464例广西人群miR-365基因rs30230C/T遗传多态性研究

目的 研究miR-365基因rs30230C/T位点多态性在广西人群的分布特征,并在不同种族人群比较其位点基因型和基因频率的分布差异。方法 选用SNPscan分型技术,对464名广西健康体检者miR-365基因rs30230C/T位点的基因型进行检测,并与千人基因组计划(Hapmap)公布的北京汉族人群(CHB)、欧洲人群(CEU)、日本人群(JPT)和非洲尼日利亚人群(YRI)miR-365基因多态性数据进行比较。结果 rs30230C/T位点的基因型遵循Hardy-Weinberg遗传平衡定律,样本人群具有代表性意义。rs30230C/T位点存在CC、TC、TT 3种基因型。在广西人群中,miR-365基因rs30230C/T位点存在CC(63.1%)、TC(32.3%)、TT(4.5%)3种基因型;C、T的等位基因频率分别为79.3%、20.7%。该位点的各基因型及等位基因频率分别在男女组间差异无统计学意义(χ²=1.423、1.385,P>0.05)。广西人群中的rs30230C/T位点基因型与NCBI(https：//www.ncbi.nlm.ni...     

广西人群miR-30基因rs16827546 C/T和rs10095483 A/C多态性分布特征及其与血脂水平的关系

目的 探讨miR-30基因单核苷酸多态性(SNP)位点rs16827546 C/T和rs10095483 A/C在广西人群中的分布特点,比较其与其他人群的多态性差异,并统计分析不同基因型的常见血脂检测项目水平。方法 SNPscan法对289例研究对象rs16827546 C/T和rs10095483 A/C位点进行分型,用罗氏全自动生化仪检测研究对象的常见血脂水平。结果 在广西人群中rs16827546 C/T位点存在CC、CT两种基因型;rs10095483 A/C位点存在AA、AC两种基因型。广西人群两位点基因型和等位基因频率与HanpMap计划公布的欧洲人(CEU)、约鲁巴人(YRI)、意大利人(TSI)比较,差异有统计学意义(P<0.05);广西人群rs16827546基因型和等位基因频率与与日本人(JPT)比较,差异有统计学意义(P<0.05);广西人群两位点基因型和等位基因频率与北京汉族人(HCB)比较,差异无统计学意义(P>0.05)。广西人群rs16827546 C/T位点两种基因型血脂之间比较,携带CT基因型的TC和LDL-C与携带CC基因型组比较,...     

广西壮族及汉族人群CD40配体基因rs7050168G/A遗传多态性

目的 研究CD40配体基因rs7050168G/A位点多态性在广西壮族及汉族人群中的分布,同时比较其在不同种族人群间以及同一种族不同性别之间,基因型和等位基因频率分布的差异.方法 采用单碱基延伸PCR (PCR-SBE)的方法,分析201名广西汉族人和199名广西壮族人的CD40配体基因rs7050168G/A多态性. 结果 CD40配体基因rs7050168G/A位点表现出AA、AG和GG三种基因型,其在壮族人中的频率分别为97.0％、1.5％和1.5％,而在汉族人中频率分别为98.0％、1.0％和1.0％.CD40配体基因多态性在在广西壮族和汉族人群之间比较差异都没有显著性(P均＞0.05).进一步将广西汉族人群分型数据同人类基因组计划公布的4个人群相比,我们发现在广西汉族人群中CD40配体基因rs7050168G/A位点基因型和等位基因频率与日本和北京人群比较,差异均具有显著性(P均＜0.05),但与欧洲和非洲人群比较,差异没有显著性(P均＞0.05).结论 在广西地区壮族及汉族人群中存在着CD40配体基因多态性,其基因多态性的分布频率没有显著性的差异,但与其他种族人群比较存在着显著差异.这种差异可能是导致一部分疾病在不同种族人群之间的临床表现以及发病率存在显著不同的因素之一.     

LSM1基因多态性与江苏地区汉族人精神分裂症的关联性研究

目的探讨LSM1基因多态性与江苏地区汉族人精神分裂症的关联性。方法用连接酶检测反应PCR(LDR-PCR)单核苷酸多态性(SNP)分型技术对506例精神分裂症患者和522例健康对照者LSM1基因rs16887244、rs2843738、rs2843746 3个标签单核苷酸多态性(tgSNP)进行基因分型,比较各组间等位基因、基因型分布频率。结果与健康对照组比较,精神分裂症组rs16887244等位基因分布频率差异不显著(OR=0.992,P=0.935);rs2843738和rs2843746等位基因分布频率也无显著差异(OR分别为1.036,1.013,P均>0.05);rs16887244基因型(AA/AG/GG)、rs2843738基因型(CC/CG/GG)和rs2843746基因型(CC/CT/TT)分布频率均无显著差异(χ2分别为0.511,0.147,5.981,P均>0.05)。结论江苏地区汉族精神分裂症患者与LSM1基因rs16887244、rs2843738、rs2843746多态性不相关。     

广西百色人群miR-210基因rs7935908C/T位点遗传多态性

目的分析miR-210基因rs7935908C/T位点单核苷酸多态性(SNP)在广西百色地区健康人群中的分布特点,并对比其基因型和等位基因频率在不同种族人群间的分布差异。方法收集298例广西百色地区体检健康者的外周血标本,采用SNa Pshot SNP分型技术和DNA测序法检测miR-210基因rs7935908C/T位点多态性。统计该位点的基因型和等位基因的分布频率,并结合国际人类基因组单体型图(HapMap)计划公布的SNP分型数据进行不同种族间的比较分析。结果广西百色地区健康人群中miR-210基因rs7935908C/T位点存在CC、CT和TT 3种基因型,频率分别为10.1%、44.6%、45.3%; C、T等位基因频率分别为32.4%、67.6%。该位点的基因型和等位基因频率在广西百色地区健康人群的不同性别间比较差异均无统计学意义(分别为P=0.185和P=0.590)。其基因型频率与HapMap计划公布的北京汉族人群、日本人群、非洲人群、墨西哥人群及意大利人群分型数据比较,差异均有统计学意义(分别为P0.001、P=0.025、P0.001、P0.001及P=0.009);与欧洲人群和丹佛市华人比较,差异均无统计学意义(分别为P=0.065和P=0.735)。其等位基因频率与欧洲人群、非洲人群、墨西哥人群及意大利人群比较,差异均有统计学意义(分别为P=0.040、P0.001、P0.001及P=0.003);与北京汉族人群、丹佛市华人、日本人群比较,差异均无统计学意义分别为(分别为P=0.411、P=0.451及P=0.755)。结论广西百色地区人群miR-210基因rs7935908C/T位点存在遗传多态性,其基因多态性的分布与其他种族、地区人群比较存在不同程度的差异。     

IRF6和RARA基因多态性与非综合征性唇腭裂的相关性研究

目的探讨干扰素调节因子-6(IRF6)基因rs2235371位点和视黄酸受体-α(RARA)基因rs2229773位点单核苷酸多态性(SNP)与非综合征性唇腭裂的关系,以及2个位点在患者和健康者之间的基因型和等位基因型频率差异。方法选取153例非综合征性唇腭裂(NSCL/P)患者作为NSCL/P组,体检健康者150例作为健康对照组。运用聚合酶链式反应-限制性片段长度多态性(PCR-RELF)技术,分析IRF6、RARA基因的多态性,比较2组研究对象基因型和等位基因型频率差异。结果 IRF6基因rs2235371位点基因型CC、TT和等位基因C、T频率在NSCL/P组和健康对照组的分布,差异有统计学意义(P0.05),NSCL/P组等位基因C频率高于健康对照组,差异有统计学意义(P0.05)。RARA基因rs2229773位点基因型CT、TT频率在NSCL/P组和健康对照组的分布,差异有统计学意义(P0.05),NSCL/P组基因型为CT杂合子,显著多于健康对照组,差异有统计学意义(P0.05)。结论 NSCL/P与IRF6基因rs2235371位点等位基因C及RARA基因rs2229773位点CT基因型具有相关性。     

广西壮族及汉族人群CD40基因rs4810485 G/T遗传多态性

目的 研究CD40基因rs4810485 G/T多态性各等位基因及基因型在广西地区壮族及汉族人群中的分布频率,比较其在不同种族间分布的差异. 方法 采用单碱基延伸的PCR技术和DNA测序法检测195例壮族人和200例汉族人的CD40基因rs4810485 G/T多态性,比较两组CD40基因型及等位基因的分布频率;并结合文献进行不同种族间的比较分析. 结果 在壮族人中GG基因型占24.1％、GT基因型占49.2％、Tr基因型占26.7％;在汉族人中GG基因型占30.0％、GT基因型占47.0％、Tr基因型占23.0％.在广西壮族及汉族人群中CD40基因多态性的分布频率差异均无显著性(P＞0.05),但与波兰人、英国人及西班牙人比较,CD40基因多态性的分布频率均存在显著性差异(P＜0.05). 结论 在广西地区壮族及汉族人群中存在CD40基因多态性,其基因多态性的分布频率差异无显著性,但与其他种族人群比较存在显著性差异.这种差异对于人类学的研究可能起重要的作用.     

中国广西人群P-选择素基因rs6131 C/T多态性的研究

目的研究P-选择素基因单核苷酸多态性rs6131C/T等位基因及其基因型在中国广西地区人群中的分布频率,并比较其与不同种族间分布的差异。方法采用单碱基延伸PCR扩增技术和DNA测序检测199例中国广西人群的P-选择素基因rs6131C/T多态性,并与人类基因组计划（HapMap）公布的欧洲人、非洲人、日本人和中国北京人的SNP分型数据比较,分析这5个人群的基因型及等位基因的分布频率。结果 P-选择素基因rs6131C/T存在多态性,其基因型及等位基因频率男女组间比较无统计学意义（P〉0.05）,但与非洲人、日本人比较存在显著性差异（P〈0.05）,与欧洲人和北京人比较差异无统计学意义（P〉0.05）。结论在中国广西人群中P-选择素基因rs6131C/T存在多态性,与其他种族人群比较存在差异,这种差异对于人类学的研究可能起重要的作用。     

吉林省地区汉族和朝鲜族健康人群ACE基因多态性分布的研究

目的 分析我国吉林省地区朝鲜族和汉族人群血管紧张素转换酶(angiotersin converting enzyme,ACE)基因多态性的分布.方法 应用聚合酶链反应(polymerase chain reaction,PCR)等技术检测81名健康汉族和96名朝鲜族ACE基因插入/缺失(I/D)多态性及其分布.结果 汉族人群Ⅱ型、ID型和DD型频率分别为34.38%,28.12%和37.50%;朝鲜族人群分别为38.27%,19.75%和41.98%,两组ACE基因基因型的分布差异无显著性(P=0.433);汉族Ⅰ等位基因总数为78,D等位基因总数为84,朝鲜族Ⅰ等位基因总数为93,D等位基因总数为99,两组等位基因的分布差异亦没有显著性(P=0.957).结论 中国吉林省地区朝鲜族和汉族健康人群中ACE基因I/D多态性及等位基因型的分布没有明显差异.     

广西百色地区壮族人群红细胞补体受体I型基因遗传多态性研究

目的探讨红细胞补体受体I型(CR1)基因单核苷酸多态性(SNP)在广西百色地区壮族人群中的分布频率以及其在不同种族间分布的差异。方法用TaqMan荧光探针定量PCR和DNA测序技术检测503例壮族人群CR1基因rs2296160 C/T、rs2274567 G/A和rs4844600 G/A位点,并结合人类基因组计划公布的欧洲人、非洲人、日本人和北京人群的SNP分型数据,比较分析各人群的基因型及等位基因的分布频率。结果广西壮族人群中CR1基因rs2296160 C/T、rs2274567 G/A和rs4844600 G/A位点存在多态性,3个位点基因型频率在男女性别间比较,P分别为0.591、0.293和0.525;而等位基因分布频率在男女性别间比较,P分别为0.310、0.122和0.268,差异均无统计学意义(P0.05)。rs2296160 C/T、rs2274567 G/A和rs4844600 G/A 3个位点的基因型和等位基因分布频率与欧洲和非洲人群比较,差异均有统计学意义(P均0.05);而与日本人及北京人比较,差异无统计学意义(P0.05)。结论广西百色地区壮族人群中存在CR1基因多态性,与欧洲及非洲人群比较存在显著性差异,为人类学及群体遗传学研究提供了实验数据。     

Pharmacokinetic studies of 5-fluorouracil and 5'-deoxy-5-fluorouridine in rats

The pharmacokinetics of 5-fluorouracil (FU) and its metabolic prodrug, 5'-deoxy-5-fluorouridine (dFUR), were investigated in 5- to 9-month-old rats without tumors. Intravenous bolus injections and infusions of FU (25-35 mg X kg-1) and dFUR (500-750 mg X kg-1) had activity against transplanted colon tumors in 2- to 4-month-old rats. Blood and plasma concentrations of FU and dFUR were analyzed by high-pressure liquid chromatography using 5-bromouracil as the internal standard. Free fractions of these drugs in plasma were indistinguishable from unity, indicating little or no protein binding. The area under the blood concentration-time profiles and the steady-state concentrations of unchanged dFUR were 40- to 100-fold higher than those of unchanged FU. The respective blood clearances of FU and dFUR were 44 and 18 ml X kg-1 X min-1 after i.v. bolus injections, which were significantly lower than the 108 and 26 ml X kg-1 X min-1 after infusion. FU clearance decreased when its infusion rate was increased from 25 to 50 mg X kg-1 X day-1. Renal clearances of both drugs remained the same after either route of administration. These data suggest that both drugs were eliminated by nonlinear kinetics and that their metabolism was saturated at a more rapid administration rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of C5a-C5aR interaction in sepsis

C5a-C5aR signaling plays an essential role in innate immunity of neutrophils. However, excessive interaction of C5a-C5aR results in harmful effects in these cells. In sepsis, robust generation of C5a occurs; blockade of either C5a or C5aR greatly improves survival in experimental sepsis following cecal ligation and puncture (CLP). The beneficial effects derived from C5a-C5aR interaction are associated with preservation of neutrophil innate immune functions (chemotaxis, phagocytosis, respiratory burst), attenuation of the inflammatory reaction, amelioration of coagulopathy, alteration in adhesion molecule expression, and modulation of apoptosis. Following CLP, C5aR expression is significantly elevated in organs, perhaps setting the stage for C5a-induced organ dysfunction. In contrast, C5aR content on neutrophils drops significantly at early stages of sepsis and progressively increases at later time points. Re-expression of C5aR on neutrophils during sepsis appears to be associated with the functional recovery of neutrophil innate immune functions. Following CLP, there is a positive correlation between C5aR content on blood neutrophils and survival of individual animals; high levels of C5aR on neutrophils are associated with survival, whereas low levels of C5aR on neutrophils predict mortality. These data suggest that in sepsis C5a-C5aR signaling is excessive, resulting in paralysis of neutrophil function. Interception of either C5a or C5aR dramatically improves survival during experimental sepsis.     

Evidence for Conversion of 5-Fluorocytosine to 5-Fluorouracil in Humans: Possible Factor in 5-Fluorocytosine Clinical Toxicity

A gas chromatographic-mass spectrometric method for detecting 5-fluorouracil (5-FU) in serum at concentrations as low as 10 ng/ml was used to determine to what extent 5-FU was present in the serum of patients taking oral 5-fluorocytosine (5-FC). Preliminary studies in two patients and two healthy volunteers given an initial 2-g oral dose of 5-FC demonstrated sustained serum 5-FU levels (>100 ng/ml) during the 5 h after ingestion of drug. Pharmaceutical preparations of 5-FC used in these studies were shown to be insignificantly contaminated with 5-FU (<0.03%), suggesting in vivo conversion of 5-FC to 5-FU had occurred. Serum samples from seven patients with cryptococcal meningitis treated with amphotericin B and 5-FC were examined for 5-FU. Five of these patients had experienced hematological or other toxicity attributed to 5-FC at some time during the course of therapy. Of 41 serum samples, 20 were observed to have 5-FU levels greater than 1,000 ng/ml in the range observed with cancer chemotherapeutic doses of 5-FU known to be associated with hematological toxicity. It is concluded that conversion of 5-FC to 5-FU occurs in humans and furthermore that 5-FU may account for some of the toxicity observed with 5-FC.     

On the mechanism of 5-oxoproline overproduction in 5-oxoprolinuria.

The primary metabolic defect in 5-oxoprolinuria (pyroglutamic aciduria) is the lack of glutathione synthetase. The mechanism of the concomitant overproduction of 5-oxoproline was studied using cell-free extracts of erythrocytes from control individuals and from patients with 5-oxoprolinuria. Such extracts catalyzed the synthesis of 5-oxoproline from L-glutamate. Addition of ATP, Mg ions and alpha-aminobutyrate was needed for optimal activity. The conversion of glutamate to 5-oxoproline occurred in two steps, catalyzed by gamma-glutamyl-cysteine synthetase and gamma-glutamyl cyclotransferase, respectively. Extracts of erythrocytes from control subjects and patients with 5-oxoprolinuria had identical capacity to synthesize 5-oxoproline. The conversion of glutamate to 5-oxoproline was markedly inhibited by reduced glutathione, which exerted its effect on the gamma-glutamyl-cysteine synthetase step. The following mechanism is postulated for the overproduction of 5-oxoproline in 5-oxoprolinuria: the deficiency of glutathione synthetase causes a lack of glutathione which is an essential feed-back inhibitor in the initial step of its biosynthesis. Therefore gamma-glutamyl-cysteine is produced in excessive amounts and it is subsequently converted to 5-oxoproline (and cysteine) by gamma-glutamyl cyclotransferase. This overproduction of 5-oxoproline exceeds the capacity of the 5-oxoprolinase and 5-oxoproline accumulates in body fluids.     

C5aR与C5L2在脓毒症中的作用

脓毒症时补体系统过度激活产生大量过敏毒素C5a,C5a与其受体相互作用在脓毒症的发生过程中十分重要,成为研究脓毒症发生机制中的一个新热点.     

细胞周期素依赖性激酶-5研究进展

细胞周期素依赖性激酶 5属于小丝氨酸 /苏氨酸周期素依赖性激酶家族成员 ,虽与其他成员序列具有同源性 ,但功能却完全不一样 ,即与细胞周期关系不大 ,却在中枢神经系统的发育和神经元正常功能的维持中发挥重要作用 ,并与一些退行性疾病及药物成瘾有密切联系 ,是神经系统中重要的蛋白激酶之一 ,可能成为防治中枢神经系统疾病的靶分子。现就细胞周期素依赖性激酶 5的一些最新研究进展进行综述     

5-Hydroxytryptamine 5-HT2A receptor and 5-hydroxytryptamine transporter polymorphisms in acute myocardial infarction

This study was designed to analyse possible associations between DNA polymorphisms in the 5-hydroxytryptamine (5-HT; serotonin) 5-HT(2A) receptor and the 5-HT transporter (5-HTT) genes, and myocardial infarction (MI). 5-HT has been shown to be involved in cardiovascular pathophysiology. In addition to platelet aggregation and vascular contraction, 5-HT induces hyperplasia of artery smooth muscle cells. Recently, a 5-HT transporter gene polymorphism has been associated with MI. To determine the influence of genetic variation at the 5-HT(2A) receptor (T102C polymorphism) and the 5-HTT (insertion/deletion polymorphism) on the risk of developing early MI, we genotyped 210 MI patients of < 55 years old and 238 healthy control subjects for DNA polymorphisms in these genes. In addition, we genotyped 95 patients with late-onset MI (> 60 years old) to analyse the effects of these polymorphisms on the age at which the first MI episode occurred. The 5-HT(2A) receptor polymorphism was not associated with MI in our population. In addition, since the 5-HT(2A) receptor gene and genotype frequencies did not differ between patients with early and late onset of MI, this polymorphism does not appear to have an effect on age at the first MI episode. Gene and genotype frequencies for the 5-HTT promoter did not differ between patients < 55 years old and healthy controls (independent of smoking status). However, homozygotes for the deletion (the ss genotype, where s denotes the short allele) were present at a significantly higher frequency in patients >60 years old compared with patients < 55 years old (P = 0.009; P = 0.004 when only smokers were compared). According to our data, the ss genotype would seem to have a protective role against MI, delaying the age of onset of the first episode, especially among smokers. This could be a consequence of the lower 5-HTT levels linked to the s allele, so that individuals homozygous for the ss genotype may have lower 5-HT re-uptake by platelets.     

The role of 5-hydroxytryptamine (5-HT) receptor subtypes and plasticity in the 5-HT systems in the regulation of nociceptive sensitivity

This review shows that the role of 5-hydroxytryptamine (5-HT) in the regulation of nociception depends on the 5-HT receptor subtypes involved and on long-term functional changes in the 5-HT receptors. Stimulation of the 5-HT₁ receptors, as well as of the 5-HT₂ and 5-HT₃ receptors, may reduce nociceptive sensitivity. In addition, activation of 5-HT₂ and 5-HT₃ receptors may also enhance nociceptive sensitivity. Up- or down-regulation of the 5-HT receptors may result in long-lasting changes, plasticity, in the 5-HT systems. Lesioning of 5-HT neurons induces denervation supersensitivity to 5-HT, and prolonged stimulation of 5-HT receptors may produce subsensitivity to 5-HT. In the spinal cord denervation supersensitivity to 5-HT may depend on reduced release of substance P (SP). An increase in the release of SP, on the other hand, may reduce the effects of 5-HT receptor activation. Long-term treatment with antidepressants which are used in clinical pain therapy appears to up-regulate the 5-HT₁ receptors and to down-regulate the 5-HT₂ receptors.     

Radioimmunoassay of 5-methoxytryptophol in plasma

5-Methoxytryptophol (ML) is synthesized by the pineal gland, but no radioimmunoassay has been described for its routine measurement in human plasma. We have developed and validated such an RIA. The assay is sensitive (detecting as little as 8 ng/L) and specific, and requires no extraction stage. A preliminary study of healthy volunteers showed an intra-individual variation in plasma ML that was independent of the sex of the subject and the time of daytime collection. Investigation of the 24-h pattern of ML in seven men revealed a low-amplitude daily rhythm (P less than 0.03). Mean concentrations of ML between noon and midnight significantly exceeded those between 0030 and 1130 hours in each individual (P less than 0.05). This assay is practical and convenient, and it should greatly assist in investigation of factors affecting concentrations of ML in human plasma.     

Role of MetMAb (OA-5D5) in c-MET active lung malignancies

Introduction: MetMAb (OA-5D5) is a one-armed monoclonal antibody developed to bind to and inhibit c-MET receptor tyrosine kinase. Though only in early clinical testing, this agent holds great promise in diseases thought to be driven by c-MET activation, as evidenced by the Phase II results in NSCLC where a benefit in overall survival was observed in patients with MET-diagnostic-positive disease. Thus far, both alone and in combination with other targeted agents, this drug has been well tolerated and no new significant safety signals have been identified.

Areas covered: This review summarizes the structure and function of the c-MET receptor and its ligand hepatic growth factor (HGF), provides an overview of select targeted monotherapies developed to interfere in the MET–HGF signaling pathway, discusses pre-clinical and clinical data surrounding MetMAb, and concludes with an expert opinion regarding this novel agent.

Expert opinion: MetMAb has been well tolerated and based on Phase II data testing it, in combination with erlotinib in advanced NSCLC, may have a role in improving survival in patients with disease driven by c-MET activation. However, Phase III validation is underway and the results of these studies will help elucidate which patients will benefit most from this novel agent.