Targeted Thrombolytic Liposomes

Becauseofvariousthrombolyticagentsnowavailableassociatedwithlowthrombolyticspecificity ,largedoserequiredforclinicaltreatment,andperplexingsideeffectofhemorrhage ,westudiedthethrombus targetedliposomeswhichhavespecificaffinitytoactivatedplatelets .WithtetrapeptideRGDSasthehomingdevice ,theobtainedliposomescanspecifi callyrecognizethereceptorGPIIb IIIaoftheactivatedplateletsinthrombus ,bywhichthrombustargetabilityisachieved .Thefollowingpartsareincludedinthestudy .Eggphosphatidylcholine (E…     

微创治疗迟发性脑内血肿(附78例报告)

目的：评价微创治疗迟发性脑内血肿的疗效。方法：采取锥颅穿刺置管 尿激酶灌注引流方法，回顾分析78例迟发脑内血肿的临床资料。结果：78例迟发脑内血肿经微创治疗后存活71例，死亡5例，总死亡率6％。格拉斯哥昏迷指数(GCS)、年龄、瞳孔变化、血肿大小、脑挫伤程度及并发症等6项指标可影响治疗效果。结论：迟发性脑内血肿采取微创治疗具有安全性、少创、经济、恢复时间短、并发症少、死亡率低等优点。是一种有效可靠的方法。     

Growth factor-dependent activation of the MAPK pathway in human pancreatic cancer: MEK/ERK and p38 MAP kinase interaction in uPA synthesis

Increased expression of the hepatocyte growth factor (HGF) receptor (c-met) and urokinase type plasminogen (uPA) correlated with the development and metastasis of cancers. To investigate the role of HGF/c-met signaling on metastasis in cancer cells stimulated with HGF, we examined the effects of a specific MEK1 inhibitor (PD98059) and a p38 MAP kinase inhibitor (SB203580) on HGF-induced uPA expression in pancreatic cancer cell lines, L3.6PL and IMIM-PC2. Pretreatment of PD98059 decreased HGF-mediated phosphorylation of extracellular receptor kinase (ERK), uPA secretion and expression of matrix metalloproteinases (MMP-2 and MMP-9) in a dose-dependent manner. In contrast, SB203580 pretreatment increased HGF-stimulated ERK phosphorylation, uPA secretion and expression of MMPs. SB203580 also reversed the inhibition of HGF-mediated ERK activation and uPA secretion in the PD98059-pretreated cells. These results suggest that ERK activation by HGF might play important roles in the metastasis of pancreatic cancer and the p38 MAPK pathway also involved in the HGF-mediated uPA secretion and metastasis by regulation of ERK pathway. This revised version was published online in July 2006 with corrections to the Cover Date.     

Plasminogen activator inhibitor-1 as a measure of vascular remodelling in breast cancer

The generation of urokinase plasminogen activator (uPA) by tumours is an important pathway for neoplastic cell invasion and metastasis. Indeed in several tumour types, elevated levels of uPA, its receptor (uPAR) or its inhibitor plasminogen activator inhibitor-1 (PAI-1) is associated with a poorer prognosis. Since endothelial cells also use this proteolytic system to remodel the extracellular matrix during angiogenesis and since angiogenesis, as assessed by microvessel density, is also a predictor of patient survival, this study was designed to investigate the relationship between angiogenesis and the urokinase system in breast tumours. The aims were to assess whether the uPA, uPAR and/or PAI-1 correlates with angiogenic activity and could therefore be a useful objective clinical measure of tumour neovascularization; and to clarify whether the poor outcome associated with high levels of the urokinase system is due to its association with angiogenesis. The study also sought to examine the relationship between the uPA system and vessel remodelling using loss of a basement membrane epitope (LH39) normally associated with established capillaries. The cytosolic levels of uPA, PAI-1 and uPAR were therefore measured by enzyme linked immunoabsorbent assay, together with tumour vascularity, in 136 well-characterized invasive breast carcinomas. There were significant relationships between uPA and uPAR (Spearman r=0.37, p<0.0001), uPA and PAI-1 (Spearman r=0.19, p=0.03) and between uPAR and PAI-1 (Spearman r=0.23 p=0.01). A significant correlation was also observed between PAI-1 and vessel remodelling (Spearman r=0.34, p=0.04), patient age (p=0.01), nodal status (p=0.047) and tumour grade (p=0.04), but no association between tumour vascularity and PAI (p=0.96), uPA (p=0.69) or uPAR (p=0.81) was present. No significant association was seen between any of the urokinase variables and expression of the angiogenic factor thymidine phosphorylase. Furthermore, no significant associations were found between any of the studied parameters and overall survival in a univariate analysis of the cancer patients. A multivariate Cox proportional hazard model of overall survival showed that uPA (p=0.15), but not uPAR (p=0.52) or PAI-1 (p=0.61), gave no additional prognostic information. These findings show that uPA may work via an independent pathway to angiogenesis and therefore combined blockade of uPA and angiogenesis may have additional therapeutic benefits. It also shows, as recently demonstrated in animal models, that PAI-1 may be a key regulator of vascular remodelling in human cancer.     

Regulation of tissue-degrading factors and in vitro invasiveness in progression of breast cancer cells

Hormone-independent growth and invasiveness represent phenotypic properties acquired during early progression of breast cancer. We compared human mammary adenocarcinoma cells, MCF-7, which are estrogen-dependent and poorly metastatic, with the estrogen-independent and highly metastatic subline, MCF7/LCC1, with regard to expression of tissue-degrading factors of the matrix metalloproteinase (MMP)-and urokinase (uPA)-dependent degradative pathways, as well as for their in vitro invasive properties. Both cell lines showed low constitutive mRNA expression of the MMP inhibitor TIMP-1. Baseline expression of TIMP-2 mRNA was also very low in MCF-7 cells, whereas the MCF7/LCC1 level was much higher (~10- fold). Furthermore, both cell lines revealed low constitutive capacity to migrate in an in vitro invasion assay. Treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA; 100 nM) induced the mRNAs for TIMP-1 as well as for MMP-1, MMP-9, the uPA receptor, and the uPA inhibitor PAI-1, am ongst which only the responses of MMP-9 and PAI-1 were cell-specific. The mRNA levels of MMP-9 and PAI-1 were ~10-fold and ~15-fold higher in MCF7/LCC1 cells compared to MCF-7 cells. The secretion of immuno-reactive PAI-1 was considerably elevated (. 20-fold) in TPA-treated MCF7/LCC1 cells, whereas the TPA-dependent level of 92-kDa MMP-9 was only ~2-fold higher in MCF7/LCC1 cells than in MCF-7 cells. In both cell lines treatment with TPA was associated with an increase (~10-fold) in in vitro migration, which in the MCF7/LCC1 cells was significantly attenuated by a reconstituted basement membrane extract (Matrigel). These data suggest that TPA-responsive in vitro invasive properties that are probably associ-ated with PAI-1 expression may co-vary with progression from hormone-dependent to -independent breast cancer. © Rapid Science 1998     

Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: Overview of results on mortality, reinfarction and side-effects from 33 randomized controlled trials

During the past 25 years, 24 randomized trials of intravenous(IV) fibrinolytic treatment have been reported, involving atotal of some 6000 patients in the acute phase of myocardialinfarction. Most tested IV streptokinase (SK), but a few testedIV urokinase (UK). In the past 2 or 3 years numerous small randomizedtrials of intracoronary (IC) SK have been started, 9 of which,involving a total of about 1000 such patients have been reported.Because all of these IV and IC trials were small (the largestincluding only 747 patients), their separate results appearcontradictory and unreliable. But, an overview of the data fromthese trials indicates that IV treatment produces a highly significant(22%±5%, (P<0.001) reduction in the odds of death,an even larger reduction in the odds of reinfarction, and anabsolute frequency of serious adverse effects to set againstthis that is much smaller than the absolute mortality reduction.The apparent size of the mortality reduction in the IV trialswas similar whether anticoagulants were compulsory or optional,whether treatment was in a coronary cure unit or an ordinaryward and, surprisingly, whether treatment began early ( <6h from onset of symptoms) or late (generally 12–24 h).In addition, there was no evidence that UK was more effectivethan the less expensive SK, or that, despite their technicalcomplexity, the new IC regimes were more effective than theold IV regimes. Even the IV schedules that have been studied in randomized trialswere, however, quite complex, and the IC schedules were farmore so. Perhaps partly because of this, none of them is widelyused. If so, then some much simpler, and hence more widely practicable,IV SK regimes should be developed and tested. For example, asimple one hour high-dose IV SK infusion, without anticoagulation,will successfully convert virtually all of the available plasminogeninto plasmin. But, it may be several years before the net effectson mortality of any more widely practicable IV SK regimes canbe agreed unless many of the hospitals that do not wish routinelyto use IC regimes or the complex previous IV regimes will collaboratein multicentre randomized trials that can, if necessary, continuerapid intake until some tens of thousands of patients have beenrandomized, and some thousands of deaths have been observedamong the control and treated patients. The same, of course,may be true for any other fibrinolytic regimes (e.g. infusionof tissue plasminogen activator) if their net effects on mortalityare comparable to those of IV SK.     

High resolution real-time B-mode echotomography in the diagnosis of extracranial carotid lesions. Comparison with traditional angiography

Summary Tumour growth essentially requires fibrin formation and fibrinopeptide A (FPA) is liberated into the circulation on fibrin formation. In the present study, a possible elevation of serum FPA level was examined in patients with metastatic brain tumour. A significant elevation of serum FPA level was shown in all 6 patients with metastatic brain tumour, when blood was drawn from the internal jugular vein. It was extremely high in 2 patients with rapidly growing tumour. However, such a significant elevation was not shown in 3 cancer patients without brain metastasis or in 1 patient with a huge meningioma. This suggests the possibility that the presence of metastatic brain tumour could be detected by measuring FPA in blood drawn form the internal jugular vein. This also suggests the tendency that elevation of serum FPA is higher in patients with more rapidly growing tumour.Infusion of urokinase into the internal carotid artery resulted in an elevation of serum fibrinopeptide B (1)15–42 (FPB) in 5 patients with metastatic brain tumour, when blood was drawn from the internal jugular vein. This suggests that urokinase could induce fibrinolysis in the tumour tissue, though this remains in conclusive because of the lack of complete controls.     

鼠抗人纤维蛋白单链抗体-低相对分子质量单链尿激酶融合基因真核分泌表达载体的构建

目的 构建鼠抗人纤维蛋白单链抗体－低相对单链尿激酶融合基因真核分泌表达载体。方法 应用重组ＤＮＡ技 术,将人工合成的尿激酶原信号肽基因与鼠抗人纤维蛋白单链抗体－低相对分子质量单链尿激酶融合基因连接,并保 证在同一阅读框架,然后分别插科到pcＤＮＡ３和ＰＭＪＫ３两种真核表达载体中。结果构建成可以在真核细胞中分泌表 达鼠抗人纤维蛋白单链抗体－低相对分子质量单链尿激酶融合蛋白的重组质粒pcＤＮＡ３－Ｄ１和ｐＭＪＫ３－Ｄ１。结论为建 立稳定分泌表达鼠抗人纤维蛋白单链抗体－低相对分子质量单链尿激酶融合蛋白的细胞工程株奠定了基础。     

Proteolysis and invasiveness of brain tumors: Role of urokinase-type plasminogen activator receptor

Summary The cellular receptor for urokinase-type plasminogen activator (uPAR) in glioblastoma cell lines has been identified and found to be similar to the uPAR expressed by other tumor cell lines. Increased levels of uPAR have been found in primary malignant brain tumor tissues, especially highly malignant glioblastoma, and, to a lesser degree, in malignant astrocytomas, suggesting that this receptor might be involved in efficient activation of pro-uPA and confinement of uPA activity on the cell surface of invading brain tumors. The cell surface uPARs in gliomas could constitute an optimum environment for the generation and activity of plasmin, which is known to play a crucial role in the dissolution of the extracellular matrix during tumor cell invasion.In situ hybridization studies have shown that uPAR mRNA is expressed abundantly in tumor cells and is consistently present at the invasive edges of malignant gliomas. These results imply that uPAR is involved in plasmincatalyzed proteolysis during glioma invasion and that interference with the uPAuPAR interactions could constitute a novel approach for developing therapeutic strategies to counteract invasion of brain tumors.     

uPA系统在4株非小细胞性肺癌细胞中的表达

目的：研究尿激酶型纤溶酶原（ｕ Ｐ Ａ） 激活系统中４ 种主要成分ｕ Ｐ Ａ、 Ｐ Ａ Ｉ１ 、 Ｐ Ａ Ｉ２ 、ｕ Ｐ Ａ Ｒ 在非小细胞性肺癌细胞株中的表达及各因子之间的作用方式。方法：应用免疫组化、蛋白免疫印迹技术对培养细胞中４ 种成分进行定位、定性及半定量分析;应用斑点杂交技术检测４ 种细胞中ｕ Ｐ Ａ ｍ Ｒ Ｎ Ａ 和ｕ Ｐ Ａ Ｒｍ Ｒ Ｎ Ａ 的表达。结果：４ 种成分在４ 株细胞的胞浆及胞膜均有表达。蛋白免疫印迹法检测ｕ Ｐ Ａ、 Ｐ Ａ Ｉ１ 、 Ｐ Ａ Ｉ２ 、ｕ Ｐ Ａ Ｒ,４ 株细胞均在约１４０ ｋｕ 和约８０ ｋｕ 处出现特异性条带,且两种腺癌细胞的表达水平显著高于其他两株细胞。斑点杂交结果示４ 株细胞中均有ｕ Ｐ Ａ ｍ Ｒ Ｎ Ａ 和ｕ Ｐ Ａ Ｒ ｍ Ｒ Ｎ Ａ 的表达。结论：此４ 株细胞中均能合成与分泌ｕ Ｐ Ａ 系统的４ 种主要成分,各因子以二联及三联复合物（ｕ Ｐ Ａ／ Ｐ Ａ Ｉ１ 、ｕ Ｐ Ａ／ Ｐ Ａ Ｉ２ 、ｕ Ｐ Ａ／ｕ Ｐ Ａ Ｒ、ｕ Ｐ Ａ／ Ｐ Ａ Ｉ１／ｕ Ｐ Ａ Ｒ、ｕ Ｐ Ａ／ Ｐ Ａ Ｉ２／ｕ Ｐ Ａ Ｒ） 的形式存在;ｕ Ｐ Ａ 系统的表达与这４ 种细胞的恶性程度并不一致。