Showing papers by "University of Perugia published in 2011"
TL;DR: It is shown for the first time in humans that adoptive transfer of Tregs prevented GVHD in the absence of any posttransplantation immunosuppression, promoted lymphoid reconstitution, improved immunity to opportunistic pathogens, and did not weaken the graft-versus-leukemia effect.
982 citations
TL;DR: The BRAF V600E mutation was present in all patients with HCL who were evaluated, and may have implications for the pathogenesis, diagnosis, and targeted therapy of HCL.
Abstract: Background Hairy-cell leukemia (HCL) is a well-defined clinicopathological entity whose underlying genetic lesion is still obscure. Methods We searched for HCL-associated mutations by performing massively parallel sequencing of the whole exome of leukemic and matched normal cells purified from the peripheral blood of an index patient with HCL. Findings were validated by Sanger sequencing in 47 additional patients with HCL. Results Whole-exome sequencing identified five missense somatic clonal mutations that were confirmed on Sanger sequencing, including a heterozygous mutation in BRAF that results in the BRAF V600E variant protein. Since BRAF V600E is oncogenic in other tumors, further analyses were focused on this genetic lesion. The same BRAF mutation was noted in all the other 47 patients with HCL who were evaluated by means of Sanger sequencing. None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant, including 38 patients with spl...
861 citations
TL;DR: In this article, the transverse momentum balance in dijet and γ/Z+jets events is used to measure the jet energy response in the CMS detector, as well as the transversal momentum resolution.
Abstract: Measurements of the jet energy calibration and transverse momentum resolution in CMS are presented, performed with a data sample collected in proton-proton collisions at a centre-of-mass energy of 7TeV, corresponding to an integrated luminosity of 36pb−1. The transverse momentum balance in dijet and γ/Z+jets events is used to measure the jet energy response in the CMS detector, as well as the transverse momentum resolution. The results are presented for three different methods to reconstruct jets: a calorimeter-based approach, the ``Jet-Plus-Track'' approach, which improves the measurement of calorimeter jets by exploiting the associated tracks, and the ``Particle Flow'' approach, which attempts to reconstruct individually each particle in the event, prior to the jet clustering, based on information from all relevant subdetectors
750 citations
TL;DR: In this article, the authors studied the effect of collision centrality on the transverse momentum of PbPb collisions at the LHC with a data sample of 6.7 inverse microbarns.
Abstract: Jet production in PbPb collisions at a nucleon-nucleon center-of-mass energy of 2.76 TeV was studied with the CMS detector at the LHC, using a data sample corresponding to an integrated luminosity of 6.7 inverse microbarns. Jets are reconstructed using the energy deposited in the CMS calorimeters and studied as a function of collision centrality. With increasing collision centrality, a striking imbalance in dijet transverse momentum is observed, consistent with jet quenching. The observed effect extends from the lower cut-off used in this study (jet transverse momentum = 120 GeV/c) up to the statistical limit of the available data sample (jet transverse momentum approximately 210 GeV/c). Correlations of charged particle tracks with jets indicate that the momentum imbalance is accompanied by a softening of the fragmentation pattern of the second most energetic, away-side jet. The dijet momentum balance is recovered when integrating low transverse momentum particles distributed over a wide angular range relative to the direction of the away-side jet.
621 citations
TL;DR: This work presents a search for dark matter consisting of weakly interacting massive particles, applying a joint likelihood analysis to 10 satellite galaxies with 24 months of data of the Fermi Large Area Telescope, and is able to rule out models with the most generic cross section, using gamma rays.
Abstract: Satellite galaxies of the Milky Way are among the most promising targets for dark matter searches in gamma rays. We present a search for dark matter consisting of weakly interacting massive particl ...
602 citations
TL;DR: It is found that IDO was involved in intracellular signaling events responsible for the self-amplification and maintenance of a stably regulatory phenotype in pDCs and has a tonic, nonenzymic function that contributes to TGF-β-driven tolerance in noninflammatory contexts.
Abstract: Regulation of tryptophan metabolism by indoleamine 2,3-dioxygenase (IDO) in dendritic cells (DCs) is a highly versatile modulator of immunity. In inflammation, interferon-γ is the main inducer of IDO for the prevention of hyperinflammatory responses, yet IDO is also responsible for self-tolerance effects in the longer term. Here we show that treatment of mouse plasmacytoid DCs (pDCs) with transforming growth factor-β (TGF-β) conferred regulatory effects on IDO that were mechanistically separable from its enzymic activity. We found that IDO was involved in intracellular signaling events responsible for the self-amplification and maintenance of a stably regulatory phenotype in pDCs. Thus, IDO has a tonic, nonenzymic function that contributes to TGF-β-driven tolerance in noninflammatory contexts.
586 citations
TL;DR: The potential use of BDDCS to estimate the disposition characteristics of novel chemicals (new molecular entities) in the early stages of drug discovery and development and the influence of several measured and in silico parameters in the process of B DDCS category assignment is discussed in detail.
Abstract: Here, we compile the Biopharmaceutics Drug Disposition Classification System (BDDCS) classification for 927 drugs, which include 30 active metabolites. Of the 897 parent drugs, 78.8% (707) are administered orally. Where the lowest measured solubility is found, this value is reported for 72.7% (513) of these orally administered drugs and a dose number is recorded. The measured values are reported for percent excreted unchanged in urine, LogP, and LogD
7.4 when available. For all 927 compounds, the in silico parameters for predicted Log solubility in water, calculated LogP, polar surface area, and the number of hydrogen bond acceptors and hydrogen bond donors for the active moiety are also provided, thereby allowing comparison analyses for both in silico and experimentally measured values. We discuss the potential use of BDDCS to estimate the disposition characteristics of novel chemicals (new molecular entities) in the early stages of drug discovery and development. Transporter effects in the intestine and the liver are not clinically relevant for BDDCS class 1 drugs, but potentially can have a high impact for class 2 (efflux in the gut, and efflux and uptake in the liver) and class 3 (uptake and efflux in both gut and liver) drugs. A combination of high dose and low solubility is likely to cause BDDCS class 4 to be underpopulated in terms of approved drugs (N = 53 compared with over 200 each in classes 1–3). The influence of several measured and in silico parameters in the process of BDDCS category assignment is discussed in detail.
536 citations
TL;DR: ShRNA-mediated knockdown of EF-Tu mitochondrial translation factor in leukemic cells reproduced the antileukemia activity of tigecycline, derivative of mitochondrial biogenesis, which proved to be enhanced in AML versus normal hematopoietic cells and were also important for their difference in tIGecy Cline sensitivity.
530 citations
TL;DR: IGRAs may have a relative advantage over the TST in detecting LTBI and allow the exclusion of M. tuberculosis infection with higher reliability.
Abstract: We conducted a systematic review and meta-analysis to compare the accuracy of the QuantiFERON-TB® Gold In-Tube (QFT-G-IT) and the T-SPOT®.TB assays with the tuberculin skin test (TST) for the diagnosis of latent Mycobacterium tuberculosis infection (LTBI). The Medline, Embase and Cochrane databases were explored for relevant articles in November 2009. Specificities, and negative (NPV) and positive (PPV) predictive values of interferon-γ release assays (IGRAs) and the TST, and the exposure gradient influences on test results among bacille Calmette-Guerin (BCG) vaccinees were evaluated. Specificity of IGRAs varied 98-100%. In immunocompetent adults, NPV for progression to tuberculosis within 2 yrs were 97.8% for T-SPOT®.TB and 99.8% for QFT-G-IT. When test performance of an immunodiagnostic test was not restricted to prior positivity of another test, progression rates to tuberculosis among IGRA-positive individuals followed for 19-24 months varied 8-15%, exceeding those reported for the TST (2-3%). In multivariate analyses, the odd ratios for TST positivity following BCG vaccination varied 3-25, whereas IGRA results remained uninfluenced and IGRA positivity was clearly associated with exposure to contagious tuberculosis cases. IGRAs may have a relative advantage over the TST in detecting LTBI and allow the exclusion of M. tuberculosis infection with higher reliability.
478 citations
TL;DR: It is demonstrated that activation of TGR5 in macrophages by 6α-ethyl-23(S)-methylcholic acid (6-EMCA, INT-777), a semisynthetic BA, inhibits proinflammatory cytokine production, an effect mediated by T GR5-induced cAMP signaling and subsequent NF-κB inhibition.
446 citations
TL;DR: This mutant collection should facilitate a wide range of systematic studies aimed at understanding the functions of essential genes, including roles for cohesin and condensin genes in spindle disassembly.
Abstract: Conditional temperature-sensitive (ts) mutations are valuable reagents for studying essential genes in the yeast Saccharomyces cerevisiae. We constructed 787 ts strains, covering 497 (∼45%) of the 1,101 essential yeast genes, with ∼30% of the genes represented by multiple alleles. All of the alleles are integrated into their native genomic locus in the S288C common reference strain and are linked to a kanMX selectable marker, allowing further genetic manipulation by synthetic genetic array (SGA)-based, high-throughput methods. We show two such manipulations: barcoding of 440 strains, which enables chemical-genetic suppression analysis, and the construction of arrays of strains carrying different fluorescent markers of subcellular structure, which enables quantitative analysis of phenotypes using high-content screening. Quantitative analysis of a GFP-tubulin marker identified roles for cohesin and condensin genes in spindle disassembly. This mutant collection should facilitate a wide range of systematic studies aimed at understanding the functions of essential genes.
TL;DR: Two separate gamma-ray flares from a young and energetic pulsar powers the well-known Crab Nebula are described and it is suggested that the gamma rays were emitted via synchrotron radiation from peta–electron-volt electrons in a region smaller than 1.4 × 10−2 parsecs.
Abstract: A young and energetic pulsar powers the well-known Crab Nebula. Here, we describe two separate gamma-ray (photon energy greater than 100 mega-electron volts) flares from this source detected by the Large Area Telescope on board the Fermi Gamma-ray Space Telescope. The first flare occurred in February 2009 and lasted approximately 16 days. The second flare was detected in September 2010 and lasted approximately 4 days. During these outbursts, the gamma-ray flux from the nebula increased by factors of four and six, respectively. The brevity of the flares implies that the gamma rays were emitted via synchrotron radiation from peta-electron-volt (10(15) electron volts) electrons in a region smaller than 1.4 × 10(-2) parsecs. These are the highest-energy particles that can be associated with a discrete astronomical source, and they pose challenges to particle acceleration theory.
University of Gothenburg1, Tohoku University2, University of Rome Tor Vergata3, VU University Amsterdam4, Alzheimer's Association5, New York State Office for People With Developmental Disabilities6, Innogenetics7, University of Perugia8, Karolinska Institutet9, Washington University in St. Louis10, University of São Paulo11, University of California, San Diego12, University of Milan13, Goethe University Frankfurt14, Aarhus University15, University of Bonn16, Harvard University17, University of Eastern Finland18, Innsbruck Medical University19, University of Tübingen20, Heidelberg University21, National and Kapodistrian University of Athens22, Janssen Pharmaceutica23, University of Szeged24, Edith Cowan University25, University of Erlangen-Nuremberg26, University of Melbourne27, Johnson & Johnson28, Johns Hopkins University29, University of Washington30, University of Ulm31, Mayo Clinic32, Radboud University Nijmegen33, University of Pennsylvania34, University of Oslo35, University of Göttingen36
TL;DR: The cerebrospinal fluid biomarkers amyloid β (Aβ)‐42, total‐Tau (T‐tau), and phosphorylated‐t Tau (P‐tAU) demonstrate good diagnostic accuracy for Alzheimer's disease (AD), but there are large variations in biomarker measurements between studies, and between and within laboratories.
Abstract: Background
The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer’s disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer’s Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.
TL;DR: In fludarabine-refractory CLL, SF3B1 mutations and TP53 disruption distributed in a mutually exclusive fashion points to splicing regulation as a novel pathogenetic mechanism of potential clinical relevance in CLL.
TL;DR: Evidence is provided that stimulation-induced motor improvement was sustained overall at 10 years, although part of the initial benefit wore off mainly because of progressive loss of benefit on axial signs over time.
Abstract: Objective To assess the 10-year motor outcome of deep brain stimulation of the subthalamic nucleus (STN-DBS) in patients with Parkinson disease (PD). Design Patients with PD with bilateral STN-DBS were assessed according to the Core Assessment Program for Surgical Interventional Therapies in Parkinson's Disease protocol and videotaped at baseline and 1, 5, and 10 years after surgery. An independent rater blinded to stimulation and medication condition scored the 10-year video assessments. Setting Movement Disorders Centre, Toronto Western Hospital, University Health Network, University of Toronto. Patients Eighteen patients with advanced PD and 10-year follow-up of STN-DBS. Intervention Bilateral STN-DBS surgery. Main Outcome Measures The primary outcome was the change in blinded Unified Parkinson's Disease Rating Scale (UPDRS) motor scores/subscores between the no medication/stimulation condition vs the no medication/no stimulation condition at 10 years. Secondary outcomes were the changes in blinded UPDRS motor scores between the medication/no stimulation and medication/stimulation conditions, UPDRS II scores, UPDRS IV dyskinesia and motor fluctuations scores, and anti-PD medication dose (levodopa equivalent daily dose) at different points. Results In the 18 patients available for follow-up at 10 years, STN-DBS still significantly improved the UPDRS total motor score (P = .007) and resting and action tremor (P Conclusion This class III study provides evidence that stimulation-induced motor improvement was sustained overall at 10 years, although part of the initial benefit wore off mainly because of progressive loss of benefit on axial signs over time.
TL;DR: Filtration of purified NK cells is feasible in elderly patients with high-risk acute myeloid leukemia, and donor NK cells were shown in vivo by the detection of donor-derived NK clones that killed recipient's targets.
TL;DR: In this paper, the gamma-ray activity of the high-synchrotron-peaked BL Lacertae object Markarian 421 (Mrk 421) during the first 1.5 years of Fermi operation was reported.
Abstract: We report on the gamma-ray activity of the high-synchrotron-peaked BL Lacertae object Markarian 421 (Mrk 421) during the first 1.5 years of Fermi operation, from 2008 August 5 to 2010 March 12. We find that the Large Area Telescope (LAT) gamma-ray spectrum above 0.3 GeV can be well described by a power-law function with photon index Gamma = 1.78 +/- 0.02 and average photon flux F(>0.3 GeV) = (7.23 +/- 0.16) x 10(-8) ph cm(-2) s(-1). Over this time period, the Fermi-LAT spectrum above 0.3 GeV was evaluated on seven-day-long time intervals, showing significant variations in the photon flux (up to a factor similar to 3 from the minimum to the maximum flux) but mild spectral variations. The variability amplitude at X-ray frequencies measured by RXTE/ASM and Swift/BAT is substantially larger than that in gamma-rays measured by Fermi-LAT, and these two energy ranges are not significantly correlated. We also present the first results from the 4.5 month long multifrequency campaign on Mrk 421, which included the VLBA, Swift, RXTE, MAGIC, the F-GAMMA, GASP-WEBT, and other collaborations and instruments that provided excellent temporal and energy coverage of the source throughout the entire campaign (2009 January 19 to 2009 June 1). During this campaign, Mrk 421 showed a low activity at all wavebands. The extensive multi-instrument (radio to TeV) data set provides an unprecedented, complete look at the quiescent spectral energy distribution (SED) for this source. The broadband SED was reproduced with a leptonic (one-zone synchrotron self-Compton) and a hadronic model (synchrotron proton blazar). Both frameworks are able to describe the average SED reasonably well, implying comparable jet powers but very different characteristics for the blazar emission site.
TL;DR: This work directly observes a propagating spin wave launched from a spin torque oscillator with a nanoscale electrical contact into an extended Permalloy (nickel iron) film through the spin transfer torque effect, and shows that spin waves with tunable frequencies can propagate for several micrometres.
Abstract: Spin torque oscillators with nanoscale electrical contacts are able to produce coherent spin waves in extended magnetic films, and offer an attractive combination of electrical and magnetic field control, broadband operation, fast spin-wave frequency modulation, and the possibility of synchronizing multiple spin-wave injection sites. However, many potential applications rely on propagating (as opposed to localized) spin waves, and direct evidence for propagation has been lacking. Here, we directly observe a propagating spin wave launched from a spin torque oscillator with a nanoscale electrical contact into an extended Permalloy (nickel iron) film through the spin transfer torque effect. The data, obtained by wave-vector-resolved micro-focused Brillouin light scattering, show that spin waves with tunable frequencies can propagate for several micrometres. Micromagnetic simulations provide the theoretical support to quantitatively reproduce the results.
TL;DR: In this paper, the use of a commercial ionic liquid as a convenient solvent medium for graphite exfoliation in mild and easy conditions without any chemical modification is presented, and it is noteworthy that, by gravimetric analysis, a graphene concentration as high as 5.33 mg ml−1 was determined.
Abstract: In the present work, the use of a commercial ionic liquid as a convenient solvent medium for graphite exfoliation in mild and easy conditions without any chemical modification is presented. To confirm the presence of few layer graphene, its dispersion, which exhibits Tyndall effect, was characterized by Raman and UV spectroscopies, and atomic force and field emission electron microscopies. It is noteworthy that, by gravimetric analysis, a graphene concentration as high as 5.33 mg ml−1 was determined, which is the highest value reported so far in any solvent.
University of Washington1, National Institutes of Health2, University of Minnesota3, University of Virginia4, University of Texas Health Science Center at Houston5, University of Alabama at Birmingham6, University of New Mexico7, Duke University8, University of Perugia9, University of Auckland10, Group Health Cooperative11, Cedars-Sinai Medical Center12, Hebrew University of Jerusalem13, Veterans Health Administration14, University of Western Australia15, Erasmus University Rotterdam16, Harvard University17
TL;DR: It is shown that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n- 3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.
Abstract: Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3×10−64) and lower levels of eicosapentaenoic acid (EPA, p = 5×10−58) and docosapentaenoic acid (DPA, p = 4×10−154). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2×10−12) and DPA (p = 1×10−43) and lower docosahexaenoic acid (DHA, p = 1×10−15). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1×10−8). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.
TL;DR: Potentially inappropriate drug prescribing and the omission of beneficial drugs are highly prevalent in acutely ill hospitalized older people in six European centres.
Abstract: Purpose
Potentially inappropriate prescribing is common in older people presenting to hospital with acute illness in Ireland. The aim of this study was to determine if this phenomenon is unique to Ireland or whether it is a more widespread problem in hospitals across Europe.
TL;DR: It is demonstrated that a synthetic genetic element, consisting of mosquito regulatory regions and the homing endonuclease gene I-SceI, can substantially increase its transmission to the progeny in transgenic mosquitoes of the human malaria vector Anopheles gambiae.
Abstract: Genetic approaches to manipulating or eradicating disease vectors have been proposed as alternatives to malaria eradication. The success of this approach depends on efficient spread of a genetic modification in field populations. Windbichler et al. show that a synthetic genetic element consisting of mosquito regulatory elements and the homing endonuclease gene I-SceI can spread from a small number of individual Anopheles gambiae mosquitoes into large receptive populations in just a few generations. This is the first demonstration of a synthetic gene drive system in the main human malaria vector — and a similar approach should be applicable to many other pest species. Genetic methods of manipulating or eradicating disease vector populations have long been discussed as an attractive alternative to existing control measures because of their potential advantages in terms of effectiveness and species specificity1,2,3. The development of genetically engineered malaria-resistant mosquitoes has shown, as a proof of principle, the possibility of targeting the mosquito’s ability to serve as a disease vector4,5,6,7. The translation of these achievements into control measures requires an effective technology to spread a genetic modification from laboratory mosquitoes to field populations8. We have suggested previously that homing endonuclease genes (HEGs), a class of simple selfish genetic elements, could be exploited for this purpose9. Here we demonstrate that a synthetic genetic element, consisting of mosquito regulatory regions10 and the homing endonuclease gene I-SceI11,12,13, can substantially increase its transmission to the progeny in transgenic mosquitoes of the human malaria vector Anopheles gambiae. We show that the I-SceI element is able to invade receptive mosquito cage populations rapidly, validating mathematical models for the transmission dynamics of HEGs. Molecular analyses confirm that expression of I-SceI in the male germline induces high rates of site-specific chromosomal cleavage and gene conversion, which results in the gain of the I-SceI gene, and underlies the observed genetic drive. These findings demonstrate a new mechanism by which genetic control measures can be implemented. Our results also show in principle how sequence-specific genetic drive elements like HEGs could be used to take the step from the genetic engineering of individuals to the genetic engineering of populations.
TL;DR: This review has mainly considered the findings from general population studies and studies on clinical samples, in adults and children, focusing on the association between migraine and psychiatric disorders (axis I of the DSM), carried over after the first classification of IHS (1988).
Abstract: Migraine is an extremely common disorder. The underlying mechanisms of this chronic illness interspersed with acute symptoms appear to be increasingly complex. An important aspect of migraine heterogeneity is comorbidity with other neurological diseases, cardiovascular disorders, and psychiatric illnesses. Depressive disorders are among the leading causes of disability worldwide according to WHO estimation. In this review, we have mainly considered the findings from general population studies and studies on clinical samples, in adults and children, focusing on the association between migraine and psychiatric disorders (axis I of the DSM), carried over after the first classification of IHS (1988). Though not easily comparable due to differences in methodology to reach diagnosis, general population studies generally indicate an increased risk of affective and anxiety disorders in patients with migraine, compared to non-migrainous subjects. There would also be a trend towards an association of migraine with bipolar disorder, but not with substance abuse/dependence. With respect to migraine subtypes, comorbidity mainly involves migraine with aura. Patients suffering from migraine, however, show a decreased risk of developing affective and anxiety disorders compared to patients with daily chronic headache. It would also appear that psychiatric disorders prevail in patients with chronic headache and substance use than in patients with simple migraine. The mechanisms underlying migraine psychiatric comorbidity are presently poorly understood, but this topic remains a priority for future research. Psychiatric comorbidity indeed affects migraine evolution, may lead to chronic substance use, and may change treatment strategies, eventually modifying the outcome of this important disorder.
TL;DR: Four-dimensional ultrasound has been used to assess Kurjak antenatal neurodevelopmental test (KANET) in low- and high-risk pregnancies after randomization in prospective longitudinal cohort study and it has the potential to detect and discriminate normal from borderline and abnormal fetal behavior in normal and in high- risk pregnancies.
Abstract: Objective. To assess differences of fetal behavior in normal and high-risk pregnancies.Methods. In the 1-year period (1 January 2007–31 December 2007), four-dimensional ultrasound has been used to assess Kurjak antenatal neurodevelopmental test (KANET) in low- and high-risk pregnancies after randomization in prospective longitudinal cohort study. Based on the KANET scores, the fetuses were considered as normal (≥14 points), borderline (6–13), or abnormal (0–5).Results. Comparison of KANET scores in low- and high-risk pregnancies were expectedly statistically significant. The largest incidence of fetuses with abnormal KANET was in the group of fetuses who had siblings with cerebral palsy. The largest incidence of the borderline KANET has been found in the group of fetuses whose mothers had fever during pregnancy. The following parameters of KANET test significantly differed between the fetuses from low- and high-risk pregnancies: overlapping cranial sutures, head circumference, isolated eye blinking, facia...
TL;DR: In this paper, the Fermi Large Area Telescope (LAT) was used to detect a source positionally coincident with the young supernova remnant (SNR) RX J1713.7-3946.
Abstract: We present observations of the young Supernova remnant (SNR) RX J1713.7-3946 with the Fermi Large Area Telescope (LAT). We clearly detect a source positionally coincident with the SNR. The source is extended with a best-fit extension of 0.55$^{\circ} \pm 0.04^{\circ}$ matching the size of the non-thermal X-ray and TeV gamma-ray emission from the remnant. The positional coincidence and the matching extended emission allows us to identify the LAT source with the supernova remnant RX J1713.7-3946. The spectrum of the source can be described by a very hard power-law with a photon index of $\Gamma = 1.5 \pm 0.1$ that coincides in normalization with the steeper H.E.S.S.-detected gamma-ray spectrum at higher energies. The broadband gamma-ray emission is consistent with a leptonic origin as the dominant mechanism for the gamma-ray emission.
TL;DR: GP-BAR1 regulates intestinal barrier structure and expression increases in rodent models of colitis and Crohn's disease and ciprofloxacin is a GP-Bar1 ligand.
Abstract: Background
GP-BAR1, a member G protein coupled receptor superfamily, is a cell surface bile acid-activated receptor highly expressed in the ileum and colon. In monocytes, ligation of GP-BAR1 by secondary bile acids results in a cAMP-dependent attenuation of cytokine generation.
Aims
To investigate the role GP-BAR1 in regulating intestinal homeostasis and inflammation-driven immune dysfunction in rodent models of colitis.
Methods
Colitis was induced in wild type and GP-BAR1−/− mice by DSS and TNBS administration. Potential GP-BAR1 agonists were identified by in silico screening and computational docking studies.
Results
GP-BAR1−/− mice develop an abnormal morphology of colonic mucous cells and an altered molecular architecture of epithelial tight junctions with increased expression and abnormal subcellular distribution of zonulin 1 resulting in increased intestinal permeability and susceptibility to develop severe colitis in response to DSS at early stage of life. By in silico screening and docking studies we identified ciprofloxacin as a GP-BAR1 ligand. In monocytes, ciprofloxacin increases cAMP concentrations and attenuates TNFα release induced by TLR4 ligation in a GP-BAR1 dependent manner. Treating mice rendered colitic by TNBS with ciprofloxacin and oleanolic acid, a well characterized GP-BAR1 ligand, abrogates signs and symptoms of colitis. Colonic expression of GP-BAR1 mRNA increases in rodent models of colitis and tissues from Crohn's disease patients. Flow cytometry analysis demonstrates that ≈90% of CD14+ cells isolated from the lamina propria of TNBS-treated mice stained positively for GP-BAR1.
Conclusions
GP-BAR1 regulates intestinal barrier structure. Its expression increases in rodent models of colitis and Crohn's disease. Ciprofloxacin is a GP-BAR1 ligand.
TL;DR: In this paper, a search for events with jets and missing transverse energy is performed in a data sample of pp collisions collected at 7 TeV by the CMS experiment at the LHC.
Abstract: A search for events with jets and missing transverse energy is performed in a data sample of pp collisions collected at sqrt(s) = 7 TeV by the CMS experiment at the LHC. The analyzed data sample corresponds to an integrated luminosity of 1.14 inverse femtobarns. In this search, a kinematic variable, alphaT, is used as the main discriminator between events with genuine and misreconstructed missing transverse energy. No excess of events over the standard model expectation is found. Exclusion limits in the parameter space of the constrained minimal supersymmetric extension of the standard model are set. In this model, squark masses below 1.1 TeV are excluded at 95% CL. Gluino masses below 1.1 TeV are also ruled out at 95% CL for values of the universal scalar mass parameter below 500 GeV.
TL;DR: In this paper, a population pharmacokinetic model was developed using plasma samples from these patients and various simulations were conducted to explore the pharmacokinetics of rivaroxaban in patients with DVT and to predict exposure in those with atrial fibrillation.
Abstract: Background and objective Rivaroxaban is an oral, direct Factor Xa inhibitor, which is at an advanced stage of clinical development for prevention and treatment of thromboembolic disorders. Two phase II studies, ODIXa-DVT and EINSTEIN DVT, assessed the efficacy and safety of oral rivaroxaban (once daily or twice daily) for treatment of acute deep-vein thrombosis (DVT). Population pharmacokinetic and pharmacodynamic analyses of rivaroxaban in patients in these two phase II studies were conducted to characterize the pharmacokinetics/pharmacodynamics of rivaroxaban and the relationship between important patient covariates and model parameters. Exposure simulations in patients with atrial fibrillation (AF) were also performed in order to predict the exposure of rivaroxaban, using modified demographic data reflecting the characteristics of a typical AF population. Methods A population pharmacokinetic model was developed using plasma samples from these patients. Various simulations were conducted to explore the pharmacokinetics of rivaroxaban in patients with DVT and to predict exposure in those with AF. Correlations between plasma rivaroxaban concentrations and the prothrombin time, Factor Xa activity, HepTest® and activated partial thromboplastin time were also described. Results The pharmacokinetics of rivaroxaban in patients with DVT were found to be consistent and predictable across all doses studied. The area under the plasma concentration-time curve (AUC) increased dose dependently. The same total daily doses given once daily achieved higher maximum plasma concentration (C(max)) values (∼20%) and lower trough (minimum) plasma concentration (C(trough)) values (∼60%) than when given twice daily; however, the 5th-95th percentile ranges for these parameters overlapped. Rivaroxaban clearance was moderately influenced by age and renal function, and the volume of distribution was influenced by age, body weight and sex; the effects were within the observed interindividual variability. Simulations in virtual patient populations with AF showed that a rivaroxaban dose of 15 mg once daily in patients with creatinine clearance of 30-49 mL/min would achieve AUC and C(max) values similar to those observed with 20 mg once daily in patients with normal renal function. The prothrombin time correlated almost linearly with plasma rivaroxaban concentrations (≤500 μg/L). Conclusion Population analyses of phase II clinical data indicated that the pharmacokinetics and pharmacodynamics of all rivaroxaban doses were predictable and were affected by expected demographic factors in patients with acute DVT.
TL;DR: Despite the recommendations of national and international regulatory agencies, exclusion of older individuals from ongoing trials regarding heart failure continues to be widespread.
Abstract: Methods: In the context of the Increasing the PaRticipation of the ElDerly in Clinical Trials (PREDICT) study, data from ongoing clinical trials regarding heart failure were extracted from the World Health Organization Clinical Trials Registry Platform on December 1, 2008. Main outcome measures were the proportion of trials excluding patients by an arbitrary upper age limit or by other exclusion criteria that might indirectly cause limited recruitment of older individuals. We classified exclusion criteria into 2 categories: justified or poorly justified. Results: Among 251 trials investigating treatments for heart failure, 64 (25.5%) excluded patients by an arbitrary upper age limit. Such exclusion was significantly more common in trials conducted in the European Union than in the United States (31/96 [32.3%] vs 17/105 [16.2%];P=.007) and in drug trials sponsored by public institutions vs those by private entities (21/59 [35.6%] vs 5/36 [13.9%];P=.02). Overall, 109 trials (43.4%) on heart failure had 1 or more poorly justified exclusion criteria that could limit the inclusion of older individuals. A similar proportion of clinical trials with poorly justified exclusion criteria was found in pharmacologic and nonpharmacologic trials. Conclusion: Despite the recommendations of national and international regulatory agencies, exclusion of older individuals from ongoing trials regarding heart failure continues to be widespread.
TL;DR: In this article, BIRC3, a negative regulator of noncanonical NF-κB signaling, was investigated in different chronic lymphocytic leukemia (CLL) clinical phases.