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Objective-Overexpression of elastolytic cysteine and aspartic proteases, known as cathepsins, is implicated in atherogenesis. The potential significance of imbalance in expression between cathepsins and their inhibitor cystatin C in cardiovascular disease has been highlighted by the demonstration of cystatin C deficiency in human atherosclerosis and abdominal aortic aneurysms. Methods and Results-We identified and characterized physiologically relevant polymorphisms in the promoter region of the cystatin C gene that influence cystatin C production and used these polymorphisms as a tool to examine the significance of cystatin C in coronary atherosclerosis in vivo in humans. Seven polymorphisms, all in strong-linkage disequilibrium, were identified in the cystatin C gene, of which 2 promoter polymorphisms (Ϫ82G/C and Ϫ78T/G) were functional in vitro in electromobility shift and transient transfection assays. Genotyping of 1105 individuals (237 survivors of a first myocardial infarction before age 60 and 2 independent groups comprising a total of 868 healthy individuals) revealed that the plasma cystatin C concentration was significantly lower in carriers of the mutant haplotype. Furthermore, the mutant haplotype was associated with a higher average number of stenoses per coronary artery segment in unselected postinfarction patients (Nϭ237) undergoing routine coronary angiography. Conclusions-These results provide human evidence for an important role of cystatin C in coronary artery disease.(Arterioscler Thromb Vasc Biol. 2004;24:551-557.)

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Periodate-treated, non-anticoagulant heparin-carrying polystyrene consists of about ten periodate-oxidized, alkaline-degraded low molecular weight-heparin chains linked to a polystyrene core and has a markedly lower anti-coagulant activity than heparin. In this study, we evaluated the effect of non-anticoagulant heparin-carrying polystyrene on tumour growth and metastasis. Non-anticoagulant heparin-carrying polystyrene has a higher activity to inhibit vascular endothelial growth factor-165-, fibroblast growth factor-2-or hepatocyte growth factor-induced human microvascular endothelial cell growth than heparin, ten periodate-oxidized-heparin and ten periodate-oxidized-low molecular weight-heparin, which is probably due to the heparin-clustering effect of non-anticoagulant heparin-carrying polystyrene. Non-anticoagulant heparin-carrying polystyrene inhibited human microvascular endothelial cell, B16 melanoma and Lewis lung cancer cell adhesion to Matrigel-coated plates. Non-anticoagulant heparin-carrying polystyrene also showed strong inhibitory activities in the tubular formation of endothelial cells on Matrigel and B16-melanoma and Lewis lung cancer cell invasion in a Matrigel-coated chamber assay. In vivo studies showed that growth of subcutaneous induced tumours and lung metastasis of B16-melanoma and Lewis lung cancer cells were more effectively inhibited by non-anticoagulant heparin-carrying polystyrene than ten periodate-oxidized-heparin and ten periodate-oxidized-low molecular weight-heparin. Furthermore, non-anticoagulant heparin-carrying polystyrene markedly reduced the number of CD34-positive vessels in subcutaneous Lewis lung cancer tumours, indicating a strong inhibition of angiogenesis. These results suggest that non-anticoagulant heparin-carrying polystyrene has an inhibitory activity on angiogenesis and tumour invasion and may be very useful in cancer therapy.

With these criteria, limited resection was performed safely without any recurrence, and the postoperative pulmonary function was well preserved. The outcomes of limited resection for small-sized lung cancer with GGOs that met the criteria of this study were satisfactory.

There was no evidence that any specific MMP polymorphism had a clinically significant effect on AAA expansion. The plasminogen system may have a small but clinically significant role in AAA development. Much larger studies would be needed to evaluate genes of smaller effect.

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Correlation between carcinoembryonic antigen(CEA) and carbohydrate antigen(CA) 19-9 levels of peripheral and draining venous blood, and l l histopathologic and immunohistochemical variables was examined in 83 patients with colorectal cancer. CEA levels of draining blood (mean 34.5 ng/ml and positive rate greater than 5 ng/ml, 60.2%) were significantly higher than those (13.0 ng/ml and 28.9%) of peripheral blood. However, CA19-9 levels (mean 576.1 U/ml and positive rate greater than 37 U/ml, 29.5%) of draining blood were not different from those (568.0 U/ml and 29.5%) of peripheral blood. Immunohis-tochemically, CEA was observed in all of the 83 specimens and distributed in most of all cancer cells, whereas CA19-9 was found in 52(62.5%) of the 83 specimens and sporadically distributed in some parts of cancer lesions in general. Elevation of CEA levels in draining and peripheral blood was most highly correlated with venous invasion, although the levels were related to four other histopathologic variables including liver metastasis, invasive layer of colorectal wall, lymphatic invasion, and Dukes' classification. Significant correlation between the CEA localized pattern of cancer cells was not found. Patients with CA19-9 nonlocalized cancer showed no elevation of the antigen levels in both peripheral and draining blood. The elevation of CA19-9 levels in peripheral blood of patients with CA19-9 localized cancer was most highly associated with lymphatic invasion, although the levels were correlated with five other variables consisting of liver metastasis, tumor differentiation, invasive layer of colorectal wall, venous invasion, and Dukes' classification out of 11 histopathologic and immunohistochemical variables. CEA levels of draining blood rose from 18.2 ng/ml and 40.3% to 30.1 ng/ml and 72.6%, respectively, after operative stimuli to cancer lesions, whereas the change of CA19-9 levels in draining blood of patients with CA19-9 localized cancer was not found during the time of operation. These results suggest that CEA may be drained mainly by the hematogenous portal system by the draining vein from the cancer cells in the invasive veins and that CA19-9 may be drained by the thoracic duct of the lymphatic system. It is also suggested that the CEA and CA19-9 elevation-relating variables may secondarily affect the CEA and CA19-9 elevation in the blood in association with the venous and lymphatic invasion of cancer lesions, respectively.