769 research outputs found

    ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion

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    Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal survival rate. Persistent activation of pancreatic stellate cells (PSCs) can perturb the biomechanical homoeostasis of the tumour microenvironment to favour cancer cell invasion. Here we report that ATRA, an active metabolite of vitamin A, restores mechanical quiescence in PSCs via a mechanism involving a retinoic acid receptor beta (RAR-ÎČ)-dependent downregulation of actomyosin (MLC-2) contractility. We show that ATRA reduces the ability of PSCs to generate high traction forces and adapt to extracellular mechanical cues (mechanosensing), as well as suppresses force-mediated extracellular matrix remodelling to inhibit local cancer cell invasion in 3D organotypic models. Our findings implicate a RAR-ÎČ/MLC-2 pathway in peritumoural stromal remodelling and mechanosensory-driven activation of PSCs, and further suggest that mechanical reprogramming of PSCs with retinoic acid derivatives might be a viable alternative to stromal ablation strategies for the treatment of PDAC

    Mechanical Translation

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    Contains research objectives and reports on two research objectives.National Science Foundation (Grant GN-244

    Evaluation of data-based estimates of anthropogenic carbon in the Arctic Ocean

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    The Arctic Ocean is particularly vulnerable to ocean acidification, a process that is mainly driven by the uptake of anthropogenic carbon (Cant) from the atmosphere. Although Cant concentrations cannot be measured directly in the ocean, they have been estimated using data-based methods such as the transient time distribution (TTD) approach, which characterizes the ventilation of water masses with inert transient tracers, such as CFC-12. Here, we evaluate the TTD approach in the Arctic Ocean using an eddying ocean model as a test bed. When the TTD approach is applied to simulated CFC-12 in that model, it underestimates the same model's directly simulated Cant concentrations by up to 12%, a bias that stems from its idealized assumption of gas equilibrium between atmosphere and surface water, both for CFC-12 and anthropogenic CO2. Unlike the idealized assumption, the simulated partial pressure of CFC-12 (pCFC-12) in Arctic surface waters is undersaturated relative to that in the atmosphere in regions and times of deep-water formation, while the simulated equivalent for Cant is supersaturated. After accounting for the TTD approach's negative bias, the total amount of Cant in the Arctic Ocean in 2005 increases by 8% to 3.3 ± 0.3 Pg C. By combining the adjusted TTD approach with scenarios of future atmospheric CO2, it is estimated that all Arctic waters, from surface to depth, would become corrosive to aragonite by the middle of the next century even if atmospheric CO2 could be stabilized at 540 ppm

    On the Linearization of the First and Second Painleve' Equations

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    We found Fuchs--Garnier pairs in 3X3 matrices for the first and second Painleve' equations which are linear in the spectral parameter. As an application of our pairs for the second Painleve' equation we use the generalized Laplace transform to derive an invertible integral transformation relating two its Fuchs--Garnier pairs in 2X2 matrices with different singularity structures, namely, the pair due to Jimbo and Miwa and the one found by Harnad, Tracy, and Widom. Together with the certain other transformations it allows us to relate all known 2X2 matrix Fuchs--Garnier pairs for the second Painleve' equation with the original Garnier pair.Comment: 17 pages, 2 figure

    Effects of Baseline Left Ventricular Hypertrophy and Decreased Renal Function on Cardiovascular and Renal Outcomes in Patients with Fabry Disease Treated with Agalsidase Alfa: A Fabry Outcome Survey Study

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    PURPOSE: The initiation of enzyme-replacement therapy prior to the occurrence of substantial and irreversible organ damage in patients with Fabry disease is of critical importance. The Fabry Outcome Survey is an international disease registry of patients with a confirmed diagnosis of Fabry disease. In this study, data from the Fabry Outcome Survey were used for the assessment of the risks for cardiovascular and renal events in patients who received agalsidase alfa treatment. METHODS: Eligible patients were males and females aged ≄18 years with Fabry disease treated with agalsidase alfa. Cardiovascular events included myocardial infarction, left ventricular hypertrophy (LVH), heart failure, arrhythmia, conduction abnormality, and cardiac surgery. Renal events included dialysis, transplantation, and renal failure. Kaplan-Meier curves and log-rank tests were used for comparing event-free probabilities and time to first cardiovascular or renal event, from agalsidase alfa initiation to a maximum of 120 months, in patients with LVH versus normal left ventricular mass index (LVMI; ≀50 g/m2.7 in males and ≀48 g/m2.7 in females) at treatment initiation (baseline), and in patients with a low estimated glomerular filtration rate (eGFR; <90 mL/min/1.73 m2) versus normal eGFR at baseline. Multivariate Cox regression analysis was used for examining the association between key study variables and the risks for cardiovascular and renal events. FINDINGS: Among the 560 patients (269 males; 291 females) with available LVMI data, 306 (55%) had LVH and 254 (45%) had normal LVMI at baseline. The risk for a cardiovascular event was higher in the subgroup with LVH versus normal LVMI at baseline (hazard ratio [HR] = 1.57; 95% CI, 1.21-2.05; P < 0.001), but the risk for a renal event was similar between the 2 subgroups (HR = 1.90; 95% CI, 0.94-3.85; P = 0.074). Among the 1093 patients (551 males; 542 females) with available eGFR data, 433 (40%) had a low eGFR and 660 (60%) had a normal eGFR at baseline. The subgroup with a low eGFR at baseline had a significantly higher risk for a cardiovascular event (HR = 1.33; 95% CI, 1.04-1.70; P = 0.021) or a renal event (HR = 5.88; 95% CI, 2.73-12.68; P < 0.001) compared with patients with a normal eGFR at baseline. IMPLICATIONS: In the present study, the presence of LVH and/or reduced renal function at agalsidase alfa initiation was associated with a significantly higher risk for a cardiovascular or renal event, indicating that cardiovascular and renal pathologies in Fabry disease may be inter-related. Early initiation of agalsidase alfa treatment prior to the onset of severe organ damage may improve outcomes. ClinicalTrials.gov identifier: NCT03289065

    Quasi-free photoproduction of eta-mesons of the neutron

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    Quasi-free photoproduction of eta-mesons off nucleons bound in the deuteron has been measured with the CBELSA/TAPS detector for incident photon energies up to 2.5 GeV at the Bonn ELSA accelerator. The eta-mesons have been detected in coincidence with recoil protons and recoil neutrons, which allows a detailed comparison of the quasi-free n(gamma,eta)n and p(gamma,eta)p reactions. The excitation function for eta-production off the neutron shows a pronounced bump-like structure at W=1.68 GeV (E_g ~ 1 GeV), which is absent for the proton.Comment: accepted for publication in Phys. Rev. Let

    K^0 pi^0 Sigma^+ and K^*0 Sigma^+ photoproduction off the proton

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    The exclusive reactions Îłp→K∗0ÎŁ+(1189)\gamma p \to K^{*0} \Sigma^+(1189) and Îłp→K0π0ÎŁ+(1189)\gamma p \to K^{0} \pi^{0}\Sigma^+(1189), leading to the p 4π0\pi^{0} final state, have been measured with a tagged photon beam for incident energies from threshold up to 2.5 GeV. The experiment has been performed at the tagged photon facility of the ELSA accelerator (Bonn). The Crystal Barrel and TAPS detectors were combined to a photon detector system of almost 4π\pi geometrical acceptance. Differential and total cross sections are reported. At energies close to the threshold, a flat angular distribution has been observed for the reaction Îłp→K0π0ÎŁ+\gamma p\to K^{0} \pi^{0}\Sigma^+ suggesting dominant s-channel production. Σ∗(1385)\Sigma^*(1385) and higher lying hyperon states have been observed. An enhancement in the forward direction in the angular distributions of the reaction Îłp→K∗0ÎŁ+\gamma p \to K^{*0}\Sigma^+ indicates a tt-channel exchange contribution to the reaction mechanism. The experimental data are in reasonable agreement with recent theoretical predictions.Comment: 11 pages, 13 figures, submitted to EPJ

    Photoproduction of pi0 omega off protons for E(gamma) < 3 GeV

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    Differential and total cross-sections for photoproduction of gamma proton to proton pi0 omega and gamma proton to Delta+ omega were determined from measurements of the CB-ELSA experiment, performed at the electron accelerator ELSA in Bonn. The measurements covered the photon energy range from the production threshold up to 3GeV.Comment: 8 pages, 13 figure

    In-medium ω\omega mass from the Îł+Nb→π0Îł+X\gamma + Nb \to \pi^{0}\gamma + X reaction

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    Data on the photoproduction of ω\omega mesons on nuclei have been re-analyzed in a search for in-medium modifications. The data were taken with the Crystal Barrel(CB)/TAPS detector system at the ELSA accelerator facility in Bonn. First results from the analysis of the data set were published by D. Trnka et al. in Phys. Rev. Lett 94 (2005) 192303 \cite{david}, claiming a lowering of the ω\omega mass in the nuclear medium by 14% at normal nuclear matter density. The extracted ω\omega line shape was found to be sensitive to the background subtraction. For this reason a re-analysis of the same data set has been initiated and a new method has been developed to reduce the background and to determine the shape and absolute magnitude of the background directly from the data. Details of the re-analysis and of the background determination are described. The ω\omega signal on the NbNb target, extracted in the re-analysis, does not show a deviation from the corresponding line shape on a LH2LH_2 target, measured as reference. The earlier claim of an in-medium mass shift is thus not confirmed. The sensitivity of the ω\omega line shape to different in-medium modification scenarios is discussed.Comment: 13 pages and 11 figures, submitted for publicatio
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