旁正中动脉入口部梗死82例临床分析

目的探讨急性桥脑旁正中动脉入口部梗死(branch atheromatous disease,BAD)的临床特点。方法回顾性分析1997～2003年本院神经内科收治的82例桥脑BAD的临床表现、MRI影像特点、脑干听觉诱发电位(BAEP)表现、危险因素。结果本组病例的临床特点是:平均发病年龄69.2岁,男性/女性=46/36,56/82病情呈进行性发展,75/82有构音障碍,72/82有肢体偏瘫,29/82为高度肢体瘫痪,27/82有轻度意识障碍,6/82伴有不全Homer征,49/82出现面部或(和)偏侧肢体感觉减退,25/82出现周围性面瘫,42/82有非旋转性头晕;13/82有眼球运动障碍。MRI表现有:梗死灶位于桥脑中上部、达桥脑表面,楔形,内侧位于桥脑旁正中、呈类似直线,可显示出基底动脉壁不整;危险因素方面除高血压外还与糖尿病、脂质代谢异常有关。结论根据临床特点及MRI表现正确诊断出桥脑BAD,以指导进一步的病因治疗及预防。     

Synthesis and Biological Evaluation of Pyrazolo[1,5-a]pyrimidine Compounds as Potent and Selective Pim-1 Inhibitors

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GPER-induced signaling is essential for the survival of breast cancer stem cells

G protein-coupled estrogen receptor-1 (GPER), a member of the G protein-coupled receptor (GPCR) superfamily, mediates estrogen-induced proliferation of normal and malignant breast epithelial cells. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here we showed greater expression of GPER in BCSCs than non-BCSCs of three patient-derived xenografts of ER⁻/PR⁺ breast cancers. GPER silencing reduced stemness features of BCSCs as reflected by reduced mammosphere forming capacity in vitro, and tumor growth in vivo with decreased BCSC populations. Comparative phosphoproteomics revealed greater GPER-mediated PKA/BAD signaling in BCSCs. Activation of GPER by its ligands, including tamoxifen (TMX), induced phosphorylation of PKA and BAD-Ser118 to sustain BCSC characteristics. Transfection with a dominant-negative mutant BAD (Ser118Ala) led to reduced cell survival. Taken together, GPER and its downstream signaling play a key role in maintaining the stemness of BCSCs, suggesting that GPER is a potential therapeutic target for eradicating BCSCs.     

全程护理干预对双相情感障碍患者认知功能的影响

目的 探讨全程护理干预对双相情感障碍患者认知功能的影响.方法 将100例双相情感障碍患者随机分A组与B组,每组50例,两组均维持原用抗精神病药物以及情绪稳定剂治疗,A组进行全程护理干预,B组予以认知治疗.观察16周.于干预前及干预8周、16周末,采用韦氏成人智力量表、韦氏记忆量表、威斯康星卡片分类测验进行评定分析.结果 干预16周末,A组韦氏记忆量表及韦氏成人智力量表各因子评分均较干预前显著升高(P＜0.05或0.01)、威斯康星卡片各因子评分均较干预前显著下降(P＜0.05或0.01);B组韦氏记忆量表长时记忆、短时记忆分较干预前显著升高(P＜0.05或0.01),威斯康星卡片总测验数较干预前显著下降(P＜0.05);A组韦氏记忆量表及韦氏成人智力量表各因子评分均显著高于B组(P＜0.05或0.01)、威斯康星卡片各因子评分均显著低于B组(P＜0.05).结论 全程护理干预能显著改善双相情感障碍患者的认知功能,提高临床疗效,降低复发率,有利于促进患者的全面康复.     

PPARγ、STAT-3和BAD在肝细胞肝癌的表达及相互作用研究

目的研究肝细胞肝癌中过氧化物酶体增殖物活化受体（peroxlsome proliferators activated receptorsγ，PPARγ）、信号转导和转录激活因子3（STAT-3）及bcl-2相关促凋亡蛋白（BAD）的表达情况及其与临床病理特征的关系。方法利用逆转录聚合酶链反应（RT-PCR）和Western blotting技术分别对30例肝细胞肝癌,相应癌旁组织和正常组织包括部分硬化组织中上述动三种指标的mRNA及蛋白含量进行半定量分析,将结果与临床资料进行统计分析。结果PPARγ、STAT-3及BAD mRNA和蛋白在肝细胞肝癌,癌旁和正常组织中的表达有统计学意义,其中mRNA表达分别为PPARγ（χ^2=77.268,P〈0.05）,STAT-3（F=370.187,P〈0.05）,BAD（F=82.647,P〈0.05）,蛋白表达分别为PPARγ（χ^2=7,590,P〈0.05）,STAT-3（χ^2=22.419,P〈0.05）,BAD表达与组织分化程度有关（（F=141.625,P〈0.05）,其中mRNA分别为PPARγ（t=-2.628,P〈0.05）,STAT-3（t= -3.810,P〈0.05）,BAD（t=5,042,P〈0.05）,蛋白分别为PPARγ（M=0.000,P〈0.05）,STAT-3 （t=-3.759,P〈0.05）,BAD（M=61.500,P〈0.05）与肿瘤大小,瘤栓有无,微转移灶及是否发生复发转移等无关。PPARγ与STAT-3mRNA及蛋白表达均为正相关（r=0.750,P〈0.05,r=0.717,P〈0.05）。PPARγ与BAD mRNA蛋白表达均为负相关（r=-0.401,P〈0.05,r=-0.417,P〈0.05）。STAT-3与BADmRNA蛋白表达均为负相关（r=-0.617,P〈0.05,r=-0.485,P〈0.05）。结论PPARγ、STAT-3在肝细胞肝癌高表达而BAD低表达并与其组织分化和发展有关。     

表皮生长因子受体、血管内皮生长因子受体和BAD在非小细胞肺癌中的表达

背景与目的：表皮生长因子受体（epidermal growth factor receptor，EGFR）和血管内皮生长因子受体（vascular endothelial growth factor receptor，VEGFR）均属酪氨酸激酶受体（receptor tyrosine kinase，RTK），可调控细胞的增殖、分化与生存。BAD是Bcl-2家族中的促凋亡信号成分，在调控细胞凋亡特别是肿瘤细胞凋亡过程中发挥重要作用。但目前人们对上述这些重要蛋白在非小细胞肺癌（non—small—cell lung cancer，NSCLC）中的表达与肿瘤病理学的关系所知甚少。本研究探讨ECFR、VEGFR、BAD和磷酸化BAD在NSCLC中的表达情况以及与肿瘤病理的关系。方法：使用组织微阵列（tissue microarray，TMA）切片的免疫组织化学法，NSCLC患者51例（26例腺癌，16例鳞癌，8例大细胞癌，1例大细胞神经内分泌癌）。结果：51例患者中EGFR和VEGFR分别在10例（加％）和14例（27％）中出现过度表达。大细胞癌中未见VEGFR表达（0／8例），而鳞癌和腺癌患者中VEGFR表达分别为44％（7／16）和27％（7／26）。EGFR和VEGFR的表达与性别，肿瘤细胞分化及肿瘤浸润程度（包括胸膜浸润，血管浸润，淋巴结转移，肺内播散，脑转移情况）无关。51例患者中22例（43％）出现BAD蛋白表达缺失，且NSCLC的不同病理类型间差异有显著性。BAD蛋白表达缺失在16例鳞癌患者中10例（63％），8例大细胞癌患者中5例（63％），26例鳞癌患者中有7例（27％）（P=0．04）。51例患者中25例（49％）出现磷酸化BAD蛋白过度表达[其中26例腺癌患者中有13例（50％），16例鳞癌患者中有8例（50％），8例大细胞癌患者中有4例（50％）]。BAD蛋白的表达缺失与磷酸化BAD蛋白的过度表达经统计检验与上述肿瘤浸润程度无相关性。结论：肺鳞癌出现VEGFR表达增高的可能较大，而大细胞癌出现VEGFR表达增高的可能最小。在鳞癌和大细胞癌中可见BAD蛋白表达的显著缺失。NSCLC患者EGFR，VEGFR，磷酸化BAD蛋白的过度表达以及BAD蛋白表达的缺失与病理浸润程度无关。但这些受体酪氨酸激酶表达以及与NSCLC凋亡直接相关的媒介因子可能成为未来多靶向治疗中的候选靶标。     

Differential expression of multiple anti-apoptotic proteins in epidermis of IGF-1 transgenic mice as revealed by 2-dimensional gel electrophoresis/mass spectrometry analysis

Overexpression of insulin-like growth factor-1 (IGF-1) has been associated with a number of human tumors, including breast, colon, lung, and prostate cancers. In previous studies, we found that mice overexpressing human IGF-1 in the basal layer of the epidermis (BK5.IGF-1 mice) developed skin tumors following treatment with the skin tumor initiator, 7,12-dimethylbenz[a]anthracene, indicating that IGF-1 can act as a skin tumor promoter. In the present study, we employed a proteomics approach of two-dimensional (2-D) gel electrophoresis and mass spectrometry to profile differentially expressed proteins in skin epidermis between BK5.IGF-1 transgenic and nontransgenic littermates. Two-D gels from each of three transgenic and three age/sex matched wild-type littermates were compared at two different pH ranges. Differentially expressed protein spots were identified by Bio-Rad's PDQuest image analysis, in-gel digested, and analyzed on a MALDI-TOF MS system. A total of 23 proteins were identified as differentially expressed, 17 of them overexpressed in transgenic mice. These proteins included 14-3-3 sigma, galectin-7, an apoptosis-related protein, three heat shock proteins, four calcium binding proteins, three proteases or protease inhibitors, one actin regulatory capping protein, and translation initiation factor 5A. The differential expression of GRP78, alpha enolase, and galectin-7 was verified by 1-D western blot analysis. Two-D western blot analyses of alpha enolase and galectin-7 further revealed that alpha enolase had more than one protein spot dependent on charge. The current data suggest that some of the differentially expressed proteins may play a role in the tumor promoting action of IGF-1 in mouse skin.     

The cannabinoid delta(9)-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells

Deregulation of cell survival pathways and resistance to apoptosis are widely accepted to be fundamental aspects of tumorigenesis. As in many tumours, the aberrant growth and survival of colorectal tumour cells is dependent upon a small number of highly activated signalling pathways, the inhibition of which elicits potent growth inhibitory or apoptotic responses in tumour cells. Accordingly, there is considerable interest in therapeutics that can modulate survival signalling pathways and target cancer cells for death. There is emerging evidence that cannabinoids, especially Delta(9)-tetrahydrocannabinol (THC), may represent novel anticancer agents, due to their ability to regulate signalling pathways critical for cell growth and survival. Here, we report that CB1 and CB2 cannabinoid receptors are expressed in human colorectal adenoma and carcinoma cells, and show for the first time that THC induces apoptosis in colorectal cancer cells. THC-induced apoptosis was rescued by pharmacological blockade of the CB1, but not CB2, cannabinoid receptor. Importantly, THC treatment resulted in CB1-mediated inhibition of both RAS-MAPK/ERK and PI3K-AKT survival signalling cascades; two key cell survival pathways frequently deregulated in colorectal tumours. The inhibition of ERK and AKT activity by THC was accompanied by activation of the proapoptotic BCL-2 family member BAD. Reduction of BAD protein expression by RNA interference rescued colorectal cancer cells from THC-induced apoptosis. These data suggest an important role for CB1 receptors and BAD in the regulation of apoptosis in colorectal cancer cells. The use of THC, or selective targeting of the CB1 receptor, may represent a novel strategy for colorectal cancer therapy.     

日本血吸虫促凋亡基因SjBAD的初步研究

目的了解日本血吸虫促凋亡基因Sj BAD的生物学、免疫学和转录表达特征,评估Sj BAD重组蛋白作为日本血吸虫病疫苗候选分子的潜力。方法根据Sj BAD的参考序列设计引物,应用PCR技术扩增Sj BAD基因,构建重组表达质粒p ET-28a(+)-Sj BAD。采用实时定量PCR检测Sj BAD基因在日本血吸虫不同发育期及42 d雌、雄虫体内的转录水平;应用Western blotting和间接ELISA法分析Sj BAD重组蛋白的抗原性和免疫原性。用重组抗原Sj BAD免疫BALB/c小鼠,通过计算减虫率及肝脏减卵率,评估重组抗原作为血吸虫病候选疫苗分子的潜力。结果成功克隆了日本血吸虫Sj BAD基因,构建了重组表达质粒p ET-28a(+)-Sj BAD,并在大肠杆菌中成功表达,重组蛋白分子量约为22 k Da。Western blotting表明Sj BAD具有较好的抗原性和免疫原性,间接ELISA法检测表明重组蛋白免疫小鼠产生了高水平的特异性抗体Ig G。实时定量PCR检测发现Sj BAD基因在日本血吸虫的各个发育阶段均有转录,以14 d表达量最高,且在雄虫体内的表达量高于雌虫。两次动物免疫试验表明,重组蛋白Sj BAD在BALB/c小鼠体内诱导了30.82%和27.87%的减虫率,及42.52%和45.84%的肝脏虫卵减少率,均显著高于PBS对照组(P均0.05)。结论成功克隆、表达了日本血吸虫促凋亡相关基因Sj BAD,该基因在日本血吸虫不同发育期虫体内均有表达。纯化的重组Sj BAD蛋白在小鼠体内能诱导产生部分抗血吸虫感染的免疫保护效果。