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

SUSY Simplified Models at 14, 33, and 100 TeV Proton Colliders

Results are presented for a variety of SUSY Simplified Models at the 14 TeV LHC as well as a 33 and 100 TeV proton collider. Our focus is on models whose signals are driven by colored production. We present projections of the upper limit and discovery reach in the gluino-neutralino (for both light and heavy flavor decays), squark-neutralino, and gluino-squark Simplified Model planes. Depending on the model a jets + MET, mono-jet, or same-sign di-lepton search is applied. The impact of pileup is explored. This study utilizes the Snowmass backgrounds and combined detector. Assuming 3000 fb^{-1} of integrated luminosity, a gluino that decays to light flavor quarks can be discovered below 2.3 TeV at the 14 TeV LHC and below 11 TeV at a 100 TeV machine.Comment: 81 pages, 55 figures; v2 journal versio

MISCELLANEOUS ELECTRICITY USE IN U.S. HOMES

ABSTRACT Historically, residential energy and carbon saving efforts have targeted conventional end uses such as water heating, lighting and refrigeration. The emergence of new household appliances has transformed energy use from a few large and easily identifiable end uses into a broad array of "miscellaneous" energy services. This group of so called miscellaneous appliances has been a major contributor to growth in electricity demand in the past two decades. We use industry shipment data, lifetimes, and wattage and usage estimates of over 90 individual products to construct a bottom-up end use model . The model is then used to analyze historical and forecasted growth trends, and to identify the largest individual products within the miscellaneous end use. We also use the end use model to identify and analyze policy priorities. Our forecast projects that over the period 1996 to 2010, miscellaneous consumption will increase 115 TWh, accounting for over 90% of future residential electricity growth. A large portion of this growth will be due to halogen torchiere lamps and consumer electronics, making these two components of miscellaneous electricity a particularly fertile area for efficiency programs. Approximately 20% (40 TWh) of residential miscellaneous electricity is "leaking electricity" or energy consumed by appliances when they are not performing their principal function. If the standby power of all appliances with a standby mode is reduced to one watt, the potential energy savings equal 21 TWh/yr, saving roughly $1-2 billion dollars annually

CONCEPTUAL DESIGN OF ILC DAMPING RING WIGGLER STRAIGHT VACUUM SYSTEM*

Abstract The positron and electron damping rings for the International Linear Collider will contain long straight sections consisting of twenty wiggler/quadrupole pairs. The wigglers will be based upon the CESR superconducting design. There are a number of challenges associated with the design of the wiggler straight vacuum system, in particular, the absorption of photon power generated by the wigglers. This paper will present the overall conceptual design of the wiggler straight vacuum system developed for the ILC Reference Design Report. Particular emphasis will be placed on photon power load calculations and the absorber design

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)

Computing for Perturbative QCD - A Snowmass White Paper

We present a study on high-performance computing and large-scale distributed computing for perturbative QCD calculations.Comment: 21 pages, 5 table

Examining electron-boson coupling using time-resolved spectroscopy

Nonequilibrium pump-probe time domain spectroscopies can become an important tool to disentangle degrees of freedom whose coupling leads to broad structures in the frequency domain. Here, using the time-resolved solution of a model photoexcited electron-phonon system we show that the relaxational dynamics are directly governed by the equilibrium self-energy so that the phonon frequency sets a window for "slow" versus "fast" recovery. The overall temporal structure of this relaxation spectroscopy allows for a reliable and quantitative extraction of the electron-phonon coupling strength without requiring an effective temperature model or making strong assumptions about the underlying bare electronic band dispersion.Comment: 23 pages, 4 figures + Supplementary Material and movies, to appear in PR

Direct Optical Coupling to an Unoccupied Dirac Surface State in the Topological Insulator Bi2_2Se3_3

We characterize the occupied and unoccupied electronic structure of the topological insulator Bi$_2$Se$_3$ by one-photon and two-photon angle-resolved photoemission spectroscopy and slab band structure calculations. We reveal a second, unoccupied Dirac surface state with similar electronic structure and physical origin to the well-known topological surface state. This state is energetically located 1.5 eV above the conduction band, which permits it to be directly excited by the output of a Ti:Sapphire laser. This discovery demonstrates the feasibility of direct ultrafast optical coupling to a topologically protected, spin-textured surface state.Comment: Accepted to Physical Review Letter