6,295 research outputs found
Harnessing autophagy to overcome mitogenâactivated protein kinase kinase inhibitorâinduced resistance in metastatic melanoma
Background
Patients with malignant melanoma often relapse after treatment with BRAF and/or mitogenâactivated 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 trametinibâinduced cell death and CD271 expression. MTS viability assays and zebrafish xenografts were used to evaluate the effect of CD271 and autophagy modulation on trametinibâresistant 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 BRAFâmutant melanoma induced cytotoxic autophagy, followed by the emergence of CD271âexpressing subpopulations. Trametinibâinduced CD271 reduced autophagic flux, leading to activation of prosurvival autophagy and development of MEKi resistance. Treatment of CD271âexpressing melanoma subpopulations with RNA interference and smallâmolecule inhibitors to CD271 reduced the development of MEKi resistance, while clinically applicable autophagy modulatory agents â including Î9âtetrahydrocannabinol and Vps34 â reduced survival of MEKiâresistant melanoma cells. Combined MEK/autophagy inhibition also reduced the invasive and metastatic potential of MEKiâresistant cells in an in vivo zebrafish xenograft.
Conclusions
These results highlight a novel mechanism of MEKiâinduced drug resistance and suggest that targeting autophagy may be a translatable approach to resensitize drugâresistant melanoma cells to the cytotoxic effects of MEKi
Non-equilibrium two-phase coexistence in a confined granular layer
We report the observation of the homogenous nucleation of crystals in a dense
layer of steel spheres confined between two horizontal plates vibrated
vertically. Above a critical vibration amplitude, two-layer crystals with
square symmetry were found to coexist in steady state with a surrounding
granular liquid. By analogy to equilibrium hard sphere systems, the phase
behavior can be explained through entropy maximization. However, dramatic
non-equilibrium effects are present, including a significant difference in the
granular temperatures of the two phases.Comment: 4 pages, 3 figures, RevTex4 forma
A Validation of the p-SLLOD Equations of Motion for Homogeneous Steady-state Flows
A validation of the p-SLLOD equations of motion for nonequilibrium molecular dynamics simulation under homogeneous steady-state flow is presented. We demonstrate that these equations generate the correct center-of-mass trajectory of the system, are completely compatible with (and derivable from) Hamiltonian dynamics, satisfy an appropriate energy balance, and require no fictitious external force to generate the required homogeneous flow. It is also shown that no rigorous derivation of the SLLOD equations exists to date
Renormalization and Hyperscaling for Self-Avoiding Manifold Models
The renormalizability of the self-avoiding manifold (SAM) Edwards model is
established. We use a new short distance multilocal operator product expansion
(MOPE), which extends methods of local field theories to a large class of
models with non-local singular interactions. This validates the direct
renormalization method introduced before, as well as scaling laws. A new
general hyperscaling relation for the configuration exponent gamma is derived.
Manifolds at the Theta-point, and long range Coulomb interactions are briefly
discussed.Comment: 10 pages + 1 figure, TeX + harvmac & epsf (uuencoded file),
SPhT/93-07
Dynamics of Individual Molecules of Linear Polyethylene Liquids under Shear: Atomistic Simulation and Comparison with a Free-draining Bead-rod Chain
Nonequilibrium molecular dynamics (NEMD) simulations of a dense liquid composed of linear polyethylene chains were performed to investigate the chain dynamics under shear. Brownian dynamics (BD) simulations of a freely jointed chain with equivalent contour length were also performed in the case of a dilute solution. This allowed for a close comparison of the chain dynamics of similar molecules for two very different types of liquids. Both simulations exhibited a distribution of the end-to-end vector, |Rete|, with Gaussian behavior at low Weissenberg number (Wi). At high Wi, the NEMD distribution was bimodal, with two peaks associated with rotation and stretching of the individual molecules. BD simulations of a dilute solution did not display a bimodal character; distributions of |Rete| ranged from tightly coiled to fully stretched configurations. The simulations revealed a tumbling behavior of the chains and correlations between the components of Rete exhibited characteristic frequencies of tumbling, which scaled as Wiâ0.75. Furthermore, after a critical Wi of approximately 2, another characteristic time scale appeared which scaled as Wiâ0.63. Although the free-draining solution is very different than the dense liquid, the BD simulations revealed a similar behavior, with the characteristic time scales mentioned above scaling as Wiâ0.68 and Wiâ0.66
Vacancies, disorder-induced smearing of the electronic structure, and its implications for the superconductivity of anti-perovskite MgCNi
The anti-perovskite superconductor MgCNi was studied using
high-resolution x-ray Compton scattering combined with electronic structure
calculations. Compton scattering measurements were used to determine
experimentally a Fermi surface that showed good agreement with that of our
supercell calculations, establishing the presence of the predicted hole and
electron Fermi surface sheets. Our calculations indicate that the Fermi surface
is smeared by the disorder due to the presence of vacancies on the C and Ni
sites, but does not drastically change shape. The 20\% reduction in the Fermi
level density-of-states would lead to a significant () suppression
of the superconducting for pair-forming electron-phonon coupling.
However, we ascribe the observed much smaller reduction at our
composition (compared to the stoichiometric compound) to the suppression of
pair-breaking spin fluctuations.Comment: 11 pages, 3 figure
Ultrasonic inspection and self-healing of Ge and 3C-SiC semiconductor membranes
Knowledge of the mechanical properties and stability of thin film structures is important for device operation. Potential failures related to crack initiation and growth must be identified early, to enable healing through e.g. annealing. Here, three square suspended membranes, formed from a thin layer of cubic silicon carbide (3C-SiC) or germanium (Ge) on a silicon substrate, were characterised by their response to ultrasonic excitation. The resonant frequencies and mode shapes were measured during thermal cycling over a temperature range of 20--100~C. The influence of temperature on the stress was explored by comparison with predictions from a model of thermal expansion of the combined membrane and substrate. For an ideal, non-cracked sample the stress and Q-factor behaved as predicted. In contrast, for a 3C-SiC and a Ge membrane that had undergone vibration and thermal cycling to simulate extended use, measurements of the stress and Q-factor showed the presence of damage, with the 3C-SiC membrane subsequently breaking. However, the damaged Ge sample showed an improvement to the resonant behaviour on subsequent heating. Scanning electron microscopy showed that this was due to a self-healing of sub-micrometer cracks, caused by expansion of the germanium layer to form bridges over the cracked regions, with the effect also observable in the ultrasonic inspection
Energetic and Entropic Elasticity of Nonisothermal Flowing Polymers: Experiment, Theory, and Simulation
The thermodynamical aspects of polymeric liquids subjected to nonisothermal flow are examined from the complementary perspectives of theory, experiment, and simulation. In particular, attention is paid to the energetic effects, in addition to the entropic ones, that occur under conditions of extreme deformation. Comparisons of experimental measurements of the temperature rise generated under elongational flow at high strain rates with macroscopic finite element simulations offer clear evidence of the persistence and importance of energetic effects under severe deformation. The performance of various forms of the temperature equation are evaluated with regard to experiment, and it is concluded that the standard form of this evolution equation, arising from the concept of purely entropic elasticity, is inadequate for describing nonisothermal flow processes of polymeric liquids under high deformation. Complete temperature equations, in the sense that they possess a direct and explicit dependence on the energetics of the microstructure of the material, provide excellent agreement with experimental data
Force distributions in a triangular lattice of rigid bars
We study the uniformly weighted ensemble of force balanced configurations on
a triangular network of nontensile contact forces. For periodic boundary
conditions corresponding to isotropic compressive stress, we find that the
probability distribution for single-contact forces decays faster than
exponentially. This super-exponential decay persists in lattices diluted to the
rigidity percolation threshold. On the other hand, for anisotropic imposed
stresses, a broader tail emerges in the force distribution, becoming a pure
exponential in the limit of infinite lattice size and infinitely strong
anisotropy.Comment: 11 pages, 17 figures Minor text revisions; added references and
acknowledgmen
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