Inhibiting tryptophan metabolism enhances interferon therapy in kidney cancer.

Renal cell carcinoma (RCC) is increasing in incidence, and a complete cure remains elusive. While immune-checkpoint antibodies are promising, interferon-based immunotherapy has been disappointing. Tryptophan metabolism, which produces immunosuppressive metabolites, is enhanced in RCC. Here we show indolamine-2,3-dioxygenase-1 (IDO1) expression, a kynurenine pathway enzyme, is increased not only in tumor cells but also in the microenvironment of human RCC compared to normal kidney tissues. Neither kynurenine metabolites nor IDO inhibitors affected the survival or proliferation of human RCC or murine renal cell adenocarcinoma (RENCA) cells in vitro. However, interferon-gamma (IFNγ) induced high levels of IDO1 in both RCC and RENCA cells, concomitant with enhanced kynurenine levels in conditioned media. Induction of IDO1 by IFNα was weaker than by IFNγ. Neither the IDO1 inhibitor methyl-thiohydantoin-DL-tryptophan (MTH-trp) nor IFNα alone inhibited RENCA tumor growth, however the combination of MTH-trp and IFNα reduced tumor growth compared to IFNα. Thus, the failure of IFNα therapy for human RCC is likely due to its inability to overcome the immunosuppressive environment created by increased IDO1. Based on our data, and given that IDO inhibitors are already in clinical trials for other malignancies, IFNα therapy with an IDO inhibitor should be revisited for RCC

Visualizing Spacetime Curvature via Frame-Drag Vortexes and Tidal Tendexes I. General Theory and Weak-Gravity Applications

When one splits spacetime into space plus time, the Weyl curvature tensor (vacuum Riemann tensor) gets split into two spatial, symmetric, and trace-free (STF) tensors: (i) the Weyl tensor's so-called "electric" part or tidal field, and (ii) the Weyl tensor's so-called "magnetic" part or frame-drag field. Being STF, the tidal field and frame-drag field each have three orthogonal eigenvector fields which can be depicted by their integral curves. We call the integral curves of the tidal field's eigenvectors tendex lines, we call each tendex line's eigenvalue its tendicity, and we give the name tendex to a collection of tendex lines with large tendicity. The analogous quantities for the frame-drag field are vortex lines, their vorticities, and vortexes. We build up physical intuition into these concepts by applying them to a variety of weak-gravity phenomena: a spinning, gravitating point particle, two such particles side by side, a plane gravitational wave, a point particle with a dynamical current-quadrupole moment or dynamical mass-quadrupole moment, and a slow-motion binary system made of nonspinning point particles. [Abstract is abbreviated; full abstract also mentions additional results.]Comment: 25 pages, 20 figures, matches the published versio

Synergistic drug combinations from electronic health records and gene expression.

ObjectiveUsing electronic health records (EHRs) and biomolecular data, we sought to discover drug pairs with synergistic repurposing potential. EHRs provide real-world treatment and outcome patterns, while complementary biomolecular data, including disease-specific gene expression and drug-protein interactions, provide mechanistic understanding.MethodWe applied Group Lasso INTERaction NETwork (glinternet), an overlap group lasso penalty on a logistic regression model, with pairwise interactions to identify variables and interacting drug pairs associated with reduced 5-year mortality using EHRs of 9945 breast cancer patients. We identified differentially expressed genes from 14 case-control human breast cancer gene expression datasets and integrated them with drug-protein networks. Drugs in the network were scored according to their association with breast cancer individually or in pairs. Lastly, we determined whether synergistic drug pairs found in the EHRs were enriched among synergistic drug pairs from gene-expression data using a method similar to gene set enrichment analysis.ResultsFrom EHRs, we discovered 3 drug-class pairs associated with lower mortality: anti-inflammatories and hormone antagonists, anti-inflammatories and lipid modifiers, and lipid modifiers and obstructive airway drugs. The first 2 pairs were also enriched among pairs discovered using gene expression data and are supported by molecular interactions in drug-protein networks and preclinical and epidemiologic evidence.ConclusionsThis is a proof-of-concept study demonstrating that a combination of complementary data sources, such as EHRs and gene expression, can corroborate discoveries and provide mechanistic insight into drug synergism for repurposing

Covariant equations for the three-body bound state

The covariant spectator (or Gross) equations for the bound state of three identical spin 1/2 particles, in which two of the three interacting particles are always on shell, are developed and reduced to a form suitable for numerical solution. The equations are first written in operator form and compared to the Bethe-Salpeter equation, then expanded into plane wave momentum states, and finally expanded into partial waves using the three-body helicity formalism first introduced by Wick. In order to solve the equations, the two-body scattering amplitudes must be boosted from the overall three-body rest frame to their individual two-body rest frames, and all effects which arise from these boosts, including the Wigner rotations and rho-spin decomposition of the off-shell particle, are treated exactly. In their final form, the equations reduce to a coupled set of Faddeev-like double integral equations with additional channels arising from the negative rho-spin states of the off-shell particle.Comment: 57 pages, RevTeX, 6 figures, uses epsf.st

Relativistic Corrections to the Triton Binding Energy

The influence of relativity on the triton binding energy is investigated. The relativistic three-dimensional version of the Bethe-Salpeter equation proposed by Blankenbecler and Sugar (BbS) is used. Relativistic (non-separable) one-boson-exchange potentials (constructed in the BbS framework) are employed for the two-nucleon interaction. In a 34-channel Faddeev calculation, it is found that relativistic effects increase the triton binding energy by about 0.2 MeV. Including charge-dependence (besides relativity), the final triton binding energy predictions are 8.33 and 8.16 MeV for the Bonn A and B potential, respectively.Comment: 25 pages of text (latex), 1 figure (not included, available upon request

Discovery and Follow-up Observations of the Young Type Ia Supernova 2016coj

The Type~Ia supernova (SN~Ia) 2016coj in NGC 4125 (redshift $z=0.004523$) was discovered by the Lick Observatory Supernova Search 4.9 days after the fitted first-light time (FFLT; 11.1 days before $B$-band maximum). Our first detection (pre-discovery) is merely $0.6\pm0.5$ day after the FFLT, making SN 2016coj one of the earliest known detections of a SN Ia. A spectrum was taken only 3.7 hr after discovery (5.0 days after the FFLT) and classified as a normal SN Ia. We performed high-quality photometry, low- and high-resolution spectroscopy, and spectropolarimetry, finding that SN 2016coj is a spectroscopically normal SN Ia, but with a high velocity of \ion{Si}{2} $\lambda$6355 ($\sim 12,600$\,\kms\ around peak brightness). The \ion{Si}{2} $\lambda$6355 velocity evolution can be well fit by a broken-power-law function for up to a month after the FFLT. SN 2016coj has a normal peak luminosity ($M_B \approx -18.9 \pm 0.2$ mag), and it reaches a $B$-band maximum \about16.0~d after the FFLT. We estimate there to be low host-galaxy extinction based on the absence of Na~I~D absorption lines in our low- and high-resolution spectra. The spectropolarimetric data exhibit weak polarization in the continuum, but the \ion{Si}{2} line polarization is quite strong ($\sim 0.9\% \pm 0.1\%$) at peak brightness.Comment: Submitte

Ubiquitous outflows in DEEP2 spectra of star-forming galaxies at z=1.4

Galactic winds are a prime suspect for the metal enrichment of the intergalactic medium and may have a strong influence on the chemical evolution of galaxies and the nature of QSO absorption line systems. We use a sample of 1406 galaxy spectra at z~1.4 from the DEEP2 redshift survey to show that blueshifted Mg II 2796, 2803 A absorption is ubiquitous in starforming galaxies at this epoch. This is the first detection of frequent outflowing galactic winds at z~1. The presence and depth of absorption are independent of AGN spectral signatures or galaxy morphology; major mergers are not a prerequisite for driving a galactic wind from massive galaxies. Outflows are found in coadded spectra of galaxies spanning a range of 30x in stellar mass and 10x in star formation rate (SFR), calibrated from K-band and from MIPS IR fluxes. The outflows have column densities of order N_H ~ 10^20 cm^-2 and characteristic velocities of ~ 300-500 km/sec, with absorption seen out to 1000 km/sec in the most massive, highest SFR galaxies. The velocities suggest that the outflowing gas can escape into the IGM and that massive galaxies can produce cosmologically and chemically significant outflows. Both the Mg II equivalent width and the outflow velocity are larger for galaxies of higher stellar mass and SFR, with V_wind ~ SFR^0.3, similar to the scaling in low redshift IR-luminous galaxies. The high frequency of outflows in the star-forming galaxy population at z~1 indicates that galactic winds occur in the progenitors of massive spirals as well as those of ellipticals. The increase of outflow velocity with mass and SFR constrains theoretical models of galaxy evolution that include feedback from galactic winds, and may favor momentum-driven models for the wind physics.Comment: Accepted by ApJ. 25 pages, 17 figures. Revised to add discussions of intervening absorbers and AGN-driven outflows; conclusions unchange

Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations

Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic beta-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08 x 10(-66). The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1-3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10(-4) or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases

Measurement of the production of a W boson in association with a charm quark in pp collisions at √s = 7 TeV with the ATLAS detector

The production of a W boson in association with a single charm quark is studied using 4.6 fb−1 of pp collision data at s√ = 7 TeV collected with the ATLAS detector at the Large Hadron Collider. In events in which a W boson decays to an electron or muon, the charm quark is tagged either by its semileptonic decay to a muon or by the presence of a charmed meson. The integrated and differential cross sections as a function of the pseudorapidity of the lepton from the W-boson decay are measured. Results are compared to the predictions of next-to-leading-order QCD calculations obtained from various parton distribution function parameterisations. The ratio of the strange-to-down sea-quark distributions is determined to be 0.96+0.26−0.30 at Q 2 = 1.9 GeV2, which supports the hypothesis of an SU(3)-symmetric composition of the light-quark sea. Additionally, the cross-section ratio σ(W + +c¯¯)/σ(W − + c) is compared to the predictions obtained using parton distribution function parameterisations with different assumptions about the s−s¯¯¯ quark asymmetry

Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming

Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors