肯尼迪病的临床分析及分子遗传学诊断

目的 本文通过5例经基因检测明确诊断的肯尼迪病（Kennedy＇s disease,KD）患者,探讨KD的临床表现和辅助检查特点及诊断.方法 收集5例疑似KD患者的详细病史、体格检查、血液生化、肌电图和肌肉病理等资料,用PCR扩增并测序方法测定雄性激素受体（AR）基因1号外显子CAG的重复序列拷贝数.结果 KD主要临床表现是四肢肌肉萎缩、无力和肢体震颤,舌肌萎缩和构音障碍；部分患者出现内分泌症状和肌酸激酶（CK）增高.肌电图可见广泛神经源性损害和感觉神经传导速度下降.肌肉病理为神经性损害.患者AR基因CAG重复序列的重复次数为48 ～ 58次.结论 KD有相对独特的临床、电生理及病理特征,确诊有赖于AR基因的（CAG）n拷贝数的检测.     

乙醛脱氢酶1与乳腺癌的分子亚型和临床病理特征的相关性

目的：探讨乙醛脱氢酶1（ALDH1）在乳腺癌中的表达及其与乳腺癌分子亚型和临床病理特征的相关性。方法应用免疫组织化学方法检测和比较20例乳腺癌癌旁正常乳腺组织、20例良性乳腺肿瘤组织及80例乳腺浸润性导管癌组织（Luminal A型、Luminal B型、Her-2过表达型、Basal-like型各20例）中ALDH1的表达情况,统计分析乳腺癌组织中ALDH1的表达与其分子亚型和临床病理特征的相关性。结果在20例乳腺癌癌旁正常乳腺组织及20例良性乳腺肿瘤组织中,ALDH1均呈阴性表达;80例乳腺浸润性导管癌组织中,ALDH1呈阳性表达者17例（21.25％）,阳性表达率显著高于乳腺癌癌旁正常乳腺组织及良性乳腺肿瘤组织（P0.007）。ALDH1的阳性表达与乳腺癌患者的年龄、肿瘤大小、临床分期、淋巴结转移、CK5/6、TopⅡ、Ki-67表达均无关,与ER、PR状态具有显著相关性（P〈0.01）。结论乳腺癌组织中,ALDH1呈阳性表达,与乳腺癌的发生和分子分型有关,可能有助于乳腺癌的诊断、分型及预后预测。     

肝癌患者雄激素受体表达与临床病理的相关性

应用放射配体结合分析法测定３６例手术切除的肝癌组织、癌周组织及外周血白细胞雄激素受体的含量，同时用放射免疫法测定肝癌患者及正常人血浆雄激素的水平。结果：癌组织雄激素受体含量１２０８±２８９ｆｍｏｌ／ｍｇ蛋白，高于癌周组织的７２７±２８３ｆｍｏｌ／ｍｇ蛋白（Ｐ＜００１），且与癌肿的直径及分化程度明显相关，直径越大、分化程度越高ＡＲ含量越高。肝癌患者血浆雄激素水平为６６３±３２６ｎｍｏｌ／Ｌ，略高于对照组的５５６±２７３ｎｍｏｌ／Ｌ；白细胞雄激素受体表达为１１１６±６８位点／细胞。比对照组的６５９±３２位点／细胞明显升高（Ｐ＜００１）。结果提示：肝癌患者癌组织中雄激素受体含量升高，与肿瘤的大小及分化程度相关。     

雄激素受体基因动态突变及线粒体基因分析诊断Kennedy病1例报告

目的通过对一例肌肉活检提示线粒体肌病的患者进行雄激素受体基因（androgen receptor gene,AR）进行动态突变分析和全线粒体（mtDNA）基因扫描明确诊断。方法使用PCR方法分析患者雄激素受体（androgen receptor gene,AR）基因的CAG重复序列数,使用Touch Down PCR方法分析患者全线粒体基因突变。结果该患者雄激素受体基因第一个外显子（Xqll-12）上存在46个三核普酸（CAG）重复,确诊Kennedy病。全线粒体（mtDNA）基因分析未显示线粒体疾病的相关致病突变。结论AR基因CAG动态突变分析和全mtDNA基因扫描是KD与线粒体脑肌病鉴别诊断或KD并发线粒体脑肌病诊断的重要依据。     

Pfeiffer综合征 1例遗传学与临床特征

目的 探讨Pfeiffer综合征的临床表现与遗传学特征.方法 2017年11月深圳市龙岗区妇幼保健院发现1例Pfeiffer综合征病儿,通过其临床表现,影像学检查及基因检测分析其临床特征.结果 病儿主诉胎龄35+2周,生后发现畸形20 min.出生即有典型的三叶草头颅及突眼、高腭弓、颈短、低耳位、外耳道闭锁等头面部畸形,以及其他骨骼发育异常表现,如肘关节强直、粗大倾斜的大拇指及大脚趾、尾椎骨外翻等畸形表现,通过基因检测分析,发现成纤维细胞生长因子受体2(FGFR2)基因变异,确诊为Pfeiffer综合征Ⅱ型.结论 Pfeiffer综合征是一种罕见的常染色体显性遗传病,通过病儿典型的临床特征及FGFR2基因突变最终确诊.     

miR-34a通过调控雄激素受体基因抑制前列腺癌细胞系LNCaP增殖

目的:探究miR-34a对雄激素受体(AR)基因的调控作用及对前列腺癌(PCa)LNCaP细胞增殖、凋亡的影响。方法:收集2016年10月至2019年9月本院泌尿外科行前列腺穿刺活检确诊为PCa患者组织标本36例,另取同期行手术治疗切除的良性前列腺增生(BPH)组织标本41例。体外培养LNCaP细胞,分别转染miR-34a mimics(mimics组),miR-34a mimic NC(NC组),设正常生长细胞为空白对照组(BC组),另在mimics组基础上转染AR过表达(AR过表达组)载体及其对照(AR对照组),采用CCK-8试剂盒检测细胞活性,Annexin V-FITC/PI双染色流式细胞凋亡检测试剂盒检测细胞凋亡率,实时定量PCR(RT-qPCR)检测miR-34a及AR mRNA表达水平,免疫印迹法检测AR蛋白、细胞周期蛋白D1(cyclinD1)及原癌基因产物(c-Mcy)、细胞凋亡相关蛋白(Bcl-2、Bax、capase-3)的表达水平。结果:与BPH组织比较,PCa组织中miR-34a表达水平显著降低(P<0.05),AR mRNA及蛋白表达水平均显著增加(P<0.05);与BC、NC组比较,mimics组LNCap细胞miR-34a表达水平、细胞凋亡率、Bax蛋白表达水平显著增加(P<0.05),AR、Cyclin D1、Bcl-2、Bax蛋白表达水平显著降低(P<0.05),同一时间LNCap细胞活力均显著降低(P<0.05);双荧光素酶实验结果显示,miR-34a与AR可能存在一定的调控关系,过表达AR基因可逆转miR-34a mimics对LNCaP细胞增殖抑制,促进凋亡作用。结论:miR-34a可能通过调控AR抑制前列腺癌LNCaP细胞增殖,促进其凋亡。     

雄激素受体基因第一外显子微卫星多态性与多囊卵巢综合征的相关性研究

目的:研究雄激素受体(AR)基因第一外显子微卫星多态性与多囊卵巢综合征(PCOS)发病的相关性.方法:采用聚合酶链反应(PCR)及变性聚丙烯酰胺凝胶电泳分离DNA片段的方法,检测了64例PCOS患者和58例正常对照者的AR基因第一外显子微卫星多态性.结果:①共有28个AR-CAG等位基因,其范围在PCOS组是11～36(CAG)s,在对照组是12～31(CAG)s;②在PCOS组,长等位基因、短等位基因及双等位基因的(CAG)s平均数与对照组相比,差异均无统计学意义.结论:AR基因第一外显子微卫星多态性与PCOS的发病似无直接关系.     

三阴性乳腺癌雄激素受体表达状态与临床病理特征及预后相关性分析

目的 分析三阴性乳腺癌（TNBC）雄激素受体（AR）表达状态与临床病理特征及预后相关性。方法 回顾性选取郑州大学第五附属医院2017年1月至2019年1月收治的TNBC患者108例,对所有患者的组织学标本进行采集与染色处理,分为AR阳性（n=31）与AR阴性（n=77）两个组别,并用统计学方法分析比较其临床基本资料。统计AR的阳性表达情况,分析AR表达状态与临床病理特征及预后的关系。结果 108例患者中AR阳性表达显示阳性者有31例,阳性率为28.7%;所有患者中,AR阳性组患者年龄≥50岁、绝经后状态、Ki-67指数呈现低表达（<14%）、CK5/6阴性以及P53阴性表达的患者占比均高于AR阴性组患者（P <0.05）;AR阳性组较AR阴性组3年的总生存率更高,差异有统计学意义（P <0.05）;而AR阳性组与AR阴性组3年的无病生存率差异无统计学意义（P> 0.05）;本研究中所有患者的病理类型、原发肿瘤大小、身体质量指数（BMI）、组织学分级、淋巴结状态、脉管癌栓、临床分期、表皮生长因子受体（EGFR）状态与AR表达均无显著相关性（P> 0.05）。...     

完全型雄激素不敏感综合征一家系基因诊断并文献复习

摘要：雄激素不敏感综合征（AIS）是由雄激素受体（AR）基因突变引起的罕见的X-连锁隐性遗传病,完全型雄激 素不敏感综合征（CAIS）是AIS中雄激素抵抗程度最严重的一种类型。本文对一个CAIS家系成员AR基因的二代测 序结果进行分析,发现先证者AR基因的第7外显子c.2566C>T发生突变,编码第856位精氨酸的密码子（CGC）改变 为半胱氨酸的密码子（TGC）,从而雄激素与AR受体结合受到影响,生物学效应不能有效发挥,临床表现为CAIS。经 Sanger测序验证,先证者妹妹和母亲也发现相同的突变。先证者和其妹妹为半合子突变,母亲为杂合突变。笔者认 为AR基因c.2566C>T（p.Arg856Cys）突变导致姐妹二人患CAIS,该突变遗传自她们的母亲。明确AR基因突变位点, 可为家系再次生育提供指导。     

Charcot-Marie-Tooth disease: electrophysiology, molecular genetics and clinical management

Over the past decade there has been a huge increase in the understanding of the molecular basis of Charcot-Marie-Tooth disease (CMT). Additionally there has been a better delineation of the neurophysiological deficits and clinical problems associated with CMT. This paper reviews the current molecular basis of CMT and the electrophysiological, clinical and phenotypical characteristics of the various subtypes, followed by a discussion of novel and promising therapeutic interventions that potentially could be used as part of a treatment regimen for CMT. These interventions may involve attempts to slow down or stop neurodegenerative processes through nerve growth factors, limiting oxidative stress by using antioxidants, or normalizing gene expression through genetic manipulation. Other potential therapeutic target areas include the progesterone receptor on myelin-forming Schwann cells, the immune system via modulation of nerve inflammation, and enhancing glutathione transferase activity. While ongoing molecular research continues to identify more of the mutant genes and proteins that cause the various disease subtypes, the focus of clinical research should continue to be on developing pharmaceutical and rehabilitative therapies to reverse nerve degeneration and ultimately improve the functioning of people with CMT.     

Molecular approaches to the treatment, prophylaxis, and diagnosis of Alzheimer's disease: clinical molecular and genetic studies on Alzheimer's disease

Recent advances in clinical molecular and genetic studies on Alzheimer's disease (AD) are summarized here. Cerebrospinal fluid (CSF) Aβ42 and tau are the most sensitive biomarkers for the diagnosis of AD and prediction of its onset following mild cognitive impairment (MCI). Based on this progress, new diagnostic criteria for AD dementia, MCI due to AD, and preclinical AD were proposed by the National Institute of Aging (NIA) and Alzheimer's Association (AA) in April 2011. In these new criteria, progress in CSF biomarker and amyloid imaging studies over the past 10 years has added to critical information. The marked contributions of basic and clinical studies have established clinical evidence supporting these markers. Based on this progress, essential curative therapy for AD is urgently expected.     

多巴丝肼联合多巴胺受体激动剂治疗帕金森病的临床研究

目的探讨多巴丝肼联合多巴胺受体激动剂治疗帕金森病的临床疗效。方法选择本院2011年3月～2012年5月收治的帕金森病患者38例,分为对照组和治疗组,对照组采用多巴丝肼进行治疗,治疗组在对照组的基础上采用多巴胺受体激动剂进行治疗,治疗4个月后,观察两组患者的临床效果。结果两组治疗4个月后,治疗组的Webster评分为（8.11±1.78）分,明显低于对照组的（11.33±3.98）分,两组相比差异有统计学意义（P〈0.05）;治疗组的UPDRS评分为（10.58±6.22）分,亦明显低于对照组的（23.67±7.78）分,两组比较差异有统计学意义（P〈0.05）。结论多巴丝肼联合多巴胺受体激动剂可以有效地改善帕金森患者的自主活动能力,值得在临床上推广。     

Cellular and molecular mechanisms of action of linuron: an antiandrogenic herbicide that produces reproductive malformations in male rats.

Antiandrogenic chemicals alter sex differentiation by several different mechanisms. Some, like flutamide, procymidone, or vinclozolin compete with androgens for the androgen receptor (AR), inhibit AR-DNA binding, and alter androgen-dependent gene expression in vivo and in vitro. Finasteride and some phthalate esters demasculinize male rats by inhibiting fetal androgen synthesis. Linuron, which is a weak competitive inhibitor of AR binding (reported Ki of 100 microM), alters sexual differentiation in an antiandrogenic manner. However, the pattern of malformations more closely resembles that produced by the phthalate esters than by vinclozolin treatment. The present study was designed to determine if linuron acted as an AR antagonist in vitro and in vivo. In vitro, we (1) confirmed the affinity of linuron for the rat AR, and found (2) that linuron binds human AR (hAR), and (3) acts as an hAR antagonist. Linuron competed with an androgen for rat prostatic AR (EC(50) = 100-300 microM) and human AR (hAR) in a COS cell-binding assay (EC(50) = 20 microM). Linuron inhibited dihydrotestosterone (DHT)-hAR induced gene expression in CV-1 and MDA-MB-453-KB2 cells (EC(50) = 10 microM) at concentrations that were not cytotoxic. In short-term in vivo studies, linuron treatment reduced testosterone- and DHT-dependent tissue weights in the Hershberger assay (oral 100 mg/kg/d for 7 days, using castrate-immature-testosterone propionate-treated male rats; an assay used for decades to screen for AR agonists and antagonists) and altered the expression of androgen-regulated ventral prostate genes (oral 100 mg/kg/d for 4 days). Histological effects of in utero exposure to linuron (100 mg/kg/d, day 14-18) or DBP (500 mg/kg/d, day 14 to postnatal day 3) on the testes and epididymides also are shown here. Taken together, these results support the hypothesis that linuron is an AR antagonist both in vivo and in vitro, but it remains to be determined if linuron alters sexual differentiation by additional mechanisms of action.     

Nonsteroidal tissue selective androgen receptor modulators: a promising class of clinical candidates

The androgen receptor (AR) is a nuclear hormone receptor that, upon binding to testosterone, dihydrotestosterone (DHT) and other endogenous androgens, supports the development, growth and maintenance of masculine features through activation of anabolic and androgenic metabolism. The AR has been demonstrated to be a productive therapeutic target. AR ligands in clinical practice include androgenic steroids, antiandrogenic steroids and antiandrogenic nonsteroidals. Of primary importance for this review are nonsteroidal selective AR modulators (SARMs) that have tissue-specific agonist and/or antagonist activities. The AR has a myriad of peripheral and central functions that can be modulated in a pleiotropic and tissue-specific fashion using the increasingly diverse collection of SARMs discussed herein. This suggests that SARMs will have a high level of clinical utility for a wide variety of health conditions. The patent literature focusing on SARMs is reviewed and reveals multiple chemical classes in various stages of preclinical and clinical development. Emphasis is placed on selected disease states for which SARMs show potential for therapeutic use in clinical practice.     

临床检验生化指标在病毒性肝病患者诊断中的应用与分析

目的 探讨临床检验生化指标在病毒性肝病患者诊断中的应用价值.方法 选择300例病毒性肝病患者作为观察组,同期300例健康体检者作为对照组.两组均开展生化指标检验.比较两组生化指标水平及肝功能指标阳性率.结果 观察组总胆红素(25.13±5.13)μmol/L、谷丙转氨酶(96.32±10.89)U/L、淋巴细胞计数(2...     

Discovery and biological characterization of a novel series of androgen receptor modulators

BACKGROUND AND PURPOSE: Selective androgen receptor modulators are of great value in the treatment of prostate cancer. The purpose of this study was to provide a preliminary characterization of a new class of non-steroidal androgen receptor modulators discovered in a high-throughput screening campaign. EXPERIMENTAL APPROACH: Competitive receptor binding, luciferase-based reporter methods, cell proliferation and in vivo assays were employed to evaluate an initial set of compounds from chemistry efforts. KEY RESULTS: Forty-nine analogues from the chemistry efforts showed high affinity binding to androgen receptors, agonist and/or antagonist activities in both CV-1 and MDA-MB-453 transfection assays. A proliferation assay in LNCaP cells also exhibited this profile. A representative of these non-steroidal compounds (compound 21) was devoid of activity at other nuclear receptors (oestrogen, progesterone, glucocorticoid and mineralocorticoid receptors) in the CV-1 co-transfection assay. At the same time, in an immature castrated rat model, it behaved as an androgen receptor antagonist against the growth of prostate, seminal vesicles and levator ani induced by exogenous androgen. Separation of compound 21 into its enantiomers showed that nearly all the androgen receptor modulating activity and binding resided in the dextrorotatory compound (23) while the laevorotatory isomer (22) possessed weak or little effect depending on the cell type studied. CONCLUSIONS AND IMPLICATIONS: These non-steroidal compounds may represent a new class of androgen receptor modulators for the treatment of not only prostate cancer but other clinical conditions where androgens and androgen receptors are involved in the pathological processes.     

雄激素受体基因CAG重复序列多态性与男性急性心肌梗死的关系

目的:探讨男性雄激素受体(AR)基因CAG重复序列多态性与急性心肌梗死(AMI)的关系.方法:选择112例男性AMI患者(AMI组)和118例健康男性体检者(对照组),采用聚合酶链反应(PCR)和直接测序法测定其外周血AR基因CAG重复序列的长度.结果:AMI组和对照组CAG重复序列长度范围为12～33,平均值分别为23.09±3.52和20.33±3.65,2组间的差异有统计学意义(t=5.826,P＜0.01).与CAG重复序列长度＜23相比,≥23者发生急性心肌梗死的危险性增加了4.391倍,差异有统计学意义(P＜0.01).结论:男性AR基因CAG重复序列是急性心肌梗死的危险因素.