Adaptive upregulation of FOXD3 and resistance to PLX4032/4720-induced cell death in mutant B-RAF melanoma cells.

Melanoma cells driven by mutant v-raf murine sarcoma viral oncogene homolog B1 (B-RAF) are highly resistant to chemotherapeutic treatments. Recent phase 1 results with PLX4032/RG7204/vemurafenib, which selectively inhibits B-RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)1/2 signaling in mutant B-RAF cells, has given encouragement to this struggling field. Nearly all patients in the phase 1-3 studies saw at least some response and the overall response rates ranged from 48 and 81%. However, despite initial tumor shrinkage, most responders in the trial experienced tumor relapse over time. These findings indicate that both intrinsic and acquired resistance may affect the clinical efficacy of PLX4032. It is critical to optimize PLX4032 activity to improve response rates and understand why some patients with the B-RAF mutation do not respond. We have previously shown that the stemness factor, Forkhead box D3 (FOXD3), is upregulated following inhibition of B-RAF-MEK signaling in mutant B-RAF melanoma cells. Here, we show that upregulation of FOXD3 following treatment with PLX4032 and PLX4720 (the non-clinical tool compound for PLX4032) confers resistance to cell death. Small interfering RNA-mediated knockdown of FOXD3 significantly enhanced the cell death response after PLX4032/4720 treatment in mutant B-RAF melanoma cell lines. Additionally, upregulation of FOXD3 after PLX4720 treatment was attenuated in non-adherent conditions and correlated with enhanced cell death. Ectopic expression of FOXD3 in non-adherent cells significantly reduced cell death in response to PLX4720 treatment. Together, these data indicate that upregulation of FOXD3 is an adaptive response to RAF inhibitors that promotes a state of drug resistance

Coulomb-Volkov approach of ionization by extreme ultraviolet laser pulses in the subfemtosecond regime

In conditions where the interaction betweeen an atom and a short high-frequency extreme ultraviolet laser pulse is a perturbation, we show that a simple theoretical approach, based on Coulomb-Volkov-type states, can make reliable predictions for ionization. To avoid any additional approximation, we consider here a standard case : the ionization of hydrogen atoms initially in their ground state. For any field parameter, we show that the method provides accurate energy spectra of ejected electrons, including many above threshold ionization peaks, as long as the two following conditions are simultaneously fulfilled : (i) the photon energy is greater than or equal to the ionization potential ; (ii) the ionization process is not saturated. Thus, ionization of atoms or molecules by the high order harmonic laser pulses which are generated at present may be addressed through this Coulomb-Volkov treatment.Comment: 19 pages including 5 figures and figure caption

Chiral symmetry restoration, eigenvalue density of Dirac operator and axial U(1) anomaly at finite temperature

We reconsider constraints on the eigenvalue density of the Dirac operator in the chiral symmetric phase of 2 flavor QCD at finite temperature. To avoid possible ultra-violet(UV) divergences, we work on a lattice, employing the overlap Dirac operator, which ensures the exact "chiral" symmetry at finite lattice spacings. Studying multi-point correlation functions in various channels and taking their thermodynamical limit (and then taking the chiral limit), we obtain stronger constraints than those found in the previous studies: both the eigenvalue density at the origin and its first and second derivatives vanish in the chiral limit of 2 flavor QCD. In addition we show that the axial U(1) anomaly becomes invisible in susceptibilities of scalar and pseudo scalar mesons, suggesting that the 2nd order chiral phase transition with the O(4) scaling is not realized in 2 flavor QCD. Possible lattice artifacts when non-chiral lattice Dirac operator is employed are briefly discussed.Comment: 39 pages, 1 figure(2 eps files), a version published in PR

Destabilizing Taylor-Couette flow with suction

We consider the effect of radial fluid injection and suction on Taylor-Couette flow. Injection at the outer cylinder and suction at the inner cylinder generally results in a linearly unstable steady spiralling flow, even for cylindrical shears that are linearly stable in the absence of a radial flux. We study nonlinear aspects of the unstable motions with the energy stability method. Our results, though specialized, may have implications for drag reduction by suction, accretion in astrophysical disks, and perhaps even in the flow in the earth's polar vortex.Comment: 34 pages, 9 figure

Identifying Cultural and Cognitive Proximity between Managers and Customers in Tornio and Haparanda Cross Border Region

Daily intercultural interactions in cross-border regions such as those between customers and managers can be a source of knowledge and ideas. However, such interactions can pose distinctive constraints and opportunities for learning and exchange of ideas. This study adopts a relatively fine–grained quantitative approach to study elements of cognitive and cultural proximity which have a major impact on these interactions. It is based on a survey of 91 managers of small service firms and 312 customers in the twin city of Tornio and Haparanda on the border between Finland and Sweden. Seven elements of proximity were identified and measured. Six elements of perceived cognitive and cultural proximity including values, conservative values towards new ideas, knowledge and use of technology, use of a foreign language, sufficiently focusing or providing specific details and ways of solving problems were found significant in terms of shaping perceptions of Swedish and Finnish managers and customers, which shape these interactions. The results enhance our understanding of how daily cross-border intercultural can be examined in the context of cross-border regional knowledge transfer

Surface patterning of polyacrylamide gel using scanning electrochemical cell microscopy (SECCM)

Scanning electrochemical cell microscopy is introduced as a new tool for the synthesis and deposition of polymers on SAM-functionalised Au surfaces. The deposition of poly(N-hydroxyethyl acrylamide) is shown to be enhanced through the electrochemical generation of activating Cu(I)Cl/Me6TREN catalyst. Initiation of the polymerisation reaction is most likely due to in situ generation of reactive oxygen species following oxygen reduction

Spin picture of the one-dimensional Hubbard model: Two-fluid structure and phase dynamics

We propose a scheme for investigating the quantum dynamics of interacting electron models by means of time-dependent variational principle and spin coherent states of space lattice operators. We apply such a scheme to the one-dimensional hubbard model, and solve the resulting equations in different regimes. In particular, we find that at low densities the dynamics is mapped into two coupled nonlinear Schroedinger equations, whereas near half-filling the model is described by two coupled Josephson junction arrays. Focusing then to the case in which only the phases of the spin variables are dynamically active, we examine a number of different solutions corresponding to the excitations of few macroscopic modes. Based on fixed point equation of the simpler among them, we show that the standard one-band ground state phase space is found.Comment: 10 pages, 1 figure, to appear on Phys. Rev.

Ferromagnetism in a hard-core boson model

The problem of ferromagnetism -- associated with a ground state with maximal total spin -- is discussed in the framework of a hard-core model, which forbids the occupancy at each site with more than one particle. It is shown that the emergence of ferromagnetism on finite square lattices crucially depends on the statistics of the particles. Fermions (electrons) lead to the well-known instabilities for finite hole densities, whereas for bosons (with spin) ferromagnetism appears to be stable for all hole densities.Comment: 8 pages, 7 figures, RevTex

Multiplicity Studies and Effective Energy in ALICE at the LHC

In this work we explore the possibility to perform ``effective energy'' studies in very high energy collisions at the CERN Large Hadron Collider (LHC). In particular, we focus on the possibility to measure in $pp$ collisions the average charged multiplicity as a function of the effective energy with the ALICE experiment, using its capability to measure the energy of the leading baryons with the Zero Degree Calorimeters. Analyses of this kind have been done at lower centre--of--mass energies and have shown that, once the appropriate kinematic variables are chosen, particle production is characterized by universal properties: no matter the nature of the interacting particles, the final states have identical features. Assuming that this universality picture can be extended to {\it ion--ion} collisions, as suggested by recent results from RHIC experiments, a novel approach based on the scaling hypothesis for limiting fragmentation has been used to derive the expected charged event multiplicity in $AA$ interactions at LHC. This leads to scenarios where the multiplicity is significantly lower compared to most of the predictions from the models currently used to describe high energy $AA$ collisions. A mean charged multiplicity of about 1000-2000 per rapidity unit (at $\eta \sim 0$) is expected for the most central $Pb-Pb$ collisions at $\sqrt{s_{NN}} = 5.5 TeV$.Comment: 12 pages, 19 figures. In memory of A. Smirnitski