GSE74602芯片数据中直肠癌关键基因与治疗药物的生物信息学筛选

目的:通过生物信息学方法探寻结直肠癌的诊断标志物及潜在的治疗靶点与治疗药物。方法:从美国国立生物技术信息中心(NCBI)公共数据平台基因表达大棚车(GEO)下载芯片数据GSE74602,包括60个样本,其中30例结直肠癌样本,30例正常结直肠组织样本。用R语言中的Limma包对正常组织和癌症组织进行差异表达分析,用DAVID在线数据库对筛选出来的差异表达基因进行基因本体论(GO)富集分析和京都基因与基因组百科(KEGG)信号通路分析,同时通过STRING在线数据库构建差异表达基因的蛋白互作网络,利用Cytoscape软件进行可视化编辑,并且通过MCODE插件进行子网络模块分析,筛选出结直肠癌发生过程中的核心基因。最后,用连通图数据库(c Map)分析具有潜在治疗结直肠癌的小分子药物。结果:总共筛选出231个差异表达基因,包括122个上调基因,109个下调基因。GO分析结果表明,表达上调的基因富集的生物学过程主要包括细胞周期、细胞分裂等,而表达下调的基因富集在免疫反应,细胞内信号级联和防御反应等生物学过程。KEGG通路分析发现表达上调的基因主要参与细胞中氮及矿物质的代谢和细胞中相关物质的分泌(胆汁、胰液)的信号通路,而表达下调的基因主要参与药物代谢、细胞循环以及p53信号传导通路。子网络模块分析发现了一些在结直肠癌发生的调控中起着重要作用的关键基因,如KIF20A、CENPF、NCAPG、PYY、IQGAP3;蛋白互作网络中的差异表达基因被映射到c Map上,筛选出若干个潜在治疗结直肠癌的小分子药物,如紫霉素、去甲骆驼蓬碱、斑鸠霉素等。结论:所发现的关键基因可能会成为诊断结直肠癌新的肿瘤标志物或者治疗结直肠癌的新的靶点;此外,筛选出的小分子药物有可能成为治疗结直肠癌的新型药物。     

Aberrant oligodendroglial LDL receptor orchestrates demyelination in chronic cerebral ischemia

Oligodendrocytes express low-density lipoprotein receptor (LDLR) to endocytose cholesterol for the maintenance of adulthood myelination. However, the potential role of LDLR in chronic cerebral ischemia–related demyelination remains unclear. We used bilateral carotid artery stenosis (BCAS) to induce sustained cerebral ischemia in mice. This hypoxic-ischemic injury caused a remarkable decrease in oligodendroglial LDLR, with impaired oligodendroglial differentiation and survival. Oligodendroglial cholesterol levels, however, remained unchanged. Mouse miR-344e-3p and the human homolog miR-410-3p, 2 miRNAs directly targeting Ldlr, were identified in experimental and clinical leukoaraiosis and were thus implicated in the LDLR reduction. Lentiviral delivery of LDLR ameliorated demyelination following chronic cerebral ischemia. By contrast, Ldlr^–/– mice displayed inadequate myelination in the corpus callosum. Ldlr^–/– oligodendrocyte progenitor cells (OPCs) exhibited reduced ability to differentiate and myelinate axons in vitro. Transplantation with Ldlr^–/– OPCs could not rescue the BCAS-induced demyelination. Such LDLR-dependent myelin restoration might involve a physical interaction of the Asn-Pro-Val-Tyr (NPVY) motif with the phosphotyrosine binding domain of Shc, which subsequently activated the MEK/ERK pathway. Together, our findings demonstrate that the aberrant oligodendroglial LDLR in chronic cerebral ischemia impairs myelination through intracellular signal transduction. Preservation of oligodendroglial LDLR may provide a promising approach to treat ischemic demyelination.     

活动节段脊柱脊索瘤生物学行为研究进展

脊索瘤是临床少见的原发性低度恶性骨肿瘤,源自残留的胚胎脊索或迷走的脊索组织,好发于中轴骨,具有局部侵袭性、复发率高、预后差,以及对放射治疗和药物化疗不敏感等特点,使其临床治疗存在巨大挑战。位于活动节段的脊柱脊索瘤由于脊柱特有的解剖学特点而具有其独特特点,本文通过回顾近年国内外相关文献,对脊索瘤生物学行为特点进行概述,以期为脊索瘤治疗提供新的思路。     

Mast cell corticotropin-releasing factor subtype 2 suppresses mast cell degranulation and limits the severity of anaphylaxis and stress-induced intestinal permeability

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血清肿瘤标记物与卵巢癌诊断和监控治疗的相关性研究

目的 探讨血清肿瘤标记物糖类抗原CA125、CA724、环氧化酶（COX-1）和人附睾蛋白4（HE4）联合动态检测在卵巢癌早期诊断和监控治疗、复发中的临床应用价值。方法选取82例卵巢癌患者（观察组）、79例卵巢良性病变患者（对照组）为研究对象,均经术后病理确诊。所有患者术前、术后均有血清肿瘤标记物CA125、CA724、COX—1、HE4检查资料,其中CA125、CA724、COX-1采用电化学发光法检测,HE4采用酶联免疫（ELISA）法检测,综舍评价四种肿瘤标记物联合动态检测在卵巢癌早期诊断和监控治疗、复发中的价值。结果卵巢癌组患者血清CA125、CA724、COX-1、HE4水平明显高于卵巢良性病变组（P〈0．01）;卵巢癌高分期（Ⅲ、Ⅳ期）组明显高于低分期（I、II）纽（P〈0．01）,卵巢癌术前、复发组与术后、无复发组血清肿瘤标记物水平差异有统计学意义（P（0．01）。CA125、CA724、COX-1、HE4诊断卵巢癌的敏感性分别为74．4％、70．7％、43．9％、69．5％,联合检测的敏感性高达96．3％,与各单项检测的敏感性比较差异有统计学意义（P〈0．01）。结论血清肿瘤标记物CA125、CA724、COX-1、HFA联合动态检测是卵巢癌早期诊断和监控治疗、复发的较好指标,有利于临床早期发现、早期干预。     

Endothelial Piezo1 sustains muscle capillary density and contributes to physical activity

Piezo1 forms mechanically activated nonselective cation channels that contribute to endothelial response to fluid flow. Here we reveal an important role in the control of capillary density. Conditional endothelial cell–specific deletion of Piezo1 in adult mice depressed physical performance. Muscle microvascular endothelial cell apoptosis and capillary rarefaction were evident and sufficient to account for the effect on performance. There was selective upregulation of thrombospondin-2 (TSP2), an inducer of endothelial cell apoptosis, with no effect on TSP1, a related important player in muscle physiology. TSP2 was poorly expressed in muscle endothelial cells but robustly expressed in muscle pericytes, in which nitric oxide (NO) repressed the Tsp2 gene without an effect on Tsp1. In endothelial cells, Piezo1 was required for normal expression of endothelial NO synthase. The data suggest an endothelial cell–pericyte partnership of muscle in which endothelial Piezo1 senses blood flow to sustain capillary density and thereby maintain physical capability.     

The Ca2+-gated channel TMEM16A amplifies capillary pericyte contraction and reduces cerebral blood flow after ischemia

Pericyte-mediated capillary constriction decreases cerebral blood flow in stroke after an occluded artery is unblocked. The determinants of pericyte tone are poorly understood. We show that a small rise in cytoplasmic Ca²⁺ concentration ([Ca²⁺]_i) in pericytes activated chloride efflux through the Ca²⁺-gated anion channel TMEM16A, thus depolarizing the cell and opening voltage-gated calcium channels. This mechanism strongly amplified the pericyte [Ca²⁺]_i rise and capillary constriction evoked by contractile agonists and ischemia. In a rodent stroke model, TMEM16A inhibition slowed the ischemia-evoked pericyte [Ca²⁺]_i rise, capillary constriction, and pericyte death; reduced neutrophil stalling; and improved cerebrovascular reperfusion. Genetic analysis implicated altered TMEM16A expression in poor patient recovery from ischemic stroke. Thus, pericyte TMEM16A is a crucial regulator of cerebral capillary function and a potential therapeutic target for stroke and possibly other disorders of impaired microvascular flow, such as Alzheimer’s disease and vascular dementia.     

血清CA19-9在胆道系统疾病中的临床意义

目的 评价CA19-9对胆道系统疾病的诊断价值.方法 回顾分析第二军医大学东方肝胆外科医院621例胆道疾病病例,测定血清CA19-9值,分析了血清CA19-9和临床诊断、血清胆红素水平、手术方式、病理及预后结果的关系.结果 在取37U/ml为阳性界值时,CA19-9具有最好的诊断准确率(93.9%),在胆道恶性肿瘤中的阳性率较良性疾病组增高有显著的意义;黄疸病例CA19-9阳性率较无黄疸对照组显著增高,而特异性降低.结论 血清CA19-9在胆道疾病的诊断、治疗监视及预后判断上具有较高的临床价值.     

P21WA F_1/CIP_1和P53基因表达与膀胱癌生物学行为的关系

目的 :探讨膀胱癌 P2 1WAF1 / CIP1 、P5 3基因的表达、相互间的调控及其与生物学行为的关系。方法 :采用免疫组织化学 ABC方法检测 12 2例有随访结果的膀胱癌患者的 P2 1WAF1 / CIP1 、P5 3基因表达 ,并采用双变量相关分析、L ogistic回归分析和 Kaplan- Meier法分析。结果 :P5 3野生型肿瘤中 P2 1WA F1 / CIP1 阳性表达率明显高于 P5 3突变型肿瘤 ;P5 3突变型肿瘤中保持 P2 1WAF1 / CIP1 阳性表达者具有与 P5 3野生型肿瘤同样低的复发率和较长的生存期。结论 :维持 P2 1WAF1 / CIP1 的表达可清除 P5 3突变蛋白的有害作用 ;根据 P2 1WAF1 /CIP1 表达状况 ,结合临床分期可对膀胱癌的恶性程度及预后作出更准确的评估 ,对拟定治疗方案有重要的指导意义     

丙型肝炎病毒核心蛋白反式激活基因HCTP4启动子序列的确定及转录活性的鉴定

目的：研究丙型肝炎病毒(HCV)核心蛋白(core)反式激活基因HCTP4基因序列表达的调控机制。方法：选取翻译起始密码子ATG上游44l bp的DNA序列为启动子序列，应用聚合酶链反应技术(PCR)，以肝母细胞瘤细胞系HepG2基因组DNA为模板，扩增该启动子DNA片段，将其克隆至pCAT3中，构建pCAT3-HCTP4-promoter报告基因表达载体，以该质粒转染HepG2细胞，用酶联免疫吸附方法(ELISA)检测报告基因编码产物氯霉素乙酰转移酶(CAT)的表达活性。结果：发现质粒pCAT3-HCTP4-promoter能够指导CAT的表达，吸光度(A值)是pCAT3对照质粒的5倍。结论：本研究克隆的启动子DNA序列具有转录活性，这一结果为研究HCTP4的调节机制，进一步阐明丙型肝炎病毒核心蛋白的作用机制奠定了基础。