1,355 research outputs found

    The novel CXCR4 antagonist POL5551 mobilizes hematopoietic stem and progenitor cells with greater efficiency than Plerixafor

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    Mobilized blood has supplanted bone marrow (BM) as the primary source of hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Pharmacologically enforced egress of hematopoietic stem cells from BM, or mobilization, has been achieved by directly or indirectly targeting the CXCL12/CXCR4 axis. Shortcomings of the standard mobilizing agent, granulocyte colony-stimulating factor (G-CSF), administered alone or in combination with the only approved CXCR4 antagonist, Plerixafor, continue to fuel the quest for new mobilizing agents. Using Protein Epitope Mimetics technology, a novel peptidic CXCR4 antagonist, POL5551, was developed. In vitro data presented herein indicate high affinity to and specificity for CXCR4. POL5551 exhibited rapid mobilization kinetics and unprecedented efficiency in C57BL/6 mice, exceeding that of Plerixafor and at higher doses also of G-CSF. POL5551-mobilized stem cells demonstrated adequate transplantation properties. In contrast to G-CSF, POL5551 did not induce major morphological changes in the BM of mice. Moreover, we provide evidence of direct POL5551 binding to hematopoietic stem and progenitor cells (HSPCs) in vivo, strengthening the hypothesis that CXCR4 antagonists mediate mobilization by direct targeting of HSPCs. In summary, POL5551 is a potent mobilizing agent for HSPCs in mice with promising therapeutic potential if these data can be orroborated in humans

    Association of Trauma Molecular Endotypes With Differential Response to Transfusion Resuscitation Strategies

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    IMPORTANCE: It is not clear which severely injured patients with hemorrhagic shock may benefit most from a 1:1:1 vs 1:1:2 (plasma:platelets:red blood cells) resuscitation strategy. Identification of trauma molecular endotypes may reveal subgroups of patients with differential treatment response to various resuscitation strategies. OBJECTIVE: To derive trauma endotypes (TEs) from molecular data and determine whether these endotypes are associated with mortality and differential treatment response to 1:1:1 vs 1:1:2 resuscitation strategies. DESIGN, SETTING, AND PARTICIPANTS: This was a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized clinical trial. The study cohort included individuals with severe injury from 12 North American trauma centers. The cohort was taken from the participants in the PROPPR trial who had complete plasma biomarker data available. Study data were analyzed on August 2, 2021, to October 25, 2022. EXPOSURES: TEs identified by K-means clustering of plasma biomarkers collected at hospital arrival. MAIN OUTCOMES AND MEASURES: An association between TEs and 30-day mortality was tested using multivariable relative risk (RR) regression adjusting for age, sex, trauma center, mechanism of injury, and injury severity score (ISS). Differential treatment response to transfusion strategy was assessed using an RR regression model for 30-day mortality by incorporating an interaction term for the product of endotype and treatment group adjusting for age, sex, trauma center, mechanism of injury, and ISS. RESULTS: A total of 478 participants (median [IQR] age, 34.5 [25-51] years; 384 male [80%]) of the 680 participants in the PROPPR trial were included in this study analysis. A 2-class model that had optimal performance in K-means clustering was found. TE-1 (n = 270) was characterized by higher plasma concentrations of inflammatory biomarkers (eg, interleukin 8 and tumor necrosis factor α) and significantly higher 30-day mortality compared with TE-2 (n = 208). There was a significant interaction between treatment arm and TE for 30-day mortality. Mortality in TE-1 was 28.6% with 1:1:2 treatment vs 32.6% with 1:1:1 treatment, whereas mortality in TE-2 was 24.5% with 1:1:2 treatment vs 7.3% with 1:1:1 treatment (P for interaction = .001). CONCLUSIONS AND RELEVANCE: Results of this secondary analysis suggest that endotypes derived from plasma biomarkers in trauma patients at hospital arrival were associated with a differential response to 1:1:1 vs 1:1:2 resuscitation strategies in trauma patients with severe injury. These findings support the concept of molecular heterogeneity in critically ill trauma populations and have implications for tailoring therapy for patients at high risk for adverse outcomes

    Regulation of neutrophil senescence by microRNAs

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    Neutrophils are rapidly recruited to sites of tissue injury or infection, where they protect against invading pathogens. Neutrophil functions are limited by a process of neutrophil senescence, which renders the cells unable to respond to chemoattractants, carry out respiratory burst, or degranulate. In parallel, aged neutrophils also undergo spontaneous apoptosis, which can be delayed by factors such as GMCSF. This is then followed by their subsequent removal by phagocytic cells such as macrophages, thereby preventing unwanted inflammation and tissue damage. Neutrophils translate mRNA to make new proteins that are important in maintaining functional longevity. We therefore hypothesised that neutrophil functions and lifespan might be regulated by microRNAs expressed within human neutrophils. Total RNA from highly purified neutrophils was prepared and subjected to microarray analysis using the Agilent human miRNA microarray V3. We found human neutrophils expressed a selected repertoire of 148 microRNAs and that 6 of these were significantly upregulated after a period of 4 hours in culture, at a time when the contribution of apoptosis is negligible. A list of predicted targets for these 6 microRNAs was generated from http://mirecords.biolead.org and compared to mRNA species downregulated over time, revealing 83 genes targeted by at least 2 out of the 6 regulated microRNAs. Pathway analysis of genes containing binding sites for these microRNAs identified the following pathways: chemokine and cytokine signalling, Ras pathway, and regulation of the actin cytoskeleton. Our data suggest that microRNAs may play a role in the regulation of neutrophil senescence and further suggest that manipulation of microRNAs might represent an area of future therapeutic interest for the treatment of inflammatory disease

    Performance of the LHCb vertex locator

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    The Vertex Locator (VELO) is a silicon microstrip detector that surrounds the proton-proton interaction region in the LHCb experiment. The performance of the detector during the first years of its physics operation is reviewed. The system is operated in vacuum, uses a bi-phase CO2 cooling system, and the sensors are moved to 7 mm from the LHC beam for physics data taking. The performance and stability of these characteristic features of the detector are described, and details of the material budget are given. The calibration of the timing and the data processing algorithms that are implemented in FPGAs are described. The system performance is fully characterised. The sensors have a signal to noise ratio of approximately 20 and a best hit resolution of 4 μm is achieved at the optimal track angle. The typical detector occupancy for minimum bias events in standard operating conditions in 2011 is around 0.5%, and the detector has less than 1% of faulty strips. The proximity of the detector to the beam means that the inner regions of the n+-on-n sensors have undergone space-charge sign inversion due to radiation damage. The VELO performance parameters that drive the experiment's physics sensitivity are also given. The track finding efficiency of the VELO is typically above 98% and the modules have been aligned to a precision of 1 μm for translations in the plane transverse to the beam. A primary vertex resolution of 13 μm in the transverse plane and 71 μm along the beam axis is achieved for vertices with 25 tracks. An impact parameter resolution of less than 35 μm is achieved for particles with transverse momentum greater than 1 GeV/c

    Precision luminosity measurements at LHCb

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    Measuring cross-sections at the LHC requires the luminosity to be determined accurately at each centre-of-mass energy √s. In this paper results are reported from the luminosity calibrations carried out at the LHC interaction point 8 with the LHCb detector for √s = 2.76, 7 and 8 TeV (proton-proton collisions) and for √sNN = 5 TeV (proton-lead collisions). Both the "van der Meer scan" and "beam-gas imaging" luminosity calibration methods were employed. It is observed that the beam density profile cannot always be described by a function that is factorizable in the two transverse coordinates. The introduction of a two-dimensional description of the beams improves significantly the consistency of the results. For proton-proton interactions at √s = 8 TeV a relative precision of the luminosity calibration of 1.47% is obtained using van der Meer scans and 1.43% using beam-gas imaging, resulting in a combined precision of 1.12%. Applying the calibration to the full data set determines the luminosity with a precision of 1.16%. This represents the most precise luminosity measurement achieved so far at a bunched-beam hadron collider

    Quantum numbers of the X(3872)X(3872) state and orbital angular momentum in its ρ0Jψ\rho^0 J\psi decay

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    Angular correlations in B+X(3872)K+B^+\to X(3872) K^+ decays, with X(3872)ρ0J/ψX(3872)\to \rho^0 J/\psi, ρ0π+π\rho^0\to\pi^+\pi^- and J/ψμ+μJ/\psi \to\mu^+\mu^-, are used to measure orbital angular momentum contributions and to determine the JPCJ^{PC} value of the X(3872)X(3872) meson. The data correspond to an integrated luminosity of 3.0 fb1^{-1} of proton-proton collisions collected with the LHCb detector. This determination, for the first time performed without assuming a value for the orbital angular momentum, confirms the quantum numbers to be JPC=1++J^{PC}=1^{++}. The X(3872)X(3872) is found to decay predominantly through S wave and an upper limit of 4%4\% at 95%95\% C.L. is set on the fraction of D wave.Comment: 16 pages, 4 figure

    Observation of two new Ξb\Xi_b^- baryon resonances

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    Two structures are observed close to the kinematic threshold in the Ξb0π\Xi_b^0 \pi^- mass spectrum in a sample of proton-proton collision data, corresponding to an integrated luminosity of 3.0 fb1^{-1} recorded by the LHCb experiment. In the quark model, two baryonic resonances with quark content bdsbds are expected in this mass region: the spin-parity JP=12+J^P = \frac{1}{2}^+ and JP=32+J^P=\frac{3}{2}^+ states, denoted Ξb\Xi_b^{\prime -} and Ξb\Xi_b^{*-}. Interpreting the structures as these resonances, we measure the mass differences and the width of the heavier state to be m(Ξb)m(Ξb0)m(π)=3.653±0.018±0.006m(\Xi_b^{\prime -}) - m(\Xi_b^0) - m(\pi^{-}) = 3.653 \pm 0.018 \pm 0.006 MeV/c2/c^2, m(Ξb)m(Ξb0)m(π)=23.96±0.12±0.06m(\Xi_b^{*-}) - m(\Xi_b^0) - m(\pi^{-}) = 23.96 \pm 0.12 \pm 0.06 MeV/c2/c^2, Γ(Ξb)=1.65±0.31±0.10\Gamma(\Xi_b^{*-}) = 1.65 \pm 0.31 \pm 0.10 MeV, where the first and second uncertainties are statistical and systematic, respectively. The width of the lighter state is consistent with zero, and we place an upper limit of Γ(Ξb)<0.08\Gamma(\Xi_b^{\prime -}) < 0.08 MeV at 95% confidence level. Relative production rates of these states are also reported.Comment: 17 pages, 2 figure
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