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

The Western Australian Clinical Senate as a Model for State-Wide Clinical Engagement

International reforms in healthcare have established the principal that embracing clinical engagement can drive healthcare reform and improved safety and quality outcomes. Most attention has focussed on how clinicians might be engaged at a local or hospital level. However, healthcare reforms are usually initiated at a state or national level. Less attention has gone into exploring the key elements of a model to achieve clinical engagement at state or national level. This paper explores the key elements of a successful state-wide clinical engagement model including culture and leadership, membership, decision-making processes and accountability and discusses how the current model of the Western Australian Clinical Senate addresses these elements. This model may be applicable in other jurisdictions and healthcare systems

Energy transfer in a fast-slow Hamiltonian system

We consider a finite region of a lattice of weakly interacting geodesic flows on manifolds of negative curvature and we show that, when rescaling the interactions and the time appropriately, the energies of the flows evolve according to a non linear diffusion equation. This is a first step toward the derivation of macroscopic equations from a Hamiltonian microscopic dynamics in the case of weakly coupled systems

Thermal description of hadron production in e+e- collisions revisited

We present a comprehensive analysis of hadron production in e+e- collisions at different center-of-mass energies in the framework of the statistical model of the hadron resonance gas. The model is formulated in the canonical ensemble with exact conservation of all relevant quantum numbers. The parameters of the underlying model were determined using a fit to the average multiplicities of the latest measurements at $\sqrt{s}$ = 10, 29-35, 91 and 130-200 GeV. The results demonstrate that, within the accuracy of the experiments, none of the data sets is satisfactorily described with this approach, calling into question the notion that particle production in e+e- collisions is thermal in origin.Comment: 13 pages, 3 figures; v2: final version accepted for publication in Phys. Lett.

The QCD sign problem and dynamical simulations of random matrices

At nonzero quark chemical potential dynamical lattice simulations of QCD are hindered by the sign problem caused by the complex fermion determinant. The severity of the sign problem can be assessed by the average phase of the fermion determinant. In an earlier paper we derived a formula for the microscopic limit of the average phase for general topology using chiral random matrix theory. In the current paper we present an alternative derivation of the same quantity, leading to a simpler expression which is also calculable for finite-sized matrices, away from the microscopic limit. We explicitly prove the equivalence of the old and new results in the microscopic limit. The results for finite-sized matrices illustrate the convergence towards the microscopic limit. We compare the analytical results with dynamical random matrix simulations, where various reweighting methods are used to circumvent the sign problem. We discuss the pros and cons of these reweighting methods.Comment: 34 pages, 3 figures, references added, as published in JHE

Carbon storage and DNA absorption in allophanic soils and paleosols

Andisols and andic paleosols dominated by the nanocrystalline mineral allophane sequester large amounts of carbon (C), attributable mainly to its chemical bonding with charged hydroxyl groups on the surface of allophane together with its physical protection in nanopores within and between allophane nanoaggregates. C near-edge X-ray absorption fine structure (NEXAFS) spectra for a New Zealand Andisol (Tirau series) showed that the organic matter (OM) mainly comprises quinonic, aromatic, aliphatic, and carboxylic C. In different buried horizons from several other Andisols, C contents varied but the C species were similar, attributable to pedogenic processes operating during developmental upbuilding, downward leaching, or both. The presence of OM in natural allophanic soils weakened the adsorption of DNA on clay; an adsorption isotherm experiment involving humic acid (HA) showed that HA-free synthetic allophane adsorbed seven times more DNA than HA-rich synthetic allophane. Phosphorus X-ray absorption near-edge structure (XANES) spectra for salmonsperm DNA and DNA-clay complexes indicated that DNA was bound to the allophane clay through the phosphate group, but it is not clear if DNA was chemically bound to the surface of the allophane or to OM, or both. We plan more experiments to investigate interactions among DNA, allophane (natural and synthetic), and OM. Because DNA shows a high affinity to allophane, we are studying the potential to reconstruct late Quaternary palaeoenvironments by attempting to extract and characterise ancient DNA from allophanic paleosol

Leading nucleon and inelasticity in hadron-nucleus interactions

We present in this paper a calculation of the average proton-nucleus ine- lasticity. Using an Iterative Leading Particle Model and the Glauber model, we relate the leading particle distribution in nucleon-nucleus interactions with the respective one in nucleon-proton collisions. To describe the leading particle distribution in nucleon-proton collisions, we use the Regge-Mueller formalism. To appear in Journal of Physics G.Comment: 11 pages, 2 figure

Studies of multiplicity in relativistic heavy-ion collisions

In this talk I'll review the present status of charged particle multiplicity measurements from heavy-ion collisions. The characteristic features of multiplicity distributions obtained in Au+Au collisions will be discussed in terms of collision centrality and energy and compared to those of p+p collisions. Multiplicity measurements of d+Au collisions at 200 GeV nucleon-nucleon center-of-mass energy will also be discussed. The results will be compared to various theoretical models and simple scaling properties of the data will be identified.Comment: "Focus on Multiplicity" Internationsl Workshop on Particle Multiplicity in Relativistic Heavy Ion Collisions, Bari, Italy, June 17-19, 2003, 16 pages, 15 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