脑膜瘤细胞性激素受体表达与其中心供血动脉起源的关系

目的探讨脑膜瘤细胞性激素受体的表达及其与肿瘤中心供血动脉起源的关系。方法对43份脑膜瘤标本行免疫组化检测,观察性激素受体表达情况,分析其与中心供血动脉起源的关系。结果脑膜瘤细胞雌激素受体(ER)表达与肿瘤中心供血动脉起源无明显相关性;肿瘤中心供血动脉源于颈外动脉组时其孕激素受体(PR)和雄激素受体(AR)阳性率(26.9%,23.1%)明显低于颈内动脉组(88.9%,77.8%)及颈内外动脉联合组(87.5%,87.5%)(均P<0.05),而颈内动脉组与颈内外动脉联合组间PR和AR阳性率差异无显著性。结论脑膜瘤细胞PR、AR阳性表达率高可能与肿瘤中心供血动脉的起源有关。     

Overexpression of mdm2 and p53 and association with progesterone receptor expression in benign meningiomas

The progesterone receptor is frequently found expressed in meningiomas at robust levels. As several studies of breast and endometrial tumors have shown an inverse correlation between progesterone receptor expression and p53 overexpression, we sought to determine if a similar relationship existed in meningiomas. As p53 may also be inactivated by the overexpression of mdm2, we examined a cohort of 90 benign meningiomas immunohistochemically for the presence of the progesterone receptor as well as overexpression of p53 and mdm2. The progesterone receptor was detected in 67% (61/90) of cases, while p53 and mdm2 overexpression were detected in 14% (13/90) and 46% (42/90) of cases, respectively. An absolute correlation was observed between the overexpression of nuclear mdm2 and overexpression of the progesterone receptor, with nuclear mdm2 overexpression being confined to progesterone receptor‐positive tumors (P = 0.001). While p53 overexpression was not associated with progesterone receptor expression, a combination of mdm2 overexpression and/or p53 overexpression was significantly associated with the presence of the progesterone receptor (P = 0.025). These results suggest the existence of a novel relationship between p53 (and its regulatory control) and the presence of the progesterone receptor and, as such, may have fundamental consequences in developing progesterone receptor‐targeted therapies for meningiomas.     

Childhood meningiomas associated with meningioangiomatosis: report of five cases and literature review

Meningioangiomatosis is a unique, rare hamartomatous lesion. Meningiomas arising in the background of meningioangiomatosis are rare conditions which pathologically and radiologically mimic invasive meningiomas, but have a benign clinical course in children and young adults. In this study, five such cases are reported. To our knowledge, this is the largest reported collection of meningiomas associated with meningioangiomatosis. Less immunoreactivity for progesterone receptor and high Ki-67 labelling index are generally known to be associated with invasive meningiomas. However, high expression of progesterone receptor and low Ki-67 labelling index in the present cases supports the idea that brain invasion is not an indicator of malignancy but an independent finding associated with meningiomas which have arisen from meningioangiomatosis. We emphasize the good prognosis of such tumours and discuss pathogenesis of meningiomas with meningioangiomatosis.     

流式细胞术分析脑膜瘤细胞增殖与凋亡的实验研究

目的探讨脑膜瘤细胞增殖和凋亡在肿瘤发生、发展中的意义。方法应用流式细胞术检测42例脑膜瘤病人新鲜标本的肿瘤细胞周期分布、DNA倍性和细胞凋亡,比较不同病理级别间的差异。结果脑膜瘤增殖指数(PI)为8.91%±4.04%,异倍体率为21.4%,凋亡指数(AI)为9.16%±3.59%;非典型及恶性脑膜瘤的PI为11.56%±3.06%,异倍体率为50.0%,AI为11.26%±2.38%,均显著高于良性脑膜瘤(PI8.08%±3.99%,异倍体率12.5%,AI8.50%±3.68%)。结论脑膜瘤的增殖活性和细胞凋亡与肿瘤级别相关;细胞增殖和凋亡在脑膜瘤的发生、发展中具有重要的意义。     

Immunohistochemical expression of aromatase and estrogen,androgen and progesterone receptors in normal and neoplastic human meningeal cells

Evidence suggests that sex hormones may play a role in the tumorigenesis of meningiomas, and studies have demonstrated the expression of hormone receptors in these tumors. Aromatase expression has been detected in several normal tissues, including neurons in the CNS, and tumor tissues. We aim to assess the expression of aromatase (ARO) and of progesterone receptor (PR), estrogen receptor (ER) and androgen receptor (AR) in both normal and neoplastic meningeal cells. A cross‐sectional study was conducted with 126 patients diagnosed with meningioma (97 women and 29 men; mean age, 53.6 years) submitted to neurosurgery at Hospital São José, Complexo Hospitalar Santa Casa de Porto Alegre, southern Brazil. Control sections of normal meningeal cells, 19 patients, were obtained by evaluating the arachnoid tissue present in the arachnoid cyst resected material. Immunohistochemistry was applied to assess ARO, PR, ER and AR. Aromatase expression was detected in 100% of the control patients and in 0% of the patients with meningioma. ER was present in 24.6% of the meningiomas and in 0% of the controls, AR in 18.3% of the meningiomas and in 0% of the controls, and PR in 60.3% of the meningiomas and in 47.4% of the controls. A positive association was observed between the presence of AR and ER (OR 3.7; P = 0.01) in meningiomas. There were no significant differences in the presence of hormone receptors between meningioma histological subtypes. PR expression in women with meningioma was significantly higher than that found in men (OR 2.3; P = 0.08). Behavior pattern differences observed between aromatase expression, present in normal tissues and absent in meningiomas, and estrogen and androgen hormone receptors, absent in normal tissues and present in meningiomas, suggest that there is heterogeneity in modulation by sex steroids in the development of these tumors.     

Cannabinoid agonist WIN55,212-2 induces apoptosis in cerebellar granule cells via activation of the CB1 receptor and downregulation of bcl-xL gene expression

The endogenous cannabinoid system is involved in the regulation of a number of physiologic effects in both the central and peripheral nervous systems. Its role in the control of neuronal cell proliferation has attracted major attention because of its potential implications for new therapeutic strategies. In the present study, we demonstrated that treatment of cultured cerebellar granule cells with the synthetic cannabinoid WIN55,212-2, causes cell-body and nuclear shrinkage, which are hallmarks of neuronal apoptosis, as well as concentration-dependent decrease in cell viability. Staining with the fluorescent nuclear dye, Hoechst 33258, revealed apoptosis in 27.1% and 58.5% of cells exposed to 1 and 10 microM of WIN55,212-2, respectively (P < 0.01 and P < 0.001 vs. control respectively) after 36 hr. After 24 hr of exposure to WIN55,212-2, mRNA levels for the anti-apoptotic gene bcl-xL were reduced to 45.6% of those found in control (P < 0.01). These effects were completely reverted when cells were exposed to the synthetic cannabinoid in the presence of the specific CB1-receptor antagonist, SR141716A (1 microM). Moreover, the pro-apoptotic effect of 10 microM WIN55,212-2 could be reduced by the addition to the incubation medium of a cell-permeant inhibitor of caspase-1 (50 nM). Finally, WIN55,212-2 significantly increased caspase-1 activity after 24 hr. These findings show that the activation of CB1 receptors on cerebellar granule cells induces apoptotic cell death, which is associated with downregulation of the anti-apoptotic gene, bcl-xL, and at least in part, activation of caspase-1.     

Immunohistochemical expression of progesterone and estrogen receptors in meningiomas

In this study we present results of investigations of progesterone and estrogen receptors in most frequent, WHO grade I histological types of meningiomas (meningothelial, fibrous, and transitional) and in atypical--WHO grade II variant of these tumors. Samples from 64 tumors were examined. The cohort consisted of 46 WHO grade I (21 transitional, 13 fibrous and 12 meningothelial histologic variants) and of 18 atypical meningiomas. Apart from immunohistochemical examination of progesterone and estrogen receptors, MIB 1 labeling index was estimated. Positive immunoreaction for progesterone receptors was found in 100% meningothelial, 95% transitional, 46% fibrous and 78% atypical variant of meningiomas. Intensity of immunoreaction was stronger in grade I than in grade II tumors. Immunoexpression of estrogen receptors was found in 48% of the investigated meningiomas. No correlation was stated between WHO grade I and grade II tumors, and between meningothelial, transitional and fibrous variants of the neoplasms.     

Distribution of sex steroid hormone receptors in the brain of an African cichlid fish,Astatotilapia burtoni

Sex steroid hormones released from the gonads play an important role in mediating social behavior across all vertebrates. Many effects of these gonadal hormones are mediated by nuclear steroid hormone receptors, which are crucial for integration in the brain of external (e.g., social) signals with internal physiological cues to produce an appropriate behavioral output. The African cichlid fish Astatotilapia burtoni presents an attractive model system for the study of how internal cues and external social signals are integrated in the brain as males display robust plasticity in the form of two distinct, yet reversible, behavioral and physiological phenotypes depending on the social environment. In order to better understand where sex steroid hormones act to regulate social behavior in this species, we have determined the distribution of the androgen receptor, estrogen receptor alpha, estrogen receptor beta, and progesterone receptor mRNA and protein throughout the telencephalon and diencephalon and some mesencephalic structures of A. burtoni. All steroid hormone receptors were found in key brain regions known to modulate social behavior in other vertebrates including the proposed teleost homologs of the mammalian amygdalar complex, hippocampus, striatum, preoptic area, anterior hypothalamus, ventromedial hypothalamus, and ventral tegmental area. Overall, there is high concordance of mRNA and protein labeling. Our results significantly extend our understanding of sex steroid pathways in the cichlid brain and support the important role of nuclear sex steroid hormone receptors in modulating social behaviors in teleosts and across vertebrates. J. Comp. Neurol. 518:3302–3326, 2010. © 2010 Wiley‐Liss, Inc.     

Cytoplasmic iron deposition is associated with the expression of oxidative DNA damage marker in meningiomas

Angiomatous meningiomas are rare meningioma subtypes, which are characterized by abundant, well‐formed vessels. We encountered two cases of newly diagnosed angiomatous meningiomas exhibiting tumor cells with brown pigments, which were histochemically proven to be iron. In an attempt to understand its pathological significance, we assessed this unusual finding in representatives for each grade of meningiomas and immunoexpression of transferrin receptor (CD71) and the oxidative DNA damage marker, 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG). Iron deposition in the tumor cells was observed in 8/15 (53%) angiomatous meningioma cases, 2/6 (33%) microcystic meningiomas and 2/20 (10%) meningothelial meningiomas, which included clustered microvessels, but not in fibrous, atypical or anaplastic meningiomas (P = 0.001). Cytoplasmic CD71 expression was largely negative in angiomatous meningioma cases, but positive in meningothelial and high‐grade meningiomas, suggesting that the transferrin‐dependent iron transporter was involved in iron uptake in meningiomas. Nuclear expression of 8‐OHdG was observed in ≥50% of the tumor cells in all 15 cases of angiomatous meningioma and was associated with the presence of regressive histopathological findings, such as hyalinized vessels and cystic changes. In addition, the fraction of iron‐containing tumor cells was correlated to those expressing 8‐OHdG (P = 0.005). Our finding indicates that cytoplasmic iron deposition in tumor cells is characteristic of highly vascularized benign meningiomas and related to increased oxidative DNA damage markers.     

Erythropoietin receptor is expressed in meningiomas and lower levels are associated with tumour recurrence

Aims: The Epo‐EpoR pathway plays a role in tumour growth, metastasis and treatment resistance and is a potential target in oncological treatment. As the EpoR status in human meningiomas is unknown, our aim was to characterize EpoR expression in these tumours. Methods: We examined 131 meningioma samples of all WHO grades from 116 patients by immunohistochemistry for EpoR. Among these, 25 meningiomas showed brain invasion and 29 patients had a further tumour recurrence. A group of 20 patients without tumour recurrence served as controls. In 12 cases we were able to compare both the primary and the following recurrent tumours. The presence of EpoR in meningiomas was confirmed by RT‐PCR and Western blot. Results: EpoR was expressed in all meningiomas. Statistical analysis revealed that the mean expression levels of EpoR were significantly lower in primary tumours with known recurrence compared with a recurrence‐free control group. Additional matched pair analysis in individual cases showed no significant differences between primary and recurrent tumours. No significant correlation between EpoR expression and WHO grade, age, sex or brain invasion was detected. Using specific primer pairs for RT‐PCR, we were able to detect all three known isoforms of EpoR: the full‐length isoform EpoR‐F, the truncated isoform EpoR‐T and the soluble isoform EpoR‐S. Conclusions: Our results demonstrate the expression of EpoR in meningiomas. Lower EpoR mean levels might be a useful marker for a higher recurrence risk, but further studies are needed to clarify the influence of EpoR on recurrences and the role of the different isoforms.     

幕上星形细胞瘤的凋亡及相关基因p53、bcl—2的表达

目的 探讨幕上星形细胞瘤的细胞凋亡以及p53、bcl-2在凋亡中的意义。方法 免疫组化TUNEL法检测细胞凋亡,SP法检测p53、bcl-2,实验数据由SPSS软件包分析处理。结果 细胞凋亡指数（AI）随着肿瘤级别的增高而增加,各级别肿瘤间AI的差异均有显著性意义（P＜0．01）;死亡组与存活组的AI的差异有显著性意义（P＜0．01）,AI＞0．5％组与AI＜0．5％组的术后1年生存率的差异有显著性意义（P＜0．05）;AI／MI（分裂指数）在高、低级别的星形细胞瘤中的差异有显著性意义（P＜0．05）。p53阳性组与p53阴性组的AI、MI术后1年生存率的差异均有显著性意义（均P＜0．05）。bcl-2阳性组与阴性组的AI、MI、预后均无统计学意义（均P＞0．05）。多因素logistic回归分析年龄分组、AI、AI／MI、放疗均与预后优劣相关。结论 AI可以作为提示预后的指标,并对判断幕上星形细胞瘤的生物学行为及肿瘤分级有指导意义;AI／MI值越小,肿瘤的恶性转化能力越强,预后越差;p53过度表达提示肿瘤恶性程度高、预后差;AI＜0．5％、AI／MI值大的、年龄较轻的、术后放疗病人预后较好。     

Immunohistochemical analysis of cyclooxygenase‐2 and brain fatty acid binding protein expression in grades I‐II meningiomas: Correlation with tumor grade and clinical outcome after radiotherapy

This study was done to evaluate the association of cyclooxygenase 2 (COX‐2) and brain fatty acid binding protein (BFABP) with tumor grade and outcome of grades I‐II meningiomas treated with radiotherapy. From 1996 to 2008, 40 patients with intracranial grades I‐II meningiomas were treated with radiotherapy. Immunohistochemical staining for COX‐2 and BFABP were performed on formalin‐fixed paraffin‐embedded tissues. COX‐2 expression was significantly associated with BFABP status and both COX‐2 (P < 0.01) and BFABP (P = 0.01) expression were stronger in the grade II meningiomas than in grade I tumors. Among the clinicopathologic factors, age and COX‐2 status were prognostic in progression‐free survival. Patients with moderate or strong COX‐2 expression had worse outcome than those with negative or weak COX‐2 expression (P = 0.03) after controlling for potential confounders. Our results suggest that the molecular biomarker COX‐2 has prognostic significance in intracranial grades I‐II meningiomas following radiotherapy.     

Accumulation of wild-type p53 in meningiomas

The p53 tumour suppressor gene contributes to the regulation of DNA repair and the initiation of apoptosis. Mutations of this gene and nuclear accumulation of its protein product are features of a large variety of turnours. A histological spectrum of meningiomas, including anaplastic examples and a meningosarcoma. was analysed for accumulation of the p53 protein and mutations in exons 4–9 of the p53 gene. No mutations were found, but 9134 (26%) tumours showed accumulation of the p53 protein. The p53-positive meningiomas came from across the histological spectrum and were not restricted to the anaplastic group. The accumulation of wild-type p53 in a proportion of meningiomas may reflect this gene's role in DNA repair, or its enhanced stability when bound to cellular proteins such as the mdm-2 gene product.     

脑膜瘤FASN、HER-2的表达与术后复发的关系

目的 探讨脑膜瘤脂肪酸合成酶（FASN）、人表皮生长因子受体2（HER-2）的表达与术后复发的关系。方法回顾性分析2017年9月至2020年9月手术治疗的121例脑膜瘤的临床资料。免疫组化染色检测脑膜瘤组织FASN和HER-2表达水平,术后1年复查影像学检查判断肿瘤复发情况。结果 121例中,WHO分级2级84例,3级37例;术后肿瘤复发52例（43.0%）,未复发69例。复发组脑膜瘤组织FASN、HER-2表达水平明显高于未复发组（P<0.05）。多因素Cox回归分析显示,FASN、HER-2高表达是间变性脑膜瘤术后复发的独立危险因素（P<0.05）。结论 间变性脑膜瘤FASN、HER-2呈高表达,与术后复发相关。     

NF2 gene expression in sporadic meningiomas: Relation to grades or histotypes real time‐PCR study

One of the most common regions involved in the meningiomas tumorigenesis is chromosome 22q where the NF2 gene resides. The deficiency or loss of the NF2 gene product, merlin/schwannomin, plays a role in tumor development and metastatization. Conflicting results have been reported on the prognostic value of merlin in meningiomas. Several studies have indicated NF2 gene inactivation as an early tumorigenic event unrelated to the histological grade or clinical behavior. On the contrary, the NF2 gene alteration rate differs between the different histotypes. A pathogenesis independent from the NF2 gene has been suggested in meningothelial meningiomas. In the present work, we studied the NF2 gene expression through real time‐PCR (RT‐PCR) in 30 meningiomas. The average of the NF2 gene expression of all meningiomas was considered as reference value. The average of expression of WHO grade I and II meningiomas was higher than the average of all meningiomas, whereas that of WHO grade III meningiomas was lower. When we compared the NF2 gene expression in the different meningioma grades we did not note a significant difference (P = 0.698) despite the tendency to decrease from grade I to grade III. The average expression of meningothelial meningiomas was higher than the reference value, and that of non‐meningothelial meningiomas was lower. The difference in NF2 gene expression between meningothelial and non‐meningothelial meningiomas was statistically significant (P = 0.013). Our data supports the finding that alterations in NF2 gene alteration are histotype related but not grade related.     

Expression of ovarian steroid hormone receptors in tuberoinfundibular dopaminergic neurones during pregnancy and lactation

During late-pregnancy, tuberoinfundibular dopaminergic (TIDA) neurones, a critical component of the negative-feedback loop regulating prolactin secretion, become unresponsive to the stimulatory effects of prolactin. The change in TIDA responsiveness to prolactin at this time results in a decrease in dopamine secretion and a prolactin surge. As the onset of parturition and the antepartum prolactin surge depend on the withdrawal of progesterone in the presence of oestrogen, it is likely that ovarian steroid hormones mediate this change in TIDA responsiveness. To determine whether ovarian steroids can directly modulate TIDA activity, and whether changes of receptor numbers might contribute to overall steroid-regulation of these neurones, we investigated the level of oestrogen receptor alpha (ERalpha) and progesterone receptor (PR) expression within TIDA neurones during pregnancy and lactation. Animals were sacrificed on dioestrous, days 12, 19 and 21 of pregnancy and day 5 of lactation, and the proportion of TIDA neurones expressing ERalpha or PR, as well as the total number of PR expressing cells within the arcuate nucleus, was determined. Approximately 75% and 55% of tyrosine hydroxylase neurones expressed ERalpha and PR, respectively. Levels of steroid receptor expression within TIDA neurones remained fairly constant, except for an increase in ERalpha on days 12 and 19 of pregnancy compared to dioestrous and lactation day 5. The presence of steroid receptors on TIDA neurones during pregnancy and lactation supports the concept of a direct effect of steroid hormones on these neurones at this time. Thus, steroid hormones may directly act on TIDA neurones to regulate maternal prolactin secretion. The relatively stable level of expression during late pregnancy suggests that a shift in steroid receptor expression during late pregnancy does not contribute to the change in TIDA responsiveness to prolactin at this time.     

TGF-beta induces cell death in the oligodendroglial cell line OLI-neu

We have shown that TGF-beta plays an important role during the period of developmental cell death in the nervous system. Immunoneutralization of TGF-beta prevents ontogenetic neuron death in vivo. Like neurons, oligodendrocytes are generated in excess and eliminated by apoptosis. It has been shown that oligodendrocyte progenitors and newly formed oligodendrocytes are especially susceptible to apoptosis. We choose the oligodendrocyte precursor cell line OLI-neu to address the question if TGF-beta could play a role for the control of oligodendrocyte proliferation and cell death. Flow cytometric analysis revealed that OLI-neu cells arrested in the G1 phase of the cell cycle underwent apoptosis in response to TGF-beta. TUNEL assays, apoptosis ELISA, and caspase assays substantiated the finding that OLI-neu cells died after TGF-beta treatment. Cell death could be inhibited by application of pan-caspase or caspase 8 and 9 inhibitors, whereas the inhibition of calpain was unaffected. Furthermore, we found a reduction of bcl-X(L) at the protein as well as at the mRNA level, while p27 was upregulated. The Smad cascade was activated while TGF-beta reduced the activity of the p42/p44 MAP kinase pathway. Together, these data show that TGF-beta induced apoptotic cell death in cells of oligodendroglial origin, whereby the signaling cascade involved the downregulation of antiapoptotic signaling such as bcl-X(L) leading to the activation of caspases.     

垂体腺瘤雌孕激素受体的研究

目的:为了解垂体腺瘤的雌、孕激素受体分布情况及临床意义。方法:采用免疫组化方法检测了60例手术治疗的垂体腺瘤的雌激素受体(ER)、孕激素受体(PR),并结合内分泌功能分类和临床影像学检查进行研究。结果:研究表明,垂体腺瘤ER阳性率为77％,PR阳性率为67％。大的巨腺瘤ER、PR阳性率低于微腺瘤(PR间x~2=8.158,P=0.017<0.05)。细胞生长活跃的腺瘤ER、PR常阴性。不同功能类型的垂体腺瘤ER、PR阳性率亦不同。结论:研究提示ER、PR与垂体腺瘤的分化侵袭有关,ER、PR检测可能是垂体腺瘤选择治疗和评估预后的一项指标。     

脑胶质瘤中端粒酶活性表达及与增殖、凋亡的相关性

目的观察不同级别人脑胶质瘤中端粒酶活性表达及与增殖、凋亡的相关性。方法采集手术中切除的不同级别人脑新鲜胶质瘤标本26例,脑外伤内减压脑组织8例,用TRAP法及TUNEL法、PCNA免疫荧光染色流式细胞仪法检测不同级别脑胶质瘤端粒酶活性以及凋亡、增殖细胞百分率。结果脑胶质瘤中端粒酶活性阳性表达率及代表端粒酶活性的平均△A值,在Ⅰ、Ⅱ级和Ⅲ、Ⅳ级之间差别显著(P<0.05),各个级别与对照组之间均差别显著(P<0.05),对照组脑组织端粒酶活性均为阴性。平均PCNA阳性细胞率在正常组,Ⅰ、Ⅱ级和Ⅲ、Ⅳ级之间存在显著性差异(P<0.01)。TUNEL阳性细胞率在正常组与其余各组之间均存存显著差异(P<0.01),Ⅳ级与其余各组之间亦均存在显著差异(P<0.05)。代表端粒酶活性的平均△A值(r=0.78,P<0.05)以及平均PCNA阳性细胞率(r=0.86,P<0.01)分别与胶质瘤恶性级别呈正相关。结论脑胶质瘤中,端粒酶活性阳性及PCNA阳性表达细胞率可作为预测胶质瘤化疗效果和脑胶质瘤恶性程度的标志之一,端粒酶活性表达水平和增殖活性与胶质瘤细胞恶性级别具有相关性。