasospasm after SAH. Transfer of neuroprotective genes or small interfering RNA for neurotoxic genes has good potential for ischemic stroke. In this brief report, we review recent developments in experimental gene therapy for stroke. Fundamental advances, including development of safer, more specific gene transfer vectors, are discussed.

  6. NIH Researchers Identify OCD Risk Gene