Fms-like tyrosine kinase-3 ligand (Flt3L) uniquely binds the Flt3 (CD135) receptor expressed on hematopoietic stem cells (HSCs), early progenitor cells, immature thymocytes and steady-state dendritic ...cells (DCs) and induces their proliferation, differentiation, development and mobilization in the bone marrow, peripheral blood and lymphoid organs. CDX-301 has an identical amino-acid sequence and comparable biological activity to the previously tested rhuFlt3L, which ceased clinical development over a decade ago. This Phase 1 trial assessed the safety, pharmacokinetic, pharmacodynamic and immunologic profile of CDX-301, explored alternate dosing regimens and examined the impact of rhuFlt3L on key immune cell subsets. Thirty healthy volunteers received CDX-301 (1-75 μg/kg/day) over 5-10 days. One event of Grade 3 community-acquired pneumonia occurred. There were no other infections, dose-limiting toxicities or serious adverse events. CDX-301 resulted in effective peripheral expansion of monocytes, hematopoietic stem and progenitor cells and key subsets of myeloid DCs and plasmacytoid DCs, with no clear effect on regulatory T cells. These data from healthy volunteers support the potential for CDX-301, as monotherapy or in combination with other agents, in various indications including allogeneic HSC transplantation and immunotherapy, but the effects of CDX-301 will need to be investigated in each of these patient populations.
We present the first limits on inelastic electron-scattering dark matter and dark photon absorption using a prototype SuperCDMS detector having a charge resolution of 0.1 electron-hole pairs (CDMS ...HVeV, a 0.93 g CDMS high-voltage device). These electron-recoil limits significantly improve experimental constraints on dark matter particles with masses as low as 1 MeV/c^{2}. We demonstrate a sensitivity to dark photons competitive with other leading approaches but using substantially less exposure (0.49 g d). These results demonstrate the scientific potential of phonon-mediated semiconductor detectors that are sensitive to single electronic excitations.
This article presents an analysis and the resulting limits on light dark matter inelastically scattering off of electrons, and on dark photon and axionlike particle absorption, using a ...second-generation SuperCDMS high-voltage eV-resolution detector. The 0.93 g Si detector achieved a 3 eV phonon energy resolution; for a detector bias of 100 V, this corresponds to a charge resolution of 3% of a single electron-hole pair. The energy spectrum is reported from a blind analysis with 1.2 g-days of exposure acquired in an above-ground laboratory. With charge carrier trapping and impact ionization effects incorporated into the dark matter signal models, the dark matter-electron cross section σe is constrained for dark matter masses from 0.5 to 104 MeV / c2; in the mass range from 1.2 to 50 eV / c2 the dark photon kinetic mixing parameter ϵ and the axioelectric coupling constant gae are constrained. The minimum 90% confidence-level upper limits within the above-mentioned mass ranges are σe = 8.7 × 10−34 cm2, ϵ = 3.3 × 10−14, and gae = 1.0 × 10−9.
We report the result of a blinded search for weakly interacting massive particles (WIMPs) using the majority of the SuperCDMS Soudan data set. With an exposure of 1690 kg d, a single candidate event ...is observed, consistent with expected backgrounds. This analysis (combined with previous Ge results) sets an upper limit on the spin-independent WIMP-nucleon cross section of 1.4×10^{-44} (1.0×10^{-44}) cm^{2} at 46 GeV/c^{2}. These results set the strongest limits for WIMP-germanium-nucleus interactions for masses >12 GeV/c^{2}.
We present an analysis of electron recoils in cryogenic germanium detectors operated during the SuperCDMS Soudan experiment. The data are used to set new constraints on the axioelectric coupling of ...axionlike particles and the kinetic mixing parameter of dark photons, assuming the respective species constitutes all of the galactic dark matter. This study covers the mass range from 40 eV/c2to 500 keV/c2for both candidates, excluding previously untested parameter space for masses below ∼ 1 keV/c2. For the kinetic mixing of dark photons, values below 10−15 are reached for particle masses around 100 eV/c2; for the axioelectric coupling of axionlike particles, values below 10−12 are reached for particles with masses in the range of a few-hundred eV/c2.
Peak rapid filling rate (PRFR) is often used clinically as an index of left ventricular relaxation, i.e., of early diastolic function. This study tests the hypothesis that early filling rate is a ...function of the atrioventricular pressure difference and hence is influenced by the left atrial pressure as well as by the rate of left ventricular relaxation. As indexes, we chose the left atrial pressure at the atrioventricular pressure crossover (PCO), and the time constant (T) of an assumed exponential decline in left ventricular pressure. We accurately determined the magnitude and timing of filling parameters in conscious dogs by direct measurement of phasic mitral flow (electromagnetically) and high-fidelity chamber pressures. To obtain a diverse hemodynamic data base, loading conditions were changed by infusions of volume and angiotensin II. The latter was administered to produce a change in left ventricular pressure of less than 35% (A-1) or a change in peak left ventricular pressure of greater than 35% (A-2). PRFR increased with volume loading, was unchanged with A-1, and was decreased with A-2; T and PCO increased in all three groups (p less than .005 for all changes). PRFR correlated strongly with the diastolic atrioventricular pressure difference at the time of PRFR (r = .899, p less than .001) and weakly with both T (r = .369, p less than .01) and PCO (r = .601, p less than .001). The correlation improved significantly when T and PCO were both included in the multivariate regression (r = .797, p less than .0001). PRFR is thus determined by both the left atrial pressure and the left ventricular relaxation rate and should be used with caution as an index of left ventricular diastolic function.
String inspired models with millimeter scale extra dimensions provide a natural way to understand an ultralight sterile neutrino needed for a simultaneous explanation of the solar, atmospheric and ...Liquid Scintillation Neutrino Detector neutrino oscillation results. The sterile neutrino is the bulk neutrino ({nu}{sub B}) postulated to exist in these models, and it becomes ultralight in theories that prevent the appearance of its direct mass terms. Its Kaluza-Klein (KK) states then add new oscillation channels for the electron neutrino emitted from the solar core. We show that successive Mikheyev-Smirnov-Wolfenstein transitions of solar {nu}{sub e} to the lower lying KK modes of {nu}{sub B} in conjunction with vacuum oscillations between the {nu}{sub e} and the zero mode of {nu}{sub B} provide a new way to fit the solar neutrino data. The characteristic predictions can be tested by solar neutrino observations and forthcoming solar neutrino experiments. We discuss both intermediate and low string scale models where the desired spectrum can emerge naturally.
Left ventricular (LV) pressure (P)-diameter, LVP-area, or LVP-volume relationships used to evaluate LV diastolic function assume uniform LV wall motion and constant LVP. Contrary to these ...assumptions, there are significant differences in ventricular dynamic geometry and in LV pressures measured simultaneously in different parts of the LV, particularly during early diastole. We instrumented six anesthetized open-chest dogs with three pairs of orthogonal ultrasonic crystals (anterior-posterior and septal-free wall minor axes, and base-apex major axis) and two micromanometers (in the apex and in the LV base). The mitral valve occluder was implanted during standard cardiopulmonary bypass in the mitral annulus. Data were recorded during 11 transient vena caval occlusions. The mitral valve was occluded for 1 beat every 6-8 beats during each vena caval occlusion to produce nonfilling diastole. With the decrease of the LV end-systolic volume (Ves) below the equilibrium volume Veq (volume of the completely relaxed LV at LVP = 0); the minimum negative LVP in nonfilling beats increases, the shape of the ventricle is more ellipsoidal in both filling and nonfilling beats, and the base-to-apex pressure gradient at the time of LVP minimum increases regardless of the presence or absence of filling. Thus heterogeneous myocardial stresses during isovolumic relaxation and early diastole result in ventricular shape changes, intraventricular redistribution of chamber volume, local accelerations of blood, and associated intraventricular LVP gradients. The role of elastic recoil assumes greater importance at Ves smaller than Veq, when the left ventricle becomes more ellipsoidal in shape during isovolumic relaxation, leading, in turn, to greater shape changes and greater LVP gradient.
Solar, atmospheric, and LSND neutrino oscillation results require a light sterile neutrino, nu(B), which can exist in the bulk of extra dimensions. Solar nu(e), confined to the brane, can oscillate ...in the vacuum to the zero mode of nu(B) and via successive Mikheyev-Smirnov-Wolfenstein transitions to Kaluza-Klein states of nu(B). This new way to fit solar data is provided by both low and intermediate string scale models. From average rates seen in the three types of solar experiments, the Super-Kamiokande spectrum is predicted with 73% probability, but dips characteristic of the 0.06 mm extra dimension should be seen in the SNO spectrum.
Left ventricular (LV) diastolic pressure-volume (P-V) relations arise from a complex interplay of active decay of force (i.e., relaxation), passive elastic myocardial properties, and time-varying ...inflow across the mitral orifice. This study was designed to quantify the passive properties of the intact ventricle and the effects of elastic recoil by separating filling from relaxation with a method of LV volume clamping with a remote-controlled mitral valve. Eleven open-chest fentanyl-anesthetized dogs were instrumented with aortic and mitral flow probes, LV and left atrium micromanometers, and a remote-controlled mitral valve. We prevented complete (end-systolic volume clamping) or partial filling at different times in diastole. The ventricle thus relaxed completely at different volumes, and we generated P-V coordinates for the passive ventricle that included negative, as well as positive, values of pressure. We then estimated ventricular volumes from ventricular weight in eight dogs, using regression equations based on data in the literature, to determine the equilibrium volume (V0), that is, volume at zero transmural pressure, in the working ventricle. We abandoned the traditional exponential approach and characterized the P-V relation with a logarithmic approach that included maximum LV volume (Vm), minimum volume (Vd), and stiffness parameters (Sp and Sn) for the positive (p) and negative (n) phasesPp = -Sp In(Vm - V)/(Vm-V0) and Pn = Sn In(V-Vd)/(V0-Vd). With this formulation, the chamber compliance, dP/dV, is normalized by the LV operating volume, and Sp and Sn are size-independent chamber stiffness parameters with the units of stress. In eight ventricles with LV weight = 131 ± 20 g, Vm = 116 ± 18 ml, V0 = 37 ± 6 ml, and Vd = 13 ± 2ml, stiffness Sp = 14.6 mm Hg and Sn = 5.1 mm Hg were determined from the slopes of the log-linearized equations. Also, the duration of LV relaxation is increased by the process of ventricular filling (161 ± 31 msec, filling versus 108 ± 36 msec, nonfilling, measured from dP/dtmin, p < 0.0001). We conclude that volume clamping is a useful method of studying restoring forces and that the logarithmic approach is conceptually and quantitatively useful in characterizing the passive properties of the intact ventricle.
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