Novel azapeptide inhibitors of cathepsins B and K. Structural background to increased specificity for cathepsin B

Abstract: We have designed and synthesized a new series of azapeptides which act as potential inhibitors of cathepsin B and/or cathepsin K. Their structures are based upon the inhibitory sites of natural cysteine protease inhibitors, cystatins. For the synthesized azapeptides, the equilibrium constants for dissociation of inhibitor–enzyme complex, K_i, were determined. Comparison of these values indicated that all of the azainhibitors act much stronger toward cathepsin B. Z‐Arg‐Leu‐His‐Agly‐Ile‐Val‐OMe ( 7 ) proved to be approximately 500 times more potent for cathepsin B than for cathepsin K. To be able to explain the obtained experimental values we used the molecular dynamics procedures to analyze the interactions between cathepsin B and compound 7 . We also determined the structure of the most potent and selective cathepsin B azainhibitor by means of NMR studies and theoretical calculations. In this report, we describe SAR studies of azapeptide inhibitors indicating the influence of the conformational flexibility of the examined compounds on inhibition of cathepsins B and K.     

小切口股骨近端解剖钢板治疗股骨转子间骨折

目的 探讨股骨转子间骨折的治疗方法和疗效。方法小切口微创股骨近端解剖钢板内固定治疗股骨转子间骨折17例。结果 随访时间8个月～3年，平均1.6年，优良16例，占94%（16/17）。结论 小切口微创股骨近端解剖钢板内固定治疗股骨转子间骨折具有切口小、出血少等优点，是一种微创手术。     

Treatment of horizontal root‐fractured maxillary incisors – a case report

Abstract – Traumatic dental injuries often occur to the teeth and their supporting tissues and they are the main reasons for emergency visit to a dental clinic. Management of a fracture depends on its position and the extent of root involvement. Horizontal root fractures are not seen frequently and the treatment consists of reduction and long‐term rigid fixation of the coronal segment. The present case demonstrates the successful management of two horizontally fractured maxillary central incisors with a follow‐up period of 9 months.     

Extragastrointestinal stromal tumor possibly originating from the prostate

We report a case of extragastrointestinal stromal tumor possibly originating from the prostate. The patient underwent radical prostatectomy because of no metastatic evidence. No recurrence and metastasis have been found during 14 months of follow up. To our knowledge, this may be the third such case published in a report in terms of pathological type.     

Low HDL‐cholesterol is common in European Type 2 diabetic patients receiving treatment for dyslipidaemia: data from a pan‐European survey

Aims To measure the prevalence of low high‐density lipoprotein (HDL)‐cholesterol (men < 1.03 mmol/l; women < 1.29 mmol/l) in European Type 2 diabetic patients receiving treatment for dyslipidaemia. Methods The pan‐European Survey of HDL‐cholesterol measured lipids and other cardiovascular risk factors in 3866 patients with Type 2 diabetes and 4436 non‐diabetic patients undergoing treatment for dyslipidaemia in 11 European countries. Results Diabetic patients were more likely to be obese or hypertensive than non‐diabetic patients. Most patients received lifestyle interventions (87%) and/or a statin (89%); treatment patterns were similar between groups. Diabetic patients had [means (SD)] lower HDL‐cholesterol [1.22 (0.37) vs. 1.35 mmol/l (0.44) vs. non‐diabetic patients, P < 0.001] and higher triglycerides [2.32 (2.10) vs. 1.85 mmol/l (1.60), P < 0.001]. More diabetic vs. non‐diabetic patients had low HDL‐cholesterol (45% vs. 30%), high triglycerides (≥ 1.7 mmol/l; 57% vs. 42%) or both (32% vs. 19%). HDL‐cholesterol < 0.9 mmol/l was observed in 18% of diabetic and 12% of non‐diabetic subjects. Differences between diabetic and non‐diabetic groups were slightly greater for women. LDL‐ and total cholesterol were lower in the diabetic group [3.02 (1.05) vs. 3.30 mmol/l (1.14) and 5.12 (1.32) vs. 5.38 mmol/l (1.34), respectively, P < 0.001 for each]. Conclusions Low HDL‐cholesterol is common in diabetes: one in two diabetic women has low HDL‐cholesterol and one diabetic man in four has very low HDL‐cholesterol. Management strategies should include correction of low HDL‐cholesterol to optimize cardiovascular risk in diabetes.     

Nerve growth factor and tyrosine kinase A in human salivary adenoid cystic carcinoma: expression patterns and effects on in vitro invasive behavior.

PURPOSE: Perineural invasion is a frequent occurrence in salivary adenoid cystic carcinoma (ACC) and may prevent complete surgical resection. Studies have indicated that nerve growth factor (NGF) and its high-affinity receptor tyrosine kinase A (TrkA) may play a role in perineural invasion in several malignancies in which perineural invasion is observed. The present study was conducted to investigate the expression of NGF and TrkA in salivary ACC and to examine the effects of NGF on adhesion, migration and invasion capacities of a salivary ACC cell line (SACC-83) in vitro. PATIENTS AND METHODS: Expression of NGF and TrkA was explored using immunohistochemistry in paraffin-embedded tissues of 32 cases of salivary ACC. The effects of NGF on in vitro adhesion, migration, and invasion capacities of the SACC-83 cell line were examined using an MTT assay and a modified Boyden chamber assay respectively. RESULTS: In ACC specimens, 31 (96.9%) and 32 (100%) tumors showed immunoreactivity for NGF and TrkA respectively. Significant correlations were found between NGF/TrkA expression levels and perineural invasion (P < .05). In cell adhesion assay, the percent adherences of SACC-83 cells co-cultured with 25 ng/ml NGF at 1.5 hours and 5, 25 ng/ml NGF at 6 hours were significantly higher than that co-cultured with 0 ng/ml NGF (P < .05). However, high concentration of NGF (500 ng/ml) resulted in a significant inhibition of invasion (P < .05). CONCLUSION: Overexpression of NGF and TrkA in human salivary ACC tissues may constitute a reason for perineural invasion in salivary ACC.     

胸部类癌

本文报道了３１例胸部类癌，其中胸腺类癌１４例，支气管类癌１７例，伴有异位ＡＣＴＨ综合征者１７例。１２例患者发生转移（３９％），２４例行原发肿瘤全部或部分切除，术后放疗或化疗或两者均有者１７例，４例仅行探查并取活检，２８例经手术及病理证实。