垂体瘤中PTEN及CyclinD1抑癌基因的表达及临床意义

本研究以垂体瘤患者垂体组织为研究对象,探讨了抑癌基因PTEN及CyclinD1表达的临床意义,分析了其与垂体瘤侵袭性的相关性。结果发现,垂体瘤患者垂体组织抑癌基因PTEN的表达低于正常垂体组织,同时垂体瘤患者垂体组织CyclinD1表达高于正常垂体组织(p0.05)。垂体瘤组织PTEN的mRNA表达低于正常垂体组织,而CyclinD1的mRNA表达高于正常垂体组织(p0.05)。垂体瘤患者垂体组织抑癌基因PTEN低表达的患者CyclinD1呈现高表达,相关性分析发现两者呈负相关(p0.05)。抑癌基因PTEN及CyclinD1表达与垂体瘤侵袭性相关,可作为垂体瘤患者的诊断和预后指标。     

替莫唑胺治疗胶质母细胞瘤的耐药性产生机制研究进展

胶质母细胞瘤作为胶质瘤中恶性程度最高的原发性脑部肿瘤,具有治愈率低、复发率高、呈浸润性生长等特点,在不使用化疗药物的情况下,患者中位生存期仅为12.1个月。胶质母细胞瘤患者的标准治疗方法以手术切除为主,放化疗为辅,其中替莫唑胺（temozolomide,TMZ）作为一种新型的口服烷化剂,是目前用于胶质瘤化学治疗的一线药物。但经过替莫唑胺治疗后,患者中位生存期仅提高了2个月,主要原因为胶质母细胞瘤可对TMZ产生耐药性。胶质母细胞瘤对TMZ产生的耐药机制主要为DNA修复机制,其包括了O⁶?甲基鸟嘌呤DNA甲基转移酶（O⁶?methyl guanine DNA methyltransferase,MGMT）对药物作用位点进行的直接修复、错配修复（mismatch repair,MMR）及碱基切除修复（base excision repair,BER）,这些修复机制可修复TMZ引起的DNA损伤,从而降低肿瘤细胞对TMZ敏感性。通过对近年来胶质母细胞瘤的TMZ耐药机制的研究进展进行介绍,旨在为发展新的治疗手段提供理论基础。     

垂体瘤微环境免疫细胞浸润与肿瘤侵袭性的相关性研究

目的:探讨垂体瘤免疫微环境中免疫细胞浸润情况及其与垂体瘤侵袭性的相关性。方法:选取35例垂体瘤病理组织切片,通过免疫组化染色分析巨噬细胞、T细胞以及中性粒细胞的特异性标记蛋白CD68、CD4、CD8和MPO的表达情况。结合临床和影像学数据分析,分析生长激素腺瘤、泌乳素腺瘤和无功能腺瘤的侵袭性与免疫细胞浸润数量的相关性。结果:在15例生长激素腺瘤,10例泌乳素腺瘤和10例无功能性腺瘤患者中,侵袭性垂体瘤中有更多的巨噬细胞浸润(P分别为0.014,0.032和0.032)。侵袭性促生长激素腺瘤、泌乳素腺瘤和无功能性腺瘤巨噬细胞浸润数量均明显多于非侵袭性促生长激素腺瘤、泌乳素腺瘤和无功能性腺瘤(P0.05)。结论:在垂体腺瘤中,巨噬细胞是肿瘤免疫微环境的主体。巨噬细胞浸润可能促进垂体瘤的进展。     

GSTP1、E-cadherin 在垂体腺瘤中的表达及临床意义

目的:研究谷胱甘肽S-转移酶P1(GSTP1)、上皮钙粘蛋白(E-cadherin)在垂体腺瘤中的表达及临床意义。方法:应用免疫组化SP染色法检测30例侵袭性垂体腺瘤与30例非侵袭性垂体腺瘤中GSTP1、E-cadherin的表达。结果:GSTP1在侵袭性垂体腺瘤中的表达较非侵袭性垂体腺瘤显著降低(P<0.05);E-cadherin在侵袭性垂体腺瘤中的表达较非侵袭性垂体腺瘤显著降低(P<0.05);GSTP1、E-cadherin在垂体腺瘤中的表达呈正相关(r=0.82,P<0.05)。结论:GSTP1、E-cadherin在垂体腺瘤中的表达与肿瘤侵袭程度显著相关,两者联合检测有助于判断垂体腺瘤侵袭性及预后。     

HIF-1α 在垂体腺瘤中的表达及与垂体腺瘤侵袭性的关系

目的:研究缺氧诱导因子-1α(HIF-1α)在人垂体腺瘤中的表达,对HIF-1α蛋白表达与肿瘤分级进行相关性分析,探讨其表达水平与垂体腺瘤侵袭性的关系.方法:集影像学检查、内分泌学检查及病理诊断的垂体腺瘤60例,分为侵袭组和非侵袭组,其中侵袭组36例,非侵袭组24例;对照组正常脑组织5例.免疫组织化学技术检测HIF-1α蛋白的表达,结合临床资料进行统计学分析.分析垂体腺瘤HIF-1α蛋白的表达水平并与对照组进行比较,比较侵袭组和非侵袭组垂体腺瘤之间HIF-1α蛋白表达水平的差异.结果:HIF-1α蛋白在垂体腺瘤中的表达明显高于对照组,二者比较,x20.05,1=12.392,P＜0.001,有显著性差异;侵袭组HIF-1α蛋白的表达较非侵袭组显著增高,二者比较,x20.05.1=24.658,P＜0.001,有显著性差异.结论:H1F-1α是垂体腺瘤侵袭过程中的重要调控因子,与垂体腺瘤的大小、分级以及侵袭性密切相关,其作用机制有待进一步研究,其表达程度可用作垂体腺瘤预后的评估指标,为垂体腺瘤术后的复发以及相应的辅助治疗提供判断依据.有可能为人们靶向肿瘤缺氧来开发新药物提供新的作用靶点.     

氧调节蛋白150在人肝细胞癌中的过度表达及其对凋亡的作用

在前期研究中发现,氧调节蛋白150(ORP150)是与肝细胞癌相关的糖蛋白．进一步研究了ORP150的表达水平与肝细胞癌的相关性．免疫印迹、细胞免疫化学和定量PCR分别在蛋白质水平和mRNA水平检测了ORP150的表达．运用RNA干扰技术检测了其对凋亡和肝细胞癌侵袭性的影响．发现：无论是蛋白质水平还是mRNA水平,与正常肝细胞相比,ORP150在肝细胞癌中表达明显上调;经RNA干扰后,肝细胞癌的凋亡明显增加,但肿瘤细胞的侵袭性无改变．肝细胞癌中,ORP150表达上调,它可能抑制肿瘤细胞的凋亡而促进其生长．ORP150有可能成为肝细胞癌的治疗靶点．     

乳腺浸润性导管癌中PTTG与MMP-2和MMP-9 的表达及相关性

垂体瘤转化基因（PTTG）具有促进体外细胞转化和体内致瘤的能力,在乳腺癌组织中高表达,并与乳腺癌的复发和淋巴结转移有关.但PTTG 能否通过调节基质金属蛋白酶(MMP-2、MMP-9) 调控乳腺癌的侵袭与转移尚不清楚.本研究证明,PTTG可能因促进乳腺癌细胞中 MMP-2、MMP-9 分泌而在乳腺癌细胞侵袭、转移中发挥重要作用.免疫组织化学 PV 9000 通用型两步法显示,60例乳腺浸润性导管癌组织中,PTTG、MMP-2 和 MMP-9表达定位于肿瘤细胞胞浆,阳性率与周围正常乳腺组织相比,差异均具有统计学意义(P＜0.05).三者阳性表达均与淋巴结转移及TNM分期有关(P＜0.05);与患者年龄、肿瘤大小等无关(P＞0.05).乳腺浸润性导管癌中PTTG分别与MMP-2、MMP-9的表达呈正相关(P＜0.05).小RNA干扰技术干扰乳腺癌细胞株 MDA-MB-231 中的PTTG,Western印迹结果显示,干扰组与对照组相比,PTTG、MMP-2 和 MMP-9蛋白的表达水平明显下降. Transwell 侵袭实验显示,干扰组肿瘤细胞体外侵袭能力明显降低(P＜0.01).本研究表明,PTTG可能通过促进乳腺癌细胞中 MMP-2、MMP-9分泌,促进乳腺癌细胞的侵袭、转移.     

Ets-1和c-Jun在腺样囊性癌中表达的临床病理研究

目的:观察Ets-1和c-Jun在腺样囊性癌中的表达及在肿瘤侵袭中的意义.方法:收集80例腺样囊性癌病例,根据组织病理学观察分为侵袭组和非侵袭组,用免疫组织化学SP方法分别检测Ets-1和c-Jun在腺样囊性癌组织中的表达.结果:(1)Ets-1、c-Jun在腺样囊性癌组织中的总阳性表达率分别为76.25%(61/80),62.5%(50/80);(2)Ets-1和c-Jun表达在侵袭组和非侵袭组间均有差异,有统计学意义(P(0.05);(3)Ets-1和c-Jun表达间无显著相关性.结论:Ets-1和c-Jun表达与腺样囊性癌的侵袭有关.     

过表达TNFAIP1促进替莫唑胺对人脑胶质瘤细胞U251迁移和侵袭的抑制作用

为了深入研究人脑胶质瘤治疗时耐药的发生机制,并寻求潜在的治疗手段,以人脑胶质瘤细胞U251为研究对象,研究肿瘤坏死因子α诱导蛋白1(TNFAIP1)对其迁移和侵袭的影响。半定量PCR和蛋白质免疫印迹(Western blot)试验发现,替莫唑胺(TMZ)会上调U251细胞内TNFAIP1的表达。在U251细胞中过表达TNFAIP1后,发现上调TNFAIP1的表达能促进TMZ对U251细胞迁移及侵袭的抑制作用,并且这一作用是通过抑制上皮-间充质转化(EMT)信号通路来实现的。这一发现有助于为人脑胶质瘤的临床治疗提供新的理论依据,为其治疗方法提供新的策略。     

GSTP1、E-cadherin在垂体腺瘤中的表达及临床意义

目的：研究谷胱甘肽S-转移酶P1（GSTP1）、上皮钙粘蛋白（E-cadherin）在垂体腺瘤中的表达及临床意义。方法：应用免疫组化SP染色法检测30例侵袭性垂体腺瘤与30例非侵袭性垂体腺瘤中GSTP1、E-cadherin的表达。结果：GSTP1在侵袭性垂体腺瘤中的表达较非侵袭性垂体腺瘤显著降低（P〈0.05）;E-cadherin在侵袭性垂体腺瘤中的表达较非侵袭性垂体腺瘤显著降低（P〈0.05）;GSTP1、E-cadherin在垂体腺瘤中的表达呈正相关（r=0.82,P〈0.05）。结论：GSTP1、E-cadherin在垂体腺瘤中的表达与肿瘤侵袭程度显著相关,两者联合检测有助于判断垂体腺瘤侵袭性及预后。     

Pituitary Apoplexy in Five Patients with Pituitary Tumours

Five cases of pituitary apoplexy occurring in patients with pituitary tumours are described. This uncommon condition is characterized by headache, sudden loss of vision, alteration in the level of consciousness, and usually an abnormal cerebrospinal fluid. The whole picture may be complicated by endocrine dysfunction. The diagnosis is strengthened by a radiologically abnormal pituitary fossa and confirmed by the operative finding of haemorrhagic necrotic tissue. Surgical decompression under steroid cover offers the only hope of restoration of vision. Frequent postoperative follow-up is obligatory.     

Pituitary Apoplexy in Nonfunctioning Pituitary Macroadenomas: A Case-Control Study

ObjectivePituitary apoplexy (PA) is an endocrinologie emergency characterized by headache, visual abnormalities, and hemodynamic instability in the context of hemorragic infarction of a pituitary adenoma. Our goal was to estimate the incidence, precipitating factors, clinical characteristics, and outcome of PA in a cohort of patients with nonfunctioning pituitary macroadenomas (NFPMAs).MethodsA retrospective, case-control study of 46 patients with PA and 47 controls matched for age, gender, and tumor invasiveness. Clinical, hormonal, and tumoral charactersitics, as well as the presence of potential precipitating factors and long-term outcome were evaluated using both bivariate and multivariate analysis.ResultsThe prevalence of PA was 8%. Cases and controls were similar in regards to the prevalence of diabetes, hypertension, use of antiplatelet agents, and the presence of headaches and visual field defects. Oculomotor paralysis was present in 18% of cases and in none of the controls (P = .001). Prior use of dopamine agonists was significantly more frequent among cases than in controls on both bivariate and multivariate analysis. Pituitary hormone deficiencies were more common among cases than in controls on bivariate but not on multivariate analysis. Early and late surgical treatment was carried out in 11 and 25 patients, respectively; 11 patients were managed conservatively. Visual and endocrine outcomes were similar among the 3 groups.ConclusionPA represents a life-threatening medical emergency. Prior use of dopamine agonists and the presence of oculomotor abnormalities clearly distinguished patients with NFPMA who developed PA from those who did not. (Endocr Pract 2014;20:1274-1280)     

垂体偶发瘤的研究进展

垂体偶发瘤(Pituitary Incidentalomas)是指因进行尸检或进行与垂体病变无关的头部影像学检查过程中偶然发现的垂体病变,其特点是不具有与垂体疾病相关的临床表现。其尸检发现率约10.7%,影像学检查发现率低于尸检,不同文献报道差异较大。垂体偶发瘤如不进行治疗,10%的偶发微腺瘤和24%的偶发大腺瘤会出现瘤体增大,瘤体增大是明确的手术指征。因此,患者应定期进行头部MRI扫描以明确瘤体有无增大。本文对垂体偶发瘤的相关文献进行回顾分析。     

Pituitary Carcinoma in Situ

ObjectivePituitary carcinomas are extremely rare tumors associated with poor prognosis despite surgery, radiation, and chemotherapy. The hallmark of diagnosis implies subarachnoid, brain, or systemic tumor spread.MethodsWe report a case of rapid transformation of atypical nonfunctioning pituitary adenoma to a carcinoma.ResultsA 64-year-old woman presented with sudden onset of ophthalmoplegia. Magnetic resonance imaging (MRI) scan showed a pituitary macroadenoma (2.2 × 2.1 cm) with invasion of the right cavernous sinus. Biochemical data was consistent with a nonfunctioning pituitary adenoma. Pathology showed a pituitary adenoma with negative immunohistochemistry for pituitary hormones. The patient returned a month later with weakness, lethargy, and a dilated nonreactive right pupil. MRI showed an invasive large mass (5 × 4.7 cm). After an emergent second transsphenoidal surgery, histopathologic examination revealed a widely infiltrative neoplasm invading the overlying mucosa and showing a high mitotic activity and necrosis and a very high Ki-67 (MIB-1) proliferation index (80%). MIB-1 retrospectively performed on the first specimen was also elevated (30%). Soon after the second surgery, MRI showed a 7.9 × 8.0 cm mass that metastasized to dura mater and extended into the right orbit, right middle cranial fossa, nasopharynx, clivus, posterior fossa, and along the right tentorium cerebelli, resulting in significant compression of the brainstem.ConclusionDevelopment of a pituitary carcinoma from an adenoma is an exceptional occurrence and predictors of such course are currently lacking. A very high Ki-67 proliferation index should raise concern of a pituitary carcinoma in situ or premetastatic carcinoma. (Endocr Pract. 2013;19:e69-e73)     

Pituitary endopeptidases

This review summarizes our knowledge of pituitary endopeptidases. Emphasis has been placed on well-characterized enzymes and their potential roles in proteolytic processes of the pituitary. Because of space limitations, degradation of biologically active peptide by crude preparations has generally not been discussed. Only a few proteolytic enzymes are at present adequately characterized, and knowledge of their physiological function in vivo is insufficient. Among the many functions of proteolytic enzymes, those that are specific for the pituitary as an endocrine gland are of primary interest. Such functions include inactivation of neuropeptides and factors that control the secretory function of the pituitary, processing of precursors destined for secretion, selective cleavage of prohormones into active fragments, and degradation of inactive fragments. While some of the enzymes described here, such as cathepsin D, could be expected to have primarily a degradative function, others could potentially be involved in hormonal metabolism, since they exhibit trypsin-like, chymotrypsin-like, and dipeptidyl carboxypeptidase-like activities, all potentially useful in hormonal conversions. Data suggestive of the presence in the pituitary of enzymes involved in removal of the 'signal sequence', and enzymes involved in hormone processing by cleavage of bonds after a pair of basic residues and in the subsequent removal of these residues by a carboxypeptidase B-like activity have been published. None of these enzymes, however, has been isolated or purified to a degree that would allow determination of its specificity, mechanisms of action, physicochemical properties, and susceptibility to specific inhibitors. Questions that remain unresolved ask whether differences in the processing pathways in various anatomical parts of the pituitary are due to the presence of proteases with different specificities, or to different disposition of these enzymes, and factors, such as conformation of the substrate and its secondary modification, for example by glycosylation or phosphorylation. Proof of a functional involvement of a protease in hormonal processing should include demonstration that inhibition of activity results in inhibition of processing in the intact cell. Specific inhibitors of processing enzymes could potentially be used to modulate pituitary function, and thus have pharmacological interest. Although there are few answers to the above problems at present, the questions are well defined, and it can be expected that the rapidly expanding research on pituitary proteases will soon provide some of the answers.     

Localization of Carboxyl Ester Lipase in Human Pituitary Gland and Pituitary Adenomas

Carboxyl ester lipase (CEL) is an enzyme that hydrolyzes a wide variety of lipid substrates, including ceramides, which are known to show inhibitory regulation of pituitary hormone secretion in experimental models. Because no studies on CEL expression in human pituitary and pituitary adenomas have been reported in the literature, we investigated CEL expression in 10 normal pituitary glands and 86 well-characterized pituitary adenomas [12 FSH/LH cell, 17 α-subunit/null cell, 6 TSH cell, 21 ACTH cell, 11 prolactin (PRL) cell, and 19 GH cell adenomas] using IHC, immunoelectron microscopy, Western blotting, and quantitative RT-PCR. In normal adenohypophysis, CEL was localized in GH, ACTH, and TSH cells. In adenomas, it was mainly found in functioning GH, ACTH, and TSH tumors, whereas its expression was poor in the corresponding silent adenomas and was lacking in FSH/LH cell, null cell, and PRL cell adenomas. Ultrastructurally, CEL was localized in secretory granules close to their membranes. This is the first study demonstrating CEL expression in normal human pituitary glands and in functioning GH, ACTH, and TSH adenomas. Considering that CEL hydrolyzes ceramides, inactivating their inhibitory function on pituitary hormone secretion, our findings suggest a possible role of CEL in the regulation of hormone secretion in both normal and adenomatous pituitary cells. (J Histochem Cytochem 58:881–889, 2010)