MCL-1 antagonism enhances the anti-invasive effects of dasatinib in pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies. It is phenotypically heterogeneous with a highly unstable genome and provides few common therapeutic targets. We found that MCL1, Cofilin1 (CFL1) and SRC mRNA were highly expressed by a wide range of these cancers, suggesting that a strategy of dual MCL-1 and SRC inhibition might be efficacious for many patients. Immunohistochemistry revealed that MCL-1 protein was present at high levels in 94.7% of patients in a cohort of PDACs from Australian Pancreatic Genome Initiative (APGI). High MCL1 and Cofilin1 mRNA expression was also strongly predictive of poor outcome in the TCGA dataset and in the APGI cohort. In culture, MCL-1 antagonism reduced the level of the cytoskeletal remodeling protein Cofilin1 and phosphorylated SRC on the active Y416 residue, suggestive of reduced invasive capacity. The MCL-1 antagonist S63845 synergized with the SRC kinase inhibitor dasatinib to reduce cell viability and invasiveness through 3D-organotypic matrices. In preclinical murine models, this combination reduced primary tumor growth and liver metastasis of pancreatic cancer xenografts. These data suggest that MCL-1 antagonism, while reducing cell viability, may have an additional benefit in increasing the antimetastatic efficacy of dasatinib for the treatment of PDAC

Surface versus bulk electronic/defect structures of transparent conducting oxides: I. Indium oxide and ITO

Carefully prepared bulk ceramic specimens of In2O3 and Sn-doped In2O3 (ITO) were analysed with x-ray and UV photoelectron spectroscopy before and after heat treatment in vacuum and oxygen atmosphere. The results on ex situ prepared ceramic specimens were shown to be comparable to those of in situ deposited-measured thin films in terms of core levels, Fermi levels and ionization potentials. This suggests a viable path for rapid synthesis and screening of surface electronic-defect properties for other transparent conducting oxides (TCO) materials. A strong correlation exists between the surface electronic-defect structure of In2O3-based TCOs and their underlying electronic-defect structure, owing to the unique crystal-defect properties of the bixbyite structure. This leads to formation of a chemical depletion at the surface and the formation of a peroxide surface species for higher preparation temperatures. The results are discussed with respect to the use of ITO as hole injection electrode in organic light emitting devices

Surface potentials of magnetron sputtered transparent conducting oxides

Work functions, ionization potentials (electron affinities) and Fermi level positions measured in-situ by photoelectron spectroscopy at surfaces of transparent conducting oxides are presented. Thin films of ZnO, ZnO:Al, SnO2, SnO2:Sb, In2O3, In2O3:Sn, and In2O3:(Zn,Sn) are prepared by magnetron sputtering. The Fermi level position is strongly affected by the oxygen content in the sputter gas. The ionization potential and work function of ZnO are strongly affected by surface orientation. In contrast, SnO2-based and In2O3-based materials show pronounced changes of ionization potential and work function induced by surface oxidation and reduction. Unlike SnO2, the oxidation of the In2O3-based TCO surfaces does not occur during deposition but can be induced by post-deposition treatments

Surface studies of crystalline and amorphous Zn–In–Sn–O transparent conducting oxides

X-ray and ultraviolet photoelectron spectroscopy (UPS) studies were made of in situ RF magnetron-sputtered crystalline (c) and amorphous (a) Zn–In–Sn–O (ZITO) thin films, ex situ pulsed laser deposited c- and a-ZITO thin films, and bulk ZITO ceramics. Cosubstitution of Zn and Sn for In results in an increase of the In core level binding energy at a given Fermi level compared to that measured in undoped and Sn-doped In2O3 (ITO). In plots of work function vs. Fermi level, in situ c-ZITO and a-ZITO films have low ionization potentials (7.0–7.7 eV) that are similar to undoped In2O3. In contrast, dry-air-annealed in situ films, ex situ films, and bulk ceramics have higher ionization potentials (7.7–8.1 eV) that are more similar to ITO and match well with previous work on air-exposed surfaces. Kelvin Probe measurements were made of select a-ZITO films exposed to air and ultraviolet/ozone-treated so as to measure work functions under conditions commonly employed for device fabrication. Results (4.8–5.3 eV) were in good agreement with the UPS work functions of oxygen-exposed materials and with literature values. Lastly, a parallelogram plot of work function vs. Fermi level shows that a wider range of work functions is achievable in ZITO materials as compared to other transparent conducting oxides (Sb-doped SnO2, Al-doped ZnO, Sn-doped In2O3), making ZITO more versatile for applications