Harnessing autophagy to overcome mitogen‐activated protein kinase kinase inhibitor‐induced resistance in metastatic melanoma

Background Patients with malignant melanoma often relapse after treatment with BRAF and/or mitogen‐activated protein kinase kinase (MEK) inhibitors (MEKi) owing to development of drug resistance. Objectives To establish the temporal pattern of CD271 regulation during development of resistance by melanoma to trametinib, and determine the association between development of resistance to trametinib and induction of prosurvival autophagy. Methods Immunohistochemistry for CD271 and p62 was performed on human naevi and primary malignant melanoma tumours. Western blotting was used to analyse expression of CD271, p62 and LC3 in melanoma subpopulations. Flow cytometry and immunofluorescence microscopy was used to evaluate trametinib‐induced cell death and CD271 expression. MTS viability assays and zebrafish xenografts were used to evaluate the effect of CD271 and autophagy modulation on trametinib‐resistant melanoma cell survival and invasion, respectively. Results CD271 and autophagic signalling are increased in stage III primary melanomas vs. benign naevi. In vitro studies demonstrate MEKi of BRAF‐mutant melanoma induced cytotoxic autophagy, followed by the emergence of CD271‐expressing subpopulations. Trametinib‐induced CD271 reduced autophagic flux, leading to activation of prosurvival autophagy and development of MEKi resistance. Treatment of CD271‐expressing melanoma subpopulations with RNA interference and small‐molecule inhibitors to CD271 reduced the development of MEKi resistance, while clinically applicable autophagy modulatory agents – including Δ9‐tetrahydrocannabinol and Vps34 – reduced survival of MEKi‐resistant melanoma cells. Combined MEK/autophagy inhibition also reduced the invasive and metastatic potential of MEKi‐resistant cells in an in vivo zebrafish xenograft. Conclusions These results highlight a novel mechanism of MEKi‐induced drug resistance and suggest that targeting autophagy may be a translatable approach to resensitize drug‐resistant melanoma cells to the cytotoxic effects of MEKi

Molecular Model for Prenucleation Water Clusters

A molecular model applicable to prenucleation water clusters is described. As an illustration the model is applied to water clusters having clathrate-like structures composed of five-menibered rings. This work was motivated by the apparent inadequacies of the corrected liquid drop model which (in addition to applying bulk properties to small clusters) predicts nucleation rates which may be as much as 1017 larger than experiment. We present the energy of formation at a temperature of 277°K for our molecular model for clusters ranging in size from 5 to 57 molecules. These results agree qualitatively with experiment and, we believe, provide a motivation for further development of the molecular approach

Molecular Model for Ice Clusters in a Supersaturated Vapor

A molecular model previously applied to prenucleation water clusters is used to examine ice Ih, embryos. The canonical partition function is evaluated for clusters having from 6 to 64 water molecules. The intermolecular vibrational free energies are extrapolated to clusters containing up to 120 molecules and free energies of formation, nucleation rates, and critical supersaturation ratios are calculated and compared with experiment. For the clusters studied, the ice Ih structure appears to be much less stable at all temperatures than the more spherical clathratelike cluster

Transition from film boiling to nucleate boiling in forced convection vertical flow

The mechanism of collapse of forced cnnvection annular vertical flow film boiling, with liquid core, is investigated using liquid nitrogen at low pressures. The report includes the effect of heat flux from the buss bar. Tests include runs with mass fluxes varying from 44,000 lbm/hr-ft2 2 2 to 186,000 lbm/hr-ft , and buss bar heat fluxes from 0 to 107,000 BTU/hr-ft The channel was a 0.4 inch I. D. by 0.5 inch O.D. by 8 feet long Inconel 600 tube. Two modes of collapse were isolated, in the absence of rewet by dispersed cooling within the mist flow region. These were axial conduction controlled collapse originating at the entrance to the test section for zero or negative buss bar heat flux; and impulse cooling collapse originating downstream of the entrance for heat into the test section from the buss bar. Collapse heat flux was found to be a function of mass flux, but the collapse wall temperature difference (T - T ) was independent w S of mass flux and could be successfully predicted within 6% by pool boiling minimum transition correlation (e.g. Berenson [5]).Sponsored by the National Science Foundation DSR Projec

Applications of the Gauss-Bonnet theorem to gravitational lensing

In this geometrical approach to gravitational lensing theory, we apply the Gauss-Bonnet theorem to the optical metric of a lens, modelled as a static, spherically symmetric, perfect non-relativistic fluid, in the weak deflection limit. We find that the focusing of the light rays emerges here as a topological effect, and we introduce a new method to calculate the deflection angle from the Gaussian curvature of the optical metric. As examples, the Schwarzschild lens, the Plummer sphere and the singular isothermal sphere are discussed within this framework.Comment: 10 pages, 1 figure, IoP styl

Layer dependent band dispersion and correlations using tunable Soft X-ray ARPES

Soft X-ray Angle-Resolved Photoemission Spectroscopy is applied to study in-plane band dispersions of Nickel as a function of probing depth. Photon energies between 190 and 780 eV were used to effectively probe up to 3-7 layers. The results show layer dependent band dispersion of the Delta_2 minority-spin band which crosses the Fermi level in 3 or more layers, in contrast to known top 1-2 layers dispersion obtained using ultra-violet rays. The layer dependence corresponds to an increased value of exchange splitting and suggests reduced correlation effects in the bulk compared to the surface.Comment: 7 pages, 3 figures Revised text and figur

Evidence for Strong Itinerant Spin Fluctuations in the Normal State of CeFeAsO(0.89)F(0.11) Iron-Oxypnictides

The electronic structure in the normal state of CeFeAsO0.89F0.11 oxypnictide superconductors has been investigated with x-ray absorption and photoemission spectroscopy. All the data exhibit signatures of Fe d-electron itinerancy. Exchange multiplets appearing in the Fe 3s core level indicate the presence of itinerant spin fluctuations. These findings suggest that the underlying physics and the origin of superconductivity in these materials are likely to be quite different from those of the cuprate high-temperature superconductors. These materials provide opportunities for elucidating the role of magnetic fluctuations in high-temperature superconductivity.Comment: Shorter version. Accepted in Phys. Rev. Let

Roche Lobe Overflow from Dwarf Stellar Systems

We use both analytical analyses and numerical simulations to examine the evolution of residual gas within tidally-limited dwarf galaxies and globular clusters. If the gas sound speed exceeds about 10% of the central velocity dispersion, as is the case for ionized gas within small stellar systems, the gas shall have significant density at the tidal radius, and the gas may be lost on timescales as short as a few times the sound crossing time of the system. In colder systems, the density at the tidal radius is much lower, greatly reducing the mass loss rate, and the system may retain its gas for a Hubble time. The tidally removed gas shall follow an orbit close to that of the original host system, forming an extended stream of ionized, gaseous debris. Tidal mass loss severely limits the ability of dwarf systems to continuously form stars. The ordinary gas content in many dwarf galaxies is fully ionized during high red-shift epochs, possibly preventing star formation in some systems, leading to the formation of starless, dark-matter concentrations. In either the field or in the center of galaxy clusters, ionized gas may be retained by dwarf galaxies, even though its sound speed may be comparable to or even exceed the velocity dispersion. These processes may help to explain some observed differences among dwarf galaxy types, as well as observations of the haloes of massive galaxies.Comment: 28 pages, LaTeX, AASTex macro

Attractiveness of periodic orbits in parametrically forced systemswith time-increasing friction

We consider dissipative one-dimensional systems subject to a periodic force and study numerically how a time-varying friction affects the dynamics. As a model system, particularly suited for numerical analysis, we investigate the driven cubic oscillator in the presence of friction. We find that, if the damping coefficient increases in time up to a final constant value, then the basins of attraction of the leading resonances are larger than they would have been if the coefficient had been fixed at that value since the beginning. From a quantitative point of view, the scenario depends both on the final value and the growth rate of the damping coefficient. The relevance of the results for the spin-orbit model are discussed in some detail.Comment: 30 pages, 6 figure