细胞外基质对胶质瘤侵袭性影响的研究进展

胶质瘤恶性程度高,其侵袭性生长方式使得手术不能有效切除,是预后较差的主要原因,研究发现细胞外基质中的透明质酸及其受体、肌腱生长蛋白、整合素、基质金属蛋白酶和生长因子等与胶质瘤的侵袭性密切相关,并且已有多种针对细胞外基质起作用的药物被证明对胶质瘤有效,深入研究细胞外基质在胶质瘤发展中的作用机制,可以为胶质瘤的治疗提供更多的方向。     

细胞外基质对胶质瘤侵袭性影响的研究进展

胶质瘤恶性程度高,其侵袭性生长方式使得手术不能有效切除,是预后较差的主要原因,研究发现细胞外基质中的透明质酸及其受体、肌腱生长蛋白、整合素、基质金属蛋白酶和生长因子等与胶质瘤的侵袭性密切相关,并且已有多种针对细胞外基质起作用的药物被证明对胶质瘤有效,深入研究细胞外基质在胶质瘤发展中的作用机制,可以为胶质瘤的治疗提供更多的方向。     

恶性脑胶质瘤预后相关多因素分析

目的 了解恶性脑胶质瘤的治疗现状,分析不同治疗方法对患者生存期的影响,研究影响恶性脑胶质瘤预后的相关因素,为规范化、个体化治疗恶性脑胶质瘤提供指导.方法 依据治疗方式不同,对我院自2001年1月至2010年1月经术后病理证实为恶性脑胶质瘤,且随访成功的68例患者进行回顾性分析.结果 全组病例1、2、5年生存率分别为54.2％、41.9％、16.2％.平均生存时间(29.4±5.18)个月.Cox模型多因素分析显示影响预后的独立因素有:年龄、肿瘤级别、肿瘤切除程度(P＜0.05);Log - rank检验单因素分析发现与预后相关的因素有:年龄、肿瘤级别、治疗方式(P＜0.05).结论 恶性胶质瘤的预后较差,特别是Ⅳ级的胶质母细胞瘤.术后采取以手术、放化疗为主的综合治疗可以延长患者生存时间,改善预后.     

缺氧诱导细胞外基质重塑在胶质瘤抗血管治疗耐药中的研究进展

细胞外基质（ECM）是肿瘤微环境的重要组成部分,参与调控多种肿瘤的恶性表型。在胶质瘤中,缺氧微环境可刺激细胞诱导ECM重塑,为肿瘤新生血管的形成提供空间。此外,缺氧可调控一系列信号分子诱导血管生成拟态（VM）的形成。VM是一种缺氧驱动肿瘤细胞自身胞外基质重塑、不依赖内皮细胞的肿瘤血管形成方式,可在内皮源性肿瘤血管被抑制时依然为肿瘤供氧,故成为胶质瘤高侵袭性表型和治疗抗性的重要原因之一。因此,靶向血管拟态中ECM重塑关键因子及环节有望为胶质瘤治疗方案提供新思路。     

骨髓基质细胞向脑胶质瘤迁移的趋化机制研究进展

骨髓基质细胞作为载体治疗颅脑疾病是近年来神经科学研究热点之一,但是其向病灶的趋化机制还不清楚。趋化因子和其受体以及黏附分子参与粒细胞向炎症灶的趋化过程,基质水解酶参与肿瘤细胞外渗出血管的浸润转移过程。近来的研究显示骨髓基质细胞表达众多趋化因子受体和黏附分子,及分泌基质金属蛋白酶,与其生物学功能相关。     

骨髓基质干细胞及其在脑胶质瘤基因治疗中的应用

骨髓基质干细胞(BMSCs)是近来神经科学领域研究的热点之一。BMSCs来源丰富,转染外源基因后能在体内、外稳定表达,可分泌多种神经营养因子,具有很低的免疫排斥反应,是基因治疗的良好载体,但仍存在一些亟待明确的问题。现主要综述BMSCs部分生物学特性及其作为基因载体治疗胶质瘤的研究现状。     

p16基因抑制脑胶质瘤细胞恶性增殖并诱导细胞凋亡

目的：探索p16基因在脑胶质瘤发生过程中的作用及其与脑胶质瘤细胞凋亡的关系。方法：采用脂质体,磷酸钙＋DMSO休克转染的方法,分别将外源野生型p16基因导入胶质瘤细胞株U251,SWO,观察p16基因短暂转染与长期稳定转染对胶质瘤细胞的作用,并筛选阳性克隆。同时以空载体质粒pCDNA3为对照,免疫组化,Northern杂交检测p16基因表达,对转染后细胞生长的抑制,细胞周期,凋亡及裸鼠致瘤能力的变化进行分析,结果：外源p16基因的高水平表达显著抑制了胶质瘤U251,SWO细胞的生长,克隆形成率减少,肿瘤细胞发生了G1期阻滞,p16基因短暂转染可诱导胶质瘤细胞凋亡,而长期稳定转染无明显的凋亡诱导作用。结论：外源野生型p16基因可抑制胶质瘤细胞恶性增殖并诱导细胞凋亡,肿瘤细胞的异质性特点与p16基因转染后的“自然选择”作用可能是p16基因长期稳定转染无明显凋亡诱导作用的主要机制。     

脑星形胶质瘤预后的多因素COX模型分析

通过多因素COX模型方法对82例脑星形胶质瘤患者的19项可能影响病人预后的指标进行分析。结果证实,病人年龄、肿瘤囊性变、手术切除肿瘤程度、肿瘤级别以及胶质瘤细胞的DNA倍体特性五项因素与病人的预后密切相关。     

脑胶质瘤手术的预后分析

颅内肿瘤中脑胶质瘤最常见,发病率占原发性颅内肿瘤的37.8％～57.37％［1］。脑胶质瘤呈浸润性生长,且无根治手段,术后复发率高,严重影响患者的生活质量。脑胶质瘤的综合治疗是影响预后的重要因素,但手术切除是脑胶质瘤综合治疗策略中最为关键的一步,决定了胶质瘤手术的预后。我科于2008‐11—2013‐11采用显微外科手术切除胶质瘤42例,术后恢复良好,现报告如下。     

RECK基因在脑胶质瘤细胞中的表达及其临床意义

目的探讨肿瘤抑制基因RECK作为胶质瘤预后指标的潜在价值，及相关金属蛋白酶MMP-9、MMP-2在胶质瘤中的变化与RECK的相互关系。方法应用逆转录-聚合酶链式反应（RT-PCR）检测58例胶质瘤及12例良性脑肿瘤组织，3例正常脑组织中RECK、MMP-9和MMP-2 mRNA的表达情况。结果RECK在58例胶质瘤中19例表达相对定量值〉0．50，39例表达相对定量值〈0．50；12例良性肿瘤及3例正常脑组织中表达相对定量值均〉0．50。RECK表达相对定量值〉0．50的肿瘤患者有较好的预后（P〈0．05）。RECK表达与MMP-2和MMP-9的表达在脑胶质瘤中无相关性。结论RECK在脑肿瘤组织中表达与患者生存时间之间有显著的相关性。RECK表达相对值〈0．50可以作为脑胶质瘤患者预后的准确标记物。     

基于细胞周期相关基因的胶质瘤患者预后模型构建与验证

目的 探讨细胞周期相关基因在胶质瘤患者中的表达及预后价值。方法 利用CGGA数据库筛选与胶质瘤患者预后相关的细胞周期基因,并基于CGGA与TCGA中胶质瘤患者的临床数据,通过LASSO回归分析,构建预测患者生存情况的预后模型。根据计算公式,区分高低风险组患者,组间进行GSEA富集分析与ssGSEA免疫微环境分析。结果 筛选到10个与患者预后密切相关的细胞周期基因,LASSO回归分析纳入4个基因[细胞周期蛋白依赖性激酶抑制剂2C（CDKN2C）、姐妹染色单体分离的PTTG1调控因子（PTTG1）、细胞周期蛋白依赖性激酶2（CDK2）、WEE1 G2检查点激酶（WEE1）]构建预后模型,计算公式为：风险值（risk socre）=（0.008）×CDKN2C表达量+（0.022）×PTTG1表达量+（0.031）×CDK2表达量+（0.127）×WEE1表达量。生存分析显示,高风险组患者生存率低于低风险组,ROC曲线表明,模型在CGGA与TCGA队列中,均具有较好的预测能力。GSEA富集分析显示,高风险组富集到多个细胞周期进程相关的信号通路,提示可能参与胶质瘤的恶性进程。免疫微环境分析表明,高风险组患者的免疫细胞浸润与免疫反应激活程度均高于低风险组。结论 基于细胞周期相关基因的预后模型可较好地应用于胶质瘤患者的预后预测,纳入的关键基因可能是胶质瘤治疗的可靠靶点。 [国际神经病学神经外科学杂志, 2023, 50(4): 15-24]     

CD44 plays a role in adhesive interactions between glioma cells and extracellular matrix components

Glioma invasion is a complex process involving interactions of tumour cells with host cells and extracellular matrix (ECM). The initial event in the process is recognition and attachment of glioma cells to specific ECM molecules prior to migration into proteolytically modified matrix. In comparison with other tissues, brain ECM is a relatively amorphous matrix which contains glycosaminoglycans including hyaluronan (HA). Recently CD44 which is a transmembrane adhesion molecule found on a wide variety of cells, has been suggested as the principal cell surface receptor for HA. In the present in vitro investigation we have analysed the role of CD44 in adhesive interactions between human gliomas and ECM. Our experimental procedures included immunocytochemistry, immunoblotting, in vitro adhesion assay and flow cytometry. CD44 was expressed on the surface of all gliomas analysed (9) and the level of expression showed no correlation with tumour grade. Eighty, 95 and 120 kDa isoforms were demonstrated by immunoblotting. In an adhesion blocking assay it was found that ligation of CD44 with specific antibody resulted in reduced adhesion to hyaluronan. chondroitin sulphate, fibronectin, laminin, collagen IV and Matrigel™. We conclude that CD44 is involved in adhesion of glioma cells to a wide range of ECM components.     

基于列线图模型的多指标检测对缺血性脑卒中预后预测价值分析

目的 构建多指标列线图模型以预测缺血性脑卒中患者的预后。方法 对2019年1月至2021年6月湖北医药学院附属国药东风总医院接诊的126例缺血性脑卒中患者的资料进行回顾性分析。根据格拉斯哥预后评分将患者分为2组：1～3分者为预后不良组,4～5分者为预后良好组。收集可能影响缺血性脑卒中患者预后的因素,比较2组患者各预后因素,并进行多因素分析,根据多因素分析结果构建列线图模型。结果 126例患者中,45例预后不良。多因素分析结果显示,有吸烟史、入院时美国国立卫生研究院脑卒中量表评分升高、低密度脂蛋白胆固醇水平升高、神经肽P物质水平升高为缺血性脑卒中预后不良的危险因素（P<0.05）;高密度脂蛋白胆固醇水平升高为保护性因素（P<0.05）。根据多因素分析结果构建列线图模型,受试者操作特征曲线下面积为0.892,灵敏度为93.1%,特异度为68.2%,95%CI为0.836～0.949。计算机模拟充分采样法内部验证结果显示,平均绝对误差为0.03,模型表现与理想模型基本拟合,提示模型预测准确度较高。结论 缺血性脑卒中患者的预后与吸烟、入院时美国国立卫生研究院脑卒中量表评分、低密度脂蛋白胆固醇水平、神经肽P物质水平等因素有关。根据上述因素构建的列线图模型用于缺血性脑卒中患者预后预测具有较高的准确度与区分度。 [国际神经病学神经外科学杂志, 2023, 50(6): 13-18]     

Role of high molecular weight extracellular matrix proteins in glioma cell migration

Malignant human gliomas are characterized by an uncontrolled cell proliferation and infiltrative growth within the brain. Complete surgical removal is difficult due to disseminated tumour cells, and the fundamental mechanisms responsible for this spread are poorly understood. An extensive tumour cell movement along blood vessels is frequently observed and this may be due to specific interactions between tumour cell surface receptors and specific extracellular matrix (ECM) components present in conjunction with vascular elements. In order to investigate the influence of ECM on glioma cell migration, three different human glioma cell lines (U-373 MG, A-172 MG and HF-66) were exposed to known ECM components of the basement membrane (laminin, fibronectin and collagen type IV). Cell migration from multicellular spheroids was studied, using a custom-made medium which was prepared by removing the high molecular weight protein fraction (>100 kDa) from newborn calf serum by ultrafiltration. To this medium, the specific ECM components were added. For two of the cell lines (A-172 MG and U-373 MG), laminin was the most potent stimulator of glioma cell migration; the effect of laminin exceeded that evoked by ordinary serum-supplemented medium. For the HF-66 cell line, fibronectin was the most potent stimulator of migration. Western blot analysis showed that the A-172 MG and HF-66 cell lines expressed low amounts of laminin compared with U-373 MG, which showed extensive intrinsic synthesis of this ligand. U-373 MG was the only cell line that migrated in pure filtered medium. The cells stimulated by fibronectin expressed a different morphology from those stimulated by laminin suggesting that specific ECM-receptor binding may activate different cytoskeletal components within the cells. Furthermore, it was shown that there was no difference in the amount of protein synthesis between cells grown in filtered medium and in filtered medium supplemented with different ECM components. This suggests that ECM-induced cell migration is not dependent on a high level of protein synthesis. It is also shown that α3 integrin, which is a receptor-subunit for laminin, fibronectin and collagen type IV, was highly expressed in all cell lines. This study indicates that glioma cells need serum proteins with a molecular weight >100 kDa to migrate in vitro, and that laminin and fibronectin play an important role in this process.     

microRNA-328 is a favorable prognostic marker in human glioma via suppressing invasive and proliferative phenotypes of malignant cells

Objective: microRNA (miR)-328 has been reported to be implicated into tumorigenesis and tumor progression in human gliomas. However, there were controversial study results in relation to its expression pattern as well as functions in this disease. The aim of the current study was to determine the clinical significance of miR-328 expression in patients with gliomas and its effect in tumor cell malignant phenotypes. Methods: Quantitative real-time PCR was performed to detect the expression levels of miR-328 in 116 glioma and 15 non-neoplastic brain tissues. Then, the correlations of miR-328 expression with selected clinicopathologic parameters and clinical outcome of glioma patients were statistically evaluated. Moreover, CCK-8 and transwell assays were performed to investigate the functions of miR-328 in cell proliferation, invasion and migration, respectively. Results: Compared to non-neoplastic brain tissues, the expression levels of miR-328 were significantly downregulated in glioma tissues (p < 0.001). In addition, miR-328 downregulation was significantly associated with WHO grade (p < 0.001) and Karnofsky performance status score (p = 0.02). Moreover, glioma patients with low miR-328 expression exhibited markedly shorter overall survival than those with high expression (p < 0.001). Furthermore, functional assays in vitro system demonstrated that enforced expression of miR-328 could notably attenuate cell proliferation, invasion and migration of two glioma cell lines, including U251 and U87. Conclusions: Our data offer the convincing evidence that loss of miR-328 expression may stimulate advanced tumor progression and adverse outcome via promoting cellular proliferation and invasion. We propose a tumor suppressive role of miR-328 and its potential therapeutic value in human glioma.     

血小板相关参数对胶质瘤患者预后的影响

目的 探讨术前血小板相关参数对胶质瘤患者肿瘤复发的预测作用。方法 分析联勤保障部队第九〇九医院2015—2017年收治的93例胶质瘤患者临床病理资料,根据随访期间肿瘤是否复发分为无复发组（n=52）和复发组（n=41）,分析血小板相关参数与胶质瘤分级的相关性,采用ROC曲线分析血小板计数（PLT）、血小板体积分布宽度（PDW）、血小板压积(PCT)、平均血小板体积（MPV）、平均血小板体积/血小板计数（MPV/PLT）对肿瘤复发的预测作用,多因素Cox分析肿瘤复发的影响因素,采用Kaplan-Meier曲线分析这些因素对肿瘤复发的影响。结果 胶质瘤Ⅲ、Ⅳ级患者PLT、PCT、高于胶质瘤Ⅰ、Ⅱ级患者（t=-2.388、-2.335,均P<0.05）;胶质瘤Ⅲ、Ⅳ级患者中MPV、MPV/PLT低于胶质瘤Ⅰ、Ⅱ级患者（均P<0.05）;无复发组患者PLT和PCT低于复发组（均P<0.05）;无复发组患者MPV和MPV/PLT高于复发组（均P<0.05）;PLT的ROC曲线下面积（UAC）为0.630（95%CI=0.517~0.743,P=0.032）,阈值为216×10⁹/L;MPV的UAC为0.633（95%CI=0.518~0.747,P=0.029）,阈值为8.65 fL;MPV/PLT的UAC为0.731（95%CI=0.626~0.835,P<0.001）,阈值为0.040;多因素分析结果发现,肿瘤分级（Ⅲ、Ⅳ）、MPV≤8.65 fL、MPV/PLT≤0.040是术后肿瘤复发的危险因素（95%CI分别为1.778~3.530、1.730~4.450、1.811~6.067,均P<0.05）;肿瘤分级（Ⅲ、Ⅳ）预测术后肿瘤复发曲线下面积为0.679（95%CI=0.569~0.789,P=0.003）。Kaplan-Meier曲线分析显示,MPV≤8.65 fL患者术后3年复发率高于MPV>8.65 fL患者（Long Rank=10.990,P=0.001）;MPV/PLT≤0.040患者术后3年复发率高于MPV/PLT>0.040患者（Long Rank=6.289,P=0.012）。结论 胶质瘤患者术前MPV和MPV/PLT与术后肿瘤复发有关,可以用于肿瘤预后预测,具有一定临床意义。 [国际神经病学神经外科学杂志, 2023, 50(4): 29-33]     

加速康复外科理念联合清醒麻醉对脑胶质瘤预后的影响

目的 探讨加速康复外科（ERAS）理念联合清醒麻醉下开颅对脑功能区胶质瘤患者预后的影响。方法 分析2019年9月—2020年9月西京医院神经外科收治的脑功能区胶质瘤患者90例,根据不同麻醉及处理方式分为全身麻醉（GA）组、清醒麻醉（AA）组和清醒麻醉联合加速康复外科理念（AA+ERAS）组各30例,收集并比较3组患者的性别、年龄、术前症状、肿瘤位置、侧别、病理级别、失血量、手术时间、切除程度、术后恶心呕吐、住院时间、术后癫痫、术后1周功能改善、术后2个月卡诺夫斯凯计分（KPS）等资料。所有病例都有2年随访资料,根据随访对死亡情况绘制生存曲线。结果 3组患者的预后指标中,AA+ERAS组的肿瘤全切程度高、术后恶心呕吐发生率低、住院时间短、术后2个月KPS高,结果均优于GA组和AA组,差异具有统计学意义（P<0.05）,其余指标差异无统计学意义（P>0.05）。生存曲线结果显示术后2年的无进展生存率、总存活率均高于GA组和AA组,差异具有统计学意义（P<0.05）。结论 ERAS理念联合清醒麻醉可明显改善脑胶质瘤患者的预后,术后近期可减少患者术后应激反应和并发症,术后远期可延长患者生存率、提高患者生活质量,为临床治疗提供有力的理论依据和指导意义。国际神经病学神经外科学杂志, 2023, 50(2): 34-39]