Fibrinogen and flbrinogen/flbrin-related antigen (total FRA) was measured In human normal Intima and different types of atherosclerotic lesions and mural thrombi. The amount showed marked variation between groups of tissue samples, but within each group there was a significant correlation between levels of total FRA and low density llpoproteln (LDL), suggesting that some common factor must Influence their influx or retention. The total FRA were analyzed by gradient sodium dodecyl sutfate polyacrylamlde gel electrophoresis and ImmunoblottJng with antisera to whole fibrinogen and fragments D and E, and fibrinopeptlde A (FPA). All intimal samples (but not thrombi) contained fragment X, the first product of plasmln digestion of fibrinogen, but fragment Y was present In only half the samples, and no core-fragment E containing FPA was detected in any sample, suggesting that flbr/nogenolysis Is limited. By contrast, all samples contained fragment E, which was negative for FPA, so presumably derived from fibrin; they also contained fragments D-dlmer and DY, which are characteristic degradation products of cross-linked fibrin. There were no differences between samples obtained during reconstructive 1 The early proliferative lesions appear first as small translucent elevations but may progress to massive translucent proliferate mounds, up to 2500 tun In thickness, which are particularly characterized by their high water content; this gives them a soft and wobbly texture, and they are described as gelatinous lesions. 23 In a high proportion of these lesions, neither extracellular lipid nor lipid within fat-filled SMC or macrophages can be demonstrated in frozen microscopical sections, suggesting that lipid deposition cannot be the factor initiating SMC proliferation. These lesions contain large amounts of plasma macromolecules, including low density lipoprotein (LDL), fibrinogen and fibrin-related antigens (FRA), other components of the hemostatic system, and insoluble fibrins** In a preliminary study of the FRA fraction, Smith and Walker 6 found that about naff was comprised of intact fibrinogen, but the remainder consisted of fragments, mainly of high molecular mass, which showed characteristic patterns in different types of lesions. Different fibrin or fibrinogen degradation products have a wide range of pharmacobiological activities, including stimulation of growth of cultured cells; modification of clotting, vascular all of which might influence atherogenesis. In the present study we have attempted a detailed identification of the FRA present in lesions to relate them to particular biological activities, and, by determining if they are derived from fibrinogen or fibrin, to gain a better insight Into the handling of hemostatic factors in the arterial wall. Previously, we isolated the FRA from intimal extracts by affinity chromatography on Sepharose-antjfibrinogen columns, followed by elution with 8 M urea and separation by sodium dodecyl sutfate polyacrylamide gel electrophoresis (SDS-PAGE) and staining with Coomassie ...
SummaryWe have studied the expression of p53 in 206 patients with gastric adenocarcinomas. A standard immunohistochemical technique employing the CM-1 anti-p53 polyclonal antibody was applied to the routinely fixed and paraffin-embedded material from these tumours; overexpression of p53 was defined as positive nuclear staining: 46% (94/206) of gastric carcinomas expressed high levels of p53. There was no significant correlation between p53 positivity and the tumour grade, growth pattern, the Lauren type or lymph node metastases. Correlation with disease stage was only marginally significant (P = 0.05). Life table analysis revealed a highly significant association between p53 expression and survival (P = 0.0062), the odds ratio of death being 1.89 (95% confidence interval 1.33-2.69). The overall 5-year survival of patients with p53-positive tumours was 3% compared with 16% for those with p53-negative tumours (median survival time being 5.6 and 11.4 months respectively). These data suggest that overexpression of the p53 oncoprotein is an independent marker of shortened survival in gastric cancer patients.
ABSTRACT:Maternal administration of betamethasone to enhance fetal lung maturation for women who threaten preterm labor is common clinical practice. However, recommendations regarding the choice of betamethasone formulations for perinatal use are vague. The disposition of betamethasone from two commonly used antenatal formulations is poorly understood. We therefore designed a study to capture the true pharmacokinetic profiles of betamethasone from these fast acting and dual-release formulations. Betamethasone in sheep plasma was measured by a newly designed, highly sensitive liquid chromatography/tandem mass spectrometry assay after intramuscular injection (n ؍ 4) of 0.25 mg/kg betamethasone phosphate and 0.5 mg/kg betamethasone phosphate/acetate formulations. Compartmental modeling was performed using the ADAPT II program. Betamethasone pharmacokinetics could be captured for 24 h for the phosphate and for 5 days for the phosphate/acetate formulations. The phosphate formulation profile had the appearance of a traditional Bateman function with a terminal half-life of 4 h, whereas the phosphate/acetate formulation produced a biexponential decline with a terminal half-life of 14 h. The latter is much longer than is commonly reported and has been missed in the literature due to assay limitations. Extrapolations to humans indicate that although both formulations might have similar therapeutic indices, the dual formulation might be associated with a lower safety profile. In light of this newly identified long terminal half-life for the betamethasone dual formulation, dosing practices for betamethasone in pregnancy need to be reassessed.Preterm birth occurs in about 10% of pregnancies, and complications associated with prematurity, especially respiratory distress syndrome, are the leading cause of mortality in prematurely born infants (NIH Consensus Panel, 1995). Betamethasone is administered maternally to enhance fetal lung maturation in women who threaten preterm labor during 24 to 34 weeks gestation. The National Institutes of Health recommends administration of two maternal intramuscular injections of 12-mg betamethasone 24 h apart for this condition. Although the doses of betamethasone are stated, the exact formulation recommendation is not clear. Betamethasone is available as a fast releasing phosphate ester prodrug formulation and as a dual acting suspension formulation containing phosphate and acetate ester prodrugs. Both formulations have been tested in clinical trials and have been shown to be efficacious in producing precocious fetal lung maturation (Liggins and Howie, 1972;Gamsu et al., 1989). However, there is controversy regarding the betamethasone-releasing properties of the acetate prodrug, and a recent meta-analysis suggests that this prodrug is probably of little therapeutic benefit for antenatal use (Jobe and Soll, 2004). Although the release properties of the acetate prodrug have been questioned, long-duration studies looking at the release pattern of betamethasone from this prodrug do not exist. ...
Mutations in the p53 nuclear oncogene are the most frequent genetic abnormalities encountered in human malignancies. Using the polyclonal antibody CM-1, we have examined the expression of the p53 oncoprotein immunohistochemically in archival material of normal, dysplastic, and malignant gastric mucosa. Abnormal expression of this protein was not observed in biopsies of normal gastric tissue (n = 30) but was detected in 22 of the 36 gastric cancers analysed (61 per cent). Nuclear staining was diffuse in 15 of the positive cancer cases, the remaining seven showing a more varied heterogeneous staining pattern. Abnormal p53 protein was not detected in mild (n = 14) or moderate (n = 16) gastric dysplasia but was present in 3 out of 15 severe dysplasia cases. The results suggest that expression of the p53 oncoprotein is a common finding in gastric cancer and occurs as a late event in the malignant transformation process.
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