19 research outputs found
Dual inhibition of histone deacetylases and phosphoinositide 3-kinase enhances therapeutic activity against B cell lymphoma
Phosphoinositide 3-kinase (PI3K) and Myc are known to cooperate in promoting the survival and growth of a variety of B-cell lymphomas. While currently there are no small molecule inhibitors of Myc protein, histone deacetylase (HDAC) inhibitors have been shown to reduce levels of Myc protein by suppressing its transcription. We assessed the efficacy of CUDC-907, a new rationally designed dual inhibitor of PI3K and HDACs, in a panel of lymphoma cell lines. CUDC-907 treatment resulted in a dose- and time-dependent growth inhibition and cell death of DLBCL cell lines, irrespective of the cell of origin. CUDC-907 treatment down-regulated the phosphorylation of PI3K downstream targets, including AKT, PRAS40, S6, and 4EBP1, increased histone 3 acetylation, and decreased Myc protein levels. SILAC-based quantitative mass spectrometry demonstrated that CUDC-907 treatment decreased the protein levels of several components of the B cell receptor (BCR) and Toll like receptor (TLR) pathways, including BTK, SYK, and MyD88 proteins. These cellular changes were associated with an inhibition of NF-kB activation. CUDC-907 demonstrated in vivo efficacy with no significant toxicity in a human DLBCL xenograft mouse model. Collectively, these data provide a mechanistic rationale for evaluating CUDC-907 for the treatment of patients with Myc and PI3K-dependent lymphomas
Measurement of forward charged hadron flow harmonics in peripheral PbPb collisions at âsNN = 5.02 TeV with the LHCb detector
Flow harmonic coefficients,
v
n
, which are the key to studying the hydrodynamics of the quark-gluon plasma (QGP) created in heavy-ion collisions, have been measured in various collision systems and kinematic regions and using various particle species. The study of flow harmonics in a wide pseudorapidity range is particularly valuable to understand the temperature dependence of the shear viscosity to entropy density ratio of the QGP. This paper presents the first LHCb results of the second- and the third-order flow harmonic coefficients of charged hadrons as a function of transverse momentum in the forward region, corresponding to pseudorapidities between 2.0 and 4.9, using the data collected from PbPb collisions in 2018 at a center-of-mass energy of 5.02
TeV
. The coefficients measured using the two-particle angular correlation analysis method are smaller than the central-pseudorapidity measurements at ALICE and ATLAS from the same collision system but share similar features
Helium identification with LHCb
The identification of helium nuclei at LHCb is achieved using a method based on measurements of ionisation losses in the silicon sensors and timing measurements in the Outer Tracker drift tubes. The background from photon conversions is reduced using the RICH detectors and an isolation requirement. The method is developed using pp collision data at â(s) = 13 TeV recorded by the LHCb experiment in the years 2016 to 2018, corresponding to an integrated luminosity of 5.5 fb-1. A total of around 105 helium and antihelium candidates are identified with negligible background contamination. The helium identification efficiency is estimated to be approximately 50% with a corresponding background rejection rate of up to O(10^12). These results demonstrate the feasibility of a rich programme of measurements of QCD and astrophysics interest involving light nuclei
Curvature-bias corrections using a pseudomass method
Momentum measurements for very high momentum charged particles, such as muons from electroweak vector boson decays, are particularly susceptible to charge-dependent curvature biases that arise from misalignments of tracking detectors. Low momentum charged particles used in alignment procedures have limited sensitivity to coherent displacements of such detectors, and therefore are unable to fully constrain these misalignments to the precision necessary for studies of electroweak physics. Additional approaches are therefore required to understand and correct for these effects. In this paper the curvature biases present at the LHCb detector are studied using the pseudomass method in proton-proton collision data recorded at centre of mass energy â(s)=13 TeV during 2016, 2017 and 2018. The biases are determined using ZâÎŒ + ÎŒ - decays in intervals defined by the data-taking period, magnet polarity and muon direction. Correcting for these biases, which are typically at the 10-4 GeV-1 level, improves the ZâÎŒ + ÎŒ - mass resolution by roughly 18% and eliminates several pathological trends in the kinematic-dependence of the mean dimuon invariant mass
Cost-effectiveness evaluation of sunitinib as first-line targeted therapy for metastatic renal cell carcinoma in Spain.
INTRODUCTION Sunitinib, an oral, multitargeted receptor tyrosine kinase inhibitor, delays disease progression, with a median overall survival (OS) of more than 2 years, improves quality of life and is becoming the first-line standard of care for metastatic renal carcinoma (mRCC). PURPOSE To assess the economic value of sunitinib as fi rst-line therapy in mRCC within the Spanish healthcare system. METHODS An adapted Markov model with a 10-year time horizon was used to analyse the cost effectiveness of sunitinib vs. sorafenib (SFN) and bevacizumab/interferon-α (BEV/IFN) as first-line mRCC therapy from the Spanish third-party payer perspective. Progression-free survival (PFS) and OS data from sunitinib, SFN and BEV/IFN pivotal trials were extrapolated to project survival and costs in 6-week cycles. Results, in progression-free life-years (PFLY), life years (LY) and quality-adjusted life-years (QALY) gained, expressed as incremental cost-effectiveness ratios (ICER) with costs and benefits discounted annually at 3%, were obtained using deterministic and probabilistic analyses. RESULTS Sunitinib was more effective and less costly than both SFN (gains of 0.52 PFLY, 0.16 LY, 0.17 QALY) and BEV/IFN (gains of 0.19 PFLY, 0.23 LY, 0.16 QALY) with average cost savings/patients of âŹ1,124 and âŹ23,218, respectively. Using a willingness-to-pay (WTP) threshold of âŹ50,000/QALY, sunitinib achieved an incremental net benefit (INB) of âŹ9,717 and âŹ31,211 compared with SFN and BEV/IFN, respectively. At this WTP, the probability of sunitinib providing the highest INB was 75%. CONCLUSION Our analysis suggests that sunitinib is a costeffective alternative to other targeted therapies as first-line mRCC therapy in the Spanish healthcare setting
Angiosperm association from the RĂo Turbio Formation (Eoceneâ?Oligocene) Santa Cruz, Argentina: revision of HĂŒnickenâs (1955) fossil leaves collection
The RĂo Turbio Formation (Eoceneâ?Oligocene) is of particular paleobotanical interest owing to its combination of high fossil plant diversity associated with the coexistence of warm-temperate and cool-temperate components. As the first suite of fossils related to a documented stratigraphic section, HĂŒnickenâs fossil plant collection is one of the most important from the Paleogene of South America. A total of 34 angiosperm species from the collection were reviewed and taxonomically updated, with Nothofagus as the dominant genus. The taxa identified indicate a warm and humid climate with the development of some elements of a cool-temperate climate marked by a transitional climate change to cooler conditions. The comparison of angiosperms from different paleofloras from the southernmost of South America confirms that the assemblage of RĂo Turbio Formation was similar to that of the RĂo PichileufĂș area, both from Patagonia, Argentina.Fil: Vento, Barbara. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Mendoza. Instituto Argentino de NivologĂa, GlaciologĂa y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de NivologĂa, GlaciologĂa y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de NivologĂa, GlaciologĂa y Ciencias Ambientales; ArgentinaFil: Pramparo, Mercedes Beatriz. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Centro CientĂfico TecnolĂłgico Conicet - Mendoza. Instituto Argentino de NivologĂa, GlaciologĂa y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de NivologĂa, GlaciologĂa y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de NivologĂa, GlaciologĂa y Ciencias Ambientales; Argentin
Measurement of the longitudinal polarization in decays â
The longitudinal polarization fraction of the meson is measured in decays, where the lepton decays to three charged pions and a neutrino, using proton-proton collision data collected by the LHCb experiment at center-of-mass energies of 7, 8 and 13 TeV and corresponding to an integrated luminosity of 5 fb. The polarization fraction is measured in two regions, below and above 7 GeV/c, where is defined as the squared invariant mass of the system. The values are measured to be and for the lower and higher regions, respectively. The first uncertainties are statistical and the second systematic. The average value over the whole range is: These results are compatible with the Standard Model predictions.The longitudinal polarization fraction of the meson is measured in decays, where the lepton decays to three charged pions and a neutrino, using proton-proton collision data collected by the LHCb experiment at center-of-mass energies of 7, 8 and 13 TeV and corresponding to an integrated luminosity of 5 fb. The polarization fraction is measured in two regions, below and above 7 GeV, where is defined as the squared invariant mass of the system. The values are measured to be and for the lower and higher regions, respectively. The first uncertainties are statistical and the second systematic. The average value over the whole range is:
These results are compatible with the Standard Model predictions