抗人巨细胞病毒免疫球蛋白G在脑胶质瘤的表达及与预后的相关性

目的:探讨抗人巨细胞病毒免疫球蛋白G（HCMV IgG）水平在脑胶质瘤的表达及与预后的相关性。方法:选择2013年1月至2017年8月在我院就诊并接受手术切除的脑胶质瘤患者作为研究对象，入组后测定患者抗HCMV IgG水平，观察抗HCMV IgG表达及水平与脑胶质瘤患者特征与预后的相关性。结果:患者抗HCMV IgG阳性表达率为76.17％。抗HCMV IgG与年龄、性别、肿瘤部位、肿瘤大小、病程、KPS评分等均无相关性（P＞0.05），与肿瘤分级存在正相关（P＜0.05）。肿瘤分级、手术方式、替莫唑胺疗程和抗HCMV IgG表达是影响患者1年死亡率的独立预后因素（P均＜0.05）。对IgG阳性患者进一步分析显示，抗HCMV IgG＜10 U/ml患者生存期低于10～29 U/ml和≥30 U/ml患者（P＜0.05），抗HCMV IgG≥30 U/ml患者生存期高于10～29 U/ml患者但差异无统计学意义（P＞0.05）。结论:抗HCMV IgG表达与胶质瘤恶性程度呈正相关，与生存期呈负相关，抗HCMV IgG低表达患者具有更差的预后，应引起临床关注。     

全反式维甲酸对荷瘤Wistar大鼠生存期的影响及其机制

目的研究全反式维甲酸对荷瘤鼠生存期的影响及其机制。方法建立wistar大鼠脑内C6胶质瘤模型，待肿瘤生长至第7天，随机将荷瘤鼠分为维甲酸治疗组和对照组。于接种后的第22天，免疫组化检测各组P27Kip1蛋白的表达并观察动物生存期。结果与对照组相比，治疗组动物p27kip1蛋白的表达增高（P〈0．05），生存期延长（P〈0．05），两者呈正相关。结论全反式维甲酸延长动物生存期的机制同上调p27kip1蛋白的表达有关。p27kip1蛋白的表达高低可作为判断胶质瘤预后的指标。     

全反式维甲酸对荷瘤Wistar大鼠生存期的影响及其机制

 目的研究全反式维甲酸对荷瘤鼠生存期的影响及其机制。方法建立wistar大鼠脑内C6胶质瘤模型，待肿瘤生长至第7天，随机将荷瘤鼠分为维甲酸治疗组和对照组。于接种后的第22天，免疫组化检测各组P27Kip1蛋白的表达并观察动物生存期。结果与对照组相比，治疗组动物p27kip1蛋白的表达增高（P〈0．05），生存期延长（P〈0．05），两者呈正相关。结论全反式维甲酸延长动物生存期的机制同上调p27kip1蛋白的表达有关。p27kip1蛋白的表达高低可作为判断胶质瘤预后的指标。     

全反式维甲酸治疗大鼠C6脑胶质瘤的实验研究

[目的]探讨全反式维甲酸治疗大鼠C6脑胶质瘤的疗效及其机制。[方法]建立大鼠C6脑胶质瘤模型,腹腔注射全反式维甲酸后,MRI检测胶质瘤的体积变化,免疫组化检测胶质纤维酸性蛋白（GFAP）的表达并观察生存期。[结果]治疗组较对照组肿瘤体积明显减小（P〈0.05）;生存期延长（P〈0.05）;GFAP表达增加（P〈0.05）。GFAP的表达同肿瘤体积呈负相关（P〈0.05）。[结论]全反式维甲酸治疗可延长荷瘤鼠生存期,其机制与上调GFAP的表达有关。     

lnc SNHG20和miR-495在胶质瘤中的表达关系及临床意义

目的:探讨lnc SNHG20和miR-495在人胶质瘤中的表达关系及临床意义。方法:通过实时荧光定量PCR（qRT-PCR）检测85例人胶质瘤组织和85例正常脑组织中lnc SNHG20和miR-495的表达水平，并分析lnc SNHG20和miR-495表达与临床病理特征的关系，采用Spearman相关分析法分析人胶质瘤组织中lnc SNHG20和miR-495表达相关性，Kaplan-Meier法评估lnc SNHG20和miR-495与患者生存期的关系，采用Cox回归模型分析影响患者预后因素。结果:与正常脑组织相比，人胶质瘤组织中lnc SNHG20表达水平显著升高（P＜0.05），miR-495表达水平显著下降（P＜0.05）。lnc SNHG20和miR-495表达与胶质瘤患者年龄、性别以及肿瘤位置无关（P＞0.05），与肿瘤直径和肿瘤分级相关（P＜0.05）。Spearman相关分析结果显示，lnc SNHG20和miR-495表达呈负相关（r=-0.795，P＜0.05）。Kaplan-Meier生存分析结果显示，lnc SNHG20高表达患者3年总存活率明显低于lnc SNHG20低表达患者（P＜0.05），miR-495高表达患者3年总存活率明显高于miR-495低表达患者（P＜0.05）。lnc SNHG20和miR-495是影响胶质瘤患者预后的独立因素。结论:人胶质瘤组织中lnc SNHG20和miR-495表达异常，两者呈负相关，且与胶质瘤的恶性程度、患者的生存期及预后关系密切，可能成为胶质瘤诊断、治疗及预后的新靶点。     

82例脑胶质瘤立体定向放射治疗的疗效观察

目的探讨立体定向放射治疗（SRT）对于脑胶质瘤患者的治疗效果。方法采用SRT治疗82例脑胶质瘤，其中初治63例，复治19例。所有患者均采用分次立体定向放射治疗（FSRT）。中位照射剂量46Gy，中位随访期为25个月（12-36个月）。结果全组局部病灶控制率为68．3％（56／82），中位生存期（MST）为12．5个月。初治和复治者MST分别为19．5和9．5个月。1年生存率为58．5％（48／82）。结论SRT可有效控制局部病灶，可作为瘤体较小、边界较清楚胶质瘤的一种安全有效治疗手段。     

胶质瘤侵袭性研究相关进展

胶质瘤（glioma）是成人最常见、致死率最高的颅内恶性肿瘤。尽管在手术、放疗、化疗等治疗方法已经取得了进步,但胶质瘤病人的中位生存期仅为（14～15）个月。胶质瘤细胞能沿着血管渗透、侵袭至周边正常的脑组织,使肿瘤无法整体切除,也限制了局部放疗的效果,无法避免肿瘤复发,并且会损伤正常的脑组织。因此对胶质瘤细胞生物学行为及其机制的研究对胶质瘤的治疗具有重大意义。本文将对影响胶质瘤的侵袭性信号通路及 micro －RNA 研究进展予以概述。     

淋巴细胞功能相关抗原3在低分级胶质瘤中的表达及临床意义

  目的  探索CD58又称淋巴细胞功能相关抗原3（lymphocyte function-associated antigen 3,LFA-3）在低分级胶质瘤中的表达及其与临床特征之间的关系,并探讨其在临床预后判断中的作用。  方法  收集癌症基因图谱（The Cancer Genome Atlas,TCGA）数据库中514例低分级胶质瘤患者的临床资料和mRNA芯片数据,对LFA-3（CD58）进行表达分析。Cox多因素回归分析CD58的表达水平与脑胶质瘤患者无病生存期（disease free survival,DFS）以及总生存期（overall survival,OS）之间的关系。进一步通过χ2检验分析,研究CD58与患者年龄、性别以及脑胶质瘤病理级别等之间的关系。  结果  CD58表达水平随脑胶质瘤病理级别升高而升高,CD58表达量与肿瘤分级的分层χ2检验结果表明,在考虑肿瘤类型、性别和诊断年龄这3个因素后,CD58表达量与肿瘤分级仍然相关,均P < 0.05。CD58的表达水平显著影响胶质瘤患者的DFS和OS,CD58表达越高患者DFS和OS越短（P < 0.000 1）。  结论  CD58在脑胶质瘤中可能起到促进肿瘤的作用,可以作为潜在的肿瘤诊断标志物以及个体化治疗的靶点。      

胶质瘤中MicroRNA-184的表达及其预后价值

目的 研究人脑胶质瘤石蜡包埋组织（formalin-fixed paraffin-embedded, FFPE）中微小RNA-184（microRNA-184, miR-184）的表达及其与临床病理特征之间的关系,探讨其在预测胶质瘤患者预后中的价值。方法 采用微阵列芯片法和RT-PCR检测108例胶质瘤FFPE和32例正常脑组织中的miR-184表达,同时Kaplan-Meier法分析胶质瘤患者总生存期和无病生存期情况。结果 胶质瘤组织中miR-184的表达下调,并用RT-PCR进一步验证; miR-184低表达与WHO分级（P=0.007）、Karnofsky 评分（KPS）（P=0.029）、复发时间（P=0.037）和生存时间（P=0.019）显著相关;Kaplan-Meier 分析结果表明,miR-184低表达与高表达患者总生存期（OS）（P=0.001）和无病生存期（DFS）（P=0.006）差异有统计学意义,miR-184低表达患者预后较差。多因素分析显示胶质瘤中miR-184的差异表达是预测OS[风险比（HR）：7.52;95％CI：2.63~21.42;P=0.002]和DFS[HR：11.56;95％CI：5.17~25.93;P<0.001]的独立危险因素。结论 miR-184的表达与胶质瘤患者预后显著相关,表明miR-184可作为预测胶质瘤患者预后的独立标志物。     

miR-210/VMP1信号传导通路在脑胶质瘤中作用的研究进展

脑胶质瘤是目前临床上最常见的中枢神经系统恶性肿瘤之一，全球发病率约为每年7/10万。在我国胶质瘤的发病率占据颅内肿瘤第一位。临床上胶质瘤的治疗手段主要为手术切除，但是术后复发率高、生存期短，通常只有15～19个月。因此对于胶质瘤寻找有效的治疗靶点，在临床上就显得尤为重要。有研究表明胶质瘤患者脑组织中miR-210水平明显高于正常脑组织，且表达越高患者预后越差。空泡膜蛋白1(vacuole membrane protein 1,VMP1)为大分子跨膜蛋白,研究发现VMP1在蛋白分泌、细胞器形成及多细胞发育过程中起重要作用,另外在人体许多肿瘤组织中如乳腺癌、肾癌、肝癌等均有表达,且在原发与转移性肿瘤中表达不一致,被预测其可能是一个肿瘤相关蛋白，但其在胶质瘤中的机制目前仍未涉及到。故本文简要综述当前miR-210/VMP1信号传导通路在胶质瘤中作用机制的研究进展。     

贝伐单抗治疗高级别脑胶质瘤的研究进展

脑胶质瘤中3/4以上的患者为高级别脑胶质瘤,其恶性程度高,术后易复发,预后极差。虽然术后同步放化疗能使高级别脑胶质瘤患者生存获益,但其仅能延长有限的生存时间。近年来,肿瘤的分子靶向治疗逐渐成为研究热点。血管内皮生长因子在脑胶质瘤及其周围组织中高表达,调控着肿瘤的生长过程,是脑胶质瘤治疗的有效靶点。贝伐单抗能够特异性地阻止血管内皮生长因子与其受体结合,抑制肿瘤血管的形成;同时还能使肿瘤血管正常化,改善血管通透性,增加肿瘤组织有效药物浓度,从而达到其抗肿瘤的作用。本文就贝伐单抗的作用机制及近些年贝伐单抗单药与联合化疗或其他药物治疗高级别脑胶质瘤的研究进展进行综述。      

CX3CR1/CX3CL1 axis negatively controls glioma cell invasion and is modulated by transforming growth factor-beta1

The chemokine CX3CL1 is constitutively expressed in the central nervous system by neurons and astrocytes controlling neuronal survival and neurotransmission. In this work, we analyzed the expression and function of the chemokine CX3CL1 and its receptor, CX3CR1, by human glioma cells. We show that both molecules are expressed on the tumor cell plasma membrane and that soluble CX3CL1 accumulates in the culture supernatants, indicating that the chemokine is constitutively released. We found that CX3CR1 is functional, as all the cell lines adhered to immobilized recombinant CX3CL1 and migrated in response to the soluble form of this chemokine. In addition, the blockade of endogenous CX3CL1 function by means of a neutralizing monoclonal antibody markedly delayed tumor cell aggregation and increased their invasiveness. We also show that CX3CL1 expression is potently modulated by the transforming growth factor-beta1 (TGF-beta1), a key regulator of glioma cell invasiveness. Indeed, both the treatment of glioma cells with recombinant TGF-beta1 and the inhibition of its endogenous expression by siRNA showed that TGF-beta1 decreases CX3CL1 mRNA and protein expression. Overall, our results indicate that endogenously expressed CX3CL1 negatively regulates glioma invasion likely by promoting tumor cell aggregation, and that TGF-beta1 inhibition of CX3CL1 expression might contribute to glioma cell invasive properties.     

自杀基因治疗恶性胶质瘤的研究

目的：单纯疱疹病毒Ⅰ型胸苷激酶（ＨＳＶ－ｔｋ）基因治疗恶性胶质瘤体内外试验。方法：分子克隆及真核细胞基因转染技术构建逆转录病毒（ＲＶ）载体ｐＭＶ７（ｔｋ）及ＰＡ３１７ｔｋ包装细胞系;体外不同比例混合鼠Ｃ６胶质瘤细胞与ＰＡ３１７ｔｋ细胞,在ＧＣＶ（Ｇａｎｃｉｃｌｏｖｉｒ）作用下观察细胞存活率;建立ＳＤ大鼠颅内Ｃ６胶质瘤模型（种植５×１０５Ｃ６细胞）,治疗组第３天原位注射５×１０６ＰＡ３１７ｔｋ细胞,５天后腹腔给予ＧＣＶ（３０ｍｇ／ｋｇ．ｄ）,ＭＲＩ全程监测肿瘤消长,观察病症及存活期,并行病理检查。结果：在ＧＣＶ０．１～１０１μｇ／ｍｌ浓度范围内,Ｃ６细胞存活率随ＰＡ３１７ｔｋ细胞混入比例增加而逐渐减低（Ｐ＜０．００１）,并具有ＧＣＶ剂量依赖性（Ｐ＜０．０１）;体内试验治疗组病症轻,生存期延长,ＭＲＩ表明治疗组肿瘤体积较对照组明显减小（Ｐ＜０．０１）,１个月时病理检查见肿瘤细胞消失,代之以小胶质细胞增生并形成坏死囊。结论：应用本实验室构建的ＲＶ载体ｐＭＶ７（ｔｋ）及其ＰＡ３１７ｔｋ包装细胞系治疗恶性胶质瘤是一种有效及具有前途的治疗方法。     

Fibulin-5 is a Prognostic Marker that Contributes to Proliferation and Invasion of Human Glioma Cells

Fibulin-5 has recently been considered as a potential tumor suppressor in human cancers. Several studieshave shown that it is down-regulated in a variety of tumor types and inhibits tumor growth and metastasis. Thisstudy was aimed to investigate the clinical significance of fibulin-5 in glioma and its role in cell proliferationand invasion. We found that the expression of fibulin-5 in glioma tissues was significantly lower than those innormal brain (NB) tissues. Negative expression was significantly correlated with advanced clinical stage (gradeIII+IV) . Furthermore, Fibulin-5 negative expression was correlated with a shorter overall survival of gliomapatients. Multivariate Cox repression analysis indicated that fibulin-5 was an independent factor for predictingoverall survival of glioma patients. Overexpression obviously inhibited cell proliferation in U251 and U87cells. Furthermore, it significantly reduced the number of migrating and invading glioma cells. In conclusion,impaired expression of fibulin-5 is correlated with the advanced tumor stage in glioma. Otherwise, Fibulin-5 isan independent prognostic marker for predicting overall survival of glioma patients. Mechanistically, it mayfunction as a tumor suppressor via inhibiting cell proliferation and invasion in gliomas.     

维生素C对神经胶质瘤的影响作用

神经胶质瘤是中枢神经系统(CNS)最常见的一类肿瘤,占了颅内原发肿瘤的35%～60%。2007年世界卫生组织(WHO)中枢神经系统肿瘤分类中将胶质瘤分为I～Ⅳ级,其中Ⅲ、Ⅳ级为恶性胶质瘤,大约占所有胶质瘤的77.5%。目前对神经胶质瘤的临床治疗采取以手术治疗为主,结合放疗、化疗等疗法的综合治疗,虽然能延长患者生存时间,但存在高复发率、高致残率、高病死率等问题,总体预后仍然较差。自20世纪70年代以来,维生素C(VC)抗肿瘤作用的研究日益进展,国外的医疗工作者已将其作为肿瘤治疗的补充和替代疗法之一,并报道了静脉注射维生素C治疗神经胶质瘤、卵巢癌、肾细胞癌、乳腺癌、大肠癌、非霍奇金淋巴瘤、前列腺癌、膀胱癌等肿瘤的临床病例,认为其能改善患者的临床症状、提高生存质量、延长生存期。本文就维生素C对神经胶质瘤的治疗作用做一综述。     

Bortezomib sensitizes primary human astrocytoma cells of WHO grades I to IV for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis.

PURPOSE: Malignant gliomas are the most aggressive human brain tumors without any curative treatment. The antitumor effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in gliomas has thus far only been thoroughly established in tumor cell lines. In the present study, we investigated the therapeutic potential of TRAIL in primary human glioma cells. EXPERIMENTAL DESIGN: We isolated primary tumor cells from 13 astrocytoma and oligoastrocytoma patients of all four WHO grades of malignancy and compared the levels of TRAIL-induced apoptosis induction, long-term tumor cell survival, caspase, and caspase target cleavage. RESULTS: We established a stable culture model for isolated primary human glioma cells. In contrast to cell lines, isolated primary tumor cells from all investigated glioma patients were highly TRAIL resistant. Regardless of the tumor heterogeneity, cotreatment with the proteasome inhibitor bortezomib efficiently sensitized all primary glioma samples for TRAIL-induced apoptosis and tremendously reduced their clonogenic survival. Due to the pleiotropic effect of bortezomib-enhanced TRAIL DISC formation upon TRAIL triggering, down-regulation of cFLIP(L) and activation of the intrinsic apoptosis pathway seem to cooperatively contribute to the antitumor effect of bortezomib/TRAIL cotreatment. CONCLUSION: TRAIL sensitivity of tumor cell lines is not a reliable predictor for the behavior of primary tumor cells. The widespread TRAIL resistance in primary glioma cells described here questions the therapeutic clinical benefit of TRAIL as a monotherapeutic agent. Overcoming TRAIL resistance by bortezomib cotreatment might, however, provide a powerful therapeutic option for glioma patients.     

Silencing of R-Spondin1 increases radiosensitivity of glioma cells

Although radiation therapy is the most effective postoperative adjuvant treatment, it does not substantially improve the long-term outcomes of glioma patients because of the characteristic radioresistance of glioma. We found that R-Spondin1 (Rspo1) expression was elevated in high-grade gliomas and was associated with worse overall survival and disease-free survival. Rspo1 expression was also associated with reduced survival rates in glioma patients after treatment with radiotherapy and temozolomide (RT-TMZ). Importantly, Rspo1 was dramatically upregulated after radiation treatment in patients with glioma. Rspo1 silencing by shRNA potentiated glioma cell death upon radiation treatment. In a xenograft nude mouse model, combining radiation and silencing of Rspo1 potentiated tumor growth inhibition. Thus, combining radiotherapy with silencing of Rspo1 is a potential therapeutic approach.     

Glioma‐derived galectin‐1 regulates innate and adaptive antitumor immunity

Galectin‐1 is a glycan‐binding protein, which is involved in the aggressiveness of glioblastoma (GBM) in part by stimulating angiogenesis. In different cancer models, galectin‐1 has also been demonstrated to play a pivotal role in tumor‐mediated immune evasion especially by modulating cells of the adaptive immune system. It is yet unknown whether the absence or presence of galectin‐1 within the glioma microenvironment also causes qualitative or quantitative differences in innate and/or adaptive antitumor immune responses. All experiments were performed in the orthotopic GL261 mouse high‐grade glioma model. Stable galectin‐1 knockdown was achieved via transduction of parental GL261 tumor cells with a lentiviral vector encoding a galectin‐1‐targeting miRNA. We demonstrated that the absence of tumor‐derived but not of host‐derived galectin‐1 significantly prolonged the survival of glioma‐bearing mice as such and in combination with dendritic cell (DC)‐based immunotherapy. Both flow cytometric and pathological analysis revealed that the silencing of glioma‐derived galectin‐1 significantly decreased the amount of brain‐infiltrating macrophages and myeloid‐derived suppressor cells (MDSC) in tumor‐bearing mice. Additionally, we revealed a pro‐angiogenic role for galectin‐1 within the glioma microenvironment. The data provided in this study reveal a pivotal role for glioma‐derived galectin‐1 in the regulation of myeloid cell accumulation within the glioma microenvironment, the most abundant immune cell population in high‐grade gliomas. Furthermore, the prolonged survival observed in untreated and DC‐vaccinated glioma‐bearing mice upon the silencing of tumor‐derived galectin‐1 strongly suggest that the in vivo targeting of tumor‐derived galectin‐1 might offer a promising and realistic adjuvant treatment modality in patients diagnosed with GBM.     

Dendritic cell-based glioma immunotherapy (review)

Despite advances in radiation and chemotherapy along with surgical resectioning, the prognosis of patients with malignant glioma is poor. Among the new treatments currently being investigated for malignant glioma, immunotherapy is theoretically very attractive, since it offers the potential for high tumor-specific cytotoxicity. There are increasing reports demonstrating that systemic immunotherapy using dendritic cells is capable of inducing an antiglioma response. Therefore, dendritic cell-based immunotherapy could be a new treatment modality for patients with glioma. In this review, we will discuss the implications of these findings for glioma therapy. A literature review of dendritic cell-based glioma immunotherapy was used to overview the dendritic cell in immunobiology, in the central nervous system and in tumor immunology, glioma-associated antigens, dendritic cell therapy in animal glioma model, dendritic cell therapy in clinical trials and future directions in dendritic cell therapy. Dendritic cell-based immunotherapy strategies appear promising as an approach to successfully induce an antitumor immune response and increase survival in patients with glioma. Dendritic cell therapy of glioma seems to be safe and without major side effects. Its efficacy should be further determined in randomized, controlled clinical trials. The development of methods for manipulating dendritic cells for the purpose of vaccination will enhance the clinical usefulness of these cells for biotherapy for malignant glioma.