Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of nafamostat mesilate on coagulation and fibrinolysis was investigated in a study of 22 patients with hepatocellular carcinoma who underwent a hepatic resection. The patients were divided into two groups: group 1, control (n = 11) and group 2, those with the intraoperative and postoperative use of nafamostat mesilate (0.2 to 0.4 milligram per kilogram per hour, n = 11). Nafamostat mesilate tended to suppress the coagulation expressed by thrombin-antithrombin III complex and fibrinopeptide A both during and immediately after operation. Moreover, nafamostat mesilate significantly suppressed the fibrinolysis expressed by euglobulin lysis activity both during and after operation. With regard to the initial stage of the fibrinolytic system, such as tissue-type plasminogen activator and plasminogen activator inhibitor-1, there was no difference between the groups. Therefore, the suppression of the euglobulin lysis activity may be caused by the inhibition of plasmin activity. There was no difference between the groups regarding operative blood loss. However, the rate of blood transfusion in group 2 was lower than that in group 1, and no fresh frozen plasma was required for the patients who lost over 2,000 milliliters of blood. Nafamostat mesilate can suppress euglobulin lysis activity both intraoperatively and postoperatively, and thus decrease the amount of blood transfusion needed. Therefore, at present, nafamostat mesilate seems to be one of the most useful agents for stabilizing the coagulant and fibrinolytic systems in hepatic resection.
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PMID:Effect of nafamostat mesilate on coagulation and fibrinolysis in hepatic resection. 816 88

Tissue factor pathway inhibitor is a multivalent, Kunitz-type proteinase inhibitor. It directly inhibits factor Xa and, in a factor Xa-dependent fashion, produces feedback inhibition of the factor VIIa/tissue factor catalytic complex which is responsible for the initiation of coagulation. Human recombinant TFPI (rTFPI) produced in Escherichia coli was used to define the kinetic constants describing the human factor Xa:TFPI interaction. The inactivation of factor Xa by E. coli-rTFPI is indistinguishable from that of rTFPI produced in mammalian SK-hepatoma cells, suggesting that post-translational modifications such as glycosylation and phosphorylation do not play a major role in the inhibitory process. The slow, tight-binding inhibition of factor Xa follows the scheme: [formula: see text] Where the enzyme (E) and inhibitor (I) form an initial, immediate collision complex (EI) that then isomerizes slowly to a tightened final EI* complex. In the absence of other additions, the initial Ki (=k2/k1) and final Ki* for the inhibition of factor Xa by E. coli-rTFPI are 1.24 nM and 26.4 pM, respectively. In the presence of calcium ions (5 mM) the interaction between factor Xa and rTFPI is substantially weaker, with a Ki of 42.7 nM and Ki* of 85.2 pM. The addition of other components of the prothrombinase complex produces enhanced factor Xa inhibition predominantly through an effect on the initial Ki. In the presence of calcium ions and saturating concentrations of phospholipids and factor Va, the Ki and Ki* for factor Xa inactivation are 2.04 nM and 52.3 pM. The enhancing effect of heparin on the inhibitory process is concentration dependent and exhibits an optimum, reminiscent of the "template" model for heparin's acceleration of thrombin and factor IXa inhibition by antithrombin III. At optimal concentrations, the major mechanism of heparin action is also a reduction in the Ki of the initial encounter complex between factor Xa and rTFPI.
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PMID:Kinetics of factor Xa inhibition by tissue factor pathway inhibitor. 826 29

Hepatocyte-like mhAT3F cells have been derived from the hepatoma of a transgenic mouse expressing the SV40 large T antigen under the control of the antithrombin III gene regulatory region (Antoine, B., Levrat, F., Vallet, V., Berbar, T., Cartier, N., Dubois, N., Briand, P., and Kahn, A. (1992) Gene expression in hepatocyte-like lines established by targeted carcinogenesis in transgenic mice. Exp. Cell. Res. 200, 175-185; F. Levrat et al., unpublished results). In these cells, the L-PK gene is transcriptionally activated by glucose, as it is in vivo and in cultured hepatocytes. However, in contrast to the L-PK gene regulation in the liver and isolated hepatocytes, the glucose responsiveness does not require insulin and is not blocked by cyclic AMP. In mhAT3F cells, the insensitivity to insulin might be due to the replacement of insulin-dependent glucokinase by insulin-independent hexokinases able to phosphorylate glucose in the absence of the hormone. The glucose-dependent activation of the L-PK gene is delayed, requires ongoing protein synthesis, and is mediated by the same glucose response element as in vivo and in isolated hepatocytes. These results suggest that the glucose-dependent signaling pathway responsible for the transcriptional activation of glycolytic and lipogenic genes requires glucose phosphorylation, a phenomenon that is insulin-dependent in the liver but insulin-independent in cultured hepatoma cells. Nevertheless, the action of glucose 6-phosphate is most likely indirect.
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PMID:Glucose-dependent regulation of the L-pyruvate kinase gene in a hepatoma cell line is independent of insulin and cyclic AMP. 829 94

Two patients with abnormal antithrombin III manifested abnormality in heparin binding activity (abnormal antithrombin III "Toyma") or protease binding activity (abnormal antithrombin III "Aomori"). Antithrombin III "Toyama" is hereditarily homozygous with Arg47 to Cys47 (TGC-->TGT) mutation, and antithrombin III "Aomori" is hereditarily heterozygous with Arg393 to His393 (CGT-->CAT). The former is classified as type II-c, and the latter as type II-b according to Lane's classification2). Both patients showed cerebral thrombosis after age 20. Heparin cofactor II activity in the former case was slightly higher than normal. Oral anticoagulant therapy was used in the both cases. These cases were examined by biological and immunological assay, heparin sepharose column chromatography, binding activity to cultured porcine endothelial cells, restriction fragment length polymorphysm and polymerase chain reaction. The authors developed an antithrombin III assay method to be able to estimate real activity without the influence of heparin cofactor II activity11), and to apply the low molecular weight heparin to prevent relapse of thrombosis, and finally to find an anticoagulant substance in an interesting case of hepatocellular carcinoma (Edmondson type 1) producing normal antithrombin III30).
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PMID:[Abnormal antithrombin III: abnormalities of heparin or protease binding domain]. 835 May 12

The prevalence of the alternative alleles of an unusual length polymorphism in the promoter of the human antithrombin III (AT3) gene was determined in a sample of 155 unrelated individuals from the Northern Irish population. The 108bp L allele and the 32bp S allele occurred at frequencies of 0.21 and 0.79 respectively. Some homology was noted between the L-specific sequence and the region immediately downstream. Residual homology was also evident between the L and S sequences, suggesting that the S allele was derived from the L allele during evolution by partial deletion followed by sequence divergence. The functional significance of the polymorphism was investigated by transient transfection of AT3 promoter/luciferase reporter gene constructs into two human hepatoma cell lines in vitro. The promoter strength of the L allele was found to be 1.6-fold higher than the S allele in HepG2 cells whereas in Hep3B cells, the strength of the S allele was 1.7-fold higher than that of the L allele. In order to evaluate the phenotypic consequences of the AT3 promoter polymorphism in vivo, plasma samples from the 155 control individuals were assayed for antithrombin III (ATIII) activity. Mean activities of the different promoter polymorphism genotypes (SS, LL, SL) were not significantly different. These results suggest that the AT3 promoter polymorphism does not contribute to the variation in plasma ATIII activity that occurs in the general population.
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PMID:Functional analysis of an unusual length polymorphism in the human antithrombin III (AT3) gene promoter. 856 37

As a basis for regulatory studies on the influence of hormones on (anti)coagulant protein production by hepatocytes, we examined the amounts of the plasma proteins antithrombin III (AT III), protein C, protein S, factor II, factor X, fibrinogen, and prealbumin produced by the hepatoma cell line HepG2, into the culture medium, in the absence and presence of insulin, beta-estradiol, dexamethasone and thyroid hormone. Without hormones these cells produced large amounts of fibrinogen (2,452 +/- 501 ng/mg cell protein), AT III (447 +/- 16 ng/mg cell protein) and factor II (464 +/- 31 ng/mg cell protein) and only small amounts of protein C (50 +/- 7 ng/mg cell protein) and factor X (55 +/- 5 ng/mg cell protein). Thyroid hormone had a slight but significant effect on the enrichment in the culture medium of the anticoagulant protein AT III (1.34-fold) but not on protein C (0.96-fold) and protein S (0.91-fold). This hormone also significantly increased the amounts of the coagulant proteins factor II (1.28-fold), factor X (1.45-fold) and fibrinogen (2.17-fold). Insulin had an overall stimulating effect on the amounts of all the proteins that were investigated. Neither dexamethasone nor beta-estradiol administration did substantially change the amounts of these proteins. We conclude that the HepG2 cell is a useful tool to study the hormonal regulation of the production of (anti)coagulant proteins. We studied the overall process of protein production, i.e., the amounts of proteins produced into the culture medium. Detailed studies have to be performed to establish the specific hormonal effects on the underlying processes, e.g., transcription, translation, cellular processing and transport, and secretion.
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PMID:The influence of insulin, beta-estradiol, dexamethasone and thyroid hormone on the secretion of coagulant and anticoagulant proteins by HepG2 cells. 858 7

Thirteen patients with hepatocellular carcinoma who underwent transcatheter arterial embolization (TAE) were studied to evaluate the incidence of pulmonary embolism and methods for diagnosing this complication. Pulmonary perfusion scans and changes in indexes of coagulation and of fibrinolysis, and in the partial pressure of oxygen in arterial blood were evaluated as possible signs of pulmonary embolism complicating TAE. In 3 out of 13 patients (23%), perfusion lung scans showed perfusion defects. These 3 patients were asymptomatic and their perfusion defects had disappeared by 4 weeks later. TAE was followed by significant decreases in platelet counts (p < 0.01) and in serotonin levels (p < 0.05); and by increases in A-aDO2 (p < 0.01), in levels of fibrinogen in plasma (p < 0.01), and in levels of thrombin-antithrombin III complex (TAT) (p < 0.05), with no significant increase in levels of D-dimer in plasma. Similar hematologic changes were observed in patients without perfusion defects after TAE. In 3 patients with perfusion defects, plasma levels of TAT before TAE were significantly higher than the levels in patients without perfusion defects (p < 0.01). Perfusion defects that occur after TAE may be caused by pulmonary thromboemboli, by pulmonary fat emboli, and by microatelectasis or discoid atelectasis, and the most common cause is probably pulmonary thromboemboli. We conclude that the risk of pulmonary embolism complicating TAE is higher in patients with hepatocellular carcinoma who have high levels of TAT in plasma.
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PMID:[Abnormalities in pulmonary perfusion scans after transcatheter arterial embolization of the liver]. 869 61

Alpha 1-Antitrypsin deficiency predisposes to pulmonary emphysema, liver cirrhosis and hepatocellular carcinoma. Anecdotal evidence and a large autopsy study suggest that severe lung and liver disease rarely coexist in the same subject, but this has not been studied in patients. Therefore we investigated 27 patients with severe alpha 1-deficiency (Pi ZZ) and pulmonary emphysema for signs of liver disease and impaired hepatic function. A subgroup of 7 patients underwent quantitative liver function tests. On physical examination or ultrasonography, cirrhosis or tumor was not suspected in any patient. Conventional liver function tests were completely normal in 17 patients. Elevated serum activities of gamma-glutamyltranspeptidase and/or aminotransferases were seen in 10 patients. In some, the elevation was only marginal and in none more than twice normal. The serum bilirubin concentration and activity of alkaline phosphatase were increased in 1 patient. Serum protein, albumin, fibrinogen, antithrombin III, alpha 1-fetoprotein concentrations, serum activities of cholinesterase and glutamate dehydrogenase, activated partial thromboplastin time and prothrombin time were normal in all patients. The indocyanine green half-life was abnormal only in 1 of 6 patients, suggesting that hepatic blood flow was not impaired in the study group. However, the lidocaine half-life and galactose elimination capacity, parameters of hepatic metabolization, were impaired in 4 and 6 of 7 patients, respectively. We conclude that liver disease or impaired liver function is not a clinically relevant problem in most patients with pulmonary emphysema due to alpha 1-antitrypsin deficiency. But results of quantitative liver function tests, although performed in only a small group of patients, suggest that hepatic metabolization might be impaired even in those patients who present with pulmonary disease.
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PMID:Liver function in patients with pulmonary emphysema due to severe alpha-1-antitrypsin deficiency (Pi ZZ). 873 89

The early stage of the state in which coagulation or fibrinolytic pathway is activated has been difficult to estimate. It has become possible to detect disseminated intravascular coagulation (DIC) at an early stage due to the development of highly sensitive methods which quantitate so called "molecular markers". Herein, to evaluate the clinical usefulness of plasmin-alpha 2-plasmin inhibitor complex (PIC) and tissue factor activity in plasma were examined. The first time, monitoring the plasma levels of PIC might be useful for the diagnosis of a pre-DIC condition and for effective control of therapy. We believed that combination assay for both PIC and D dimer will be adequate to differentiate whether the hemostatic abnormalities are induced mainly by DIC or hepatic insufficiency. Recently, new clinical usefulness of PIC has been reported. The PIC/thrombin-antithrombin III complex ratio was lower in patients with poor prognosis than in those with good prognosis, and it was also lower in those with organ failure than in those without it. The tissue factor is a major activator of the coagulation cascade and may play a role in initiating thrombosis. A simple chromogenic substrate assay for the quantitation of tissue factor activity in plasma samples was developed. Abnormally high levels were found in 80% of the patients with DIC, predominantly in patients with non-hematological solid tumors and acute leukemia. Serial determinations of plasma tissue factor demonstrated that plasma tissue factor changes immediately with the course of DIC. Plasma tissue factor did not correlate with hemostatic markers of DIC such as thrombin-antithrombin III complex, PIC, FDP D-dimer. Tissue factor activity correlated well with membrane anchoring region of tissue factor protein levels. Tissue factor activity correlate with tumor necrosis factor alpha levels in patients with non-hematological solid tumors without hepatocellular carcinoma. These findings suggest that the plasma tissue factor is potentially valuable for monitoring the progress of DIC in a limited population of patients.
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PMID:[Clinical usefulness of the measurements of plasmin-alpha 2-plasmin inhibitor complex and plasma tissue factor activity in patients with disseminated intravascular coagulation]. 881 61

The use of genetically modified tumor cells as vaccines has been successful in numerous animal models of grafted syngenic tumors and has provided the groundwork for many clinical trials of gene therapy in cancer patients. To investigate the real efficacy of ex vivo gene therapy-based vaccines, we used transgenic mice that express the SV40 large T and small t antigens under the control of hepatic antithrombin III (ASV-B)-regulatory sequences. These mice systematically develop hepatocarcinoma. Hepatoma cells, derived from ASV-B transgenic mice, were gene-transduced to express either interleukin-2, interleukin-4, the granulocyte-macrophage colony-stimulating factor, or the T-cell costimulatory molecule B7.1. First, we demonstrated the vaccine potential of engineered hepatoma cells by immunizing nontransgenic mice with these cells, which prevented the growth of subsequent grafted nontransduced hepatoma cells. However, vaccination of pretumoral transgenic animals with various combinations of engineered hepatoma cells failed to inhibit hepatoma onset and progression. Rather, tumor development in ASV-B mice appears to be dependent on the immune system, since neonatal induction of immunotolerance to tumor in ASV-B mice cells was associated with a moderate, but significant, acceleration of tumor development. These results seriously call into question the efficacy of this strategy of active vaccinotherapy against natural tumors.
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PMID:Does preventive vaccination with engineered tumor cells work in cancer-prone transgenic mice? 957 Mar


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