The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion oncogene represents a molecular target in a small subset of non-small cell lung cancers (NSCLCs). This fusion leads to constitutive ALK activation with potent transforming activity. In a pivotal phase 1 clinical trial, the ALK tyrosine kinase inhibitor (TKI) crizotinib (PF-02341066) demonstrated impressive antitumor activity in the majority of patients with NSCLC harboring ALK fusions. However, despite these remarkable initial responses, cancers eventually develop resistance to crizotinib, usually within 1 y, thereby limiting the potential clinical benefit. To determine how cancers acquire resistance to ALK inhibitors, we established a model of acquired resistance to crizotinib by exposing a highly sensitive EML4-ALK–positive NSCLC cell line to increasing doses of crizotinib until resistance emerged. We found that cells resistant to intermediate doses of crizotinib developed amplification of the EML4-ALK gene. Cells resistant to higher doses (1 μM) also developed a gatekeeper mutation, L1196M, within the kinase domain, rendering EML4-ALK insensitive to crizotinib. This gatekeeper mutation was readily detected using a unique and highly sensitive allele-specific PCR assay. Although crizotinib was ineffectual against EML4-ALK harboring the gatekeeper mutation, we observed that two structurally different ALK inhibitors, NVP-TAE684 and AP26113, were highly active against the resistant cancer cells in vitro and in vivo. Furthermore, these resistant cells remained highly sensitive to the Hsp90 inhibitor 17-AAG. Thus, we have developed a model of acquired resistance to ALK inhibitors and have shown that second-generation ALK TKIs or Hsp90 inhibitors are effective in treating crizotinib-resistant tumors harboring secondary gatekeeper mutations.

Crystalline zinc oxide (ZnO) thin films with highly preferential c-axis-oriented crystals were prepared using the reactive e-beam evaporation technique. Prior to deposition, ZnO targets were prepared from ZnO (99.999%) powder. Post-deposition thermal annealing was performed at various temperatures ranging from 200 to 700 °C for 2 h in air to investigate the effect of annealing on the structural and optical properties. Structural characterization including that of the crystal structure, crystal orientation, phase, stress, strain, grain size and surface morphology was carried out using x-ray diffraction (XRD) and atomic force microscopy (AFM). Optical characterization including transmission, absorption coefficient and band gap estimation was carried out using a spectrophotometer. The XRD results showed that the films were highly c-axis oriented before and after annealing. Crystallinity and grain size improved with annealing temperature. AFM results showed that the surface morphology improved with annealing temperature. Optical transmittance increases slightly and the band gap decreases with increasing annealing temperature. The effect of the stress formation during thin film deposition and its variation with post-deposition heat treatment and the effect of this stress on optical properties of the thin films were also studied. The residual compressive stress in as-deposited thin films relaxes with heat treatment and becomes tensile with further increase in annealing temperature. The optical band gap decreases with increasing grain size and decreases with increasing tensile stress.

For further uptake in the solar cell industry, n-ZnO/p-Si single heterojunction solar cell has attracted much attention of the research community in recent years. This paper reports the influence of bandgap and/or electron affinity tuning of zinc oxide on the performance of n-ZnO/p-Si single heterojunction photovoltaic cell using PC1D simulations. The simulation results reveal that the open circuit voltage and fill factor can be improved significantly by optimizing valence-band and conduction-band off-sets by engineering the bandgap and electron affinity of zinc oxide. An overall conversion efficiency of more than 20.3% can be achieved without additional cost or any change in device structure. It has been found that the improvement in efficiency is mainly due to reduction in conduction band offset that has a significant influence on minority carrier current.