Role of cathepsin K in structural changes in brachiocephalic artery during progression of atherosclerosis in apoE-deficient mice

Cathepsin K, a potent extracellular matrix degrading cysteine protease, has been linked to the pathogenesis of osteoporosis, arthritis, cardiovascular and respiratory diseases. Here, we report the effects of cathepsin K deficiency (ctsK−/−) on atherosclerotic plaque formation in brachiocephalic arteries in an aggressive atherosclerosis model using apoE-deficient mice on cholate-containing high fat diet (HFD). On this diet, apoE−/− mice displayed severe lesions with buried fibrous caps after 8 weeks, whereas the apoE−/−ctsK−/− mice revealed a significantly decreased number of buried fibrous caps accompanied by increased collagen content in plaque areas and fibrous cap thickness. After 16 weeks of HFD, ctsK−/− mice had smaller plaque areas and maintained the structure of the tunica media in terms of their smooth muscle cell content and elastic lamina integrity. Overall macrophage content in the tunica media was lower in ctsK−/− mice but higher in the plaque area after 8 weeks of HFD. Decreased apoptosis rates in atherosclerotic plaques in brachiocephalic arteries of cathepsin K-deficient indicated a lower level of inflammation. In conclusion, cathepsin K deficiency appears to increase lesion stability in brachiocephalic arteries by maintaining the integrity of the tunica media and by decreasing plaque vulnerability to rupture.     

Synthesis of New 6-{[ω-(Dialkylamino(heterocyclyl)alkyl]thio}-3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones and Evaluation of their Anticancer and Antimicrobial Activities

Several novel 6-thio-3-R-2-oxo-2H-[1,2,4]triazino[2,3-c]quinazoline-based compounds containing an ω-(dialkylamino(heterocyclyl)]alkyl fragment were synthesized to examine their anticancer activity. Some of the 6-{[ω-(hetero-cyclyl)alkyl]thio}-3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones (3.1-3.10) were obtained by the nucleophilic substitution of 6-[ω-halogenalkyl]thio-3-R-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones (2.1-2.8) with azaheterocycles. Alternatively, compounds 3.1-3.22 were synthesized by alkylation of 3-R-6-thio-2H-[1,2,4]triazino[2,3-c]quinazoline-2-ones potassium salts (1.1-1.4) with (2-chloroethyl)-N,N-dialkylamine hydrochlorides or 1-(2-chloroethyl)heterocycle hydrochlorides. The structures of compounds were elucidated by (1)H, (13)C NMR, LC-MS and EI-MS analysis. Then anticancer and antibacterial, bioluminescence inhibition of Photobacterium leiognathi Sh1 activities of the substances were tested in vitro. It was found that compound 3.18 possessed a wide range of anticancer activity against 27 cell lines of cancer: non-small cell lung, colon, CNS, ovarian, renal, prostate, breast, melanoma and leukemia (log GI(50) < -5.65). The "structure-activity" relationship was discussed. COMPARE analysis for synthesized anticancer active compounds was performed.     

High-pressure crystal structures and superconductivity of Stannane (SnH4)

There is great interest in the exploration of hydrogen-rich compounds upon strong compression where they can become superconductors. Stannane (SnH₄) has been proposed to be a potential high-temperature superconductor under pressure, but its high-pressure crystal structures, fundamental for the understanding of superconductivity, remain unsolved. Using an ab initio evolutionary algorithm for crystal structure prediction, we propose the existence of two unique high-pressure metallic phases having space groups Ama2 and P6₃/mmc, which both contain hexagonal layers of Sn atoms and semimolecular (perhydride) H₂ units. Enthalpy calculations reveal that the Ama2 and P6₃/mmc structures are stable at 96–180 GPa and above 180 GPa, respectively, while below 96 GPa SnH₄ is unstable with respect to elemental decomposition. The application of the Allen-Dynes modified McMillan equation reveals high superconducting temperatures of 15–22 K for the Ama2 phase at 120 GPa and 52–62 K for the P6₃/mmc phase at 200 GPa.     

Effect of implantation site and growth of hepatocellular carcinoma on apparent diffusion coefficient of water and sodium MRI

Hepatocellular carcinoma (HCC) and liver metastases are an increasing problem worldwide. Non-invasive methods for the early detection of HCC and understanding of the tumor growth mechanisms are highly desirable. Both the diffusion-weighted (1)H (DWI) and (23)Na MRI reflect alterations in tissue compartment volumes in tumors, as well as physiological and metabolic transformation in cells. Effects of untreated growth on apparent diffusion coefficient of water (ADC), single quantum (SQ) and triple quantum-filtered (TQF) (23)Na MRI were compared in intrahepatically and subcutaneously implanted HCCs in rats. Animals were examined weekly for 4 weeks after injection of N1S1 cells. ADC of intrahepatic HCC was 1.5-times higher compared to the nearby liver tissue, and with growth, the ADC did not increase. ADC of subcutaneous HCC was lower compared to intrahepatic HCC and it increased with growth. Untreated growth of both intrahepatic and subcutaneous HCCs was associated with an increase in SQ and TQF (23)Na signal intensity suggesting an increase in tissue Na(+) and intracellular Na(+) (Na(+)(i)), respectively, most likely due to an increase in relative extracellular space and Na(+)(i) concentration as a result of changes in tissue structure and cellular metabolism. Thus, SQ and TQF (23)Na MRI may be complementary to diffusion imaging in areas susceptible to motion for characterizing hepatic tumors and for other applications, such as, predicting and monitoring therapy response.     

Evaluation of spinal instrumentation rod bending characteristics for in-situ contouring

Bending characteristics were studied in rods used for spinal instrumentation at in-situ contouring conditions. Five groups of five 6 mm diameter rods made from: cobalt alloy (VITALLIUM), titanium-aluminum-vanadium alloy (SDI?), β-titanium alloy (TNTZ), cold worked stainless steel (STIFF), and annealed stainless steel (MALLEABLE) were studied. The bending procedure was similar to that typically applied for in-situ contouring in the operating room and included two bending cycles: first--bending to 21-24° under load with further release of loading for 10 min, and second--bending to 34-37° at the previously bent site and release of load for 10 min. Applied load, bending stiffness, and springback effect were studied. Statistical evaluation included ANOVA, correlation and regression analysis. TNTZ and SDI? rods showed the highest (p < 0.05) springback at both bending cycles. VITALLIUM and STIFF rods showed mild springback (p < 0.05). The least (p < 0.05) springback was observed in the MALLEABLE rods. Springback significantly correlated with the bend angle under load (p < 0.001). To reach the necessary bend angle after unloading, over bending should be 37-40% of the required angle in TNTZ and SDI? rods, 27-30% in VITALLIUM and STIFF rods, and around 20% in MALLEABLE rods.