Oxidative Stress Resulting From Helicobacter pylori Infection Contributes to Gastric Carcinogenesis.

Helicobacter pylori is a gram-negative, microaerophilic bacterium that infects the stomach and can lead to, among other disorders, the development of gastric cancer. The inability of the host to clear the infection results in a chronic inflammatory state with continued oxidative stress within the tissue. Reactive oxygen species and reactive nitrogen species produced by the immune and epithelial cells damage the host cells and can result in DNA damage. H pylori has evolved to evoke this damaging response while blunting the host's efforts to kill the bacteria. This long-lasting state with inflammation and oxidative stress can result in gastric carcinogenesis. Continued efforts to better understand the bacterium and the host response will serve to prevent or provide improved early diagnosis and treatment of gastric cancer

Pricing in the Market for Anticancer Drugs

In 2011, Bristol-Myers Squibb set the price of its newly approved melanoma drug ipilimumab— brand name Yervoy—at $120,000 for a course of therapy. The drug was associated with an incremental increase in life expectancy of four months. Drugs like ipilimumab have fueled the perception that the launch prices of new anticancer drugs and other drugs in the so-called "specialty" pharmaceutical market have been increasing over time and that increases are unrelated to the magnitude of the expected health benefits. In this paper, we discuss the unique features of the market for anticancer drugs and assess trends in the launch prices for 58 anticancer drugs approved between 1995 and 2013 in the United States. We restrict attention to anticancer drugs because the use of median survival time as a primary outcome measure provides a common, objective scale for quantifying the incremental benefit of new products. We find that the average launch price of anticancer drugs, adjusted for inflation and health benefits, increased by 10 percent annually—or an average of$8,500 per year—from 1995 to 2013. We argue that the institutional features of the market for anticancer drugs enable manufacturers to set the prices of new products at or slightly above the prices of existing therapies, giving rise to an upward trend in launch prices. Government-mandated price discounts for certain classes of buyers may have also contributed to launch price increases as firms sought to offset the growth in the discount segment by setting higher prices for the remainder of the market

ELMO1 has an essential role in the internalization of Salmonella Typhimurium into enteric macrophages that impacts disease outcome.

Backgrounds and aims4-6 million people die of enteric infections each year. After invading intestinal epithelial cells, enteric bacteria encounter phagocytes. However, little is known about how phagocytes internalize the bacteria to generate host responses. Previously, we have shown that BAI1 (Brain Angiogenesis Inhibitor 1) binds and internalizes Gram-negative bacteria through an ELMO1 (Engulfment and cell Motility protein 1)/Rac1-dependent mechanism. Here we delineate the role of ELMO1 in host inflammatory responses following enteric infection.MethodsELMO1-depleted murine macrophage cell lines, intestinal macrophages and ELMO1 deficient mice (total or myeloid-cell specific) was infected with Salmonella enterica serovar Typhimurium. The bacterial load, inflammatory cytokines and histopathology was evaluated in the ileum, cecum and spleen. The ELMO1 dependent host cytokines were detected by a cytokine array. ELMO1 mediated Rac1 activity was measured by pulldown assay.ResultsThe cytokine array showed reduced release of pro-inflammatory cytokines, including TNF-α and MCP-1, by ELMO1-depleted macrophages. Inhibition of ELMO1 expression in macrophages decreased Rac1 activation (~6 fold) and reduced internalization of Salmonella. ELMO1-dependent internalization was indispensable for TNF-α and MCP-1. Simultaneous inhibition of ELMO1 and Rac function virtually abrogated TNF-α responses to infection. Further, activation of NF-κB, ERK1/2 and p38 MAP kinases were impaired in ELMO1-depleted cells. Strikingly, bacterial internalization by intestinal macrophages was completely dependent on ELMO1. Salmonella infection of ELMO1-deficient mice resulted in a 90% reduction in bacterial burden and attenuated inflammatory responses in the ileum, spleen and cecum.ConclusionThese findings suggest a novel role for ELMO1 in facilitating intracellular bacterial sensing and the induction of inflammatory responses following infection with Salmonella

Twenty-Four Hour Tonometry in Patients Suspected of Chronic Gastrointestinal Ischemia

Background and aims: Gastrointestinal tonometry is currently the only clinical diagnostic test that enables identification of symptomatic chronic gastrointestinal ischemia. Gastric exercise tonometry has proven its value for detection of ischemia in this patients group, but has its disadvantages. Earlier studies with postprandial tonometry gave unreliable results. In this study we challenged (again) the use of postprandial tonometry in patients suspected of gastrointestinal ischemia. Methods: Patients suspected for chronic gastrointestinal ischemia had standard diagnostic work up, including gastric exercise tonometry and 24-h tonometry using standard meals. Results: Thirty-three patients were enrolled in the study. Chronic gastrointestinal ischemia was diagnosed in 17 (52%) patients. The 24-h tonometry correctly predicted the presence of ischemia in 13/17 patients, and absence of ischemia in 15/16 patients. Conclusions: The use of 24-h tonometry after meals in patients suspected of gastrointestinal ischemia seems feasible, with promising accuracy for the detection of ischemia

New, efficient, and accurate high order derivative and dissipation operators satisfying summation by parts, and applications in three-dimensional multi-block evolutions

We construct new, efficient, and accurate high-order finite differencing operators which satisfy summation by parts. Since these operators are not uniquely defined, we consider several optimization criteria: minimizing the bandwidth, the truncation error on the boundary points, the spectral radius, or a combination of these. We examine in detail a set of operators that are up to tenth order accurate in the interior, and we surprisingly find that a combination of these optimizations can improve the operators' spectral radius and accuracy by orders of magnitude in certain cases. We also construct high-order dissipation operators that are compatible with these new finite difference operators and which are semi-definite with respect to the appropriate summation by parts scalar product. We test the stability and accuracy of these new difference and dissipation operators by evolving a three-dimensional scalar wave equation on a spherical domain consisting of seven blocks, each discretized with a structured grid, and connected through penalty boundary conditions.Comment: 16 pages, 9 figures. The files with the coefficients for the derivative and dissipation operators can be accessed by downloading the source code for the document. The files are located in the "coeffs" subdirector

Effective theories for real-time correlations in hot plasmas

We discuss the sequence of effective theories needed to understand the qualitative, and quantitative, behavior of real-time correlators in ultra-relativistic plasmas. We analyze in detail the case where A is a gauge-invariant conserved current. This case is of interest because it includes a correlation recently measured in lattice simulations of classical, hot, SU(2)-Higgs gauge theory. We find that simple perturbation theory, free kinetic theory, linearized kinetic theory, and hydrodynamics are all needed to understand the correlation for different ranges of time. We emphasize how correlations generically have power-law decays at very large times due to non-linear couplings to long-lived hydrodynamic modes.Comment: 28 pages, Latex, uses revtex, epsf macro packages [Revised version: t -> sqrt{t} in a few typos on p. 10.

Recoil velocities from equal-mass binary black-hole mergers: a systematic investigation of spin-orbit aligned configurations

Binary black-hole systems with spins aligned with the orbital angular momentum are of special interest, as studies indicate that this configuration is preferred in nature. If the spins of the two bodies differ, there can be a prominent beaming of the gravitational radiation during the late plunge, causing a recoil of the final merged black hole. We perform an accurate and systematic study of recoil velocities from a sequence of equal-mass black holes whose spins are aligned with the orbital angular momentum, and whose individual spins range from a = +0.584 to -0.584. In this way we extend and refine the results of a previous study and arrive at a consistent maximum recoil of 448 +- 5 km/s for anti-aligned models as well as to a phenomenological expression for the recoil velocity as a function of spin ratio. This relation highlights a nonlinear behavior, not predicted by the PN estimates, and can be readily employed in astrophysical studies on the evolution of binary black holes in massive galaxies. An essential result of our analysis is the identification of different stages in the waveform, including a transient due to lack of an initial linear momentum in the initial data. Furthermore we are able to identify a pair of terms which are largely responsible for the kick, indicating that an accurate computation can be obtained from modes up to l=3. Finally, we provide accurate measures of the radiated energy and angular momentum, finding these to increase linearly with the spin ratio, and derive simple expressions for the final spin and the radiated angular momentum which can be easily implemented in N-body simulations of compact stellar systems. Our code is calibrated with strict convergence tests and we verify the correctness of our measurements by using multiple independent methods whenever possible.Comment: 24 pages, 15 figures, 5 table

Aluminum-, Calcium- And Titanium-Rich Oxide Stardust In Ordinary Chondrite Meteorites

We report isotopic data for a total of 96 presolar oxide grains found in residues of several unequilibrated ordinary chondrite meteorites. Identified grain types include Al2O3, MgAl2O4, hibonite (CaAl12O19) and Ti oxide. This work greatly increases the presolar hibonite database, and is the first report of presolar Ti oxide. O-isotopic compositions of the grains span previously observed ranges and indicate an origin in red giant and asymptotic giant branch (AGB) stars of low mass (<2.5 MSun) for most grains. Cool bottom processing in the parent AGB stars is required to explain isotopic compositions of many grains. Potassium-41 enrichments in hibonite grains are attributable to in situ decay of now-extinct 41Ca. Inferred initial 41Ca/40Ca ratios are in good agreement with model predictions for low-mass AGB star envelopes, provided that ionization suppresses 41Ca decay. Stable Mg and Ca isotopic ratios of most of the hibonite grains reflect primarily the initial compositions of the parent stars and are generally consistent with expectations for Galactic chemical evolution, but require some local interstellar chemical inhomogeneity. Very high 17O/16O or 25Mg/24Mg ratios suggest an origin for some grains in binary star systems where mass transfer from an evolved companion has altered the parent star compositions. A supernova origin for the hitherto enigmatic 18O-rich Group 4 grains is strongly supported by multi-element isotopic data for two grains. The Group 4 data are consistent with an origin in a single supernova in which variable amounts of material from the deep 16O-rich interior mixed with a unique end-member mixture of the outer layers. The Ti oxide grains primarily formed in low-mass AGB stars. They are smaller and rarer than presolar Al2O3, reflecting the lower abundance of Ti than Al in AGB envelopes.Comment: Accepted for publication in ApJ; 47 pages, 13 figure

Comprehensive analysis of the chromatin landscape in Drosophila melanogaster.

Chromatin is composed of DNA and a variety of modified histones and non-histone proteins, which have an impact on cell differentiation, gene regulation and other key cellular processes. Here we present a genome-wide chromatin landscape for Drosophila melanogaster based on eighteen histone modifications, summarized by nine prevalent combinatorial patterns. Integrative analysis with other data (non-histone chromatin proteins, DNase I hypersensitivity, GRO-Seq reads produced by engaged polymerase, short/long RNA products) reveals discrete characteristics of chromosomes, genes, regulatory elements and other functional domains. We find that active genes display distinct chromatin signatures that are correlated with disparate gene lengths, exon patterns, regulatory functions and genomic contexts. We also demonstrate a diversity of signatures among Polycomb targets that include a subset with paused polymerase. This systematic profiling and integrative analysis of chromatin signatures provides insights into how genomic elements are regulated, and will serve as a resource for future experimental investigations of genome structure and function

Sorting of chromosomes by magnetic separation

Chromosomes were isolated from Chinese hamster x human hybrid cell lines containing four and nine human chromosomes. Human genomic DNA was biotinylated by nick translation and used to label the human chromosomes by in situ hybridization in suspension. Streptavidin was covalently coupled to the surface of magnetic beads and these were incubated with the hybridized chromosomes. The human chromosomes were bound to the magnetic beads through the strong biotin-streptavidin complex and then rapidly separated from nonlabeled Chinese hamster chromosomes by a simple permanent magnet. The hybridization was visualized by additional binding of avidin-FITC (fluorescein) to the unoccupied biotinylated human DNA bound to the human chromosomes. After magnetic separation, up to 98% of the individual chromosomes attached to magnetic beads were classified as human chromosomes by fluorescence microscopy