Search

Treatment with the anticancer drug taxol (TXL), which polymerizes the cytoskeleton protein tubulin, may evoke cardiac arrhythmias based on reduced human cardiac sodium channel (Na(v)1.5) function. Therefore, we investigated whether enhanced tubulin polymerization by TXL affects Na(v)1.5 function and expression and whether these effects are beta(1)-subunit-mediated. Human embryonic kidney (HEK293) cells, transfected with SCN5A cDNA alone (Na(v)1.5) or together with SCN1B cDNA (Na(v)1.5 + beta(1)), and neonatal rat cardiomyocytes (NRCs) were incubated in the presence and in the absence of 100 mu M TXL. Sodium current (I-Na) characteristics were studied using patch-clamp techniques. Na(v)1.5 membrane expression was determined by immunocytochemistry and confocal microscopy. Pre-treatment with TXL reduced peak I-Na amplitude nearly two-fold in both Na(v)1.5 and Na(v)1.5 + beta(1), as well as in NRCs, compared with untreated cells. Accordingly, HEK293 cells and NRCs stained with anti-Na(v)1.5 antibody revealed a reduced membrane-labelling intensity in the TXL-treated groups. In addition, TXL accelerated I-Na decay of Na(v)1.5 + beta(1), whereas I-Na decay of Na(v)1.5 remained unaltered. Finally, TXL reduced the fraction of channels that slow inactivated from 31% to 18%, and increased the time constant of slow inactivation by two-fold in Na(v)1.5. Conversely, slow inactivation properties of Na(v)1.5 + beta(1) were unchanged by TXL. Enhanced tubulin polymerization reduces sarcolemmal Na(v)1.5 expression and I-Na amplitude in a beta(1)-subunit-independent fashion and causes I-Na fast and slow inactivation impairment in a beta(1)-subunit-dependent way. These changes may underlie conduction-slowing-dependent cardiac arrhythmias under conditions of enhanced tubulin polymerization, e.g. TXL treatment and heart failure

The work presented in this paper examines the effects of cutting parameters (cutting speed, feed rate and depth of cut) onto the surface roughness through the mathematical model developed by using the data gathered from a series of turning experiments performed. An additional investigation was carried out in order to evaluate the influence of two well-known coating layers onto the surface roughness. For this purpose, the experiments were repeated for two CNMG 120408 (with an ISO designation) carbide inserts having completely the same geometry and substrate but different coating layers, in a manner that identical cutting conditions would be ensured. The workpiece material machined was cold-work tool steel AISI P20. Of the two types of inserts employed; Insert 1 possesses a coating consisting of a TiCN underlayer, an intermediate layer of Al 2 O 3 and a TiN outlayer, all deposited by CVD; whilst Insert 2 is PVD coated with a thin TiAlN layer (3 ± 1 μm). The total average error of the model was determined to be 4.2% and 5.2% for Insert 1 and Insert 2, respectively; which proves the reliability of the equations established.