1,771 research outputs found

    Orally active antischistosomal early leads identified from the open access malaria box.

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    BACKGROUND: Worldwide hundreds of millions of schistosomiasis patients rely on treatment with a single drug, praziquantel. Therapeutic limitations and the threat of praziquantel resistance underline the need to discover and develop next generation drugs. METHODOLOGY: We studied the antischistosomal properties of the Medicines for Malaria Venture (MMV) malaria box containing 200 diverse drug-like and 200 probe-like compounds with confirmed in vitro activity against Plasmodium falciparum. Compounds were tested against schistosomula and adult Schistosoma mansoni in vitro. Based on in vitro performance, available pharmacokinetic profiles and toxicity data, selected compounds were investigated in vivo. PRINCIPAL FINDINGS: Promising antischistosomal activity (IC50: 1.4-9.5 ”M) was observed for 34 compounds against schistosomula. Three compounds presented IC50 values between 0.8 and 1.3 ”M against adult S. mansoni. Two promising early leads were identified, namely a N,N'-diarylurea and a 2,3-dianilinoquinoxaline. Treatment of S. mansoni infected mice with a single oral 400 mg/kg dose of these drugs resulted in significant worm burden reductions of 52.5% and 40.8%, respectively. CONCLUSIONS/SIGNIFICANCE: The two candidates identified by investigating the MMV malaria box are characterized by good pharmacokinetic profiles, low cytotoxic potential and easy chemistry and therefore offer an excellent starting point for antischistosomal drug discovery and development

    Trial protocol: a multicentre randomised trial of first-line treatment pathways for newly diagnosed immune thrombocytopenia: standard steroid treatment versus combined steroid and mycophenolate. The FLIGHT trial

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    Introduction Immune thrombocytopenia (ITP) is an autoimmune condition that may cause thrombocytopenia-related bleeding. Current first-line ITP treatment is with high-dose corticosteroids but frequent side effects, heterogeneous responses and high relapse rates are significant problems with only 20% remaining in sustained remission with this approach. Mycophenolate mofetil (MMF) is often used as the next treatment with efficacy in 50%–80% of patients and good tolerability but can take up to 2 months to work. Objective To test the hypothesis that MMF combined with corticosteroid is a more effective first-line treatment for immune thrombocytopenia (ITP) than current standard of corticosteroid alone. Design Multicentre, UK-based, open-label, randomised controlled trial. Setting Haematology departments in secondary care. Participants We plan to recruit 120 patients >16 years old with a diagnosis of ITP and a platelet count <30x109/L who require first-line treatment. Patients will be followed up for a minimum of 12 months following randomisation. Primary outcome Time from randomisation to treatment failure defined as platelets <30x109/L and a need for second-line treatment. Secondary outcomes Side effects, bleeding events, remission rates, time to relapse, time to next therapy, cumulative corticosteroid dose, rescue therapy, splenectomy, socioeconomic costs, patient-reported outcomes (quality of life, fatigue, impact of bleeding, care costs). Analysis The sample size of 120 achieves a 91.5% power to detect a doubling of the median time to treatment failure from 5 to 10 months. This will be expressed as an HR with 95% CI, median time to event if more than 50% have had an event and illustrated with Kaplan-Meier curves. Cost-effectiveness will be based on the first 12 months from diagnosis

    Responding to the Call: Building a Training Program to Diversify the Academy in Alzheimer’s Disease Research

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    Alzheimer\u27s disease and related dementias (ADRD) are at the forefront of the United States (US) public health agenda due to their tremendous human and financial burden. Further, disproportionately high ADRD rates among racial/ethnic minorities require incorporating the unique perspectives of racially and ethnically diverse scientists, which will necessitate diversifying the scientific workforce that investigates disparities in aging. The purpose of this paper is to describe the training and mentorship initiatives of the National Institute on Aging (NIA)-funded Carolina Center on Alzheimer\u27s Disease and Minority Research, emphasizing lessons learned from our engagement with underrepresented minority and minoritized (URM) Scientists. We highlight three aims of the Center\u27s training and mentorship component: (1) Fund pilot projects for URM Scientists conducting research on sociocultural, behavioral, and environmental factors that influence ADRD-related health disparities; (2) Provide mentorship to build the research capacity of Center Scientists; and (3) Offer research education in Health Disparities and Minority Aging Research to Center Scientists and interested researchers at all partner institutions. Our experience may be a practical resource for others developing interdisciplinary training programs to increase the pipeline of URM Scientists conducting ADRD research

    Multinucleon emission following the pion absorption in N, Ar and Xe

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    Positive pion absorption was studied in an almost 4p geometry allowing simultaneous measurements of various charge and neutral multiplicities. Total absorption cross sections and its decomposition into the most important channels is determined. The results are presented for N, Ar and Xe nuclei at incident pion energies of 118,162 and 239 MeV. The role of multinucleon emission in the absorption process is emphasized

    Pion absorption in ^4He

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    This paper presents a large solid angle measurement of the positive pion absorption cross section on ^4He and its decomposition into partial channels. A large fraction of the absorption cross section at incident pion kinetic energies of T_π+ =70, 118, 162, 239, and 330 MeV is due to multinucleon channels

    Multinucleon emission following the pion absorption in N, Ar and Xe

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    Positive pion absorption was studied in an almost 4p geometry allowing simultaneous measurements of various charge and neutral multiplicities. Total absorption cross sections and its decomposition into the most important channels is determined. The results are presented for N, Ar and Xe nuclei at incident pion energies of 118,162 and 239 MeV. The role of multinucleon emission in the absorption process is emphasized

    Energy Resolution Performance of the CMS Electromagnetic Calorimeter

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    The energy resolution performance of the CMS lead tungstate crystal electromagnetic calorimeter is presented. Measurements were made with an electron beam using a fully equipped supermodule of the calorimeter barrel. Results are given both for electrons incident on the centre of crystals and for electrons distributed uniformly over the calorimeter surface. The electron energy is reconstructed in matrices of 3 times 3 or 5 times 5 crystals centred on the crystal containing the maximum energy. Corrections for variations in the shower containment are applied in the case of uniform incidence. The resolution measured is consistent with the design goals

    Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

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    Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio
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