不同ER、PR状态乳腺癌中AR的表达及其意义

目的探讨AR在不同ER、PR状态乳腺癌中的表达及意义。方法采用免疫组化方法检测AR、ER、PR在173例乳腺癌中的表达,依据结果分组:(1)AR状态分组:AR阳性组和AR阴性组;(2)ER、PR状态分组:En组(ER、PR均阴性)、Ep组[ER和(或)PR阳性];(3)AR、ER、PR联合分组:En-AR+(En组且AR阳性)、En-AR-(En组且AR阴性)、Ep-AR+(Ep组且AR阳性)、Ep-AR-(Ep组且AR阴性),其中En-AR-又称为均阴性组,其他三组统称为部分或完全阳性组。不同分组方法比较与临床病理特征的关系。结果Ep组AR阳性率62.8%(54/86),En组AR阳性率37.9%(33/87),两组差异有显著性(P=0.001),AR阳性组体积小、核分裂少、组织学分级低(P0.05);En-AR-组表现为核分裂多、组织学分级高(P0.01),此外En组内AR阳性者核分裂少、组织学分级低(P0.05),Ep组内AR阳性者临床分期高(P=0.000),En-AR+、Ep-AR+、Ep-AR-比较均无差异。结论AR在不同激素状态乳腺癌中表达的意义不同,ER、PR均阴性乳腺癌表达AR者预后较好,ER、PR阳性乳腺癌表达AR者临床分期高。在选择针对性药物时应考虑到不同激素受体状态的组合。     

AR在ER阳性和阴性乳腺癌中的表达及临床意义

目的 探讨雄激素受体(androgen receptor, AR)在ER阳性和阴性乳腺癌中的表达及其与临床病理特征、预后的关系。方法 收集270例浸润性乳腺癌患者的临床病理资料，将ER分成阳性组与阴性组。分析两组AR表达与乳腺癌临床病理特征及多种蛋白标志物的关系，并复习相关文献。使用Kaplan-Meier Plotter数据库对AR在乳腺癌患者的预后价值进行分析。结果 270例浸润性乳腺癌患者AR阳性率为78.5%。AR与ER、PR、HER-2、CK5/6、组织学分级、Ki-67增殖指数、神经侵犯及脉管侵犯有关(P<0.05)。ER阳性组中AR阳性率(88.1%)高于ER阴性组(60.2%)。进一步分析发现ER阳性组中AR与组织学分级及CK5/6阳性有关(P<0.05);ER阴性组中AR与HER-2、CK5/6、组织学分级、神经侵犯、脉管侵犯、淋巴结转移及pTNM分期有关(P<0.05)。Kaplan-Meier Plotter预后分析发现，ER阳性组中AR高表达者总生存期显著高于低表达者，而ER阴性组中AR高表达者总生存期低于低表达者(P<0.05)。结论 ...     

雄激素受体在乳腺癌中的表达及其与雌、孕激素受体和HER2的关系

目的 研究雄激素受体(AR)在乳腺浸润性导管癌中的表达及其与雌激素受体(ER)、孕激素受体(PR)和HER2状态的关系,探讨其作为乳腺癌治疗靶点的可行性.方法 采用免疫组织化学EnVision法检测AR、ER、PR、HER2在175例乳腺浸润性导管癌中的表达,依据结果分为腺腔A型、腺腔B型、HER2过表达型和三阴性型(ER-/PR-/HER2-)组.结果 175例中AR阳性88例(50.3%),AR表达与ER、PR、HER2均呈正相关(P＜0.01).腺腔A型53例(30.3%),腺腔B型33例(18.9%),HER2过表达型23例(13.1%),三阴性型66例(37.7%),AR阳性率分别为56.6%(30/53),75.8%(25/33)、47.8%(11/23)和33.3%(22/66),组间AR阳性率差异显著(x2=17.054,P=0.001).三阴性型组AR阳性者核分裂象较少(x2=5.140,P=0.023),腺腔A型组AR阳性者多为年轻患者(x2=4.567,P=0.033),差异有统计学意义.其他组内AR表达与否和临床病理学特征比较无统计学意义.结论 AR在乳腺癌中有较高的阳性率,可作为乳腺癌,特别是三阴性型乳腺癌的治疗靶点.     

雄激素受体在乳腺癌中的表达及其与雌、孕激素受体和HER2的关系

目的 研究雄激素受体(AR)在乳腺浸润性导管癌中的表达及其与雌激素受体(ER)、孕激素受体(PR)和HER2状态的关系,探讨其作为乳腺癌治疗靶点的可行性.方法 采用免疫组织化学EnVision法检测AR、ER、PR、HER2在175例乳腺浸润性导管癌中的表达,依据结果分为腺腔A型、腺腔B型、HER2过表达型和三阴性型(ER-/PR-/HER2-)组.结果 175例中AR阳性88例(50.3%),AR表达与ER、PR、HER2均呈正相关(P＜0.01).腺腔A型53例(30.3%),腺腔B型33例(18.9%),HER2过表达型23例(13.1%),三阴性型66例(37.7%),AR阳性率分别为56.6%(30/53),75.8%(25/33)、47.8%(11/23)和33.3%(22/66),组间AR阳性率差异显著(x2=17.054,P=0.001).三阴性型组AR阳性者核分裂象较少(x2=5.140,P=0.023),腺腔A型组AR阳性者多为年轻患者(x2=4.567,P=0.033),差异有统计学意义.其他组内AR表达与否和临床病理学特征比较无统计学意义.结论 AR在乳腺癌中有较高的阳性率,可作为乳腺癌,特别是三阴性型乳腺癌的治疗靶点.     

性激素受体在直肠癌中的表达及其临床意义

目的:探讨直肠癌中雌激素受体α(ERα)、雌激素受体β(ERβ)、雄激素受体(AR)、孕激素受体(PR)的表达及其与临床病理特征的关系。方法:采用免疫组织化学Envi-sion二步法检测ERα、ERβ、AR、PR在60例直肠癌和癌旁组织及30例正常直肠黏膜组织中的表达,并分析其与直肠癌临床病理特征的关系。结果:直肠癌与癌旁组织及正常直肠黏膜组织中均未见ERα阳性表达;直肠癌组织中ERβ和PR阳性表达显著低于癌旁组织和正常直肠黏膜(P0.05),后两者间比较差异无统计学意义(P0.05);直肠癌中AR阳性表达显著高于与癌旁组织及正常直肠黏膜组织(P0.05),后两者间比较差异无统计学意义。ERβ和PR在直肠癌组织中的表达与TNM分期、分化程度、淋巴结转移、浸润程度和肝转移密切相关(P0.01),而与年龄、性别、肿瘤直径及病理类型无关(P0.05)。AR在直肠癌组织中的表达与其临床病理学特征指标均无关(P0.05)。结论:ERβ和PR在直肠癌组织中表达缺失,可能参与直肠癌的发生,且与直肠癌的恶性生物学行为有关;而AR的表达可能也参与了直肠癌的发生,但其对直肠癌的恶性生物学行为的作用不明显。     

CA125在子宫内膜癌组织中的表达及与ER和PR的相关性研究

目的探讨CA125在子宫内膜癌组织中的表达及与雌激素受体(ER)、孕激素受体(PR)的相关性,阐明CA125在子宫内膜癌病情进展中的作用。方法随机选取经病理确诊为子宫内膜癌组织60例,采用免疫组化Envision二步法检测组织CA125的表达,分析其与患者临床分级、组织学分级、肿瘤浸润程度和淋巴结转移等情况的关系,并根据CA125免疫组化结果将其分为阳性组和阴性组,分析CA125的表达与ER、PR的关系。结果 CA125在子宫内膜癌组织的阳性表达为75.00%(45/60),并随着肿瘤浸润深度的增加而表达增强(2值=9.32,P=0.001),在子宫内膜癌临床分期Ⅰ期、Ⅱ期和Ⅲ期,组织学分级Ⅰ级、Ⅱ级和Ⅲ级中差异均存在统计学意义(P0.05),但与淋巴结转移与否差异无统计学意义(P0.05)。在45例CA125表达阳性组中,ER阳性率为80.0%,PR阳性率为71.11%,而在15例CA125表达阴性组中,ER阳性率为26.67%,PR阳性率为40.00%,CA125的表达与ER、PR密切相关。结论子宫内膜癌组织中存在CA125高表达,并与肿瘤的恶性生物学行为密切相关,同时与组织ER、PR的表达密切相关,对指导临床治疗和判断预后均具有重要的临床价值。     

男性乳腺癌的性激素受体和临床病理

用直接荧光组化法测定10例男性乳腺癌的雌激素、孕激素和睾酮的受体(ER、PR和AR),发现50%的病例ER和PR含量丰富,较同一方法同一阳性标准的女性乳腺癌的阳性率高;在同一病例AR的阳性表达明显低于ER和PR(20%、50%、70%),提示男性乳腺癌更依赖于女性激素。受体贫乏者中年长于50岁的多;肿瘤     

性激素结合球蛋白在乳腺癌中的表达及意义

目的 探讨性激素结合球蛋白(sex hormone-binding globulin,SHBG)在乳腺癌中的表达及意义.方法 采用免疫组化EnVision法检测SHBG、AR、ER在83乳腺癌中的表达,每例标本中均包括浸润性乳腺癌(invasive breast carcinoma,IBC)和原位癌(carcinoma in situ,CIS)组织.结果 CIS及IBC中SHBG表达与AR、ER无相关性,CIS中SHBG阳性68例(81.9%),IBC中阳性53例(61.9%),两者差异有显著性(P=0.007),AR、ER阳性乳腺癌中表达SHBG者临床分期低,差异有显著性(P值分别为0.049和0.013),SHBG阳性的乳腺癌中AR、ER均阳性者组织学分级低,差异有显著性(P=0.000).结论 AR、ER阳性乳腺癌中SHBG具有抑制肿瘤增殖的作用,其表达缺失可能参与了激素依赖性乳腺癌的进程.     

乙醛脱氢酶1和雌激素受体在乳腺癌原发灶与复发转移灶之间的表达差异

目的 回顾性分析乙醛脱氢酶1(ALDH1)和雌激素受体(ER)在乳腺癌原发灶和对应复发转移灶之间的表达变化.方法 87例复发转移性乳腺癌,免疫组织化学方法检测复发转移灶及其对应的原发灶中ALDH1和ER的表达差异,利用图像分析软件Image-Pro Plus 6.0(IPP6.0)对免疫组织化学结果进行积分吸光度(IA)值测定,并进行统计学分析;结合临床病理特征进行相关性分析.结果 ALDH1在乳腺癌原发灶的阳性率为28.7％(25例),复发转移灶的表达率为43.7％(38例),复发转移灶的阳性率明显高于原发灶,差异有显著性(P＜0.05).ER在原发灶的阳性率为56.3％,在复发转移灶为32.2％,差异有显著性.复发转移灶与对应原发灶IA值统计分析结果显示,ALDH1的表达量明显升高(P＜0.05),而ER的表达量显著降低(P＜0.01).ALDH1阳性表达与肿块大小(＞2cm)、高组织学分级、淋巴结转移及ER阴性相关.结论 乳腺癌复发转移灶中ALDH1的表达率明显高于原发灶,而ER阳性率要显著低于原发灶.     

雌激素受体在肝癌组织中的表达及其临床意义

目的研究雌性激素受体(ER)在肝癌组织中的表达和其临床价值。方法采用免疫组化法对59例肝癌患者肝肿瘤组织中雌激素受体(ER)表达情况进行研究。结果 59例肝癌患者ER表达阳性率为72.9%。22～36岁的肝癌患者ER表达阳性率为72.22%(13/18),37～52岁的患者表达阳性率为75.01%(15/20),53～67岁的患者的阳性率为71.42%(15/21);直径≤5 cm的肝癌中ER表达阳性率为33.33%(6/18),直径大于5 cm的癌组织阳性率为90.24%(37/41);分化程度为EdmondsonⅠ级的肝癌组织中表达阳性率为96.97%(32/33),Ⅱ级的阳性率为55.56%(10/18),Ⅲ级阳性率为12.5%(1/8)。年龄组间表达差异无统计学意义(P>0.05),而不同大小肿瘤和不同分化程度组间表达差异有统计学意义(P<0.05)。结论原发性肝细胞癌具有一定的雌激素依赖性,肝癌发生、发展及预后与肝癌组织中ER表达有关。     

Cellular receptor for pixuna virus in chicken embryonic fibroblasts

In this study, we describe the isolation and partial characterization of a Pixuna virus receptor, which is a component of a plasma membrane fraction of chicken embryo fibroblast (CEF). Polyclonal antiserum was prepared from rabbits immunized with the membrane fraction. Said polyclonal antiserum reacted in a similar way as monoclonal antibodies raised against the membrane fraction. Both antisera were able to prevent CEF and Vero cells from infection with Pixuna virus. Immunofluorescence studies suggested that the receptors found in the fibroblasts and in the Vero cells shared at least some epitopes. The Western blot analysis of the purified membrane fraction antigens, which reacted with the monoclonal and polyclonal antibodies, detected a double band with a molecular mass of approximately 60 kDa. Not only immunofluorescence staining but also electron and immunoelectron microscopy studies evidenced the receptor localization in the plasma membrane. In this manner, we reported the isolation and partial characterization of a new Pixuna virus receptor in the plasma membrane of chicken embryo fibroblasts in culture. The data obtained demonstrated the receptor significance for the penetration of Pixuna virus into fibroblasts and mammalian cell and the related importance of designing new antiviral drugs by blocking the mechanism of receptor penetration of the virus into the cells.     

Ammonia-induced alterations in glutamate and muscimol binding to cerebellar synaptic membranes

Binding of glutamate and muscimol (an agonist for GABA_A receptors) to their respective receptors has been studied in the cerebellum of normal and hyperammonemic rats. There was a decrease in both high- and low-affinity binding of glutamate in the cerebellum during hyperammonemia. Kinetic studies revealed that the decrease is due to a reduction in the number of binding sites, but not due to changes in the binding affinities. Further studies also revealed that the decrease was only in the (NMDA)-specific binding sites without any alterations in the binding to non-NMDA sites represented by kianic acid (KA)- and quisqualic acid (QQ)-sensitive receptor sites. These effects were also mimicked when the membrane preparations from the cerebellum of normal animals were incubated with ammonium acetate. Enhancement of muscimol binding was observed in animals injected with ammonium acetate. It is concluded that hyperammonemic states, even in the presence of a functional liver, are capable of altering amino acid neurotransmission and this might play an important role in cerebral dysfunction under these conditions.     

IL-4 down-regulates IL-2 receptor p75 by accelerating its endocytosis

We examined the effects of interleukin 4 (IL-4) on the expressionof IL-2 receptor p75 (IL-2R p75) or ß chain on varioushuman T cells. IL-4 promptly down-regulated surface IL-2 receptor(IL-2R) p75 In these cells. Although IL-2-lnduced IL-2R p75down-regulation was seen more quickly, IL-2 did not contributeto the process of the IL-4-induced decrease of IL-2R p75. Northernblotting revealed that IL-4 did not reduce the expression ofIL-2R p75 mRNA. Studies using Pronase E, which digests cellsurface IL-2R p75, or brefeldin A, which blocks Intracytoplasmicprotein transport from endoplasmicretculum to the Golgi apparatus,suggest that IL-4-lnduced IL-2R p75 down-reguation is controlledafter IL-2R p75 is expressed on the cell surface. We found thatIL-4 accelerated the endocytosis of IL-2R p75, which was monitoredby (¹²⁵)||M||k-ß3 monocional antibody that recognizesnon-IL-2-bindlng epitope on IL-2R p75. These findings demonstratethat IL-4 down-regulates IL-2R p75 mainly by accelerating Itsendocytosis.     

Use of monoclonal antibody for assessment of estrogen and progesterone receptors in malignant effusions.

An immunocytochemical assay utilizing specific monoclonal antibodies against estrogen receptor (ER) and progesterone receptor (PgR) has been shown to be highly reliable for the detection of hormone receptors in hormone sensitive tumors. To assess the usefulness of this technique in malignant effusions, CytospinR (Shandon, Inc., Pittsburgh, PA 15275), preparations of 41 pleural and ascitic fluid were studied. The findings from the malignant cells employing estrogen and progesterone receptor immunocytochemical assay were compared with the results obtained from primary tumors by biochemical (dextran-coated charcoal) assay. The results agreed in 88% for ER and 83% for PgR. This study supports the potential value of cytochemical technique in detection of hormone receptors in malignant effusions. Assessment of hormone receptors in malignant effusions may be of clinical significance, particularly in situations where the hormone receptor status of the original tumor is not known. This information may also have some diagnostic and therapeutic importance in assessment of patients presenting with metastatic tumors of unknown origin.     

Identification of C-terminal domain residues involved in protein kinase A-mediated potentiation of kainate receptor subtype 6

Glutamate receptors are the major excitatory receptors in the vertebrate CNS and have been implicated in a number of physiological and pathological processes. Previous work has shown that glutamate receptor function may be modulated by protein kinase A (PKA)-mediated phosphorylation, although the molecular mechanism of this potentiation has remained unclear. We have investigated the phosphorylation of specific amino acid residues in the C-terminal cytoplasmic domain of the rat kainate receptor subtype 6 (GluR6) as a possible mechanism for regulation of receptor function. The C-terminal tail of rat GluR6 can be phosphorylated by PKA on serine residues as demonstrated using [gamma-32P]ATP kinase assays. Whole cell recordings of transiently transfected human embryonic kidney (HEK) 293 cells showed that phosphorylation by PKA potentiates whole cell currents in wildtype GluR6 and that removal of the cytoplasmic C-terminal domain abolishes this potentiation. This suggested that the C-terminal domain may contain residue(s) involved in the PKA-mediated potentiation. Single mutations of each serine residue in the C-terminal domain (S815A, S825A, S828A, and S837A) and a truncation after position 855, which removes all threonines (T856, T864, and T875) from the domain, do not abolish PKA potentiation. However, the S825A/S837A mutation, but no other double mutation, abolishes potentiation. These results demonstrate that phosphorylation of the C-terminal tail of GluR6 by PKA leads to potentiation of whole cell response, and the combination of S825 and S837 in the C-terminal domain is a vital component of the mechanism of GluR6 potentiation by PKA.     

Role of alpha chain-IL-2 complex in the formation of the ternary complex of IL-2 and high-affinity IL-2 receptor

Using anti-Tac (anti-alpha chain) and 2R-B (anti-beta chain) antibodies, we studied the roles of IL-2 receptor subunits (alpha and beta chains) in the formation of IL-2 and high-affinity IL-2 receptor complex, which is the initial event of IL-2 induced T cell growth. High-affinity IL-2 binding which was undetectable in the presence of 2R-B antibody at 4 degrees C became fully detectable when examined at 37 degrees C, which explained the lack of inhibition by 2R-B antibody of IL-2-induced proliferation of the cells expressing high-affinity IL-2 receptor. We further studied the mechanism of the 'reappearance' of high-affinity IL-2 binding in the presence of 2R-B antibody. The addition of IL-2 to the cells preincubated with radiolabeled or fluorescence-labeled 2R-B antibody resulted in a marked decrease in the antibody bound to the cells expressing high-affinity IL-2 receptor at 37 degrees C. This decrease was blocked by the presence of anti-Tac antibody, which inhibited IL-2 binding to alpha chain, but not by 7G7/B6 antibody, which recognized a non-IL-2 binding site of its chain. Furthermore, the decrease in cell-bound 2R-B antibody was not due to the internalization of beta chain-2R-B antibody complex, because the amount of cell-bound Mik-beta3 antibody recognizing a non-IL-2 binding epitope of beta chain remained unchanged, nor to the inhibition by simple competitive binding of IL-2 molecules to beta chain as judged from comparative studies of competitive binding inhibition. Taking these data together, the reappearance of high-affinity IL-2 binding was considered to be caused by the replacement of 2R-B antibody at the IL-2 binding site of beta chain by alpha chain-mediated IL-2, and it was strongly suggested that alpha chain-IL-2 complex has a key role in the formation of the ternary complex of IL-2 and high-affinity IL-2 receptor. alpha chain may function as a dimension converter of IL-2 to effectively deliver IL-2 molecules to a relatively small number of beta chains in the dynamics of the formation of high-affinity IL-2 binding in T cells.     

IL-1 up-regulates the expression of cytokine receptors on a factor-dependent human hemopoietic cell line, TF-1

A factor-dependent human hemopoietic cell line, TF-1, requiresinterleukln 3 (IL-3) or granulocyte/acrophage colony-stimulatingfactor (GM-CSF) for its long-term growth. We have found thatIL-4, IL-5, and IL-6 also support the growth of TF-1 and thatIL-1 enhances the proliferative effect of these cytoklnes. Augmentationby IL-1 is associated with up-regulatlon of the receptors forIL-3, IL-5, GM-CSF, and erythropoietln (Epo). IL-1 increasedthe number of binding sites forIL-3 and Epo without changingtheir affinities. In contrast, IL-1 Increased the number ofhigh affinity binding sites forGM-CSF and IL-5, whereas thetotal number of binding sites was unchanged. Chemical crossllnkingexperiments Indicated that the receptors for IL-3, IL-5, andGM-CSF were composed of two components and that the molecularmasses of the larger components of these cytokine receptorswere quite similar (120 kd). The enhanced expression of thelarger components of theIL-3, IL-5, and GM-CSF receptors byIL-1 may be responsible for IL-1-induced up-regulation of thesereceptors. These observations are consistent with the modelthat the receptors for IL-3 and GM-CSF share a common component.     

Human olfactory epithelial cells generated in vitro express diverse neuronal characteristics

The olfactory epithelium constitutes the sole source of regenerating neural cells that can be obtained from a living human. As such, primary cultures derived from human olfactory epithelial biopsies can be utilized to study neurobiological characteristics of individuals under different conditions and disease states. Here, using such human cultures, we report in vitro generation of cells that exhibit a complex neuronal phenotype, encompassing receptors and signaling pathways pertinent to both olfaction and other aspects of CNS function. Using in situ hybridization, we demonstrate for the first time the native expression of olfactory receptors in cultured cells derived from human olfactory epithelial tissue. We further establish the presence and function of olfactory transduction molecules in these cells using immunocytochemistry, calcium imaging and molecular methods. Western blot analysis revealed the expression of neurotransmitter receptors for dopamine (D2R), 5-HT (5HT2C) and NMDA subtypes 1 and 2A/2B. Stimulation with dopamine or 5-HT enhanced receptor G protein activation in a subtype specific manner, based on 35S-guanosine triphosphate incorporation assay. Functional characteristics of the cultured cells are demonstrated through enhanced tyrosine phosphorylation of NMDAR 2A/2B and recruitment of signaling partners in response to NMDA stimulation. The array of neuronal characteristics observed here establishes that proliferating cells derived from the human olfactory epithelium differentiate in vitro to express functional and molecular attributes of mature olfactory neurons. These cultured neural cells exhibit neurotransmitter pathways important in a number of neuropsychiatric disorders. Their ready availability from living humans thus provides a new tool to link functional and molecular features of neural cells with clinical characteristics of individual living patients.     

Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in inflammatory disorders

Toll-like receptors (TLRs) and Nod-like receptors (NLRs) are two major forms of innate immune sensors, which provide immediate responses against pathogenic invasion or tissue injury. Activation of these sensors induces the recruitment of innate immune cells such as macrophages and neutrophils, initiates tissue repair processes, and results in adaptive immune activation. Abnormalities in any of these innate sensor-mediated processes may cause excessive inflammation due to either hyper responsive innate immune signaling or sustained compensatory adaptive immune activation. Recent gene association studies appear to reveal strong associations of NLR gene mutations and development of several idiopathic inflammatory disorders. In contrast, TLR polymorphisms are less often associated with inflammatory disorders. Nevertheless, TLRs are up-regulated in the affected tissue of most inflammatory disorders, suggesting TLR signaling is involved in the pathogenesis of chronic and/or idiopathic inflammatory disorders. NLR signaling results in the formation of a molecular scaffold complex (termed an inflammasome) and orchestrates with TLRs to induce IL-1β and IL-18, both of which are important mediators in the majority of inflammatory disorders. Therefore, understanding the roles of TLRs and NLRs in the pathogenesis of chronic and idiopathic inflammatory disorders may provide novel targets for the prevention and/or treatment of many common and uncommon diseases involving inflammation.