Induction of Metastatic Gastric Cancer by Peroxisome Proliferator-Activated Receptorδ Activation

Peroxisome proliferator-activated receptorδ (PPARδ) regulates a multiplicity of physiological processes associated with glucose and lipid metabolism, inflammation, and proliferation. One or more of these processes likely create risk factors associated with the ability of PPARδ agonists to promote tumorigenesis in some organs. In the present study, we describe a new gastric tumor mouse model that is dependent on the potent and highly selective PPARδ agonist GW501516 following carcinogen administration. The progression of gastric tumorigenesis was rapid as determined by magnetic resonance imaging and resulted in highly metastatic squamous cell carcinomas of the forestomach within two months. Tumorigenesis was associated with gene expression signatures indicative of cell adhesion, invasion, inflammation, and metabolism. Increased PPARδ expression in tumors correlated with increased PDK1, Akt, β-catenin, and S100A9 expression. The rapid development of metastatic gastric tumors in this model will be useful for evaluating preventive and therapeutic interventions in this disease

Thermodynamic Description of the Relaxation of Two-Dimensional Euler Turbulence Using Tsallis Statistics

Euler turbulence has been experimentally observed to relax to a metaequilibrium state that does not maximize the Boltzmann entropy, but rather seems to minimize enstrophy. We show that a recent generalization of thermodynamics and statistics due to Tsallis is capable of explaining this phenomenon in a natural way. The maximization of the generalized entropy $S_{1/2}$ for this system leads to precisely the same profiles predicted by the Restricted Minimum Enstrophy theory of Huang and Driscoll. This makes possible the construction of a comprehensive thermodynamic description of Euler turbulence.Comment: 15 pages, RevTe

Biphosphonate-Mediated Gene Vector Delivery from the Metal Surfaces of Stents

The clinical use of metallic expandable intravascular stents has resulted in imporved therapeutic outcomes for coronary artery disease. However, arterial reobstruction after stenting, in-stent restenosis, remains an important problem. Gene therapy to treat in-stent restenosis by using gene vector delivery from the metallic stent surfaces has never been demonstrated. The present studies investigated the hypothesis that metal-biphosphonate binding can enable site-specific gene vector delivery from metal surfaces. Polyallylamine biphosphonate (PAA-BP) was synthesized by using Michael addition methodology. Exposure to aqueous solutions of PAA-BP resulted in the formation of a monomolecular biphosphonate later on metal alloy surfaces (steel, nitinol, and cobalt-chromium), as demonstrated by x-ray photoelectron spectroscopy. Surface-bound PAA-BP enabled adenoviral (Ad) tethering due to covalent thiol-binding of either anti-Ad antibody or a recombinant Ad-receptor protein, D1. In arterial smooth muscle cell cultures, alloy samples configured with surface-tethered Ad were demonstrated to achieve site-specific transduction with a reporter gene, (GFP). Rat carotid stent angioplasties using metal stents exposed to aqueous PAA-BP and derivatized with anti-knob antibody or D1 resulted in extensive localized Ad-GFP expression in the arterial wall. In a separate study with a model therapeutic vector, Ad-inducible nitric oxide synthase (iNOS) attached to the biphosphonate-treated metal stent surface via D1, significant inhibition of restenosis was demonstrated (neointimal/media ration 1.68 ± 0.27 and 3.4 ± 0.35; Ad-iNOS vs. control, P \u3c 0.01). Is is concluded that effective gene vector delivery from metallic stent surfaces can be achieved using this approach

Idarucizumab for Dabigatran Reversal - Full Cohort Analysis.

BACKGROUND: Idarucizumab, a monoclonal antibody fragment, was developed to reverse the anticoagulant effect of dabigatran. METHODS: We performed a multicenter, prospective, open-label study to determine whether 5 g of intravenous idarucizumab would be able to reverse the anticoagulant effect of dabigatran in patients who had uncontrolled bleeding (group A) or were about to undergo an urgent procedure (group B). The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the diluted thrombin time or ecarin clotting time. Secondary end points included the restoration of hemostasis and safety measures. RESULTS: A total of 503 patients were enrolled: 301 in group A, and 202 in group B. The median maximum percentage reversal of dabigatran was 100% (95% confidence interval, 100 to 100), on the basis of either the diluted thrombin time or the ecarin clotting time. In group A, 137 patients (45.5%) presented with gastrointestinal bleeding and 98 (32.6%) presented with intracranial hemorrhage; among the patients who could be assessed, the median time to the cessation of bleeding was 2.5 hours. In group B, the median time to the initiation of the intended procedure was 1.6 hours; periprocedural hemostasis was assessed as normal in 93.4% of the patients, mildly abnormal in 5.1%, and moderately abnormal in 1.5%. At 90 days, thrombotic events had occurred in 6.3% of the patients in group A and in 7.4% in group B, and the mortality rate was 18.8% and 18.9%, respectively. There were no serious adverse safety signals. CONCLUSIONS: In emergency situations, idarucizumab rapidly, durably, and safely reversed the anticoagulant effect of dabigatran. (Funded by Boehringer Ingelheim; RE-VERSE AD ClinicalTrials.gov number, NCT02104947 .)

Exploring Systematic Offsets Between Aerosol Products from the Two MODIS Sensors

Long-term measurements of global aerosol loading and optical properties are essential for assessing climate-related questions. Using observations of spectral reflectance and radiance, the dark-target (DT) aerosol retrieval algorithm is applied to Moderate Resolution Imaging Spectroradiometer sensors on both Terra (MODIS-T) and Aqua (MODIS-A) satellites, deriving products (known as MOD04 and MYD04, respectively) of global aerosol optical depth (AOD at 0.55microm) over both land and ocean, and an ngstrm exponent (AE derived from 0.55 and 0.86microm) over ocean. Here, we analyze the overlapping time series (since mid-2002) of the Collection 6 (C6) aerosol products. Global monthly mean AOD from MOD04 (Terra with morning overpass) is consistently higher than MYD04 (Aqua with afternoon overpass) by 13% (0.02 over land and 0.015 over ocean), and this offset (MOD04 - MYD04) has seasonal as well as long-term variability. Focusing on 2008 and deriving yearly gridded mean AOD and AE, we find that, over ocean, the MOD04 (morning) AOD is higher and the AE is lower. Over land, there is more variability, but only biomass-burning regions tend to have AOD lower for MOD04. Using simulated aerosol fields from the Goddard Earth Observing System (GEOS-5) Earth system model and sampling separately (in time and space) along each MODIS-observed swath during 2008, the magnitudes of morning versus afternoon offsets of AOD and AE are smaller than those in the C6 products. Since the differences are not easily attributed to either aerosol diurnal cycles or sampling issues, we test additional corrections to the input reflectance data. The first, known as C6+, corrects for long-term changes to each sensor's polarization sensitivity and the response versus the scan angle and to cross-calibration from MODIS-T to MODIS-A. A second convolves the detrending and cross-calibration into scaling factors. Each method was applied upstream of the aerosol retrieval using 2008 data. While both methods reduced the overall AOD offset over land from 0.02 to 0.01, neither significantly reduced the AOD offset over ocean. The overall negative AE offset was reduced. A collection (C6.1) of all MODIS Atmosphere products was released, but we expect that the C6.1 aerosol products will maintain similar overall AOD and AE offsets. We conclude that (a) users should not interpret global differences between Terra and Aqua aerosol products as representing a true diurnal signal in the aerosol. (b) Because the MODIS-A product appears to have an overall smaller bias compared to ground-truth data, it may be more suitable for some applications. However (c), since the AOD offset is only 0.02 and within the noise level for single retrievals, both MODIS products may be adequate for most applications

Comparison of greenhouse gas fluxes from tropical forests and oil palm plantations on mineral soil

In Southeast Asia, oil palm (OP) plantations have largely replaced tropical forests. The impact of this shift in land use on greenhouse gas (GHG) fluxes remains highly uncertain, mainly due to a relatively small pool of available data. The aim of this study is to quantify differences of nitrous oxide (N2O) and methane (CH4) fluxes as well as soil carbon dioxide (CO2) respiration rates from logged forests, oil palm plantations of different ages, and an adjacent small riparian area. Nitrous oxide fluxes are the focus of this study, as these emissions are expected to increase significantly due to the nitrogen (N) fertilizer application in the plantations. This study was conducted in the SAFE (Stability of Altered Forest Ecosystems) landscape in Malaysian Borneo (Sabah) with measurements every 2 months over a 2-year period. GHG fluxes were measured by static chambers together with key soil physicochemical parameters and microbial biodiversity. At all sites, N2O fluxes were spatially and temporally highly variable. On average the largest fluxes (incl. 95 % CI) were measured from OP plantations (45.1 (24.0–78.5) µg m−2 h−1 N2O-N), slightly smaller fluxes from the riparian area (29.4 (2.8–84.7) µg m−2 h−1 N2O-N), and the smallest fluxes from logged forests (16.0 (4.0–36.3) µg m−2 h−1 N2O-N). Methane fluxes were generally small (mean ± SD): −2.6 ± 17.2 µg CH4-C m−2 h−1 for OP and 1.3 ± 12.6 µg CH4-C m−2 h−1 for riparian, with the range of measured CH4 fluxes being largest in logged forests (2.2 ± 48.3 µg CH4-C m−2 h−1). Soil respiration rates were larger from riparian areas (157.7 ± 106 mg m−2 h−1 CO2-C) and logged forests (137.4 ± 95 mg m−2 h−1 CO2-C) than OP plantations (93.3 ± 70 mg m−2 h−1 CO2-C) as a result of larger amounts of decomposing leaf litter. Microbial communities were distinctly different between the different land-use types and sites. Bacterial communities were linked to soil pH, and fungal and eukaryotic communities were linked to land use. Despite measuring a large number of environmental parameters, mixed models could only explain up to 17 % of the variance of measured fluxes for N2O, 3 % of CH4, and 25 % of soil respiration. Scaling up measured N2O fluxes to Sabah using land areas for forest and OP resulted in emissions increasing from 7.6 Mt (95 % confidence interval, −3.0–22.3 Mt) yr−1 in 1973 to 11.4 Mt (0.2–28.6 Mt) yr−1 in 2015 due to the increasing area of forest converted to OP plantations over the last ∼ 40 years

Oxpholipin 11D: An Anti-Inflammatory Peptide That Binds Cholesterol and Oxidized Phospholipids

Background: Many Gram-positive bacteria produce pore-forming exotoxins that contain a highly conserved, 12-residue domain (ECTGLAWEWWRT) that binds cholesterol. This domain is usually flanked N-terminally by arginine and C-terminally by valine. We used this 14-residue sequence as a template to create a small library of peptides that bind cholesterol and other lipids. Methodology/Results: Several of these peptides manifested anti-inflammatory properties in a predictive in vitro monocyte chemotactic assay, and some also diminished the pro-inflammatory effects of low-density lipoprotein in apoE-deficient mice. The most potent analog, Oxpholipin-11D (OxP-11D), contained D-amino acids exclusively and was identical to the 14residue design template except that diphenylalanine replaced cysteine-3. In surface plasmon resonance binding studies, OxP-11D bound oxidized (phospho)lipids and sterols in much the same manner as D-4F, a widely studied cardioprotective apoA-I-mimetic peptide with anti-inflammatory properties. In contrast to D-4F, which adopts a stable a-helical structure in solution, the OxP-11D structure was flexible and contained multiple turn-like features. Conclusion: Given the substantial evidence that oxidized phospholipids are pro-inflammatory in vivo, OxP-11D and othe