Phase I study of azacitidine and oxaliplatin in patients with advanced cancers that have relapsed or are refractory to any platinum therapy.

BackgroundDemethylation process is necessary for the expression of various factors involved in chemotherapy cytotoxicity or resistance. Platinum-resistant cells may have reduced expression of the copper/platinum transporter CTR1. We hypothesized that azacitidine and oxaliplatin combination therapy may restore platinum sensitivity. We treated patients with cancer relapsed/refractory to any platinum compounds (3 + 3 study design) with azacitidine (20 to 50 mg/m(2)/day intravenously (IV) over 15 to 30 min, D1 to 5) and oxaliplatin (15 to 30 mg/m(2)/day, IV over 2 h, D2 to 5) (maximum, six cycles). Platinum content, LINE1 methylation (surrogate of global DNA methylation), and CTR1 expression changes (pre- vs. post-treatment) were assessed. Drug pharmacokinetics were analyzed.ResultsThirty-seven patients were treated. No dose-limiting toxicity (DLT) was noted at the maximum dose. The most common adverse events were anemia and fatigue. Two (5.4%) patients had stable disease and completed six cycles of therapy. Oxaliplatin (D2) and azacitidine (D1 and 5) mean systemic exposure based on plasma AUCall showed dose-dependent interaction whereby increasing the dose of oxaliplatin reduced the mean azacitidine exposure and vice versa; however, no significant differences in other non-compartmental modeled parameters were observed. Blood samples showed universal reduction in global DNA methylation. In tumor samples, hypomethylation was only observed in four out of seven patients. No correlation between blood and tumor demethylation was seen. The mean cytoplasmic CTR1 score decreased. The pre-dose tumor oxaliplatin levels ranged from <0.25 to 5.8 μg/g tumor. The platinum concentration increased 3- to 18-fold. No correlation was found between CTR1 score and oxaliplatin level, which was found to have a trend toward correlation with progression-free survival.ConclusionsOxaliplatin and azacitidine combination therapy was safe. CTR1 expression was not correlated with methylation status or tissue platinum concentration

Tribological behaviors of in-situ textured DLC films under dry and lubricated conditions

Surface texturing is emerging as one of the viable means that can be applied to improve the tribological properties of diamond like carbon (DLC) films. In this study, textured DLC films were in-situ fabricated by masking the substrate with metallic meshes during the deposition process. The tribological behaviors of the textured DLC films with micro-dimples densities of 39%, 52% and 58% were studied and compared with that of the un-textured DLC films under dry friction and liquid lubrication conditions. The results showed that the textured DLC films with micro-dimples density of 52% exhibited the lowest average coefficient of friction (COF) and wear rate both under dry friction and liquid lubrication conditions. The improved tribological performance of the textured DLC films with optimum micro-dimples density (52%) under dry friction could be attributed to the friction-induced graphitization of the textured layer and entrapment of wear debris in the micro-dimples. Under liquid lubrication condition, the micro-dimples played the double role of wear debris and lubricating oil reservoirs, then the graphitized textured layer on the worn surface combined with the liquid lubrication film formed a solid-liquid duplex lubricating, thus achieving significantly lower friction and wear

Tailoring the mechanical and tribological properties of B4C/a-C coatings by controlling the boron carbide content

Boron carbide doped DLC coating can combine the property superiority of these two materials to create high-performance carbon-based coating, while the final property of the composite coating is strongly dependent on the proportion of coating components. The aim of this study was to investigate the effect of boron carbide content on the mechanical and tribological properties of the magnetron sputtered B4C/a-C coatings, as well as the relevant low friction mechanism. It was found that both the carbon matrix and introduced boron carbide were amorphous and the composite coating exhibited typical columnar structure. Appropriate doping of boron carbide significantly enhanced coating hardness, toughness as well as the adhesion strength and carrying ability, and all of them reached the optimal value when the B concentration was 2.92 at.%. It was also found that the B4C/a-C coating with B 2.92 at.% exhibited the lowest steady friction coefficient about 0.05 and highest wear resistance at 20% RH. None of boric add was formed on the sliding interface under the tested humidity range. Thus, the improved tribological properties were mainly attributed to the enhanced mechanical properties and friction-induced formation of an intact graphitized carbon transfer layer on the counterpart under specific humidity condition

Simultaneously achieving superior mechanical and tribological properties in WC/a-C nanomultilayers via structural design and interfacial optimization

Nanomultilayered WC/a-C coatings with modulation period raning from 1.3 to 11.5 nm were successfully fabricated using unbalanced magnetron sputtering process and the evolution of their microstructure, mechanical and tribological properties with the modulation period were systemically investigated. It has been demonstrated that the columnar structure in WC/a-C nanomultilayers originates from the surface irregularities of intermediate Cr/WC/C layer and the column diameter is correlated with the initial Cr layer thickness in this intermediate stage. Hardening and toughening through the nanomultilayer structure design have been achieved and particularly pronounced when the modulation period ranges from 5.8 to 10 nm. The enhanced hardness and fracture toughness are mainly attributed to dislocation/crack pinning effect from the thin individual layer and the heterointerfaces betweenWC and a-C layers. It is also found that the more heterointerfaces, the lower internal stress. What's more, the WC/a-C nano-multilayers with small modulation period (<= 5.8 nm) exhibit low COF about 0.05 and good wear resistance due to the interfacial sliding between a WO3-rich tribofilm and a carbon-rich wear surface; once the modulation period above 5.8 nm, it fails to build up such a low friction interface between the tribopairs, which combining with the high intrinsic friction caused by its own structure characteristics result in high COF about 0.18-0.2 and poor wear resistance. (C) 2016 Elsevier B.V. All rights reserved

Probing fretting performance of DLC and MoS2 films under fluid lubrication

Transition from onefold to synergistic lubrication for solving fretting wear and fatigue problems is of great practical significance, because fluids can regulate fretting regime for minimizing wear, solid films can restrain nucleation and formation of crack. Here synergistic lubrication coatings were prepared using diamond-like carbon (DLC) and molybdenum disulfide (MoS2) films as anti-wear/fatigue layer, and high-performance lubricants (including silicone oil, ionic liquids, multialkylated cyclopentanes and perfluoropolyethers (PFPE)) as flowable lubrication layer. Their fretting performance was evaluated in detail and fretting mechanism was revealed by surface/interface analysis techniques. Results determine the synergistic lubrication coatings with good anti-wear and anti-fatigue abilities, deriving from the synergy of improved yield strength and shear strength, transfer layer and boundary film. Moreover, the fretting regime is pointedly regulated by solid films with different composition and performance, for example, DLC-based lubrication coatings under applied load of 22 N correspond to slip regime, so do as the MoS2-based coatings under 4 N, and PFPE-lubricated MoS2 films display better anti-wear ability than others, while DLC under PFPE lubrication reverses. The choice of optimal scheme depends on the working condition and lubrication state for achieving the requirements of high reliability, high precision, high efficiency, and long lifetime

Investigation of Post-deposition Annealing Effects on Microstructure, Mechanical and Tribological Properties of WC/a-C Nanocomposite Coatings

Nanocomposite WC/a-C coatings were successfully fabricated using a magnetron sputtering process, and post-deposition annealing was conducted in vacuum for 1 h at the annealing temperatures ranging from 100 to 500 degrees C. The changes in coating structure, internal stress, hardness, toughness, friction coefficient and wear have been investigated to assess the effects of annealing on microstructure, mechanical and tribological properties of the WC/a-C coatings. The results show that the nanocrystalline WC1-x partially decays to metastable W2C when annealing at 300-500 degrees C and no graphitization of amorphous carbon matrix starts up to 500 degrees C. This structural change results in a slightly increased hardness and an improved toughness as well as a gradually decreased internal stress. In addition, the time for the annealed coatings to achieve a low steady friction coefficient decreases with the increase of annealing temperature. An optimized tribological property with low friction coefficient of about 0.06 and enhanced wear resistance of the WC/a-C coating is obtained by annealing at 400 degrees C. Friction reduction and wear resistance caused by annealing can be attributed to the friction-induced WO3-rich tribofilm which slides against a thin carbon-rich layer on the coating surface resulting in a low friction, and the partition effect of the stationary WO3-rich tribofilm combining with the improved mechanical properties generates a high wear resistance

Achieving superior hot corrosion resistance by PVD/HVOF duplex design

In this study, an optimized duplex coating, consisting of a thick Cr3C2-NiCr interlayer and a top CrN film, were designed and deposited by HVOF and PVD. And then hot corrosion behaviors were systematically investigated, and corresponding corrosion mechanisms are discussed in detailed. Results showed that the thickness of the oxide scale of duplex coating is approximately one-tenth that of the Cr3C2-NiCr coating. Due to the formation of Cr2O3 oxide film, the CrN/Cr3C2-NiCr duplex coating exhibits superior hot corrosion resistance. However, chlorine-induced corrosion in uncovered holes is the main cause of local failure of duplex coating

Improving the mechanical and tribological properties of TiB2/a-C nanomultilayers by structural optimization

A novel nanomultilayered architecture was developed through magnetron sputtering to simultaneously achieve excellent mechanical and tribological properties in TiB2/a-C film. Structural optimization was conducted by adjusting the modulation period from 1 to 10.5 nm. Film hardness and toughness were significantly improved and reached the optimal value at Lambda = 6.6 nm. Combination of a sufficient number of heterointerfaces and appropriate individual layer thickness played a key role in hardening and toughening. The internal stress increased linearly with the increase in modulation period, which may be related to the reduction in the number of interfaces. Furthermore, a low friction coefficient of about 0.1 was achieved in the steady state at Lambda <= 6.6 nm due to the formation of a uniform and compact transfer film on the worn ball surface. The improved mechanical performance and the presence of an effective transfer film resulted in an outstanding anti-wear performance at Lambda = 6.6 nm

Friction-induced reconstruction of sliding interface and low friction mechanism of WC/a-C films

Tungsten carbide reinforced amorphous carbon (WC/a-C) films exhibit significantly lower coefficient of friction (COF) than typical a-C films in the atmospheric environment; thus, they are promising candidates for use as solid lubricants. However, the low friction mechanism of WC/a-C films remains poorly understood. Here, we revealed that the friction-induced formation of WO3-rich transfer film changed the real sliding interface between the initial friction pair materials into an interface between a WO3-rich transfer film and carbon-rich worn film surface (WO3/C interface). First-principles calculations indicated that the WO3/C interface showed weaker interactions than the C/C interface of the a-C film under the same conditions, particularly when the dangling carbon bonds at the sliding interface were not completely passivated. This resulted in a reduced COF of the WO3/C interface. Thus, friction-induced reconstruction of the sliding interface to an intrinsically weak-interacting interface is proposed as a new path to further improve the tribological performance of a-C-based films