Soluble protein encoded by CD44 variant exons 8-10 in the serum of patients with colorectal cancer.
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Bacterial Proteins↗
Biomedical subjects
T Urano
Publications and source records attributed to T Urano.
The effect of a 5HT2 receptor antagonist sarpogrelate (MCI-9042) treatment on platelet function in Buerger's disease.
The effect of a new, specific 5-HT2 receptor antagonist sarpogrelate (MCI-9042) treatment on platelet function and serotonin levels in both plasma and whole blood in Buerger's disease, was assessed in a pilot study. We investigated 10 patients suffering from Buerger's disease. Sarpogrelate in a dose of 3 x 100 mg a day was given p.o. for a period of 8 weeks. It was well tolerated and no major side effects were noted. It was judged to be effective in some patients as assessed by its effect on both subjective complaints and objective evaluation of ankle pressure index (API). Sarpogrelate induced a significant decrease in plasma serotonin (5-HT) concentration starting after the 4th week which lasted through to the 8th week of the study, whereas plasma tryptophan concentration increased significantly after 2 and 4 weeks. There were no changes in plasma 5-HIAA concentration. On the other hand whole blood 5-HT concentration increased significantly after 2 weeks, and there was also a tendency to increase in whole blood tryptophan concentration (p = 0.052). Platelet aggregation induced by ADP and collagen did not show any statistically significant changes. Surprisingly, platelet aggregation induced by serotonin increased significantly after 2 weeks and even more so after 4 weeks of treatment, and then it returned to baseline values after 8 weeks. There was no effect on platelet count, APTT, TT and fibrinogen concentration.
Administration, Oral↗
The inhibition of human factor Xa by plasminogen activator inhibitor type 1 in the presence of calcium ion, and its enhancement by heparin and vitronectin.
Plasminogen activator inhibitor type 1 (PAI-1), a member of serine proteinase inhibitor superfamily, is known to inhibit thrombin in the presence of either heparin or vitronectin. We analyzed possible inhibitory activity of PAI-1 on human factor Xa. PAI-1 inhibited factor Xa in the presence of calcium ion (Ca2+), whereas no inhibition was observed in the absence of Ca2+. Half maximal enhancement by Ca2+ was obtained at 0.8 mM. An equimolar complex formation between factor Xa and PAI-1 in the presence of Ca2+ was observed by SDS polyacrylamide gel electrophoresis. Both unfractionated heparin and vitronectin enhanced the inhibition only in the presence of Ca2+. Apparent second-order rate constant (ki) for the inhibition of factor Xa by PAI-1 at 5 mM Ca2+ was 1.6 x 10(4) M-1 s-1, and was enhanced 3-fold by 2 u/ml of heparin (4.6 x 10(4) M-1 s-1) and 10-fold by 100 nM vitronectin (1.6 x 10(5) M-1 s-1), respectively. The interaction between Ca(2+)-bound factor Xa and PAI-1 could be important from the view of PAI-1 neutralization and enhancement of fibrinolysis.
Calcium↗
Independent and differential expression of two isotypes of human Nm23: analysis of the promoter regions of the nm23-H1 and H2 genes.
We isolated genomic clones of two isotypes of human NDP kinase, nm23-H1 and H2. The nm23-H1 and H2 genes located in a tandem array contained 5 exons and most of the splicing sites in the exon-intron junctions of two isotypes were essentially identical. The regulatory elements of nm23-H1 and H2 genes were also analysed. One major and several minor transcriptional initiation sites were detected in the two isotypes by 5' RACE analysis in HeLa cell. We also identified them by means of an RNase protection assay and primer extension analysis. Promoter activities were found in the 5' flanking sequences of the two genes when placed upstream of the chloramphenicol acetyltransferase gene. Transcriptional activities of nm23-H1 and H2 regulatory regions were measured in a series of human cancer lines. The nm23-H1/nm23-H2 gene transcriptional activity ratio varied depending on the cell line. DNA sequencing of these two genes showed that their promoter regions contain distinct binding sites for known transcriptional factors. These studies suggest that the two isotypes of the nm23 genes might be regulated dissimilarly, and in cell type specific manner.
Base Sequence↗
Isolation of a novel GPI-anchored gene specifically regulated by p53; correlation between its expression and anti-cancer drug sensitivity.
We have identified a novel gene inducible by wild-type p53. A significant correlation between expression of this gene and p53 status in cells derived from esophageal cancers indicated that this gene is likely to be specifically regulated in a p53-dependent manner. As the predicted amino acid sequence showed a high degree of homology to the family of glycosyl-phosphatidylinositol (GPI)-anchored membrane proteins, we termed this gene GML (GPI-anchored molecule-like protein). Introduction of GML cDNA suppressed the growth of esophageal cancer cells in culture. A correlation between the presence of GML expression and the sensitivity of esophageal cancer cells to anti-cancer drugs implied that the gene product plays a significant role in the apoptotic pathway or cell-cycle regulation induced by p53 after DNA damage.
Amino Acid Sequence↗
The in vitro effects of chylomicron remnant and very low density lipoprotein remnant on platelet aggregation in blood obtained from healthy persons.
We investigated the in vitro influence of chylomicron (CM) remnant and very low density lipoprotein (VLDL) remnant on platelet aggregation in healthy persons. The separation of CM and VLDL remnants from serum was performed using an immunoaffinity gel mixture containing anti apo B-100 and anti apo A-1 antibodies coupled to Sepharose 4B. The preincubation with CM and VLDL remnants significantly enhanced the platelet aggregation in whole blood and in platelet rich plasma (PRP) induced by collagen. This effect was observed in whole blood with the addition of VLDL remnant at the concentration of 5 mu g/ml, and in PRP with the addition of CM remnant at the concentration of 1 and 5 mu g/ml, and with the addition of VLDL remnant at the concentration of 5 and 10 mu g/ml. These results may indicate that increase in remnant lipoproteins may be a part of the reasons for atherosclerotic and thrombotic complications.
Antithrombins↗
Ral-GTPases mediate a distinct downstream signaling pathway from Ras that facilitates cellular transformation.
Ral proteins (RalA and RalB) comprise a distinct family of Ras-related GTPases (Feig and Emkey, 1993). Recently, Ral-GDS, the exchange factor that activates Ral proteins, has been shown to bind specifically to the activated forms of RasH, R-Ras and Rap1A, in the yeast two-hybrid system. Here we demonstrate that although all three GTPases have the capacity to bind Ral-GDS in mammalian cells, only RasH activates Ral-GDS. Furthermore, although constitutively activated Ra1A does not induce oncogenic transformation on its own, its expression enhances the transforming activities of both RasH and Raf. Finally, a dominant inhibitory form of RalA suppresses the transforming activities of both RasH and Raf. These results demonstrate that activation of Ral-GDS and thus its target, Ral, constitutes a distinct downstream signaling pathway from RasH that potentiates oncogenic transformation.
3T3 Cells↗
Effects of short-term treatment with mevalotin on platelet aggregation, fibrinolysis, peripheral serotonergic system and serum lipids in Japanese monkeys.
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Animals↗
Characterization of the human p57KIP2 gene: alternative splicing, insertion/deletion polymorphisms in VNTR sequences in the coding region, and mutational analysis.
We have isolated human cDNA and genomic clones of a gene termed p57KIP2, which is related to the p2I WAFI and p27 KIP1 genes that encode inducible inhibitors of cyclin-dependent kinase activity. The p57 gene contains three GC-rich introns of 166 bp, 566 bp, and 83 bp, and two of the four exons correspond to coding regions. Alternative splicing generates the heterogeneity in the translational initiations. As this gene has been localized to chromosomal band 11pI5.5, a region thought to be the location of a tumor suppressor gene(s) for carcinomas of the breast, bladder, and liver, we have examined a large number of tumors for genetic alterations of p57. Although no somatic mutation has been detected, we have found several normal variations in this gene, including four types of 12-bp in-frame deletions in the proline/alanine repeating domain, in which nearly 40 motifs, viz., 5'-CCGGCC-3', are tandemly repeated.
Alternative Splicing↗
Changes in serotonergic measures in whole blood and various brain regions of rats administered with the 5-HT1A agonist tandospirone and/or exposed to electric foot-shock.
We studied the effects of foot-shock on tryptophan, serotonin [5-hydroxytryptamine (5-HT)], and its metabolite, 5-hydroxyindole acetic acid (5-HIAA) in whole blood and various brain regions of rats pretreated with tandospirone, a novel 5-HT1A receptor agonist. The administration of tandospirone did not result in changes in serotonergic measures, but stress or stress plus the administration of tandospirone resulted in an increase in blood levels of tryptophan, 5-HT, and 5-HIAA. In animals given stress, tryptophan levels rose in every part of the brain, and in animals given stress and tandospirone, tryptophan levels increased in all the brain regions except the medulla. The administration of tandospirone alone did not give rise to changes in tryptophan levels in any part of the brain. The administration of tandospirone resulted in an increase in 5-HT levles in all brain regions except the cerebellum. In rats given stress and tandospirone, 5-HT levels increased in the hypothalamus, midbrain, and cortex relative to controls. In every part of the brain, the administration of tandospirone resulted in a decrease in the turnover rate of serotonin (5-HIAA/5-HT). In the presence of stress, the administration of tandospirone resulted in a decrease in the turnover rate of serotonin in hypothalamus, hippocampus, and midbrain compared with controls and stress alone. These results suggest that tandospirone may stimulate presynaptic receptors in the midbrain and inhibit the activity of monoamine oxidase, resulting in an increase in 5-HT levels in the serotonergic nerve terminals.
Animals↗
Evidence for a Ras/Ral signaling cascade.
It is becoming clear that Ras proteins mediate their diverse biological functions by binding to, and participating in, the activation of multiple downstream targets. Recent work has identified nucleotide-exchange factors for Ral-GTPases as the newest members of the set of putative Ras 'effector molecules'. This new work has also detected two potential downstream targets of Ral proteins, a novel CDC42/Rac GTPase-activating protein and a phospholipase D.
Animals↗
Augmentation of endotoxin-induced pulmonary responses by mononuclear cell phagocytosis in the reticuloendothelial system.
OBJECTIVE: To test the hypothesis that the effects of intravenous injection of latex particles would demonstrate the contribution of phagocytosis by mononuclear phagocytes to the development of Escherichia coli-induced acute lung injury in neutropenic guinea pigs. DESIGN: Prospective, controlled, experimental study. Intravenously injected the latex particles into 41 guinea pigs to investigate the contribution of the phagocytosis in acute lung injury. SUBJECTS: Forty-one guinea pigs. INTERVENTIONS: Forty-one guinea pigs were divided into five experimental groups: a saline group (n=9); an endotoxin group (n=10) receiving 2 mg/kg of intravenous E. coli endotoxin; a latex group (n=7) receiving 2 x 10(9)/kg of intravenous polystyrene latex (mean diameter 3.19 micrometers); an endotoxin + latex group (n=8); and an E. coli group (n=7) receiving 2 x 10(9) live E. coli/kg. MEASUREMENTS AND MAIN RESULTS: The lung wet/dry ratio was increased in the live E. coli-treated guinea pigs (6.71 +/- 0.16 [SEM], p < .01) as compared with the saline control (5.40 +/- 0.16, whereas the ratio was not increased in the endotoxin (5.52 +/- 0.14) or latex (5.58 +/- 0.20) groups. However, the lung wet/dry ratio was greater in the endotoxin + latex group (6.11 +/- 0.16, p < .05) than in the saline control. The 125I albumin lung tissue/plasma ratio was greater in the E. coli (2.00 +/- 0.29, p < .01) and endotoxin + latex (0.84 +/- 0.12, p < .05) groups than in the saline group (0.18 +/- 0.07), whereas no increases were observed in the endotoxin group (0.22 +/- 0.10) and the latex (0.34 +/- 0.13) group. More than 40% of the injected radiolabeled latex was observed to have accumulated in the reticuloendothelial system (liver and spleen), in both the saline control (40.1 +/- 2.3%, n=4) and endotoxin (57.3 +/- 6.8%, n=5) groups, with 2.6 +/- 1.5% and 3.1 +/- 1.7% in the lungs for the saline control and the endotoxin groups, respectively. The percent deposition of radiolabeled latex in the liver was greater in the endotoxin group (51.7 +/- 3.8%, p < .05) than in the saline group (37.6 +/- 5.9%). CONCLUSIONS: These findings suggest that, in neutropenic guinea pigs: a) the combination of endotoxin and latex particles induces acute lung injury; and b) the phagocytic properties of mononuclear phagocytes in the reticuloendothelial system augment endotoxin-induced pulmonary responses and may play a role in the development of live E. coli-induced acute lung injury.
Animals↗
Effect of a specific neutrophil elastase inhibitor, ONO-5046, on endotoxin-induced acute lung injury.
Because excessive neutrophil elastase (NE) activity is involved in the pathogenesis of acute lung injury, we speculated that administering anti-NE might prevent lung injury. In a guinea pig model of acute lung injury induced by Escherichia coli endotoxin (lipopolysaccharide [LPS]), we investigated the effect of ONO-5046, a low-molecular-weight and specific inhibitor of NE. ONO-5046 produced concentration-dependent inhibition of guinea pig NE, whereas there were no inhibitory effects on neutrophil chemotaxis or the expression of adhesion molecules in endothelial cells. Detectable NE activity in bronchoalveolar lavage (BAL) fluid was present in the LPS-alone group. No NE activity in BAL fluid was detected in the LPS+ONO-5046 groups. Neutrophil counts in BAL fluid, the lung tissue wet to dry weight ratio, and the lung tissue or BAL fluid to plasma ratio of 125I-albumin were increased in the LPS-alone group as compared with the saline group (p < 0.05). In the LPS+ONO-5046 group, neutrophil counts in BAL fluid, the lung tissue wet to dry weight ratio and BAL fluid to plasma ratio of 125I-albumin were decreased as compared with the LPS-alone group (p < 0.05). These data suggest that ONO-5046 can attenuate LPS-induced acute lung injury.
Acute Disease↗
Protective effect of B464, a lipid A analog, on endotoxin-induced cellular responses and acute lung injury.
B464 is a novel synthetic analog of lipid A, a toxic component of endotoxin (LPS; lipopolysaccharide). We investigated the effects of B464 on both LPS-induced cellular responses in vitro and acute lung injury in vivo. In the in vitro study, B464 inhibited tumor necrosis factor-alpha (TNF-alpha) production from human monocytes, priming and stiffening of neutrophils, and expression of adhesion molecules on endothelial cells induced by LPS. We then studied the effects of B464 pretreatment on acute lung injury elicited by intravenous LPS administration in vivo. Guinea pigs were divided into saline control, B464 alone, LPS alone, and LPS + B464 groups. Animals were observed for 4 h after LPS administration, and lung injury was evaluated by extravascular lung water, 125I-albumin leakage in lung tissue, and lung neutrophil accumulation. In the LPS alone group, rapid and sustained peripheral neutropenia (p < 0.001 versus saline at 15 min and at 1, 2, and 4 h), an increased plasma TNF-alpha concentration (p < 0.005 at 1 h), and increases in lung injury parameters (p < 0.05) were observed. In the LPS + B464 group, no changes were observed in either plasma TNF-alpha or lung injury parameters. Transient peripheral neutropenia and subsequent rapid recovery (p > 0.05, p < 0.001, p < 0.01, and p > 0.05 at 15 min and 1, 2, and 4 h, respectively) were observed in the LPS + B464 group. These in vivo data, together with in vitro evidence of suppressed cellular responses, suggest that B464 (1) inhibits neutrophil accumulation in lung tissue, and (2) attenuates the development of acute lung injury by blocking the activation of neutrophils and mononuclear cells as well as the interaction between neutrophils and endothelial cells.
Animals↗
A derivative of cationic antimicrobial protein attenuates lung injury by suppressing cell adhesion.
Cationic antimicrobial protein of 18 kD (CAP18) was identified and purified from rabbit granulocytes and shown to inhibit various activities of lipopolysaccharide (LPS). We investigated the effect of a 32-amino-acid C-terminal fragment of CAP18 (CAP18-derived peptide, CDP) on the pathogenesis of acute lung injury caused by intravenous endotoxin. Guinea pigs were divided into six groups: (I) saline control (n = 8), (2) CDP-alone (n = 8), (3) LPS-alone (n = 8), (4) LPS+CDP0m (n = 8), (5) LPS+CDP10m (n = 8), and (6) LPS+CDP60m (n = 8). A CDP dose of 0.2 mg/kg was injected at various time points after LPS injection. Lung wet-to-dry weight ratio, [125I]albumin leakage in lung tissue and bronchoalveolar lavage (BAL) fluid, differential cell count in BAL fluid, and histopathologic features were examined 4 h after intravenous administration of 0.02 mg/kg of LPS. The LPS+CDP0m and the LPS+CDP10m groups showed significantly attenuated lung injury compared to that seen in the LPS-alone group, however the LPS+CDP60m group revealed no attenuation of lung injury. The accumulation of peripheral white blood cells into pulmonary vasculature was attenuated only in the LPS+CDP0m but not in the LPS+CDP10m groups. We examined the effect of CDP on the expression of adhesion molecules using human umbilical vein endothelial cells, the result of which showed that CDP suppressed the LPS-induced expression of adhesion molecules in a dose-dependent manner. We conclude that CDP attenuates inflammatory cell migration into alveoli resulting in the attenuation of lung injury.
Albumins↗
Expression of a CD44 variant containing exons 8 to 10 is a useful independent factor for the prediction of prognosis in colorectal cancer patients.
PURPOSE: To determine the expression of the CD44 variant containing a variant exon 8 to 10 product (CD44v8-10) in colorectal cancer and to evaluate its prognostic value. MATERIALS AND METHODS: CD44v8-10 was studied in resected tumors and normal mucosae obtained from 215 colorectal cancer patients (118 colon cancer and 97 rectal cancer). The expression of CD44v8-10 was analyzed immunohistochemically using the anti-CD44v8-10 monoclonal antibody (mAb) 44-1V. RESULTS: One hundred of 215 cancer tissues expressed CD44v8-10. Positive staining was intense mainly on the cell membranes. There was no significant correlation between expression of CD44v8-10 and histologic type, primary tumor, lymphatic invasion, venous invasion, or peritoneal invasion. There were significant correlations between CD44v8-10 immunoreactivity and both lymph node and hematogenous metastasis. Patients with CD44v8-10-positive tumors had a greater relative risk of death compared with those whose tumors were CD44v8-10-negative. Among 169 patients who underwent curative resection, CD44v8-10 expression correlated with a high recurrence rate. The 5- and 10-year survival rates were 90.3% of patients with CD44v8-10-negative tumors, and 72.1% and 58.0% of those with CD44v8-10-positive tumors, respectively; these differences between the two groups of patients were significant (P < .01). In multivariate analysis using the Cox regression model, CD44v8-10 expression emerged as an independent prognostic indicator. CONCLUSION: The results suggest that CD44v8-10 plays a role in metastasis of colorectal cancer, and tha CD44v8-10 expression may be a biologic marker of prognostic significance.
Antibodies, Monoclonal↗
Effects of erythromycin and roxithromycin on oxidation of testosterone and nifedipine catalyzed by CYP3A4 in human liver microsomes.
Roxithromycin and erythromycin were incubated with rat and human liver microsomal or reconstituted cytochrome P450 (P450 or CYP) monooxygenase systems in the presence of an NADPH-generating system, and the effects of these chemicals on testosterone 6 beta-hydroxylation and nifedipine oxidation activities were compared with those of typical CYP3A4 inhibitors including ketoconazole, troleandomycin, and gestodene. Roxithromycin and erythromycin were found to be relatively weak inhibitors of testosterone 6 beta-hydroxylation and nifedipine oxidation activities by rat and human liver microsomes or by reconstituted systems containing CYP3A4/5. Formation of an inhibitory P450-metabolite complex was determined spectrally by incubating troleandomycin with human liver microsomes; the extents of the complex formation were lesser in liver microsomes of humans than those of rats treated with dexamethasone. Erythromycin and roxithromycin were also activated slightly by rat liver microsomes to form P450.Fe(II)-metabolite complex, although these chemicals caused very little or undetectable levels, respectively, of spectral changes by human liver microsomes even when a human sample which contained relatively high levels of CYP3A4 was used. These results suggested that roxithromycin and erythromycin were relatively less potent to inhibit CYP3A4-catalytic activities in human liver microsomes, because of their low capabilities to form P450.Fe(II)-metabolite complex.
Animals↗
HTLV-I infections in offspring derived from HTLV-I carrier rats during the suckling period.
An experimental rat model for vertical transmission of human T cell leukemia virus type I (HTLV-I) was used to examine whether the infection of offspring derived from HTLV-I carrier rats could be established during the suckling period. MT-2 (2 x 10(7)) cells were injected into 5-week-old rats twice, at 2-week intervals. HTLV-I infected or non-infected female rats were mated with HTLV-I carrier male rats. The titer of serum antibodies against HTLV-I in the offspring derived from non-infected dams was less than 1:16 by the agglutination test during the suckling period. The serum antibodies of the offspring derived from the infected dams was less than 1:32 at 1 day after birth and increased steadily to 1:2048 at 14 days. However, the HTLV-I proviral sequences were not detected in any organs of the offspring during the suckling period as determined by the nested double polymerase chain reaction (PCR). These findings indicate that maternal antibodies against HTLV-I were not readily transmitted through the placenta and that the anti-HTLV-I antibodies in the offspring came from the milk of the dams. Furthermore, the HTLV-I infection in the offspring that was derived from the carrier dam may not be established during the suckling period but after weaning.
Animals↗