FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease

Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for therapy. We identified a subset of luminal A primary breast tumors that give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2-). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that FGFR4 likely participates in this subtype switching. To evaluate this, we developed 2 FGFR4 genomic signatures using a patient-derived xenograft (PDX) model treated with an FGFR4 inhibitor, which inhibited PDX growth in vivo. Bulk tumor gene expression analysis and single-cell RNA sequencing demonstrated that the inhibition of FGFR4 signaling caused molecular switching. In the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohort, FGFR4-induced and FGFR4-repressed signatures each predicted overall survival. Additionally, the FGFR4-induced signature was an independent prognostic factor beyond subtype and stage. Supervised analysis of 77 primary tumors with paired metastases revealed that the FGFR4-induced signature was significantly higher in luminal/ER+ tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4- induced signature also predicted site-specific metastasis for lung, liver, and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting treatment options for FGFR4-positive patients, whose high expression is not caused by mutation or amplification

An Ultra-Low Background PMT for Liquid Xenon Detectors

Results are presented from radioactivity screening of two models of photomultiplier tubes designed for use in current and future liquid xenon experiments. The Hamamatsu 5.6 cm diameter R8778 PMT, used in the LUX dark matter experiment, has yielded a positive detection of four common radioactive isotopes: 238U, 232Th, 40K, and 60Co. Screening of LUX materials has rendered backgrounds from other detector materials subdominant to the R8778 contribution. A prototype Hamamatsu 7.6 cm diameter R11410 MOD PMT has also been screened, with benchmark isotope counts measured at <0.4 238U / <0.3 232Th / <8.3 40K / 2.0+-0.2 60Co mBq/PMT. This represents a large reduction, equal to a change of \times 1/24 238U / \times 1/9 232Th / \times 1/8 40K per PMT, between R8778 and R11410 MOD, concurrent with a doubling of the photocathode surface area (4.5 cm to 6.4 cm diameter). 60Co measurements are comparable between the PMTs, but can be significantly reduced in future R11410 MOD units through further material selection. Assuming PMT activity equal to the measured 90% upper limits, Monte Carlo estimates indicate that replacement of R8778 PMTs with R11410 MOD PMTs will change LUX PMT electron recoil background contributions by a factor of \times1/25 after further material selection for 60Co reduction, and nuclear recoil backgrounds by a factor of \times 1/36. The strong reduction in backgrounds below the measured R8778 levels makes the R11410 MOD a very competitive technology for use in large-scale liquid xenon detectors.Comment: v2 updated to include content after reviewer comments (Sep 2012

LUXSim: A Component-Centric Approach to Low-Background Simulations

Geant4 has been used throughout the nuclear and high-energy physics community to simulate energy depositions in various detectors and materials. These simulations have mostly been run with a source beam outside the detector. In the case of low-background physics, however, a primary concern is the effect on the detector from radioactivity inherent in the detector parts themselves. From this standpoint, there is no single source or beam, but rather a collection of sources with potentially complicated spatial extent. LUXSim is a simulation framework used by the LUX collaboration that takes a component-centric approach to event generation and recording. A new set of classes allows for multiple radioactive sources to be set within any number of components at run time, with the entire collection of sources handled within a single simulation run. Various levels of information can also be recorded from the individual components, with these record levels also being set at runtime. This flexibility in both source generation and information recording is possible without the need to recompile, reducing the complexity of code management and the proliferation of versions. Within the code itself, casting geometry objects within this new set of classes rather than as the default Geant4 classes automatically extends this flexibility to every individual component. No additional work is required on the part of the developer, reducing development time and increasing confidence in the results. We describe the guiding principles behind LUXSim, detail some of its unique classes and methods, and give examples of usage. * Corresponding author, [email protected]: 45 pages, 15 figure

America's Rural Hospitals: A Selective Review of 1980s Research

We review 1980s research on American rural hospitals within the context of a decade of increasing restrictiveness in the reimbursement and operating environments. Areas addressed include rural hospital definitions, organizational and financial performance, and strategic management activities. The latter category consists of hospital closure, diversification and vertical integration, swing-bed conversion, sole community provider designation, horizontal integration and multihospital system affiliation, marketing, and patient retention. The review suggests several research needs, including: developing more meaningful definitions of rural hospitals, engaging in methodologically sound work on the effects of innovative programs and strategic management activities—including conversion of the facility itself—on rural hospital performance, and completing studies of the effects of rural hospital closure or conversion on the health of the communities served.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74857/1/j.1748-0361.1990.tb00682.x.pd

Synaptic processes and immune-related pathways implicated in Tourette syndrome.

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS

Measurement of the View the tt production cross-section using eμ events with b-tagged jets in pp collisions at √s = 13 TeV with the ATLAS detector

This paper describes a measurement of the inclusive top quark pair production cross-section (σtt¯) with a data sample of 3.2 fb−1 of proton–proton collisions at a centre-of-mass energy of √s = 13 TeV, collected in 2015 by the ATLAS detector at the LHC. This measurement uses events with an opposite-charge electron–muon pair in the final state. Jets containing b-quarks are tagged using an algorithm based on track impact parameters and reconstructed secondary vertices. The numbers of events with exactly one and exactly two b-tagged jets are counted and used to determine simultaneously σtt¯ and the efficiency to reconstruct and b-tag a jet from a top quark decay, thereby minimising the associated systematic uncertainties. The cross-section is measured to be: σtt¯ = 818 ± 8 (stat) ± 27 (syst) ± 19 (lumi) ± 12 (beam) pb, where the four uncertainties arise from data statistics, experimental and theoretical systematic effects, the integrated luminosity and the LHC beam energy, giving a total relative uncertainty of 4.4%. The result is consistent with theoretical QCD calculations at next-to-next-to-leading order. A fiducial measurement corresponding to the experimental acceptance of the leptons is also presented

Search for TeV-scale gravity signatures in high-mass final states with leptons and jets with the ATLAS detector at sqrt [ s ] = 13TeV

A search for physics beyond the Standard Model, in final states with at least one high transverse momentum charged lepton (electron or muon) and two additional high transverse momentum leptons or jets, is performed using 3.2 fb−1 of proton–proton collision data recorded by the ATLAS detector at the Large Hadron Collider in 2015 at √s = 13 TeV. The upper end of the distribution of the scalar sum of the transverse momenta of leptons and jets is sensitive to the production of high-mass objects. No excess of events beyond Standard Model predictions is observed. Exclusion limits are set for models of microscopic black holes with two to six extra dimensions

Search for resonances in the mass distribution of jet pairs with one or two jets identified as b-jets in proton–proton collisions at √s=13TeV with the ATLAS detector

Searches for high-mass resonances in the dijet invariant mass spectrum with one or two jets identi-fied as b-jets are performed using an integrated luminosity of 3.2fb−1of proton–proton collisions with a centre-of-mass energy of √s=13TeVrecorded by the ATLAS detector at the Large Hadron Collider. Noevidence of anomalous phenomena is observed in the data, which are used to exclude, at 95%credibility level, excited b∗quarks with masses from 1.1TeVto 2.1TeVand leptophobic Z bosons with masses from 1.1TeVto 1.5TeV. Contributions of a Gaussian signal shape with effective cross sections ranging from approximately 0.4 to 0.001pb are also excluded in the mass range 1.5–5.0TeV

Measurement of the double-differential high-mass Drell-Yan cross section in pp collisions at √s = 8 TeV with the ATLAS detector

This paper presents a measurement of the double-differential cross section for the Drell-Yan Z/γ∗ → ℓ+ℓ− and photon-induced γγ → ℓ+ℓ− processes where ℓ is an electron or muon. The measurement is performed for invariant masses of the lepton pairs, mℓℓ, between 116 GeV and 1500 GeV using a sample of 20.3 fb−1 of pp collisions data at centre-of-mass energy of √s = 8 TeV collected by the ATLAS detector at the LHC in 2012. The data are presented double differentially in invariant mass and absolute dilepton rapidity as well as in invariant mass and absolute pseudorapidity separation of the lepton pair. The single-differential cross section as a function of mℓℓ is also reported. The electron and muon channel measurements are combined and a total experimental precision of better than 1% is achieved at low mℓℓ. A comparison to next-to-next-to-leading order perturbative QCD predictions using several recent parton distribution functions and including next-to-leading order electroweak effects indicates the potential of the data to constrain parton distribution functions. In particular, a large impact of the data on the photon PDF is demonstrated

Search for high-mass new phenomena in the dilepton final state using proton–proton collisions at View the MathML sources=13TeV with the ATLAS detector

A search is conducted for both resonant and non-resonant high-mass new phenomena in dielectron and dimuon final states. The search uses View the MathML source3.2fb−1 of proton–proton collision data, collected at View the MathML sources=13TeV by the ATLAS experiment at the LHC in 2015. The dilepton invariant mass is used as the discriminating variable. No significant deviation from the Standard Model prediction is observed; therefore limits are set on the signal model parameters of interest at 95% credibility level. Upper limits are set on the cross-section times branching ratio for resonances decaying to dileptons, and the limits are converted into lower limits on the resonance mass, ranging between 2.74 TeV and 3.36 TeV, depending on the model. Lower limits on the ℓℓqqℓℓqq contact interaction scale are set between 16.7 TeV and 25.2 TeV, also depending on the mode