A synergistic anti-cancer FAK and HDAC inhibitor combination discovered by a novel chemical-genetic high-content phenotypic screen

We mutated the focal adhesion kinase (FAK) catalytic domain to inhibit binding of the chaperone Cdc37 and ATP, mimicking the actions of a FAK kinase inhibitor. We re-expressed mutant and wild-type FAK in squamous cell carcinoma (SCC) cells from which endogenous FAK had been deleted, genetically fixing one axis of a FAK inhibitor combination high-content phenotypic screen to discover drugs that may synergize with FAK inhibitors. Histone deacetylase (HDAC) inhibitors represented the major class of compounds that potently induced multiparametric phenotypic changes when FAK was rendered kinase-defective or inhibited pharmacologically in SCC cells. Combined FAK and HDAC inhibitors arrest proliferation and induce apoptosis in a sub-set of cancer cell lines in vitro and efficiently inhibit their growth as tumors in vivo. Mechanistically, HDAC inhibitors potentiate inhibitor-induced FAK inactivation and impair FAK-associated nuclear YAP in sensitive cancer cell lines. Here we report the discovery of a new, clinically actionable, synergistic combination between FAK and HDAC inhibitors

Energy spectra, wavefunctions and quantum diffusion for quasiperiodic systems

We study energy spectra, eigenstates and quantum diffusion for one- and two-dimensional quasiperiodic tight-binding models. As our one-dimensional model system we choose the silver mean or `octonacci' chain. The two-dimensional labyrinth tiling, which is related to the octagonal tiling, is derived from a product of two octonacci chains. This makes it possible to treat rather large systems numerically. For the octonacci chain, one finds singular continuous energy spectra and critical eigenstates which is the typical behaviour for one-dimensional Schr"odinger operators based on substitution sequences. The energy spectra for the labyrinth tiling can, depending on the strength of the quasiperiodic modulation, be either band-like or fractal-like. However, the eigenstates are multifractal. The temporal spreading of a wavepacket is described in terms of the autocorrelation function C(t) and the mean square displacement d(t). In all cases, we observe power laws for C(t) and d(t) with exponents -delta and beta, respectively. For the octonacci chain, 0<delta<1, whereas for the labyrinth tiling a crossover is observed from delta=1 to 0<delta<1 with increasing modulation strength. Corresponding to the multifractal eigenstates, we obtain anomalous diffusion with 0<beta<1 for both systems. Moreover, we find that the behaviour of C(t) and d(t) is independent of the shape and the location of the initial wavepacket. We use our results to check several relations between the diffusion exponent beta and the fractal dimensions of energy spectra and eigenstates that were proposed in the literature.Comment: 24 pages, REVTeX, 10 PostScript figures included, major revision, new results adde

A 1-year study to compare the efficacy and safety of once-daily travoprost 0.004%/timolol 0.5% to once-daily latanoprost 0.005%/timolol 0.5% in patients with open-angle glaucoma or ocular hypertension

European Journal of Ophthalmology172183-190EJOO