表皮生长因子及受体在甲状腺肿瘤中的表达

目的:研究表皮生长因子(Epidermal Growth Factor,EGF)及受体(Epidermal Growth Factor Receptor,EGFR)及在甲状腺肿瘤中的表达。方法:应用免疫组织化学法检测91例甲状腺病变组织中EGFR和EGF的表达情况。结果:结节性甲状腺肿、甲状腺腺瘤、分化型甲状腺癌标本中EGFR表达的阳性率分别为15%、25%、68.62%,EGF表达的阳性率分别为10%、15%、68.62%,其中EGFR、EGF在分化型甲状腺癌与其余两组间差异均有统计学意义(P<0.05)。EGFR和EGF在甲状腺乳头状癌中的表达与性别、年龄、肿瘤大小、淋巴结转移、临床分期等临床因素无明显相关。结论:EGF和EGFR的表达可作为鉴别甲状腺肿瘤良恶性的一个指标。     

甲状腺肿瘤组织VEGF-C和ERβ的表达与LVD的相关性分析

目的:探讨甲状腺肿瘤和癌旁正常甲状腺组织中VEGF-C和ERβ的表达与组织平均淋巴管密度的相关性.方法:采用SP免疫组织化学染色检测116例甲状腺癌、56例甲状腺腺瘤和20例正常甲状腺组织中VEGF-C和ERβ及D2-40的表达;以D2-40阳性结果计算组织平均淋巴管密度(LVD).观察不同甲状腺组织中VEGF-C和ERβ的表达水平并分析其与LVD的相关性.结果:甲状腺癌组织中VEGF-C的高表达阳性率显著高于正常甲状腺和甲状腺腺瘤(P＜0.05),ERβ的高表达阳性率显著低于正常甲状腺和甲状腺腺瘤(P＜0.05);两者表达呈轻度负相关(r=-0.312,P＜0.01);甲状腺癌VEGF-C表达与淋巴结转移和TNM分期有关(P＜0.01).用D2-40标记的LVD值在甲状腺癌、甲状腺腺瘤和正常甲状腺组织之间有显著性差异(P＜0.001).甲状腺癌中淋巴结转移组LVD显著高于无淋巴结转移组(P＜0.0001).VEGF-C表达与D2-40呈正相关(r=0.515,P＜0.01).结论:ERβ表达下调可能通过促进VEGF-C的表达,进而影响淋巴管增生,促进肿瘤淋巴道转移.     

EGFR和KRAS在上皮性卵巢癌组织中的表达及临床意义

目的:探讨表皮生长因子受体(EGFR)和鼠Kirsten肉瘤病毒致癌基因(KRAS)蛋白在上皮性卵巢癌组织中的表达水平及临床意义。方法:利用免疫组化SP法对上皮性卵巢癌组织(病例组,n=57)、卵巢良性肿瘤组织(良性组,n=50)以及正常卵巢组织(对照组,n=50)中的EGFR、KRAS蛋白水平进行检测,并分析其在上皮性卵巢癌发生发展中的作用。结果:病例组的EGFR、KRAS蛋白阳性率高于良性组和对照组(P0.05),良性组和对照组的EGFR、KRAS蛋白阳性率差异无统计学意义(P0.05)。浆液性腺癌组EGFR、KRAS蛋白的阳性表达率高于非浆液性腺癌组,Ⅲ~Ⅳ期的上皮性卵巢癌组织中EGFR、KRAS蛋白阳性表达率高于Ⅰ~Ⅱ期,中、低分化组中EGFR、KRAS蛋白阳性表达率高于高分化组,差异均具有统计学意义(P0.05)。上皮性卵巢癌组织中EGFR与KRAS的蛋白的阳性表达率呈正相关关系(r=0.469,P0.05)。结论:EGFR及KRAS蛋白在上皮性卵巢癌组织中的表达水平明显升高,可能参与了上皮性卵巢癌的发生发展过程,且两者之间呈正相关关系,联合检测可作为早期诊断上皮性卵巢癌的重要指标。     

子宫肌瘤患者VEGF、ER及PR的表达及相关性

目的:研究血管内皮生长因(VEGF)、雌激素受体(ER)、孕激素受体(PR)在子宫肌瘤组织中的表达及其相关性,探计三者在子宫肌瘤发生发展中的作用.方法:采用免疫组化sP法检测40例肌瘤组织及其附近正常平滑肌组织中VEGF、ER及PR的表达水平.同时采用Western-blot法检测其中VEGF的含量,结果:①经免疫组化检测,VEGF、ER及PR在子宫肌瘤组织中表达阳性率均高于相应的瘤旁组织,差异具有显著性(P＜0.05).②VEGF的表达与ER及PR成正相关.③经Western-blot检测,VEGF蛋白含量在子宫肌瘤组织中显著高于相应的瘤旁组织,差异具有显著性(P＜0.05).结论:雌孕激素及VEGF均参与了子宫肌瘤的发生发展.三者之间可能具有协同作用.     

信号转导与转录因子3和表皮生长因子受体在宫颈不同病变组织中的表达及其临床意义

目的:探讨信号转导与转录因子3(STAT3)与表皮生长因子受体(EGFR)在宫颈不同病变组织中的表达变化及其临床意义。方法:采用Western blot与免疫组化的方法检测100例上皮内瘤样病变(CIN)组织、60例宫颈癌组织及40例正常宫颈组织中STAT3与EGFR的表达;分析STAT3与EGFR的表达与宫颈癌组织病理特征的关系;对宫颈癌组织中STAT3与EGFR的表达的相关性进行分析。结果:宫颈癌组织以及CIN组织中STAT3、EGFR的表达量和阳性率显著高于正常宫颈组织(P0.05),且宫颈癌组织中STAT3、EGFR的表达量和阳性率高于CIN组织,差异有统计学意义(P0.05);STAT3与EGFR在宫颈癌组织中的染色强度较正常宫颈组织以及CIN组织显著增强;STAT3与EGFR的异常表达与宫颈癌患者的组织学分级、临床分期以及是否发生淋巴结转移有关(P0.05),而与年龄以及病理分型无关(P0.05);宫颈癌组织中STAT3和EGFR表达呈正相关(P0.05)。结论:STAT3与EGFR表达与CIN、宫颈癌的进展紧密相关,且与宫颈癌部分病理特征相关,二者有可能作为宫颈癌诊断及预后的参考指标。     

大蒜素对小鼠脾细胞雌激素和雄激素受体影响的实验研究

本研究旨在探讨大蒜素对小鼠脾细胞雌激素和雄激素受体的影响。将健康ICR清洁小鼠,按性别随机分成三组实验组和三组对照组。实验组分别连续灌服大蒜素14、21和28 d,对照组同期分别灌服等量生理盐水。采用RT-PCR法检测雌性各组小鼠脾细胞雌激素受体(ERα和ERβ)的mRNA表达水平和雄性各组小鼠脾细胞雄激素受体(AR)的mRNA水平。实验结果显示,雌性小鼠连续灌服大蒜素第14和21 d时实验组ERαmRNA表达水平明显高于对照组(P0.05),第14 d时ERβmRNA表达水平明显高于对照组(P0.05)。雄性小鼠连续灌服大蒜素第14、21和28 d时实验组AR mRNA表达水平均明显高于对照组(P0.05)。综上提示大蒜素可增强小鼠脾细胞雌激素受体(ERα和ERβ)和雄激素受体(AR)mRNA的表达水平。     

ER、PR、CA-153、Ki-67的表达与乳腺癌临床病理特征及预后的相关性研究

目的:研究雌激素受体(ER)、孕激素受体(PR)、糖类抗原-153(CA-153)、Ki-67的表达与乳腺癌临床病理特征及预后的相关性。方法:选取2015年3月-2017年4月我院收治的乳腺癌患者190例为研究对象。分别采用免疫组化法检测患者ER、PR、Ki-67表达情况,采用酶联免疫吸附法检测CA-153表达情况。分析上述四项指标的表达与临床病理特征的关系,并作指标间的相关性分析。结果:有淋巴结转移的乳腺癌组织中ER、PR阳性率明显高于无淋巴结转移,差异有统计学意义(P0.05),而年龄、肿瘤大小、TNM分期不同的乳腺癌组织中ER、PR阳性率比较差异均无统计学意义(P0.05)。肿瘤大小2cm、TNM分期为Ⅲ-Ⅳ期、有淋巴结转移乳腺癌组织中CA-153阳性率分别高于肿瘤大小≤2cm、TNM分期为Ⅰ-Ⅱ期、无淋巴结转移,差异均有统计学意义(P0.05),而年龄不同的乳腺癌组织中CA-153阳性率比较差异无统计学意义(P0.05)。TNM分期为Ⅲ-Ⅳ期、有淋巴结转移乳腺癌组织中Ki-67阳性率明显高于TNM分期为Ⅰ-Ⅱ期、无淋巴结转移,差异均有统计学意义(P0.05),而年龄、肿瘤大小不同的乳腺癌组织中Ki-67阳性率比较差异无统计学意义(P0.05)。经Pearson相关性分析显示,ER、PR、CA-153、Ki-67在乳腺癌中表达均呈正相关(P0.05)。结论:临床工作中可通过联合检测ER、PR、CA-153、Ki-67的表达情况,从而有效判断乳腺癌患者的病情严重程度以及转移情况,值得临床推广应用。     

自然发情与诱导发情小鼠子宫内膜中雌激素受体α表达的比较

目的从雌激素受体α(ERα)的角度探讨自然发情小鼠与诱导发情小鼠的子宫内膜上,雌激素受体α表达是否受内源雌激素的特异诱导而变化,两者之间是否存在差异。方法27只同日龄母鼠,根据处理方式的不同随机分为3个组:自然发情假孕组(对照组)、诱导发情处理假孕组和自然发情假孕第1天摘除卵巢组,3个组的小鼠在见栓后第4、6、8天分别取样后,采用免疫组织化学法观察小鼠子宫内膜中雌激素受体α的表达情况。结果免疫组化结果显示,3个处理组的小鼠子宫内膜上皮细胞核、胞质都有ERα存在,且主要表达在腺上皮;见栓第4、6、8天时,诱导发情处理组小鼠子宫内膜的ERα阳性率均显著高于自然发情组和自然发情第1天摘除卵巢组(P0.05);见栓第8天时,自然发情处理组小鼠子宫内膜中的ERα阳性率与自然发情第1天摘除卵巢组差异不显著(P0.05),但见栓第4、6天时两者阳性率差异显著,自然发情处理组小鼠子宫内膜中的ERα阳性率显著高于自然发情第1天摘除卵巢组(P0.05)。结论诱导发情处理的小鼠子宫内膜,其表面雌激素受体α表达显著高于自然发情小鼠,且两者都受其内源性雌激素的特异诱导而变化。     

雌激素受体β在乳腺癌生长中的作用研究进展

雌激素受体 β(ERβ) 是雌激素受体的另一亚型。众多体内外实验证明,ERβ 与乳腺癌的生长有密切联系。ERβ 低表达会促进乳腺 癌增殖,介导转移,还能抑制乳腺癌细胞的凋亡。临床数据证明,ERβ 在乳腺癌患者的癌旁组织中表达高于癌组织,且与乳腺癌患者的 总生存率相关。ERβ 与雌激素受体 α(ERα)、表皮生长因子受体(EGFR)、孕激素受体(PR)均有密切联系:ERα 和 ERβ mRNA 平 均表达水平比值(ERβ/ERα)升高,对抗癌药物有拮抗作用,反之则有协同作用;ERβ 的表达量受 PR 调节,并能通过 EGFR 及下游信 号通路,抑制上皮-间充质转化。临床乳腺癌样本表明,ERβ 低表达可能与启动子甲基化有关。因此,采用药物调节 ERβ 的表达以及敏感性, 是具有很大临床价值的潜在治疗手段。综述 ERβ 以及 ERβ 与相关受体之间的联系在乳腺癌生长中的作用。     

性激素受体在膀胱肿瘤生存预后中的临床价值

目的:观察性激素受体(雄激素受体和雌激素β受体,AR和ERβ)在膀胱癌中的表达,通过它们与临床病理特征和术后复发预后的相关分析来探讨性激素受体的临床意义与价值。方法:采用免疫组织化学SP法检测AR和ERβ蛋白在64例膀胱尿路上皮癌的表达。显微镜下随机选取5个400×高倍视野,每个视野计数100个癌细胞中的阳性细胞数,通过计算染色阳性的细胞率来评估受体蛋白的表达情况。结果:两种性激素受体蛋白均阳性定位于细胞核中。AR阳性表达率为26.6%,ERβ阳性率为81.2%。AR和ERβ的阳性表达率在男女性别方面均无统计学差别(P=0.1982,0.0669)。随着膀胱癌病理分级升高,AR和ERβ的阳性表达率均增高(P=0.0182,0.0360)。同时,AR和ERβ的表达与患病年龄,膀胱内肿瘤数目,肿瘤大小,肿瘤的临床分期均无统计学相关性(P均>0.05)。术后随访患者时间为2-81月,生存分析显示:AR与肿瘤的复发间隔期和5年复发率相关(P=0.0442)。ERβ则与肿瘤患者的总生存期相关(P=0.0001)。阳性表达AR的患者,复发间隔时间增长,5年复发率较低;ERβ阳性患者总生存期较长。结论:性激素受体AR和ERβ阳性表达于临床膀胱癌组织中,并且均与膀胱癌的分化密切相关。这提示AR和ERβ可能在膀胱癌的发生发展中起一定作用。同时,两种蛋白还能作为评估膀胱癌复发预后的预测指标。     

触觉受体NOMPC及听觉受体TMC的发现

人类感觉包括：视觉、听觉、嗅觉、味觉、触觉,还有温觉、痛觉等. 生物体是如何感知物理世界的问题一直吸引着人类,虽然在不同感知觉受体的发现及研究过程中不断取得新的突破性进展,但是对这些感知觉基础生物学层面的理解仍然有限. 2021年度诺贝尔生理学或医学奖授予感知觉研究领域,以表彰David Julius和Ardem Patapoutian 在感知温度与触觉受体的发现上做出的深远而广泛的贡献. 对于听觉研究而言,虽然早在1961年就获得诺贝尔奖,但是听觉受体的研究仍然不足. 本文着重对无脊椎动物触觉及听觉受体NOMPC、哺乳动物听觉受体TMC的发现及研究进程进行详细介绍,并对未来感知觉领域的发展提供建议.     

Nogo与Nogo受体研究

nogo是新近发现的一种基因,编码3种蛋白质：Nogo-A、Nogo-B和Nogo-C.迄今为止,已证明它有抑制成熟中枢神经系统(CNS)神经元轴突再生及诱导细胞凋亡的作用.Nogo受体是一种糖基醇磷脂结合蛋白.对Nogo和Nogo受体的研究,对于CNS再生障碍及肿瘤的认识和治疗有重要意义.     

Activation of Calcitonin Receptor and Calcitonin Receptor-like Receptor by Membrane-anchored Ligands

G protein-coupled receptors (GPCRs) are the most important pharmaceutical targets, and more than 40% of drugs in use today modulate GPCR signaling. A major hurdle in the development of therapies targeting GPCRs is the drug candidate''s nonselective actions in multiple tissues. The ability to spatially control GPCR signaling would provide a venue for developing therapies that require targeted GPCR signaling. Here, we show that the fusion of a RAMP1 co-receptor with the calcitonin gene-related peptide (CGRP), or calcitonin, transforms the RAMP1 from a co-receptor to bona fide membrane-anchored ligands (CGRP-RAMP1 and CAL-RAMP1). The CAL-RAMP1 selectively activates the calcitonin receptor (CR), whereas, the CGRP-RAMP1 activates both the calcitonin receptor-like receptor (CLR) and CR. Unlike a free peptide, which moves freely in the extracellular space and differentiates targets based on molecular affinity, the anchored CGRP-RAMP1 and CAL-RAMP1 ligands confine their activities to individual cells. In addition, our study showed that a CGRP8–37-RAMP1 chimera, but not RAMP1, functions as an antagonist for CGRP-RAMP1-mediated signaling, suggesting that the activation of CLR by CGRP-RAMP1 shares similar molecular mechanisms with the CGRP-mediated activation of CLR/RAMP1 receptor complexes. Taken together, our finding thus provides a novel class of ligands that activate CR and CLR exclusively in an autocrine manner and a proof-of-concept demonstration for future development of targeted therapies aimed at these receptors in specific cell populations.     

G Protein-coupled Receptor Kinase-2 Constitutively Regulates D2 Dopamine Receptor Expression and Signaling Independently of Receptor Phosphorylation

We investigated the regulatory effects of GRK2 on D₂ dopamine receptor signaling and found that this kinase inhibits both receptor expression and functional signaling in a phosphorylation-independent manner, apparently through different mechanisms. Overexpression of GRK2 was found to suppress receptor expression at the cell surface and enhance agonist-induced internalization, whereas short interfering RNA knockdown of endogenous GRK2 led to an increase in cell surface receptor expression and decreased agonist-mediated endocytosis. These effects were not due to GRK2-mediated phosphorylation of the D₂ receptor as a phosphorylation-null receptor mutant was regulated similarly, and overexpression of a catalytically inactive mutant of GRK2 produced the same effects. The suppression of receptor expression is correlated with constitutive association of GRK2 with the receptor complex as we found that GRK2 and several of its mutants were able to co-immunoprecipitate with the D₂ receptor. Agonist pretreatment did not enhance the ability of GRK2 to co-immunoprecipitate with the receptor. We also found that overexpression of GRK2 attenuated the functional coupling of the D₂ receptor and that this activity required the kinase activity of GRK2 but did not involve receptor phosphorylation, thus suggesting the involvement of an additional GRK2 substrate. Interestingly, we found that the suppression of functional signaling also required the Gβγ binding activity of GRK2 but did not involve the GRK2 N-terminal RH domain. Our results suggest a novel mechanism by which GRK2 negatively regulates G protein-coupled receptor signaling in a manner that is independent of receptor phosphorylation.     

Receptor Imaging by Pet and Spect: Focus on the Opiate Receptor

Abstract

Receptor imaging by PET and SPECT offers distinctive advantages over the more established flow/metabolism imaging methods, including improved chemical specificity and improved sensitivity in detecting changes in disease. Radioligands are available for PET and SPECT imaging of many neuroreceptors including the opiate receptor, the dopamine receptor and the muscarinic cholinergic receptor. A new focus of interest is the imaging and quantification of presynaptic neurotransmitter reuptake sites. Clinical applications of μ opiate receptor imaging are discussed for epilepsy, Alzheimer's disease and dementia.     

生长抑素受体介导的放射性核素治疗

生长抑素受体介导的放射性核素治疗(peptide receptor radionuclide therapy,PRRT)是用于不能手术治疗或有远处转移的胃、肠和胰腺等神经内分泌肿瘤病人的一种新型治疗方法,本文旨在综述近年来不同核素标记生长抑素类似物的临床评价及相关研究。     

The Insulin Receptor: Both a Prototypical and Atypical Receptor Tyrosine Kinase

Unlike prototypical receptor tyrosine kinases (RTKs), which are single-chain polypeptides, the insulin receptor (InsR) is a preformed, covalently linked tetramer with two extracellular α subunits and two membrane-spanning, tyrosine kinase-containing β subunits. A single molecule of insulin binds asymmetrically to the ectodomain, triggering a conformational change that is transmitted to the cytoplasmic kinase domains, which facilitates their trans-phosphorylation. As in prototypical RTKs, tyrosine phosphorylation in the juxtamembrane region of InsR creates recruitment sites for downstream signaling proteins (IRS [InsR substrate] proteins, Shc) containing a phosphotyrosine-binding (PTB) domain, and tyrosine phosphorylation in the kinase activation loop stimulates InsR’s catalytic activity. For InsR, phosphorylation of the activation loop, which contains three tyrosine residues, also creates docking sites for adaptor proteins (Grb10/14, SH2B2) that possess specialized Src homology-2 (SH2) domains, which are dimeric and engage two phosphotyrosines in the activation loop.Insulin is a highly potent anabolic hormone that is critical for tissue development and for glucose homeostasis (Taniguchi et al. 2006). Released from the β cells of the pancreas, insulin regulates glucose output from the liver and glucose uptake into (primarily) skeletal muscle and adipose tissue. In addition, insulin promotes the synthesis and storage of carbohydrates, lipids, and protein. Insulin’s actions are mediated by the insulin receptor (InsR), a plasma membrane-resident glycoprotein and member of the receptor tyrosine kinase (RTK) family. Other members of the InsR subfamily of RTKs include the insulinlike growth factor-1 receptor (IGF1R) and insulin receptor-related receptor, the latter of which has no known ligand. As an RTK, InsR is ligand-activated through mechanisms that are both prototypical and atypical of RTKs. These mechanisms will be the focus of this article.     

Testosterone-Dependent Interaction between Androgen Receptor and Aryl Hydrocarbon Receptor Induces Liver Receptor Homolog 1 Expression in Rat Granulosa Cells

Androgens play a major role in the regulation of normal ovarian function; however, they are also involved in the development of ovarian pathologies. These contrasting effects may involve a differential response of granulosa cells to the androgens testosterone (T) and dihydrotestosterone (DHT). To determine the molecular pathways that mediate the distinct effects of T and DHT, we studied the expression of the liver receptor homolog 1 (LRH-1) gene, which is differentially regulated by these steroids. We found that although both T and DHT stimulate androgen receptor (AR) binding to the LRH-1 promoter, DHT prevents T-mediated stimulation of LRH-1 expression. T stimulated the expression of aryl hydrocarbon receptor (AHR) and its interaction with the AR. T also promoted the recruitment of the AR/AHR complex to the LRH-1 promoter. These effects were not mimicked by DHT. We also observed that the activation of extracellular regulated kinases by T is required for AR and AHR interaction. In summary, T, but not DHT, stimulates AHR expression and the interaction between AHR and AR, leading to the stimulation of LRH-1 expression. These findings could explain the distinct response of granulosa cells to T and DHT and provide a molecular mechanism by which DHT negatively affects ovarian function.     

Quantitative Comparison of Human Parainfluenza Virus Hemagglutinin-Neuraminidase Receptor Binding and Receptor Cleavage

The human parainfluenza virus (hPIV) hemagglutinin-neuraminidase (HN) protein binds (H) oligosaccharide receptors that contain N-acetylneuraminic acid (Neu5Ac) and cleaves (N) Neu5Ac from these oligosaccharides. In order to determine if one of HN′s two functions is predominant, we measured the affinity of H for its ligands by a solid-phase binding assay with two glycoprotein substrates and by surface plasmon resonance with three monovalent glycans. We compared the dissociation constant (K_d) values from these experiments with previously determined Michaelis-Menten constants (K_ms) for the enzyme activity. We found that glycoprotein substrates and monovalent glycans containing Neu5Acα2-3Galβ1-4GlcNAc bind HN with K_d values in the 10 to 100 μM range. K_m values for HN were previously determined to be on the order of 1 mM (M. M. Tappert, D. F. Smith, and G. M. Air, J. Virol. 85:12146–12159, 2011). A K_m value greater than the K_d value indicates that cleavage occurs faster than the dissociation of binding and will dominate under N-permissive conditions. We propose, therefore, that HN is a neuraminidase that can hold its substrate long enough to act as a binding protein. The N activity can therefore regulate binding by reducing virus-receptor interactions when the concentration of receptor is high.