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Inhibition of anti-apoptotic BCL-2 (B-cell lymphoma 2) has recently emerged as a promising new therapeutic strategy for the treatment of a variety of human cancers, including leukemia. Here, we used T-cell acute lymphoblastic leukemia (T-ALL) as a model system to identify novel synergistic drug combinations with the BH3 mimetic venetoclax (ABT-199). In vitrodrug screening in primary leukemia specimens that were derived from patients with high risk of relapse or relapse and cell lines revealed synergistic activity between venetoclax and the BET (bromodomain and extraterminal) bromodomain inhibitor JQ1. Notably, this drug synergism was confirmed in vivousing T-ALL cell line and patient-derived xenograft models. Moreover, the therapeutic benefit of this drug combination might, at least in part, be mediated by an acute induction of the pro-apoptotic factor BCL2L11and concomitant reduction of BCL-2 upon BET bromodomain inhibition, ultimately resulting in an enhanced binding of BIM (encoded by BCL2L11) to BCL-2. Altogether, our work provides a rationale to develop a new type of targeted combination therapy for selected subgroups of high-risk leukemia patients.

Wear of materials used in artificial joints is a common failure mode of artificial joints. A low wear rate for implants is believed to be critical for extending implant service time. We developed a carbide-coated Co-Cr-Mo implant alloy created in plasma of methane and hydrogen mixed gas by a microwave plasma-assisted surface reaction. The carbide-coated Co-Cr-Mo has a unique “brain coral-like” surface morphology and is much harder than uncoated Co-Cr-Mo. The effect of plasma processing time and temperature on the surface morphology of the top carbide layer was studied toward optimizing the surface coating. The ratios of average roughness, Ra, core roughness, Rk, and summation of core roughness, reduced peak height (Rpk) and reduced valley depth (Rvk), Rk+ Rpk+ Rvk, for the 6-h/985 °C coating to those for the 0.5-h/985 °C coating were 1.9, 1.7, and 1.9, respectively. The ratios of Ra, Rk, and Rk+ Rpk+ Rvk for the 4-h/1000 °C coating to those for the 4-h/939 °C coating were 2.3, 2.3, and 2.0, respectively. With the proper combination of plasma processing time and temperature, it may be possible to change the thickness of the peak-valley top cluster by fourfold from ~ 0.6 µ m to ~ 2.5 µ m. Finally, the growth mechanism of the carbide layers on Co-Cr-Mo was discussed in the context of atomic composition analysis.

The wear behavior of a new type of metal carbide surface coating on Co–Cr–Mo implant alloy was studied. The coating was created using a microwave plasma-assisted reaction. Codeposition of impurity diamond film, diamond particles, and soot was prevented by controlling process conditions. Wear tests were carried out using a sapphire ball-on-Co–Cr–Mo disc unidirectional sliding configuration with harsh conditions of high contact stress and slow sliding speed in both no-lubrication, and deionized water lubrication environments. In the case of uncoated Co–Cr–Mo discs, the effect of deionized water lubrication was remarkable and reduced the wear factor by one order of magnitude compared to the no-lubrication tests. The wear factor of carbide coated Co–Cr–Mo discs was slightly smaller than that of uncoated Co–Cr–Mo discs with deionized water lubrication (2.7×10−6mm3N−1m−1vs. 4.2×10−6mm3N−;1m−1). The addition of deionized water lubrication did not greatly affect the wear factor of carbide coated Co–Cr–Mo discs. The influence of surface geometry resulting from the “brain coral-like” surface morphology of carbide layers on wear behavior was analyzed considering stress concentrations and effective contact area.

Polyphenylene dendrimer molecules, G2Td(COOH)16, were ionized (G2 ions) and then adsorbed on a carboxylic acid (COOH) group terminated self-assembled monolayer (SAM) on a Au substrate through the linkage with Cu²⁺ ions. The individual G2 ions were observed by noncontact atomic force microscopy (NCAFM). The strong interaction between the G2 and Cu²⁺ ions, the latter of which are preadsorbed on the COOH SAM, led to a compression or deformation of the SAM and resulted in a decreased height of the G2 ions measured by NCAFM as compared to a theoretical model of the dendrimer molecules. The present method offers an approach to bind dendrimer molecules to a solid substrate and to study the nanoscale behavior of two kinds of thiol molecules in replaced and mixed SAMs.

Mexiletine, a class lb antiarrythmic drug, is used clinically as a racemic mixture of two enantiomers. Aromatic and aliphatic hydroxylation are the two major metabolic steps. In the liver, this metabolism is catalyzed by the cytochrome P450IID6, an isoenzyme of cytochrome P450 due to genetic polymorphism in humans. In the present study, the metabolism of the two stereoisomers was compared in vitro in human liver microsomes. Parahydroxylation (aromatic hydroxylation) is favored for S (+)-mexiletine with a mean intrinsic clearance higher than for R(-)-mexiletine. The R(-) enantiomer exhibits a threefold higher mean Vmaxvalue for aliphatic hydroxylation than S(+)-mexiletine. We showed that (i) the high-affinity component of dextrometorphan O-demethylation was competitively inhibited by R(-)-and S(+)-mexiletine and that (ii) hydroxylations of the two enantiomers were very strongly competitively inhibited by quinidine. Hydroxylation reactions of mexiletine exhibit stereoselectivity in vitro in human liver microsomes and are catalyzed by P450IID6.

It is demonstrated that treatment of CaF2with a hydrogen plasma results in the formation of color centers in the region 200‐800 nm (absorption at 375, 515, and 560 nm corresponding to F, M, and colloidal Ca centers, resp.).