SK119, a Novel Shikonin Derivative,Leads to Apoptosis in Melanoma Cell Lines and Exhibits Synergistic Effects with Vemurafenib and Cobimetinib

Melanoma is a complex and heterogenous disease, displays the deadliest form of skin cancer, and accounts for approx. 80% of all skin cancer deaths. In this study, we reported on the synthesis and pharmacological effects of a novel shikonin derivative (SK119), which is active in a nano-molar range and exhibits several promising in vitro effects in different human melanoma cells. SK119 was synthesized from shikonin as part of our search for novel, promising shikonin derivatives. It was screened against a panel of melanoma and non-tumorigenic cell lines using XTT viability assays. Moreover, we studied its pharmacological effects using apoptosis and Western blot experiments. Finally, it was combined with current clinically used melanoma therapeutics. SK119 exhibited IC₅₀ values in a nano-molar range, induced apoptosis and led to a dose-dependent increase in the expression and protein phosphorylation of HSP27 and HSP90 in WM9 and MUG-Mel 2 cells. Combinatorial treatment, which is highly recommended in melanoma, revealed the synergistic effects of SK119 with vemurafenib and cobimetinib. SK119 treatment changed the expression levels of apoptosis genes and death receptor expression and exhibited synergistic effects with vemurafenib and cobimetinib in human melanoma cells. Further research indicates a promising potential in melanoma therapy.     

Could SGLT2 Inhibitors Improve Exercise Intolerance in Chronic Heart Failure?

Despite the constant improvement of therapeutical options, heart failure (HF) remains associated with high mortality and morbidity. While new developments in guideline-recommended therapies can prolong survival and postpone HF hospitalizations, impaired exercise capacity remains one of the most debilitating symptoms of HF. Exercise intolerance in HF is multifactorial in origin, as the underlying cardiovascular pathology and reactive changes in skeletal muscle composition and metabolism both contribute. Recently, sodium-related glucose transporter 2 (SGLT2) inhibitors were found to improve cardiovascular outcomes significantly. Whilst much effort has been devoted to untangling the mechanisms responsible for these cardiovascular benefits of SGLT2 inhibitors, little is known about the effect of SGLT2 inhibitors on exercise performance in HF. This review provides an overview of the pathophysiological mechanisms that are responsible for exercise intolerance in HF, elaborates on the potential SGLT2-inhibitor-mediated effects on these phenomena, and provides an up-to-date overview of existing studies on the effect of SGLT2 inhibitors on clinical outcome parameters that are relevant to the assessment of exercise capacity. Finally, current gaps in the evidence and potential future perspectives on the effects of SGLT2 inhibitors on exercise intolerance in chronic HF are discussed.     

Induced Zinc Loss Produces Heterogenous Biological Responses in Melanoma Cells

Zinc levels in serum and/or tissue are reported to be altered in melanoma with unknown effects on melanoma development and biology. The purpose of this study was to examine the effects of acute chelation of free intracellular zinc pools in melanoma cell lines Bowes and A375, as well as selected melanoma tissue explants with high or low intracellular free zinc. Zinc chelating agent TPEN at the concentration of 25 µM was employed during 48 h, which significantly reduced intracellular free zinc while decreasing melanoma cell proliferation, inducing G1/S arrest and cell damage leading to mitochondrial, caspase-dependent apoptosis. Chelation of free zinc was also associated with increased generation of superoxide in cell lines but not marked lysosomal membrane damage. Conversely, melanoma explant cultures mostly displayed time-dependent loss of lysosomal membrane integrity in the presence of slowly growing superoxide levels. Loss of free zinc-dependent p53 activity was similarly disparate in individual melanoma models. Surviving melanoma cells were arrested in the cell cycle, and varying proportions of them exhibited features characteristic of premature senescence, which increased in time despite zinc reloading. The present results show that melanoma cells with varying free zinc levels respond to its acute loss in a number of individual ways, reflecting activated mechanisms including oxidative stress, lysosomal damage, and p53 activity leading to heterogenous outcomes including cell death, transient, and/or permanent cell cycle arrest and premature senescence.     

Cumulated interference power and bit‐error‐rates in mobile packet radio

In this paper we determine the probability distribution function of cumulated instantaneous interference power in a mobile radio network, when the positions of interfering stations are distributed according to a one‐ or two‐dimensional Poisson point process, truncated at a finite horizon. The influences of Rice and Rayleigh fading, lognormal shadowing, near far effect and capture are taken into account. From the resulting distribution the probability of successful transmission and corresponding bit‐error‐rates are derived. This revised version was published online in July 2006 with corrections to the Cover Date.     

Progress in Low-temperature Surface Passivation of Silicon Solar Cells using Remote-plasma Silicon Nitride

Using a remote-plasma technique as opposed to the conventional direct-plasma technique, significant progress has been obtained at ISFH in the area of low-temperature surface passivation of p-type crystalline silicon solar cells by means of silicon nitride (SiN) films fabricated at 350–400°C in a plasma-enhanced chemical vapour deposition system. If applied to the rear surface of the low-resistivity p-type substrates, the remote-plasma SiN films provide outstanding surface recombination velocities (SRVs) as low as 4 cm s⁻¹, which is by a clear margin the lowest value ever obtained on a low-resistivity p-Si wafer passivated by a solid film, including highest quality thermal oxides. Compared to direct-plasma SiN films or thermally grown oxides, the remote-plasma films not only provide significantly better SRVs on low-resistivity p-silicon wafers, but also an enormously improved stability against ultraviolet (UV) light. The potential of these remote-plasma silicon nitride films for silicon solar cell applications is further increased by the fact that they provide a surface passivation on phosphorus-diffused emitters which is comparable to high-quality thermal oxides. Furthermore, if combined with a thermal oxide and a caesium treatment, the films induce a UV-stable inversion-layer emitter of outstanding electronic quality. Due to the low deposition temperature and the high refraction index, these remote-plasma SiN films act as highly efficient surface-passivating antireflection coatings. Application of these films to cost-effective silicon solar cell designs presently under development at ISFH turned out to be most successful, as demonstrated by diffused p-n junction cells with efficiencies above 19%, by bifacial p-n junction cells with front and rear efficiencies above 18%, by mask-free evaporated p-n junction cells with efficiencies above 18% and by MIS inversion-layer cells with a new record efficiency of above 17%. All cells are found to be stable during a UV test corresponding to more than 4 years of glass-encapsulated outdoor operation. © 1997 John Wiley & Sons, Ltd.     

Classical Capacity of Classical-Quantum Arbitrarily Varying Channels

We prove that the average error classical capacity C(W) of a classicalquantum arbitrarily varying channel (cq-AVC) W equals 0 or else the random code capacity C (Ahlswede's dichotomy). We also establish a necessary and sufficient condition for C(W)>0     

Gallium gradients in Cu(In,Ga)Se2 thin‐film solar cells

The gallium gradient in Cu(In,Ga)Se₂ (CIGS) layers, which forms during the two industrially relevant deposition routes, the sequential and co‐evaporation processes, plays a key role in the device performance of CIGS thin‐film modules. In this contribution, we present a comprehensive study on the formation, nature, and consequences of gallium gradients in CIGS solar cells. The formation of gallium gradients is analyzed in real time during a rapid selenization process by in situ X‐ray measurements. In addition, the gallium grading of a CIGS layer grown with an in‐line co‐evaporation process is analyzed by means of depth profiling with mass spectrometry. This gallium gradient of a real solar cell served as input data for device simulations. Depth‐dependent occurrence of lateral inhomogeneities on the µm scale in CIGS deposited by the co‐evaporation process was investigated by highly spatially resolved luminescence measurements on etched CIGS samples, which revealed a dependence of the optical bandgap, the quasi‐Fermi level splitting, transition levels, and the vertical gallium gradient. Transmission electron microscopy analyses of CIGS cross‐sections point to a difference in gallium content in the near surface region of neighboring grains. Migration barriers for a copper‐vacancy‐mediated indium and gallium diffusion in CuInSe₂ and CuGaSe₂ were calculated using density functional theory. The migration barrier for the In_Cu antisite in CuGaSe₂ is significantly lower compared with the Ga_Cu antisite in CuInSe₂, which is in accordance with the experimentally observed Ga gradients in CIGS layers grown by co‐evaporation and selenization processes. Copyright © 2014 John Wiley & Sons, Ltd.