Coordinate Hyperactivation of Notch1 and Ras/MAPK Pathways Correlates with Poor Patient Survival: Novel Therapeutic Strategy for Aggressive Breast Cancers

Aberrant activation of Notch and Ras pathways has been detected in breast cancers. A synergy between these two pathways has also been shown in breast cell transformation in culture. Yet, the clinical relevance of Notch-Ras cooperation in breast cancer progression remains unexplored. In this study, we show that coordinate hyperactivation of Notch1 and Ras/MAPK pathways in breast cancer patient specimens, as assessed by IHC for cleaved Notch1 and pErk1/2, respectively, correlated with early relapse to vital organs and poor overall survival. Interestingly, majority of such Notch1 (high)Erk(high) cases encompassed the highly aggressive triple-negative breast cancers (TNBC), and were enriched in stem cell markers. We further show that combinatorial inhibition of Notch1 and Ras/MAPK pathways, using a novel mAb against Notch1 and a MEK inhibitor, respectively, led to a significant reduction in proliferation and survival of breast cancer cells compared with individual inhibition. Combined inhibition also abrogated sphere-forming potential, and depleted the putative cancer stem-like cell subpopulation. Most importantly, combinatorial inhibition of Notch1 and Ras/MAPK pathways completely blocked tumor growth in a panel of breast cancer xenografts, including the TNBCs. Thus, our study identifies coordinate hyperactivation of Notch1 and Ras/MAPK pathways as novel biomarkers for poor breast cancer outcome. Furthermore, based on our preclinical data, we propose combinatorial targeting of these two pathways as a treatment strategy for highly aggressive breast cancers, particularly the TNBCs that currently lack any targeted therapeutic module. (C) 2014 AACR.

Secure Routing with an Integrated Localized Key Management Protocol in MANETs

A routing protocol in a mobile ad hoc network (MANET) should be secure against both the outside attackers which do not hold valid security credentials and the inside attackers which are the compromised nodes in the network. The outside attackers can be prevented with the help of an efficient key management protocol and cryptography. However, to prevent inside attackers, it should be accompanied with an intrusion detection system (IDS). In this paper, we propose a novel secure routing with an integrated localized key management (SR-LKM) protocol, which is aimed to prevent both inside and outside attackers. The localized key management mechanism is not dependent on any routing protocol. Thus, unlike many other existing schemes, the protocol does not suffer from the key management - secure routing interdependency problem. The key management mechanism is lightweight as it optimizes the use of public key cryptography with the help of a novel neighbor based handshaking and Least Common Multiple (LCM) based broadcast key distribution mechanism. The protocol is storage scalable and its efficiency is confirmed by the results obtained from simulation experiments.

On the critical thickness for non-localized to localized plastic flow transition in metallic glasses: A molecular dynamics study

Molecular dynamics simulations were employed to investigate the specimen thickness-dependent tensile behavior of a series of Cu(x)Z(100-x) (x = 20, 40, 50, 64 and 80 at%) metallic glass (MG) films, with a particular focus on the critical thickness, tc, below which non-localized plastic flow takes place. The simulation results reveal that while the transition occurs in all the alloys examined, t(c) is sensitive to the composition. We rationalize t(c) by postulating that the strain energy stored in the sample at the onset of plastic deformation has to be sufficient for the formation of shear bands. The composition-dependence of t(c) was found to correlate with the average activation energy of the atomic level plastic deformation events. (C) 2015 Elsevier Ltd. All rights reserved.

Localized Excitations and the Morphology of Cooperatively Rearranging Regions in a Colloidal Glass-Forming Liquid

We develop a scheme based on a real space microscopic analysis of particle dynamics to ascertain the relevance of dynamical facilitation as a mechanism of structural relaxation in glass-forming liquids. By analyzing the spatial organization of localized excitations within clusters of mobile particles in a colloidal glass former and examining their partitioning into shell-like and corelike regions, we establish the existence of a crossover from a facilitation-dominated regime at low area fractions to a collective activated hopping-dominated one close to the glass transition. This crossover occurs in the vicinity of the area fraction at which the peak of the mobility transfer function exhibits a maximum and the morphology of cooperatively rearranging regions changes from stringlike to a compact form. Collectively, our findings suggest that dynamical facilitation is dominated by collective hopping close to the glass transition, thereby constituting a crucial step towards identifying the correct theoretical scenario for glass formation.

Localized Charge Carrier Transport Properties of Zn1-x Ni (x) O/NiO Two-Phase Composites

We report the localized charge carrier transport of two-phase composite Zn1-x Ni (x) O/NiO (0 a parts per thousand currency sign x a parts per thousand currency sign 1) using the temperature dependence of ac-resistivity rho (ac)(T) across the N,el temperature T (N) (= 523 K) of nickel oxide. Our results provide strong evidence to the variable range hopping of charge carriers between the localized states through a mechanism involving spin-dependent activation energies. The temperature variation of carrier hopping energy epsilon (h)(T) and nearest-neighbor exchange-coupling parameter J (ij)(T) evaluated from the small poleron model exhibits a well-defined anomaly across T (N). For all the composite systems, the average exchange-coupling parameter (J (ij))(AVG) nearly equals to 70 meV which is slightly greater than the 60-meV exciton binding energy of pure zinc oxide. The magnitudes of epsilon (h) (similar to 0.17 eV) and J (ij) (similar to 11 meV) of pure NiO synthesized under oxygen-rich conditions are consistent with the previously reported theoretical estimation based on Green's function analysis. A systematic correlation between the oxygen stoichiometry and, epsilon (h)(T) and J (ij)(T) is discussed.

Integrals of motion for one-dimensional Anderson localized systems

Anderson localization is known to be inevitable in one-dimension for generic disordered models. Since localization leads to Poissonian energy level statistics, we ask if localized systems possess `additional' integrals of motion as well, so as to enhance the analogy with quantum integrable systems. We answer this in the affirmative in the present work. We construct a set of nontrivial integrals of motion for Anderson localized models, in terms of the original creation and annihilation operators. These are found as a power series in the hopping parameter. The recently found Type-1 Hamiltonians, which are known to be quantum integrable in a precise sense, motivate our construction. We note that these models can be viewed as disordered electron models with infinite-range hopping, where a similar series truncates at the linear order. We show that despite the infinite range hopping, all states but one are localized. We also study the conservation laws for the disorder free Aubry-Andre model, where the states are either localized or extended, depending on the strength of a coupling constant. We formulate a specific procedure for averaging over disorder, in order to examine the convergence of the power series. Using this procedure in the Aubry-Andre model, we show that integrals of motion given by our construction are well-defined in localized phase, but not so in the extended phase. Finally, we also obtain the integrals of motion for a model with interactions to lowest order in the interaction.

Localized Solid-State Amorphization at Grain Boundaries in a Nanocrystalline Al Solid Solution Subjected to Surface Mechanical Attrition

Using high-resolution electron microscopy, localized solid-state amorphization (SSA) was observed in a nanocrystalline (NC) Al solid solution (weight per cent 4.2 Cu, 0.3 Mn, the rest being Al) subjected to a surface mechanical attrition treatment. It was found that the deformation-induced SSA may occur at the grain boundary (GB) where either the high density dislocations or dislocation complexes are present. It is suggested that lattice instability due to elastic distortion within the dislocation core region plays a significant role in the initiation of the localized SSA at defective sites. Meanwhile, the GB of severely deformed NC grains exhibits a continuously varying atomic structure in such a way that while most of the GB is ordered but reveals corrugated configurations, localized amorphization may occur along the same GB.

On the transition from displacement to mixing ventilation with a localized heat source

We investigate the steady state natural ventilation of a room heated at the base and consisting of two vents at different levels. We explore how the air flow rate and internal temperature relative to the exterior vary as a function of the vent areas, position of the vents and heat load in order to establish appropriate ventilation strategies for a room. When the room is heated by a distributed source, the room becomes well mixed and the steady state ventilation rate depends on the heating rate, the area of the vents and the distance between the lower and upper level vents. However, when the room is heated by a localised source the room becomes stratified. If the effective ventilation area is sufficiently large, then the interface separating the two layers lies above the inlet vent and the lower layer is comprised of ambient fluid. In this case the upper layer is warmer than in the well mixed case and the ventilation rate is smaller. However, if the effective area for ventilation is sufficiently small, then the interface separating the two layers lies below the inlet vent and the lower layer is comprised of warm fluid which originates as the cold incoming fluid mixes during descent from the vent through the upper layer. In this case both the ventilation rate and the upper layer temperature are the same as in the case of a distributed heat load. As the vertical separation between lower and upper level vents decreases, then the temperature difference between the layers falls to zero and the room becomes approximately well mixed. These findings suggest how the appropriate ventilation strategy for a room can be varied depending on the exterior temperature, with mixing ventilation more suitable for winter conditions and displacement ventilation for warmer external temperatures.

Effects of mechanical and electrical coupling on the parametric sensitivity of mode localized sensors

We compare and contrast the effects of two distinctly different mechanisms of coupling (mechanical and electrical) on the parametric sensitivity of micromechanical sensors utilizing mode localization for sensor applications. For the first time, the strong correlation between mode localization and the phenomenon of 'eigenvalue loci-veering' is exploited for accurate quantification of the strength of internal coupling in mode localized sensors. The effects of capacitive coupling-spring tuning on the parametric sensitivity of electrically coupled resonators utilizing this sensing paradigm is also investigated and a mass sensor with sensitivity tunable by over 400% is realized. ©2009 IEEE.

Statistics of dissipation and enstrophy induced by localized vortices

The ratios of enstrophy and dissipation moments induced by localized vorticity are inferred to be finite. It follows that the scaling exponents for locally averaged dissipation and enstrophy are equal. However, enstrophy and dissipation exponents measured over finite ranges of scales may be different. The cylindrical vortex profile that yields maximal moment ratios is determined. The moment ratios for cylindrical vortices are used to interpret differences in scale dependence of enstrophy and dissipation previously found in numerical simulations.