The relationship between the concentrations of intermediate-density lipoprotein (IDL) and other lipoproteins and the extent of coronary artery disease (CAD) was studied in 182 consecutive patients evaluated by selective coronary cineangiography. On univariate analysis, the extent of CAD correlated significantly and positively with very low density lipoprotein (VLDL) cholesterol, IDL cholesterol and low-density lipoprotein (LDL) cholesterol, and negatively with high-density lipoprotein (HDL) cholesterol. Analysis of four subgroups divided by IDL cholesterol and LDL cholesterol levels indicated that moderately increased levels of IDL cholesterol were closely associated with a high frequency of CAD. Moreover, multi-variate regression analysis demonstrated that IDL cholesterol for men, LDL cholesterol for men and women and HDL cholesterol for men were significant variables of use in the final weighting procedure. IDL cholesterol was closely associated with cholesterol-rich VLDL. This study shows that IDL and cholesterol-rich VLDL combine to contribute to the development of CAD.
To overcome a lack
of selectivity during the chemical modification
of native non-engineered antibodies, we have developed a technology
platform termed “AJICAP” for the site-specific chemical
conjugation of antibodies through the use of a class of IgG Fc-affinity
reagents. To date, a limited number of antibody–drug conjugates
(ADCs) have been synthesized via this approach, and no toxicological
study was reported. Herein, we describe the compatibility and robustness
of AJICAP technology, which enabled the synthesis of a wide variety
of ADCs. A stability assessment of a thiol-modified antibody synthesized
by AJICAP technology indicated no appreciable increase in aggregation
or decomposition upon prolonged storage, indicating that the unexpectedly
stable thiol intermediate has a great potential intermediate for payload
or linker screening or large-scale manufacturing. Payload conjugation
with this stable thiol intermediate generated several AJICAP-ADCs. In vivo xenograft studies indicated that the AJICAP-ADCs
displayed significant tumor inhibition comparable to benchmark ADC
Kadcyla. Furthermore, a rat pharmacokinetic analysis and toxicology
study indicated an increase in the maximum tolerated dose, demonstrating
an expansion of the AJICAP-ADC therapeutic index, compared with stochastic
conjugation technology. This is the first report of the therapeutic
index estimation of site-specific ADCs produced by utilizing Fc affinity
reagent conjugation. The described site-specific conjugation technology
is a powerful platform to enable next-generation ADCs through reduced
heterogeneity and enhanced therapeutic index.
For the purpose of studying the clinicopathology of the biopsied myocardium in patients with diabetes mellitus, the diameter of right ventricular myocardial cells and diffuse perimysial fibrosis of biopsied myocardium were measured quantitatively. Seven healthy controls and nine diabetic patients without hypertension or coronary arterial disease were subjected to this study. The degree of diabetic complications was mild to moderate. The diameter of myocardial cells was measured and the degree of diffuse perimysial fibrosis was assessed by the point-counting method using a square grid, in which the distance between the points was 10 micron. Over 2000 points which lay on the longitudinally cut myocardial cells and on the interstitial fibrosis stained by the Mallory-Azan method were measured. Percentage fibrosis was calculated according to the formula: percentage fibrosis = (points lying on the interstitial fibrosis)/[(points lying on the myocardial cell) + (points lying on the interstitial fibrosis)] X 100. The results were as follows. The mean diameter of right ventricular myocardial cells in patients with diabetes mellitus was significantly larger than that of controls (P less than 0.01). The percentage fibrosis of diabetic patients was significantly higher than that of controls (P less than 0.01). There was no significant correlation between the histopathological measurements and clinical features. It is concluded that hypertrophy of myocardial cells and interstitial fibrosis of the myocardium exist even in mild diabetes mellitus.
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