Improved prognostic classification of breast cancer defined by antagonistic activation patterns of immune response pathway modules.

BACKGROUND: Elucidating the activation pattern of molecular pathways across a given tumour type is a key challenge necessary for understanding the heterogeneity in clinical response and for developing novel more effective therapies. Gene expression signatures of molecular pathway activation derived from perturbation experiments in model systems as well as structural models of molecular interactions ("model signatures") constitute an important resource for estimating corresponding activation levels in tumours. However, relatively few strategies for estimating pathway activity from such model signatures exist and only few studies have used activation patterns of pathways to refine molecular classifications of cancer. METHODS: Here we propose a novel network-based method for estimating pathway activation in tumours from model signatures. We find that although the pathway networks inferred from cancer expression data are highly consistent with the prior information contained in the model signatures, that they also exhibit a highly modular structure and that estimation of pathway activity is dependent on this modular structure. We apply our methodology to a panel of 438 estrogen receptor negative (ER-) and 785 estrogen receptor positive (ER+) breast cancers to infer activation patterns of important cancer related molecular pathways. RESULTS: We show that in ER negative basal and HER2+ breast cancer, gene expression modules reflecting T-cell helper-1 (Th1) and T-cell helper-2 (Th2) mediated immune responses play antagonistic roles as major risk factors for distant metastasis. Using Boolean interaction Cox-regression models to identify non-linear pathway combinations associated with clinical outcome, we show that simultaneous high activation of Th1 and low activation of a TGF-beta pathway module defines a subtype of particularly good prognosis and that this classification provides a better prognostic model than those based on the individual pathways. In ER+ breast cancer, we find that simultaneous high MYC and RAS activity confers significantly worse prognosis than either high MYC or high RAS activity alone. We further validate these novel prognostic classifications in independent sets of 173 ER- and 567 ER+ breast cancers. CONCLUSION: We have proposed a novel method for pathway activity estimation in tumours and have shown that pathway modules antagonize or synergize to delineate novel prognostic subtypes. Specifically, our results suggest that simultaneous modulation of T-helper differentiation and TGF-beta pathways may improve clinical outcome of hormone insensitive breast cancers over treatments that target only one of these pathways.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Oscillatory cAMP signaling rapidly alters H3K4 methylation

receptors (GPCRs) alter H3K4 methylation via oscillatory intracellular cAMP. Activation of Gs-coupled receptors caused a rapid decrease of H3K4me3 by elevating cAMP, whereas stimulation of Gi-coupled receptors increased H3K4me3 by diminishing cAMP. H3K4me3 gradually recovered towards baseline levels after the removal of GPCR ligands, indicating that H3K4me3 oscillates in tandem with GPCR activation. cAMP increased intracellular labile Fe(II), the cofactor for histone demethylases, through a non-canonical cAMP target—Rap guanine nucleotide exchange factor-2 (RapGEF2), which subsequently enhanced endosome acidification and Fe(II) release from the endosome via vacuolar H+-ATPase assembly. Removing Fe(III) from the media blocked intracellular Fe(II) elevation after stimulation of Gs-coupled receptors. Iron chelators and inhibition of KDM5 demethylases abolished cAMP-mediated H3K4me3 demethylation. Taken together, these results suggest a novel function of cAMP signaling in modulating histone demethylation through labile Fe(II)

Search for resonant states in positron-electron scattering using a positron gas target

Narrow correlated positron-electron peaks discovered in superheavy nuclear collisions may be signatures for previously undetected neutral particle-like objects having masses of 1--2 MeV/c{sup 2}. We have designed an experiment to definitively test this hypothesis by searching for resonant states formed directly in the scattering of monoenergetic electrons incident on a gas of cold positrons confined magnetically in a Malmberg trap. This technique will provide a hundred-fold improvement in sensitivity to e{sup +}e{sup {minus}} resonances compared to previous positron-beam, thin-foil scattering experiments. Together with a recoil-shadow technique, this experiment will explore a five decade range in neutral-particle lifetimes (10{sup {minus}13}s to 10{sup {minus}8}s) which cannot be probed directly to other methods. 14 refs., 2 figs., 1 tab

Relativistic MHD with Adaptive Mesh Refinement

This paper presents a new computer code to solve the general relativistic magnetohydrodynamics (GRMHD) equations using distributed parallel adaptive mesh refinement (AMR). The fluid equations are solved using a finite difference Convex ENO method (CENO) in 3+1 dimensions, and the AMR is Berger-Oliger. Hyperbolic divergence cleaning is used to control the $\nabla\cdot {\bf B}=0$ constraint. We present results from three flat space tests, and examine the accretion of a fluid onto a Schwarzschild black hole, reproducing the Michel solution. The AMR simulations substantially improve performance while reproducing the resolution equivalent unigrid simulation results. Finally, we discuss strong scaling results for parallel unigrid and AMR runs.Comment: 24 pages, 14 figures, 3 table

Core Functions for Production Grids

unlimited. Copyright Notice – See section 8.2. Intellectual Property Notices – See section 8.1. Copyright © Global Grid Forum (2001). All Rights Reserved. This document defines current practice for set of Grid services that are intended to be the minimal set of Grid functions needed for a functioning, production Grid. We call these the Core Grid Functions. This version of the document is a draft, and is a strawman to raise the issues that will generate the discussion needed to agree on the Core Grid Functions

The stabilizing effects of axial stretching on turbulent vortex dynamics

The evolution and dynamics of vortices in inviscid, incompressible flow under the influence of a deformation field which causes stretching in the axial direction are studied. These vortices are simulated using three-dimensional vortex methods which offer the advantages of having no inherent numerical dissipation and great computational efficiency for short to intermediate times. Two cases in particular are studied: The evolution of a stable, but strongly perturbed vortex, and the evolution of an unstable vortex. In both types of vortices, it is found that the stretching and radial inflow associated with the surrounding deformation field can suppress the growth of disturbances and slow the development of turbulence. This stabilization is even greater than what one would expect from the purely kinematic effects of the deformation field alone, indicating there is a negative feedback on the nonlinear vortex dynamics. The physical mechanisms for stabilization by stretching are discussed, along with potential applications for understanding the stability of intense geophysical vortices maintained by convection

Release rates from partitioning and transmutation waste packages

Partitioning the actinides in light-water reactor spent fuel and transmuting them in actinide-burning liquid-metal reactors has been proposed as a potential method for reducing the public risks from geologic disposal of nuclear waste. As a first step towards quantifying the benefits for waste disposal of actinide burning, we have calculated the release rates of key radionuclides from waste packages resulting from actinide burning, and compare them with release rates from LWR spent fuel destined for disposal at the potential repository at Yucca Mountain. The wet-drip water-contact mode has been used. Analytic methods and parameter values are very similar to those used for assessing Yucca Mountain as a potential repository. Once released, the transport characteristics of radionuclides will be largely determined by site geology. For the most important nuclides such as I-129 and {Tc}-99, which are undiminished by actinide-burning reactors, it is not surprising that actinide burning offers little reduction in releases. For important actinides such as Np-237 and Pu isotopes, which are reduced in inventory, the releases are not reduced because the release rates are proportional to solubility, rather than inventory