Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The debate over the potential risk of tumorigenicity attributable to the use of CCL substrates for biologicals production has continued for over 30 years and may continue for some time to come. Manufacturers and regulatory agencies are developing scientifically based guidelines for such products. It is currently possible to follow these guidelines to prepare recombinant biologicals and monoclonal antibodies in CCLs which do not pose unreasonable risks. This chapter has attempted to describe the scientific tools available to evaluate the putative risk of tumorigenicity due to potential virus DNA and protein contaminants. No theoretical or experimental basis exists to hypothesize that residual cellular protein might present a significant risk of tumorigenicity. The tools are certainly adequate for characterization of putative risks due to viruses and DNA but are not sufficiently powerful by themselves to assure product safety. The subsequent chapter on process validation describes how adequate assurances of safety ultimately can be obtained for products of CCLs against theoretical risks of tumorigenicity due to putative viruses and DNA. In addition to these safeguards, no evidence of tumorigenicity has been found in human or livestock animal recipients of the products prepared in CCL substrates. Many patients have received inoculations of tissue plasminogen activator, erythropoeitin, factor VIII, soluble CD4, GM-CSF, hepatitis B surface antigen vaccine, and various monoclonal antibodies and other recombinant products of continuous cell lines in clinical trials. For tissue plasminogen activator, large doses of 100 mg per patient or more have been used. At the time of writing over 10 kg of CHO-derived tissue plasminogen activator has been sold since late 1987 for administration to over 100,000 human patients. For recombinant factor VIII, erythropoeitin, and soluble CD4 proteins, chronic administration has been employed. Millions have received polio and rabies vaccines prepared in continuous Vero cells. In addition to this human experience, livestock animals have received annual inoculations of foot-and-mouth virus vaccine prepared in BHK-21 (a highly tumorigenic CCL) for up to 14 years without effect (69). No effects have been reported which might be attributed to oncogenic factors. Thus, scientific tools of characterization and principles of process validation are available to protect patients from putative risks of tumorigenicity associated with products prepared in CCLs. Increasing clinical experience also supports this conclusion.
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PMID:Continuous cell substrate considerations. 137 28

The hematopoietic growth factors, granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF), enhance the effector functions of mature myeloid cells, including the interaction with vascular endothelium. We examined the direct effect of recombinant human GM-CSF (rhGM-CSF) and recombinant human G-CSF (rhG-CSF) on the growth and function of cultured human umbilical vein endothelial cells (HUVEC). Endothelial cell growth supplement (ECGS) increased the proliferation of passaged and primary cells by 305% +/- 45% (mean +/- SEM, n = 5, P less than .01) over control cells at 4 days; GM-CSF and G-CSF had no effect. Endothelial cell procoagulant activity was increased after 4-hour incubation with recombinant interleukin-1 beta (IL-1 beta) 10 U/mL and recombinant tumor necrosis factor (TNF) 10 U/mL to 1,721% +/- 376% (n = 7, P less than .005) and 247% +/- 71% (n = 4) of control levels, respectively. gamma-Interferon (gamma-IFN) 50 U/mL had no direct effect of its own but was able to prime the response to IL-1 beta. There was no direct or priming effect of GM-CSF (1 ng to 1 microgram/mL) on the expression of procoagulant activity in endothelial cells. GM-CSF and G-CSF (1 ng/mL to 1 microgram/mL) had no effect on the expression of either tissue plasminogen activator (tPA) or plasminogen activator inhibitor-1 (PAI-1) by endothelial cells. The secretion of tPA by endothelial cells was increased, however, after 24-hour incubation with thrombin 4 U/mL (314% +/- 72% of control levels, n = 5, P less than .025). The production of PAI-1 was increased by TNF 200 U/mL (241% +/- 44% of control, n = 3, P less than .005), thrombin 4 U/mL (180% +/- 12% of control, n = 5, P less than .0005) and IL-1 beta 10 U/mL (275% +/- 44% of controls, n = 5, P less than .0005). In four experiments, endothelial cells showed no specific binding of 125I-GM-CSF, whereas peripheral blood (PB) neutrophils demonstrated the presence of 802 +/- 78 high-affinity receptors for GM-CSF. Thus, we found no effect of rhGM-CSF or rhG-CSF on the proliferation activities by these cells. These findings are in accordance with the lack of demonstrable receptors for GM-CSF on cultured HUVEC.
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PMID:Lack of effect of granulocyte-macrophage and granulocyte colony-stimulating factors on cultured human endothelial cells. 193 61

We have identified a leukemia-differentiating activity (LDA) in medium conditioned by the LD-1 melanoma, a G-CSF secreting human tumor line. Partially-purified LDA induces HL-60 cells to produce superoxide, become phagocytic, and to develop macrophage-like morphology and surface markers. The LDA markedly suppresses clonal growth in agar of HL-60 cells, and cells of the human myeloid leukemia lines PBL 985 and K562, but does not suppress clonal growth of the B-lymphoblast lines Raji and Daudi. The molecular weight of this material is approx. 40,000 daltons. It can be separated from the bulk of the colony stimulating activity on phenyl sepharose chromatography. The LDA is not neutralized by antibodies to G-CSF, GM-CSF, IFN alpha, IFN gamma, TNF, urokinase, and tissue plasminogen activator, and is not inhibited by preincubation with aprotinin. The LDA in conditioned medium may be different from previously described differentiating factors, and may represent an additional class of human growth regulators.
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PMID:Leukemia-differentiating activity expressed by the human melanoma cell line LD-1. 316 98

A prospective series of 20 patients with moderate to severe intraventricular haemorrhage (IVH) was studied for the effect of intraventricular administration of recombinant tissue plasminogen activator (rt-PA) on reduction of haematoma volume and prognosis. On the day of haemorrhage ventriculostomy was performed and 2 to 5 mg of rt-PA were injected via the external ventricular drainage, followed by drainage closure for two hours. In 14 patients rt-PA treatment was repeated. Computed tomography showed complete clot lysis or substantial reduction of intraventricular haematoma volume in 19 patients within 96 hours; the clearance of the third and fourth ventricle preceded the clearance of the lateral ventricles. Decrease of ventricular enlargement was seen in all but one patient with initial ventricular dilatation. Increase of haematoma volume and ventricular size was found in one patient. Outcome was minor or no neurological deficit in nine patients, disabling neurological deficit in six patients, and vegetative status in four patients. One patient did not survive the IVH. Intraventricular treatment with rt-PA seems effective in rapid lysis of intraventricular haematoma and normalisation of impaired CSF circulation. This treatment may contribute to an improvement in prognosis of moderate to severe IVH.
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PMID:Intraventricular recombinant tissue plasminogen activator for lysis of intraventricular haemorrhage. 773 52

Fibroblastoid synovial lining cells isolated from rheumatoid and other chronic inflammatory synovial tissue exhibit distinctive and sustained alterations in serial culture not commonly found in similarly cultured cells from osteoarthritic synovium. These are demonstrable using a multi-gene dot blot assay by labelling reverse transcribed fibroblast cDNA which is hybridized to plasmids containing relevant target gene inserts. Cultured synovial fibroblastoid cells from patients with chronic inflammatory synovitis expressed significantly higher levels of stromelysin, vimentin and TIMP-1 mRNA and lower levels of c-myc compared to cells isolated from osteoarthritis synovium although with considerable variation. Early fetal synovial lining cells were similar to cells from osteoarthritis synovium but vimentin expression was higher. Marked differences in patterns of gene expression between cell lines persisted through 10 serial passages over 6-8 months. In whole synovia, the average level of mRNA for stromelysin, vimentin, IL-4, IL-6, TIMP-1, cathepsin D, gelatinase, TGF alpha, c-fms and DR beta were preferentially expressed in inflammatory tissue while c-myc expression was higher in osteoarthritis synovium. Inflammatory synovium also expressed TNF alpha, IL-1 alpha, IL-1 beta, IL-2, c-sis, tissue plasminogen activator, CSF-1, and GM-CSF. This pattern resembles, in part, that found in cultured inflammatory fibroblasts but, in addition, gene products apparently reflecting the presence of activated monocytes and lymphocytes were detected. These results provide evidence that profiles of certain gene activation in cells from patients with inflammatory synovitis differ from those with non-inflammatory disease and suggest that the fibroblastoid cells are responsible for a considerable proportion of the altered phenotypic expression pattern in whole tissue. Furthermore, this modulated pattern of gene activation appears to be an intrinsic pro-inflammatory characteristic of the fibroblastoid cells initiated in response to chronic inflammation and persists for a prolonged period in the absence of other inflammatory cells.
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PMID:Sustained and distinctive patterns of gene activation in synovial fibroblasts and whole synovial tissue obtained from inflammatory synovitis. 809 Nov 28

Previous studies have indicated that intraventricular administration of tissue-type plasminogen activator (TPA) might improve the prognosis of patients with intraventricular haemorrhage (IVH). In aneurysmal IVH, fibrinolytic treatment was always preceded by surgical repair of the aneurysm, since the risk of recurrent haemorrhage from a non-occluded aneurysm was estimated to be high. We reviewed a series of patients with IVH secondary to ruptured aneurysms (n = 4) or arteriovenous malformation (AVM; n = 1) who underwent emergency intraventricular administration of TPA before repair of the bleeding source. Fibrinolysis resulted in rapid decrease of haematoma volume and of ventricular dilatation, and prevented ventricular catheters from becoming obstructed. No intracranial haemorrhages or other complications occurred. The results suggest that the presence of recently ruptured aneurysms or AVM is not necessarily a contraindication for intraventricular administration of TPA. The potentially life saving benefits might outweigh the inherent risks of recurrent haemorrhage in carefully selected patients with massive IVH, in whom ventricular distension, periventricular brain compression, obstruction of CSF flow, and elevated ICP appear to be major determinants for the outcome.
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PMID:Fibrinolytic treatment of intraventricular haemorrhage preceding surgical repair of ruptured aneurysms and arteriovenous malformations. 1061 79

This experimental study evaluated the effect of intrathecal injection of tissue-type plasminogen activator followed by cisternal drainage in the ultra-early stage of aneurysmal subarachnoid haemorrhage to prevent vasospasm. Twenty Japanese white rabbits were divided into five groups. Either tPA (groups A, B, and E) or saline (groups C and D) was injected intrathecally 1 hour (groups A, B, C, and D) or 21 hours (group E) after the intrathecal injection of blood. Cerebrospinal fluid was drained 2, 4, and 6 hours after the intrathecal injection of blood (groups A, C, and E). On day 4, the angiographic caliber of the basilar artery in each group was as follows (mean +/- SD): A, 85.9 +/- 5.0%; B, 74.6 +/- 5.3%; C, 69.1 +/- 2.7%; D, 64.0 +/- 4.9%; E, 80.2 +/- 2.7% (compared with baseline). In the two groups in which CSF was drained (groups A and C), fibrinolysis with tPA significantly suppressed vasospasm. In the two groups treated with tPA (groups A and B), cisternal drainage significantly suppressed vasospasm. In the two groups treated with saline (groups C and D), however, cisternal drainage did not suppress vasospasm. Examination of the series of CSF samples (groups A and C) showed that fibrinolysis with tPA effectively cleared clots early. In the two groups treated with tPA and CSF drainage (groups A and E), early removal of subarachnoid clots reduced the degree of vasospasm. Early fibrinolysis with tPA and early removal of subarachnoid clots by drainage is effective for preventing vasospasm.
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PMID:Experimental study of intracisternal administration of tissue-type plasminogen activator followed by cerebrospinal fluid drainage in the ultra-early stage of subarachnoid haemorrhage. 1067 5

Fibrinolytic activity in the inner ear of human beings and guinea pigs was assayed qualitatively and quantitatively. It was found that fibrinolytic activity of the stria vascularis was caused by a conversion of plasminogen to plasmin by tissue plasminogen activator and was moderate in degree compared with that of other organs in both species. In human beings, endolymph showed higher plasminogen activator activity than that of CSF. Plasminogen activator activity was not detected in either endolymph or perilymph of guinea pigs. Thrombin infusion diminished plasminogen activator activity in the stria vascularis of guinea pigs.
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PMID:Fibrinolytic activity in the inner ear of human beings and guinea pigs. 1099 33

Vascular endothelial cells play an important role in coagulation regulation of vascular tone and in a variety of synthetic and metabolic functions. Endothelial cells also have a pivotal role in immunological diseases atherogenesis and tumor angiogenesis. Endothelial cells are often used as system to study the pathophysiology of late complications in diabetes mellitus atherosclerotic damages and leukocyte adhesion in inflammatory diseases. Most of the studies have been performed on primary arterial and venous endothelial cell cultures with problems such as availability of autoptic material and reproducibility of cell cultures. We have isolated and characterized a novel system of proliferating long-term cultures of human aortic endothelial cells that maintain their differentiated characteristics for many generations in vitro. They produce antithrombotic and thrombotic factors such as t-PA and PAI-1 and respond to TNFalpha, an important factor correlated with the inflammatory process by modifying growth characteristics by producing cytokines such as GM-CSF by expressing ICAM-1 on the surface and by producing large amounts of nitric oxide and endothelin. This new system may be very useful to understand and study the molecular mechanisms involved in many vascular alteration pathologies and in the aging process.
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PMID:A new model of human aortic endothelial cells in vitro. 1112 Mar 52

Urokinase (uPA) and tissue plasminogen activator (tPA) are serine proteases implicated in fibrinolysis, but their role in the regulation of the cerebrovascular response to brain trauma has not been investigated. This study was designed to (1) characterize the cerebrovascular activity of uPA and tPA, (2) investigate the role of nitric oxide (NO) in uPA and tPA vascular activity, and (3) characterize the effect of fluid percussion brain injury (FPI) on vascular responses to uPA and tPA. The closed cranial window technique in chloralose anesthetized newborn pigs was used to measure pial artery diameter and collect CSF for radioimmunoassay (RIA) of cGMP concentration. Topical uPA (10(-9), 10(-7) M) elicited pial artery dilation that was blunted by the NO synthase inhibitor, L-NNA (10(-6) M) (8 +/- 1% and 13 +/- 1 vs. 3 +/- 1% and 7 +/- 2%, respectively). Vasodilation in response to uPA was associated with an increase in CSF cGMP concentration (645 +/- 20, 865 +/- 39 and 1088 +/- 33 fmol/mL cGMP for control, uPA 10(-9), 10(-7) M, respectively). Similar data were obtained for tPA. Pial artery dilation to uPA was blunted following FPI (7 +/- 1% and 12 +/- 1% vs. 3 +/- 1% and 6 +/- 1%, respectively), while uPA-associated release of cGMP was blocked (677 +/- 45, 909 +/- 53, and 1110 +/- 55 vs. 283 +/- 10, 316 +/- 18, and 333 +/- 26 fmol/mL for control, uPA 10(-9), 10(-7) M before and after FPI, respectively). Similar data were obtained for tPA. These data show that uPA and tPA produce pial artery dilation in an NO-dependent manner. FPI blunted uPA and tPA induced pial artery dilation as well as the associated release of cGMP. These data suggest therefore that altered NO function contributes to the impairment of uPA and tPA cerebrovasodilation after brain injury.
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PMID:Altered NO function contributes to impairment of uPA and tPA cerebrovasodilation after brain injury. 1545 90


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