While we studied pharmacokinetics of SM-12502 which was under development as an anti-PAF agent, we found three subjects showing a slow metabolic phenotype in its pharmacokinetics. Analyzing the genes for CYP2A6 from t...While we studied pharmacokinetics of SM-12502 which was under development as an anti-PAF agent, we found three subjects showing a slow metabolic phenotype in its pharmacokinetics. Analyzing the genes for CYP2A6 from the three subjects, we discovered that the three subjects possessed the whole CYP2A6 gene deletion (CYP2A6*4C), a novel genetic polymorphism of the CYP2A6 gene. Genetically engineered Salmonella YG7108 cells expressing human CYP2A6 or CYP2E1 together with the NADPH-CYP reductase were established in our laboratory to compare the mutagen-producing capacity of these enzymes for various N-nitrosamines. We found that CYP2E1 was responsible for the metabolic activation of N-nitrosamines with relatively short alkyl chains, whereas CYP2A6 was involved in the metabolic activation of N-nitrosamines possessing relatively bulky alkyl chains such as a tobacco-specific nitrosamine, NNK, which has been known to cause lung tumor in rodents. Thus, to examine a hypothesis that individuals possessing the CYP2A6*4C have the reduced risk of lung cancer due to the lack of the capacity of the metabolic activation of certain carcinogens in tobacco smoke, a case-control study was performed.展开更多
The short tandem repeat (STR) markers are widely used in human identification and paternity testing in the field of forensic genetics[1].Recent researches on polymorphic STRs have led to their applications to populati...The short tandem repeat (STR) markers are widely used in human identification and paternity testing in the field of forensic genetics[1].Recent researches on polymorphic STRs have led to their applications to population genetics,forensic DNA database,human individual identification,paternity testing,genetic mapping,disease linkage analysis,archaeology and potential inference of the ethnic origin of an individual[2].展开更多
OBJECTIVE The purpose of the present study was to investigate the impact of fluvas.tatin formulation on the pharmacokinetics-genetic polymorphis relationship.METHODS We compared the difference between the pharmacokine...OBJECTIVE The purpose of the present study was to investigate the impact of fluvas.tatin formulation on the pharmacokinetics-genetic polymorphis relationship.METHODS We compared the difference between the pharmacokinetics of fluvastatin as an extended-release(ER) 80 mg tablet and an immediate-release(IR) 40 mg capsule in terms of drug metabolism enzyme and transporter ge.netic polymorphisms.In this open-label,randomized,two-period,two-treatment,crossover study,ef.fects of BCRP,SLCO1B1,MDR1,CYP2C9,and CYP3A5 polymorphisms on the pharmacokinetics of fluvastatin were analyzed in 24 healthy individuals.Each treatment duration was 7 days with a washout period of 7 days between the crossover.Serum concentration of fluvastatin was evaluated using highperformance liquid chromatography-tandem mass spectrometry.RESULTS The SLCO1 B1 T521 C genotype had no statistically significant effect on IR 40 mg capsule of fluvastatinafter single or repeated doses.However,for the ER 80 mg tablet,the SLCO1 B1 T521 C genotype correlated with the AUC_(0-24) of repeat doses(P=0.01).The CYP2C9*3 genotype correlated with the AUC_(0-24) after the first dose IR40 mg capsule(P<0.05);however,the difference between CYP2C9*1/*1 and CYP2 C9*1/*3 was not statistically significant after repeated doses.CONCLUSION The effect of SLCO1B1T521C on fluvas.tatin exposure was observed and was more profound in ER and repeated dose administration than in IR and single dose administration.We recommend that formulation should be incorporated into future pharmacogenomics studies and clinical implication guidelines.展开更多
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 o...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 promoter activity. EGFR gene mutations and polymorphisms were also associated with EGFR kinase inhibitors response and toxicity.展开更多
The BRCA1 Associated RING Domain(BARD1) gene has been identified as a high penetrance gene for breast cancer, whose germline and somatic mutations were reported in both non-BRCA1/2 hereditary site-specific and sporadi...The BRCA1 Associated RING Domain(BARD1) gene has been identified as a high penetrance gene for breast cancer, whose germline and somatic mutations were reported in both non-BRCA1/2 hereditary site-specific and sporadic breast cancer cases. BARD1 plays a crucial role in tumor repression, along with its heterodimeric partner BRCA1. In the current study, we tested the hypothesis that common non-synonymous polymorphisms in BARD1 are associated with breast cancer susceptibility in a case-control study of 507 patients with incident breast cancer and 539 frequency-matched cancer-free controls in Chinese women. We genotyped all three common(minor allele frequency (MAF) > 0.10) non-synonymous polymorphisms(Pro24Ser, Arg378Ser, and Val507Met) in BARD1. We found that the BARD1 Pro24Ser variant genotypes(24Pro/Ser and 24Ser/Ser) and Arg378Ser variant homozygote 378Ser/Ser were associated with a significantly decreased breast cancer risk, compared with their wild-type homozygotes, respectively. Furthermore, a significant locus-locus interaction was evident between Pro24Ser and Arg378Ser (P-int = 0.032). Among the 378Ser variant allele carriers, the 24Pro/Pro wild-type homozygote was associated with a significantly increased breast cancer risk (adjusted OR = 1.81, 95% CI = 1.11-2.95), but the subjects having 24Pro/Ser or Ser/Ser variant genotypes had a significantly decreased risk(adjusted OR = 0.74, 95% CI = 0.56-0.99). In stratified analysis, this locus-locus interaction was more evident among subjects without family cancer history, those with positive estrogen receptor (ER) and individuals with negative progesterone receptor(PR). These findings indicate that the potentially functional polymorphisms Pro24Ser and Arg378Ser in BARD1 may jointly contribute to the susceptibility of breast cancer.展开更多
This paper aims to explore the ability of genetic programming(GP)to achieve the intelligent prediction of tunnelling-induced building deformation considering the multifactor impact.A total of 1099 groups of data obtai...This paper aims to explore the ability of genetic programming(GP)to achieve the intelligent prediction of tunnelling-induced building deformation considering the multifactor impact.A total of 1099 groups of data obtained from 22 geotechnical centrifuge tests are used for model development and analysis using GP.Tunnel volume loss,building eccentricity,soil density,building transverse width,building shear stiffness and building load are selected as the inputs,and shear distortion is selected as the output.Results suggest that the proposed intelligent prediction model is capable of providing a reasonable and accurate prediction of framed building shear distortion due to tunnel construction with realistic conditions,highlighting the important roles of shear stiffness of framed buildings and the pressure beneath the foundation on structural deformation.It has been proven that the proposed model is efficient and feasible to analyze relevant engineering problems by parametric analysis and comparative analysis.The findings demonstrate the great potential of GP approaches in predicting building distortion caused by tunnelling.The proposed equation can be used for the quick and intelligent prediction of tunnelling induced building deformation,providing valuable guidance for the practical design and risk assessment of urban tunnel construction projects.展开更多
文摘While we studied pharmacokinetics of SM-12502 which was under development as an anti-PAF agent, we found three subjects showing a slow metabolic phenotype in its pharmacokinetics. Analyzing the genes for CYP2A6 from the three subjects, we discovered that the three subjects possessed the whole CYP2A6 gene deletion (CYP2A6*4C), a novel genetic polymorphism of the CYP2A6 gene. Genetically engineered Salmonella YG7108 cells expressing human CYP2A6 or CYP2E1 together with the NADPH-CYP reductase were established in our laboratory to compare the mutagen-producing capacity of these enzymes for various N-nitrosamines. We found that CYP2E1 was responsible for the metabolic activation of N-nitrosamines with relatively short alkyl chains, whereas CYP2A6 was involved in the metabolic activation of N-nitrosamines possessing relatively bulky alkyl chains such as a tobacco-specific nitrosamine, NNK, which has been known to cause lung tumor in rodents. Thus, to examine a hypothesis that individuals possessing the CYP2A6*4C have the reduced risk of lung cancer due to the lack of the capacity of the metabolic activation of certain carcinogens in tobacco smoke, a case-control study was performed.
基金Acknowledgments The current research was supported by the Na- tional Natural Science Foundation of China （81302622）, the Science Technology Foundation of Lanzhou （2012-1-22）, and Youth Science and Tech- nology Foundation of Gansu （1208RYYA073）.
文摘The short tandem repeat (STR) markers are widely used in human identification and paternity testing in the field of forensic genetics[1].Recent researches on polymorphic STRs have led to their applications to population genetics,forensic DNA database,human individual identification,paternity testing,genetic mapping,disease linkage analysis,archaeology and potential inference of the ethnic origin of an individual[2].
文摘OBJECTIVE The purpose of the present study was to investigate the impact of fluvas.tatin formulation on the pharmacokinetics-genetic polymorphis relationship.METHODS We compared the difference between the pharmacokinetics of fluvastatin as an extended-release(ER) 80 mg tablet and an immediate-release(IR) 40 mg capsule in terms of drug metabolism enzyme and transporter ge.netic polymorphisms.In this open-label,randomized,two-period,two-treatment,crossover study,ef.fects of BCRP,SLCO1B1,MDR1,CYP2C9,and CYP3A5 polymorphisms on the pharmacokinetics of fluvastatin were analyzed in 24 healthy individuals.Each treatment duration was 7 days with a washout period of 7 days between the crossover.Serum concentration of fluvastatin was evaluated using highperformance liquid chromatography-tandem mass spectrometry.RESULTS The SLCO1 B1 T521 C genotype had no statistically significant effect on IR 40 mg capsule of fluvastatinafter single or repeated doses.However,for the ER 80 mg tablet,the SLCO1 B1 T521 C genotype correlated with the AUC_(0-24) of repeat doses(P=0.01).The CYP2C9*3 genotype correlated with the AUC_(0-24) after the first dose IR40 mg capsule(P<0.05);however,the difference between CYP2C9*1/*1 and CYP2 C9*1/*3 was not statistically significant after repeated doses.CONCLUSION The effect of SLCO1B1T521C on fluvas.tatin exposure was observed and was more profound in ER and repeated dose administration than in IR and single dose administration.We recommend that formulation should be incorporated into future pharmacogenomics studies and clinical implication guidelines.
文摘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 promoter activity. EGFR gene mutations and polymorphisms were also associated with EGFR kinase inhibitors response and toxicity.
文摘The BRCA1 Associated RING Domain(BARD1) gene has been identified as a high penetrance gene for breast cancer, whose germline and somatic mutations were reported in both non-BRCA1/2 hereditary site-specific and sporadic breast cancer cases. BARD1 plays a crucial role in tumor repression, along with its heterodimeric partner BRCA1. In the current study, we tested the hypothesis that common non-synonymous polymorphisms in BARD1 are associated with breast cancer susceptibility in a case-control study of 507 patients with incident breast cancer and 539 frequency-matched cancer-free controls in Chinese women. We genotyped all three common(minor allele frequency (MAF) > 0.10) non-synonymous polymorphisms(Pro24Ser, Arg378Ser, and Val507Met) in BARD1. We found that the BARD1 Pro24Ser variant genotypes(24Pro/Ser and 24Ser/Ser) and Arg378Ser variant homozygote 378Ser/Ser were associated with a significantly decreased breast cancer risk, compared with their wild-type homozygotes, respectively. Furthermore, a significant locus-locus interaction was evident between Pro24Ser and Arg378Ser (P-int = 0.032). Among the 378Ser variant allele carriers, the 24Pro/Pro wild-type homozygote was associated with a significantly increased breast cancer risk (adjusted OR = 1.81, 95% CI = 1.11-2.95), but the subjects having 24Pro/Ser or Ser/Ser variant genotypes had a significantly decreased risk(adjusted OR = 0.74, 95% CI = 0.56-0.99). In stratified analysis, this locus-locus interaction was more evident among subjects without family cancer history, those with positive estrogen receptor (ER) and individuals with negative progesterone receptor(PR). These findings indicate that the potentially functional polymorphisms Pro24Ser and Arg378Ser in BARD1 may jointly contribute to the susceptibility of breast cancer.
基金Projects(52108364,52278398)supported by the National Natural Science Foundation of ChinaProject(211179)supported by the Royal Society,UK+1 种基金Project(22CX06051A)supported by the Independent Innovation Research Plan Project of China University of Petroleum(East China)Project(ZR2023QE004)supported by the Shandong Provincial Natural Science Foundation,China。
文摘This paper aims to explore the ability of genetic programming(GP)to achieve the intelligent prediction of tunnelling-induced building deformation considering the multifactor impact.A total of 1099 groups of data obtained from 22 geotechnical centrifuge tests are used for model development and analysis using GP.Tunnel volume loss,building eccentricity,soil density,building transverse width,building shear stiffness and building load are selected as the inputs,and shear distortion is selected as the output.Results suggest that the proposed intelligent prediction model is capable of providing a reasonable and accurate prediction of framed building shear distortion due to tunnel construction with realistic conditions,highlighting the important roles of shear stiffness of framed buildings and the pressure beneath the foundation on structural deformation.It has been proven that the proposed model is efficient and feasible to analyze relevant engineering problems by parametric analysis and comparative analysis.The findings demonstrate the great potential of GP approaches in predicting building distortion caused by tunnelling.The proposed equation can be used for the quick and intelligent prediction of tunnelling induced building deformation,providing valuable guidance for the practical design and risk assessment of urban tunnel construction projects.
