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MTHFR and MTRR Genetic Polymorphism of Methotrexate Therapy Outcomes in Early Rheumatoid Arthritis. 甲氨蝶呤治疗早期类风湿关节炎疗效的MTHFR和MTRR遗传多态性
IF 1.9 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S404949
Qian Zhang, Pan Fu, Zhanglei Cao, Hua Huang, Qinwen Wen, Kaizhe Wang, Tong Kong, Xiudi Wu, Jianping Zheng

Purpose: Methotrexate (MTX) is used as an anchor drug for the treatment of rheumatoid arthritis (RA) and there may be differences in drug action between genotypes. The purpose of this study was to investigate the relationship between clinical efficacy response and disease activity of MTX monotherapy with methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) polymorphisms.

Patients and methods: In the study, a population of 32 patients in East China with early RA fulfilling the diagnostic standards of the American College of Rheumatology (ACR) were enrolled, all of them received MTX monotherapy. Genotyping of patients MTHFR C677T and A1298C, MTRR A66G using tetra-primer ARMS-PCR method and sanger sequencing to verify its accuracy.

Results: The distribution of three polymorphic genotypes that were studied is in accordance with the Hardy-Weinberg genetic equilibrium. The patient pathology variables smoke (OR = 0.088, P = 0.037), drink alcohol (OR = 0.039, P = 0.016) and males (OR = 0.088, P = 0.037) were significantly associated with non-response to MTX. Genotype, allele distribution and genetic statistical models were not found to be related to MTX treatment response and disease activity in both the response groups and non-response groups.

Conclusion: Our findings suggest that the MTHFR C677T, MTHFR A1298C and MTRR A66G polymorphisms may not predict MTX clinical treatment response and disease activity in patients with early RA. The study revealed that smoke, alcohol, and males were possible influential factors for MTX non-response.

目的:甲氨蝶呤(MTX)被用作治疗类风湿性关节炎(RA)的锚定药物,不同基因型的药物作用可能存在差异。本研究旨在探讨甲氨蝶呤单药治疗与亚甲基四氢叶酸还原酶(MTHFR)和蛋氨酸合成酶还原酶(MTRR)多态性的临床疗效、反应与疾病活动度的关系。患者和方法:本研究纳入32例符合美国风湿病学会(American College of Rheumatology, ACR)诊断标准的华东地区早期RA患者,均接受MTX单药治疗。采用四引物ARMS-PCR法对患者MTHFR C677T和A1298C、MTRR A66G进行基因分型,并进行sanger测序验证其准确性。结果:三种基因型均符合Hardy-Weinberg遗传平衡。患者病理变量吸烟(OR = 0.088, P = 0.037)、饮酒(OR = 0.039, P = 0.016)和男性(OR = 0.088, P = 0.037)与甲氨蝶呤无应答显著相关。在有反应组和无反应组中,基因型、等位基因分布和遗传统计模型均未发现与MTX治疗反应和疾病活动度相关。结论:我们的研究结果提示MTHFR C677T、MTHFR A1298C和MTRR A66G多态性可能不能预测早期RA患者MTX的临床治疗反应和疾病活动性。研究显示,吸烟、酒精和男性是MTX无反应的可能影响因素。
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引用次数: 0
Exploration and Validation of Pancreatic Cancer Hub Genes Based on Weighted Gene Co-Expression Network Analysis and Immune Infiltration Score Analysis. 基于加权基因共表达网络分析和免疫浸润评分分析的胰腺癌中心基因的探索和验证。
IF 1.9 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S403116
Xiao-Xi Li, Hong Li, Li-Quan Jin, Yun-Bo Tan

Objective: To find pancreatic cancer (PC)-related hub genes based on weighted gene co-expression network analysis (WGCNA) construction and immune infiltration score analysis and validate them immunohistochemically by clinical cases, to generate new concepts or therapeutic targets for the early diagnosis and treatment of PC.

Material and methods: In this study, WGCNA and immune infiltration score were utilized to identify the relevant core modules of PC and the hub genes within these core modules.

Results: Using WGCNA analysis, data from PC and normal pancreas integrated with TCGA and GTEX were analyzed and brown modules were chosen from the six modules. Five hub genes, including DPYD, FXYD6, MAP6, FAM110B, and ANK2, were discovered to have differential survival significance via validation tests utilizing survival analysis curves and the GEPIA database. The DPYD gene was the only gene associated with PC survival side effects. Validation of the Human Protein Atlas (HPA) database and immunohistochemical testing of clinical samples showed positive results for DPYD expression in PC.

Conclusion: In this study, we identified DPYD, FXYD6, MAP6, FAM110B, and ANK2, as immune-related candidate markers for PC. Only the DPYD gene had a negative impact on the survival of PC patients. Through validation of the HPA database and immunohistochemical testing of clinical cases, we believe that the DPYD gene brings novel ideas and therapeutic targets in the diagnosis and treatment of PC.

目的:通过加权基因共表达网络分析(WGCNA)构建和免疫浸润评分分析,寻找胰腺癌(PC)相关枢纽基因,并通过临床病例进行免疫组化验证,为胰腺癌的早期诊断和治疗提供新的理念或治疗靶点。材料与方法:本研究采用WGCNA和免疫浸润评分法鉴定PC相关核心模块及核心模块内的枢纽基因。结果:采用WGCNA分析,结合TCGA和GTEX对PC和正常胰腺数据进行分析,从6个模块中选择棕色模块。利用生存分析曲线和GEPIA数据库进行验证检验,发现DPYD、FXYD6、MAP6、FAM110B、ANK2 5个枢纽基因具有差异生存意义。DPYD基因是唯一与PC生存副作用相关的基因。人类蛋白图谱(Human Protein Atlas, HPA)数据库的验证和临床样本的免疫组化检测显示,DPYD在PC中的表达呈阳性。结论:在本研究中,我们发现DPYD、FXYD6、MAP6、FAM110B和ANK2是PC的免疫相关候选标志物。只有DPYD基因对PC患者的生存有负面影响。通过对HPA数据库的验证和对临床病例的免疫组化检测,我们认为DPYD基因为PC的诊断和治疗带来了新的思路和治疗靶点。
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引用次数: 0
Clinical and Gene Analysis of Fatty Acid Oxidation Disorders Found in Neonatal Tandem Mass Spectrometry Screening. 新生儿串联质谱筛查中脂肪酸氧化障碍的临床和基因分析。
IF 1.9 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S402760
Xiaoxia Wang, Haining Fang

Objective: To investigate the clinical and gene mutation characteristics of fatty acid oxidative metabolic diseases found in neonatal screening.

Methods: A retrospective analysis was performed on 29,948 neonatal blood tandem mass spectrometry screening samples from January 2018 to December 2021 in our neonatal screening centre. For screening positive, recall review is still suspected of fatty acid oxidation metabolic disorders in children as soon as possible to improve the genetic metabolic disease-related gene detection package to confirm the diagnosis. All diagnosed children were followed up to the deadline.

Results: Among 29,948 neonates screened by tandem mass spectrometry, 14 cases of primary carnitine deficiency, six cases of short-chain acyl coenzyme A dehydrogenase deficiency, two cases of carnitine palmitoyltransferase-I deficiency and one case of multiple acyl coenzyme A dehydrogenase deficiency were recalled. Except for two cases of multiple acyl coenzyme A dehydrogenase deficiency that exhibited [manifestations], the other 21 cases were diagnosed pre-symptomatically. Eight mutations of SLC22A5 gene were detected, including c.51C>G, c.403G>A, c.506G>A, c.1400C>G, c.1085C>T, c.706C>T, c.1540G>C and c.338G>A. Compound heterozygous mutation of CPT1A gene c.2201T>C, c.1318G>A, c.2246G>A, c.2125G>A and ETFA gene c.365G>A and c.699_701delGTT were detected, and new mutation sites were found.

Conclusion: Neonatal tandem mass spectrometry screening is an effective method for identifying fatty acid oxidative metabolic diseases, but it should be combined with urine gas chromatography-mass spectrometry and gene sequencing technology. Our findings enrich the gene mutation profile of fatty acid oxidative metabolic disease and provide evidence for genetic counselling and prenatal diagnosis in families.

目的:探讨新生儿筛查中发现的脂肪酸氧化代谢性疾病的临床及基因突变特点。方法:对2018年1月至2021年12月我院新生儿筛查中心29948份新生儿血液串联质谱筛查样本进行回顾性分析。对于筛查阳性,回顾回顾仍疑似脂肪酸氧化代谢性疾病的患儿,尽快完善遗传代谢性疾病相关基因检测包,确认诊断。所有确诊的儿童都被随访到最后期限。结果:在29948例经串联质谱筛查的新生儿中,召回原发性肉碱缺乏症14例,短链酰基辅酶A脱氢酶缺乏症6例,肉碱棕榈酰基转移酶i缺乏症2例,多种酰基辅酶A脱氢酶缺乏症1例。除2例多酰基辅酶A脱氢酶缺乏症有【表现】外,其余21例均有症状前诊断。SLC22A5基因共检测到8个突变,分别为C . 51c >G、C . 403g >A、C . 506g >A、C . 1400c >G、C . 1085c >T、C . 706c >T、C . 1540g >C和C . 338g >A。检测到CPT1A基因C . 2201t >C、C . 1318g >A、C . 2246g >A、C . 2125g >A和ETFA基因C . 365g >A、C . 699_701delgtt的复合杂合突变,并发现新的突变位点。结论:新生儿串联质谱筛查是鉴别脂肪酸氧化代谢性疾病的有效方法,但应与尿气相色谱-质谱联用及基因测序技术相结合。我们的发现丰富了脂肪酸氧化代谢性疾病的基因突变谱,为家庭遗传咨询和产前诊断提供了证据。
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引用次数: 0
Clinical Characteristics and Novel ZEB2 Gene Mutation Analysis of Three Chinese Patients with Mowat-Wilson Syndrome. 3例中国莫瓦特-威尔逊综合征患者的临床特征及ZEB2基因突变分析。
IF 1.9 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S414161
Xiao Han, Qianjuan Zhang, Chengcheng Wang, Bingjuan Han

Purpose: Mowat-Wilson syndrome (MWS) is an autosomal dominant disease caused by a pathogenic variant of the ZEB2 gene. The main clinical manifestations include special facial features, Hirschsprung disease (HSCR), global developmental delay and other congenital malformations. Here, we summarize the clinical characteristics and genetic mutation analysis of three Chinese patients with MWS.

Patients and methods: The clinical characteristics of the patients were monitored and the treatment effect was followed up. DNA was extracted from peripheral blood and analyzed by sequencing. Whole exome sequencing was then performed.

Results: Three novel ZEB2 gene mutations were identified in 3 patients (c.1147_1150dupGAAC, p.Q384Rfs*7, c.1137_1146del TAGTATGTCT, p.S380Nfs *13 and c.2718delT, p.A907Lfs*23). They all had special facial features, intellectual disability, developmental delay, microcephaly, structural brain abnormalities and other symptoms. After long-term regular rehabilitation treatment, the development quotient of each functional area of the patient was slightly improved.

Conclusion: Our study expanded the mutation spectrum of ZEB2 and enriched our understanding of the clinical features of MWS. It also shows that long-term standardized treatment is of great significance for the prognosis of patients.

目的:mowa - wilson综合征(MWS)是一种常染色体显性遗传病,由ZEB2基因的致病性变异引起。主要临床表现为特殊的面部特征、先天性巨结肠病(HSCR)、整体发育迟缓等先天性畸形。在此,我们总结了3例中国MWS患者的临床特点和基因突变分析。患者与方法:监测患者的临床特点,随访治疗效果。从外周血中提取DNA并进行测序分析。然后进行全外显子组测序。结果:在3例患者中发现3个新的ZEB2基因突变(c.1147_1150dupGAAC, p.Q384Rfs*7, c.1137_1146del TAGTATGTCT, p.S380Nfs *13和c.2718delT, p.A907Lfs*23)。他们都有特殊的面部特征、智力障碍、发育迟缓、小头畸形、大脑结构异常和其他症状。经长期正规康复治疗后,患者各功能区发育商略有改善。结论:我们的研究扩大了ZEB2的突变谱,丰富了我们对MWS临床特征的认识。这也说明长期规范化治疗对患者的预后有重要意义。
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引用次数: 0
Hsa_circ_0003489 Drives PTX Resistance of Human NSCLC Cells Through Modulating miR-98-5p/IGF2. Hsa_circ_0003489通过调节miR-98-5p/IGF2驱动人NSCLC细胞PTX抗性
IF 1.9 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S416360
Shaofeng Xia, Chenliang Wang

Background: Circular RNAs (circRNAs) demonstrated critical roles within developing tumors and treatment resistance in an increasing body of research. The aim was to look into the functions and processes of hsa_circ_0003489 in the non-small cell lung cancer (NSCLC) paclitaxel (PTX) resistance.

Methods: NSCLC cell-based cultures including A549 and H460 were employed for such an investigation. hsa_circ_0003489, miR-98-5p, and insulin-like growth factor 2 (IGF2) expression-profiles were evaluated with a quantitative real-time polymerase chain reaction (RT-qPCR). The PTX resistance was determined using MTT assay, and the ELISA test measured IGF2 expression. Facilitating corroboration for miR-98-5p relation and hsa_circ_0003489 or IGF2, a dual-luciferase reporter method was applied.

Results: The hsa_circ_0003489 level was raised in cells and tissues from PTX-resistant (PR) NSCLC. In PR NSCLC cells, hsa_circ_0003489 knockdown reduced PTX resistance. For the purpose of the mechanism study, hsa_circ_0003489 knockdown substantially reduced IGF2 expression via miR-98-5p sponging, improving PTX sensitivity in PR NSCLC.

Conclusion: Through miR-98-5p/IGF2 axis control, hsa_circ_0003489 knockdown helped NSCLC overcome PTX resistance, suggesting a potential circRNA-targeted therapy for the disease.

背景:在越来越多的研究中,环状rna (circRNAs)在肿瘤的发生和治疗耐药性中发挥了关键作用。目的是探讨hsa_circ_0003489在非小细胞肺癌(NSCLC)紫杉醇(PTX)耐药中的功能和过程。方法:采用A549、H460等非小细胞肺癌细胞培养物进行研究。hsa_circ_0003489, miR-98-5p和胰岛素样生长因子2 (IGF2)的表达谱通过定量实时聚合酶链反应(RT-qPCR)进行评估。MTT法检测PTX耐药,ELISA法检测IGF2表达。为了验证miR-98-5p与hsa_circ_0003489或IGF2之间的关系,我们采用了双荧光素酶报告方法。结果:hsa_circ_0003489水平在ptx耐药(PR) NSCLC细胞和组织中升高。在PR型NSCLC细胞中,敲低hsa_circ_0003489可降低PTX耐药性。机制研究的目的是,hsa_circ_0003489敲低通过miR-98-5p海绵显著降低IGF2表达,提高PTX在PR NSCLC中的敏感性。结论:通过miR-98-5p/IGF2轴控制,hsa_circ_0003489敲低有助于NSCLC克服PTX耐药,提示潜在的circrna靶向治疗该疾病。
{"title":"Hsa_circ_0003489 Drives PTX Resistance of Human NSCLC Cells Through Modulating miR-98-5p/IGF2.","authors":"Shaofeng Xia,&nbsp;Chenliang Wang","doi":"10.2147/PGPM.S416360","DOIUrl":"https://doi.org/10.2147/PGPM.S416360","url":null,"abstract":"<p><strong>Background: </strong>Circular RNAs (circRNAs) demonstrated critical roles within developing tumors and treatment resistance in an increasing body of research. The aim was to look into the functions and processes of hsa_circ_0003489 in the non-small cell lung cancer (NSCLC) paclitaxel (PTX) resistance.</p><p><strong>Methods: </strong>NSCLC cell-based cultures including A549 and H460 were employed for such an investigation. hsa_circ_0003489, miR-98-5p, and insulin-like growth factor 2 (IGF2) expression-profiles were evaluated with a quantitative real-time polymerase chain reaction (RT-qPCR). The PTX resistance was determined using MTT assay, and the ELISA test measured IGF2 expression. Facilitating corroboration for miR-98-5p relation and hsa_circ_0003489 or IGF2, a dual-luciferase reporter method was applied.</p><p><strong>Results: </strong>The hsa_circ_0003489 level was raised in cells and tissues from PTX-resistant (PR) NSCLC. In PR NSCLC cells, hsa_circ_0003489 knockdown reduced PTX resistance. For the purpose of the mechanism study, hsa_circ_0003489 knockdown substantially reduced IGF2 expression via miR-98-5p sponging, improving PTX sensitivity in PR NSCLC.</p><p><strong>Conclusion: </strong>Through miR-98-5p/IGF2 axis control, hsa_circ_0003489 knockdown helped NSCLC overcome PTX resistance, suggesting a potential circRNA-targeted therapy for the disease.</p>","PeriodicalId":56015,"journal":{"name":"Pharmacogenomics & Personalized Medicine","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/88/de/pgpm-16-805.PMC10488782.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10218680","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Rs11479 in Thymidine Phosphorylase Associated with Prognosis of Patients with Colorectal Cancer Who Received Capecitabine-Based Adjuvant Chemotherapy. 胸苷磷酸化酶Rs11479与结直肠癌患者卡培他滨辅助化疗预后的关系
IF 1.9 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S397382
Xiongjie Jia, Tao Zhang, Junjie Sun, Hengxue Lin, Tianliang Bai, Yating Qiao, Yaxin Li, Gang Li, Guicun Li, Xinyu Peng, Aimin Zhang

Objective: Thymidine Phosphorylase (TYMP) gene was of potential significance in the process of colorectal cancer (CRC) development and played an important role in capecitabine metabolism. This study was to identify the association between TYMP polymorphism and prognosis of postoperative patients with CRC who received capecitabine-based adjuvant chemotherapy.

Methods: A total of 218 patients with CRC who were treated with surgical resection and capecitabine-based adjuvant chemotherapy were included in this study retrospectively. Peripheral blood and peripheral blood mononuclear cell (PBMC) specimen of the patients were collected for the genotyping of TYMP polymorphism and TYMP mRNA expression, respectively. Univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis, Cox regression analysis was adopted in multivariate analysis. The mRNA expression of TYMP according to genotype status was analyzed using non-parameter test.

Results: Prevalence of rs11479 in TYMP among the 218 patients exhibited that minor allele frequency of rs11479 was 0.20 (GG 141 cases, GA 68 cases and AA 9 cases), which was in accordance with Hardy-Weinberg equilibrium (P=0.825). Association analysis suggested that the median disease-free survival (DFS) of patients with GG genotype and GA/AA genotype was 3.1 and 6.1 years, respectively (P=0.004). Furthermore, the median overall survival of patients with GG genotype and GA/AA genotype was 5.0 and 7.0 years, respectively (P=0.033). Multivariate Cox regression analysis exhibited that rs11479 polymorphism was an independent factor for DFS (HR = 1.64, P=0.009). Additionally, of the 65 PBMC specimens, mRNA expression results indicated that patients with GA/AA genotypes conferred significantly higher mRNA expression of TYMP than that of patients with GG genotype (P<0.001).

Conclusion: Polymorphism rs11479 in TYMP gene might predict the prognosis of patients with CRC who received capecitabine-based adjuvant chemotherapy through mediation of the mRNA expression of TYMP. The conclusion of this study should be validated in prospective clinical trials subsequently.

目的:胸苷磷酸化酶(TYMP)基因在结直肠癌(CRC)发生发展过程中具有潜在意义,在卡培他滨代谢中发挥重要作用。本研究旨在确定TYMP多态性与术后接受卡培他滨辅助化疗的结直肠癌患者预后的关系。方法:回顾性分析218例行手术切除加卡培他滨辅助化疗的结直肠癌患者。采集患者外周血和外周血单个核细胞(PBMC)标本,分别对TYMP多态性和TYMP mRNA表达进行基因分型。单因素分析基因型与预后采用Kaplan-Meier生存分析,多因素分析采用Cox回归分析。采用非参数检验分析不同基因型的TYMP mRNA表达情况。结果:218例TYMP患者中rs11479的患病率显示,rs11479的次要等位基因频率为0.20 (GG 141例,GA 68例,AA 9例),符合Hardy-Weinberg平衡(P=0.825)。相关性分析显示,GG基因型和GA/AA基因型患者的中位无病生存期(DFS)分别为3.1年和6.1年(P=0.004)。GG基因型和GA/AA基因型患者的中位总生存期分别为5.0年和7.0年(P=0.033)。多因素Cox回归分析显示,rs11479多态性是影响DFS的独立因素(HR = 1.64, P=0.009)。此外,在65例PBMC标本中,mRNA表达结果显示GA/AA基因型患者的TYMP mRNA表达量显著高于GG基因型患者(p结论:TYMP基因rs11479多态性可能通过介导TYMP mRNA表达来预测卡培他滨辅助化疗的结直肠癌患者的预后。本研究结论应在后续的前瞻性临床试验中得到验证。
{"title":"Rs11479 in <i>Thymidine Phosphorylase</i> Associated with Prognosis of Patients with Colorectal Cancer Who Received Capecitabine-Based Adjuvant Chemotherapy.","authors":"Xiongjie Jia,&nbsp;Tao Zhang,&nbsp;Junjie Sun,&nbsp;Hengxue Lin,&nbsp;Tianliang Bai,&nbsp;Yating Qiao,&nbsp;Yaxin Li,&nbsp;Gang Li,&nbsp;Guicun Li,&nbsp;Xinyu Peng,&nbsp;Aimin Zhang","doi":"10.2147/PGPM.S397382","DOIUrl":"https://doi.org/10.2147/PGPM.S397382","url":null,"abstract":"<p><strong>Objective: </strong><i>Thymidine Phosphorylase (TYMP)</i> gene was of potential significance in the process of colorectal cancer (CRC) development and played an important role in capecitabine metabolism. This study was to identify the association between <i>TYMP</i> polymorphism and prognosis of postoperative patients with CRC who received capecitabine-based adjuvant chemotherapy.</p><p><strong>Methods: </strong>A total of 218 patients with CRC who were treated with surgical resection and capecitabine-based adjuvant chemotherapy were included in this study retrospectively. Peripheral blood and peripheral blood mononuclear cell (PBMC) specimen of the patients were collected for the genotyping of <i>TYMP</i> polymorphism and <i>TYMP</i> mRNA expression, respectively. Univariate analysis of genotypes and prognosis was carried out by Kaplan-Meier survival analysis, Cox regression analysis was adopted in multivariate analysis. The mRNA expression of <i>TYMP</i> according to genotype status was analyzed using non-parameter test.</p><p><strong>Results: </strong>Prevalence of rs11479 in <i>TYMP</i> among the 218 patients exhibited that minor allele frequency of rs11479 was 0.20 (GG 141 cases, GA 68 cases and AA 9 cases), which was in accordance with Hardy-Weinberg equilibrium (<i>P</i>=0.825). Association analysis suggested that the median disease-free survival (DFS) of patients with GG genotype and GA/AA genotype was 3.1 and 6.1 years, respectively (<i>P</i>=0.004). Furthermore, the median overall survival of patients with GG genotype and GA/AA genotype was 5.0 and 7.0 years, respectively (<i>P</i>=0.033). Multivariate Cox regression analysis exhibited that rs11479 polymorphism was an independent factor for DFS (HR = 1.64, <i>P</i>=0.009). Additionally, of the 65 PBMC specimens, mRNA expression results indicated that patients with GA/AA genotypes conferred significantly higher mRNA expression of <i>TYMP</i> than that of patients with GG genotype (<i>P</i><0.001).</p><p><strong>Conclusion: </strong>Polymorphism rs11479 in <i>TYMP</i> gene might predict the prognosis of patients with CRC who received capecitabine-based adjuvant chemotherapy through mediation of the mRNA expression of <i>TYMP</i>. The conclusion of this study should be validated in prospective clinical trials subsequently.</p>","PeriodicalId":56015,"journal":{"name":"Pharmacogenomics & Personalized Medicine","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/4f/d2/pgpm-16-277.PMC10072144.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9260035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 1
Detection of Novel Pathogenic Variants in Two Families with Recurrent Fetal Congenital Heart Defects. 两家系复发性胎儿先天性心脏缺陷的新致病变异检测。
IF 1.9 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S394120
Rongqin Cai, Ya Tan, Mingming Wang, Huijun Yu, Jing Wang, Zhuo Ren, Zhe Dong, Yiwen He, Zhi Li, Li Lin, Ying Gu

Background: Congenital heart disease (CHD) is the most common birth defect with strong genetic heterogeneity. To date, about 400 genes have been linked to CHD, including cell signaling molecules, transcription factors, and structural proteins that are important for heart development. Genetic analysis of CHD cases is crucial for clinical management and etiological analysis.

Methods: Whole-exome sequencing (WES) was performed to identify the genetic variants in two independent CHD cases with DNA samples from fetuses and their parents, followed by the exclusion of aneuploidy and large copy number variations (CNVs). The WES results were verified by Sanger sequencing.

Results: In family A, a compound heterozygous variation in PLD1 gene consisting of c.1132dupA (p.I378fs) and c.1171C>T (p.R391C) was identified in the fetus. The two variants were inherited from the father (c.1132dupA) and the mother (c.1171C>T), respectively. In family B, a hemizygous variant ZIC3: c.861delG (p.G289Afs*119) was identified in the fetus, which was inherited from the heterozygous mother. We further confirmed that these variants PLD1: c.1132dupA and ZIC3: c.861delG were novel.

Conclusion: The findings in our study identified novel variants to the mutation spectrum of CHD and provided reliable evidence for the recurrent risk and reproductive care options to the affected families. Our study also demonstrates that WES has considerable prospects of clinical application in prenatal diagnosis.

背景:先天性心脏病(CHD)是最常见的先天缺陷,具有很强的遗传异质性。迄今为止,大约有400个基因与冠心病有关,包括细胞信号分子、转录因子和对心脏发育很重要的结构蛋白。冠心病病例的遗传分析对临床管理和病因分析至关重要。方法:采用全外显子组测序(WES)鉴定两例独立冠心病患者的遗传变异,并排除非整倍体和大拷贝数变异(CNVs)。通过Sanger测序对WES结果进行验证。结果:A家族在胎儿中发现了由c.1132dupA (p.I378fs)和c.1171C>T (p.R391C)组成的PLD1基因复合杂合变异。这两个变异分别遗传自父亲(c.1132dupA)和母亲(c.1171C>T)。在B家族中,胎儿中发现了一个半合子变异ZIC3: c.861delG (p.G289Afs*119),该变异遗传自杂合母亲。我们进一步证实这些变异PLD1: c.1132dupA和ZIC3: c.861delG是新的。结论:我们的研究结果确定了冠心病突变谱的新变异,为患病家庭的复发风险和生殖保健选择提供了可靠的证据。我们的研究也表明WES在产前诊断中具有相当的临床应用前景。
{"title":"Detection of Novel Pathogenic Variants in Two Families with Recurrent Fetal Congenital Heart Defects.","authors":"Rongqin Cai,&nbsp;Ya Tan,&nbsp;Mingming Wang,&nbsp;Huijun Yu,&nbsp;Jing Wang,&nbsp;Zhuo Ren,&nbsp;Zhe Dong,&nbsp;Yiwen He,&nbsp;Zhi Li,&nbsp;Li Lin,&nbsp;Ying Gu","doi":"10.2147/PGPM.S394120","DOIUrl":"https://doi.org/10.2147/PGPM.S394120","url":null,"abstract":"<p><strong>Background: </strong>Congenital heart disease (CHD) is the most common birth defect with strong genetic heterogeneity. To date, about 400 genes have been linked to CHD, including cell signaling molecules, transcription factors, and structural proteins that are important for heart development. Genetic analysis of CHD cases is crucial for clinical management and etiological analysis.</p><p><strong>Methods: </strong>Whole-exome sequencing (WES) was performed to identify the genetic variants in two independent CHD cases with DNA samples from fetuses and their parents, followed by the exclusion of aneuploidy and large copy number variations (CNVs). The WES results were verified by Sanger sequencing.</p><p><strong>Results: </strong>In family A, a compound heterozygous variation in <i>PLD1</i> gene consisting of c.1132dupA (p.I378fs) and c.1171C>T (p.R391C) was identified in the fetus. The two variants were inherited from the father (c.1132dupA) and the mother (c.1171C>T), respectively. In family B, a hemizygous variant <i>ZIC3</i>: c.861delG (p.G289Afs*119) was identified in the fetus, which was inherited from the heterozygous mother. We further confirmed that these variants <i>PLD1</i>: c.1132dupA and <i>ZIC3</i>: c.861delG were novel.</p><p><strong>Conclusion: </strong>The findings in our study identified novel variants to the mutation spectrum of CHD and provided reliable evidence for the recurrent risk and reproductive care options to the affected families. Our study also demonstrates that WES has considerable prospects of clinical application in prenatal diagnosis.</p>","PeriodicalId":56015,"journal":{"name":"Pharmacogenomics & Personalized Medicine","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/33/42/pgpm-16-173.PMC10008912.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9475734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A Review of the Pharmacokinetic Characteristics of Immune Checkpoint Inhibitors and Their Clinical Impact Factors. 免疫检查点抑制剂的药代动力学特性及其临床影响因素综述。
IF 1.9 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S391756
Jun-Chen Liu, Hong-Jing Yu

Immune checkpoint inhibitors (ICIs) have been shown to be significant in improving the overall survival rate in certain malignancies with poor prognoses. However, only 20-40% of patients achieve long-term benefits, highlighting the relevance of the factors that influence the treatment, which can help clinicians improve their results and guide the development of new immune checkpoint therapies. In this study, the current pharmacokinetic aspects associated with the ICIs and the factors influencing clinical efficacy were characterised, including in terms of drug metabolism, drug clearance, hormonal effects and immunosuppressive effects.

免疫检查点抑制剂(ICIs)已被证明在改善某些预后不良的恶性肿瘤的总生存率方面具有重要意义。然而,只有20-40%的患者获得长期受益,这突出了影响治疗的因素的相关性,这可以帮助临床医生改善他们的结果并指导新的免疫检查点疗法的发展。本研究从药物代谢、药物清除率、激素作用和免疫抑制作用等方面对目前与ICIs相关的药代动力学方面和影响临床疗效的因素进行了描述。
{"title":"A Review of the Pharmacokinetic Characteristics of Immune Checkpoint Inhibitors and Their Clinical Impact Factors.","authors":"Jun-Chen Liu,&nbsp;Hong-Jing Yu","doi":"10.2147/PGPM.S391756","DOIUrl":"https://doi.org/10.2147/PGPM.S391756","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) have been shown to be significant in improving the overall survival rate in certain malignancies with poor prognoses. However, only 20-40% of patients achieve long-term benefits, highlighting the relevance of the factors that influence the treatment, which can help clinicians improve their results and guide the development of new immune checkpoint therapies. In this study, the current pharmacokinetic aspects associated with the ICIs and the factors influencing clinical efficacy were characterised, including in terms of drug metabolism, drug clearance, hormonal effects and immunosuppressive effects.</p>","PeriodicalId":56015,"journal":{"name":"Pharmacogenomics & Personalized Medicine","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/33/44/pgpm-16-29.PMC9880024.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10591018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Acute Myeloid Leukemia Secondary to Chronic Lymphocytic Leukemia After Prolonged Chlorambucil Therapy: A Case Report. 长期氯霉素治疗后继发于慢性淋巴细胞白血病的急性髓性白血病一例报告。
IF 1.9 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S407940
Yan Wu, Shan Liu, Dongmei Wang, Xinjie Yao

Background: This study aimed to improve the understanding of acute myeloid leukemia (AML) secondary to chronic lymphocytic leukemia (CLL), and to explore the sequence of occurrence and clonal origin of the two diseases.

Case report: We reported a case of a 71-year-old man with a history of CLL. The patient was administrated with chlorambucil for 19 years and was admitted to our hospital due to fever. Then he was subjected with routine blood tests, bone marrow smear examination, flow cytometric immunophenotyping and cytogenetic analysis. A final diagnosis of AML-M2 secondary to CLL with -Y,del(4q),del(5q),-7,add(12p),der(17),der(18),-22,+mar was made. After rejecting the therapy with Azacitidine combined with B-cell lymphoma-2 (Bcl-2) inhibitor, the patient died of pulmonary infection.

Conclusion: This case highlights the rare occurrence of AML secondary to CLL after prolonged chlorambucil therapy and the poor prognosis of such cases, underscoring the importance of enhanced assessment of these patients.

背景:本研究旨在提高对继发于慢性淋巴细胞白血病(CLL)的急性髓系白血病(AML)的认识,探讨两种疾病的发生序列和克隆起源。病例报告:我们报告了一例71岁男性CLL病史。患者用药氯苯19年,因发热入院。然后进行血常规、骨髓涂片检查、流式细胞术免疫表型和细胞遗传学分析。最终诊断继发于CLL的AML-M2为-Y、del(4q)、del(5q)、-7、add(12p)、der(17)、der(18)、-22、+mar。在拒绝阿扎胞苷联合b细胞淋巴瘤-2 (Bcl-2)抑制剂治疗后,患者死于肺部感染。结论:本病例突出了氯霉素长期治疗后继发于CLL的AML发生率较低,且预后较差,强调了加强对这类患者评估的重要性。
{"title":"Acute Myeloid Leukemia Secondary to Chronic Lymphocytic Leukemia After Prolonged Chlorambucil Therapy: A Case Report.","authors":"Yan Wu,&nbsp;Shan Liu,&nbsp;Dongmei Wang,&nbsp;Xinjie Yao","doi":"10.2147/PGPM.S407940","DOIUrl":"https://doi.org/10.2147/PGPM.S407940","url":null,"abstract":"<p><strong>Background: </strong>This study aimed to improve the understanding of acute myeloid leukemia (AML) secondary to chronic lymphocytic leukemia (CLL), and to explore the sequence of occurrence and clonal origin of the two diseases.</p><p><strong>Case report: </strong>We reported a case of a 71-year-old man with a history of CLL. The patient was administrated with chlorambucil for 19 years and was admitted to our hospital due to fever. Then he was subjected with routine blood tests, bone marrow smear examination, flow cytometric immunophenotyping and cytogenetic analysis. A final diagnosis of AML-M2 secondary to CLL with -Y,del(4q),del(5q),-7,add(12p),der(17),der(18),-22,+mar was made. After rejecting the therapy with Azacitidine combined with B-cell lymphoma-2 (Bcl-2) inhibitor, the patient died of pulmonary infection.</p><p><strong>Conclusion: </strong>This case highlights the rare occurrence of AML secondary to CLL after prolonged chlorambucil therapy and the poor prognosis of such cases, underscoring the importance of enhanced assessment of these patients.</p>","PeriodicalId":56015,"journal":{"name":"Pharmacogenomics & Personalized Medicine","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/61/7e/pgpm-16-401.PMC10150764.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9416257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genetic Variants of CYP4F2 Associated with Ischemic Stroke Susceptibility in the Han Population from Southern China. 华南汉族人群CYP4F2基因变异与缺血性卒中易感性相关
IF 1.9 4区 医学 Q3 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2023-01-01 DOI: 10.2147/PGPM.S413632
Kang Huang, Tianyi Ma, Qiang Li, Yilei Zhou, Ting Qin, Zanrui Zhong, Shilin Tang, Wei Zhang, Jianghua Zhong, Shijuan Lu

Background: The pathophysiological mechanism of ischemic stroke is complex. Traditional risk factors cannot fully or only partially explain the occurrence and development of IS. Genetic factors are getting more and more attention. Our study aimed to explore the association between CYP4F2 gene polymorphism and susceptibility to IS.

Methods: A total of 1322 volunteers were enrolled to perform an association analysis through SNPStats online software. Using FPRP (false-positive report probability) to detect whether the result is a noteworthy finding. The interaction of SNP-SNP in IS risk was assessed by multi-factor dimensionality reduction. Statistical analysis of this study was mainly completed by SPSS 22.0 software.

Results: Mutant allele "A" (OR = 1.24) and genotype "AA" (OR = 1.49) or "GA" (OR = 1.26) of CYP4F2-rs2108622 are risk genetic factors for IS. Rs2108622 is significantly associated with an increased risk of IS among subjects who are females, aging >60 years old, with BMI ≥24 kg/m2, and smoking or drinking volunteers. CYP4F2-rs3093106 and -rs3093105 are associated with susceptibility to IS among smoking, drinking subjects, or IS patients complicated with hypertension.

Conclusion: CYP4F2-rs2108622, -rs3093106, and -rs3093105 are associated with an increased risk of IS.

背景:缺血性脑卒中的病理生理机制复杂。传统的危险因素不能完全或部分解释IS的发生和发展。遗传因素越来越受到人们的重视。我们的研究旨在探讨CYP4F2基因多态性与IS易感性之间的关系。方法:通过SNPStats在线软件对1322名志愿者进行关联分析。使用FPRP(假阳性报告概率)来检测结果是否值得注意。通过多因素降维评估SNP-SNP在IS风险中的相互作用。本研究的统计分析主要通过SPSS 22.0软件完成。结果:CYP4F2-rs2108622突变等位基因A (OR = 1.24)和基因型AA (OR = 1.49)、GA (OR = 1.26)是IS的危险遗传因素。Rs2108622在年龄>60岁、BMI≥24 kg/m2、吸烟或饮酒的女性受试者中与is风险增加显著相关。CYP4F2-rs3093106和-rs3093105与吸烟、饮酒或IS合并高血压患者的IS易感性相关。结论:CYP4F2-rs2108622、-rs3093106和-rs3093105与IS风险增加相关。
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Pharmacogenomics & Personalized Medicine
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