Immediate effects of dasatinib on the migration and redistribution of naïve and memory lymphocytes associated with lymphocytosis in chronic myeloid leukemia patients

Introduction: Dasatinib is a dual SRC/ABL tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML) that is known to have unique immunomodulatory effects. In particular, dasatinib intake typically causes lymphocytosis, which has been linked to better clinical response. Since the underlying mechanisms are unknown and SRC family kinases are involved in many cell motility processes, we hypothesized that the movement and migration of lymphocytes is modulated by dasatinib. Patients, Materials and Methods: Peripheral blood samples from CML patients treated with second-line dasatinib were collected before and 2 h after the first dasatinib intake, and follow-up samples from the same patients 3 and 6 months after the start of therapy. The migratory capacity and phenotype of lymphocytes and differential blood counts before and after drug intake were compared for all study time-points. Results: We report here for the first time that dasatinib intake is associated with inhibition of peripheral blood T-cell migration toward the homeostatic chemokines CCL19 and CCL21, which control the trafficking toward secondary lymphoid organs, mainly the lymph nodes. Accordingly, the proportion of lymphocytes in blood expressing CCR7, the chemokine receptor for both CCL19 and CCL21, decreased after the intake including both naïve CD45RA+ and central memory CD45RO+ T-cells. Similarly, naïve B-cells diminished with dasatinib. Finally, such changes in the migratory patterns did not occur in those patients whose lymphocyte counts remained unchanged after taking the drug. Discussion: We, therefore, conclude that lymphocytosis induced by dasatinib reflects a pronounced redistribution of naïve and memory populations of all lymphocyte subsets including CD4+ and CD8+ T-cells and B-cells

Measurement of the Crab Nebula Spectrum Past 100 TeV with HAWC

We present TeV gamma-ray observations of the Crab Nebula, the standard reference source in ground-based gamma-ray astronomy, using data from the High Altitude Water Cherenkov (HAWC) Gamma-Ray Observatory. In this analysis we use two independent energy-estimation methods that utilize extensive air shower variables such as the core position, shower angle, and shower lateral energy distribution. In contrast, the previously published HAWC energy spectrum roughly estimated the shower energy with only the number of photomultipliers triggered. This new methodology yields a much improved energy resolution over the previous analysis and extends HAWC's ability to accurately measure gamma-ray energies well beyond 100 TeV. The energy spectrum of the Crab Nebula is well fit to a log parabola shape $\left(\frac{dN}{dE} = \phi_0 \left(E/\textrm{7 TeV}\right)^{-\alpha-\beta\ln\left(E/\textrm{7 TeV}\right)}\right)$ with emission up to at least 100 TeV. For the first estimator, a ground parameter that utilizes fits to the lateral distribution function to measure the charge density 40 meters from the shower axis, the best-fit values are $\phi_o$=(2.35$\pm$0.04$^{+0.20}_{-0.21}$)$\times$10$^{-13}$ (TeV cm$^2$ s)$^{-1}$, $\alpha$=2.79$\pm$0.02$^{+0.01}_{-0.03}$, and $\beta$=0.10$\pm$0.01$^{+0.01}_{-0.03}$. For the second estimator, a neural network which uses the charge distribution in annuli around the core and other variables, these values are $\phi_o$=(2.31$\pm$0.02$^{+0.32}_{-0.17}$)$\times$10$^{-13}$ (TeV cm$^2$ s)$^{-1}$, $\alpha$=2.73$\pm$0.02$^{+0.03}_{-0.02}$, and $\beta$=0.06$\pm$0.01$\pm$0.02. The first set of uncertainties are statistical; the second set are systematic. Both methods yield compatible results. These measurements are the highest-energy observation of a gamma-ray source to date.Comment: published in Ap

All-particle cosmic ray energy spectrum measured by the HAWC experiment from 10 to 500 TeV

We report on the measurement of the all-particle cosmic ray energy spectrum with the High Altitude Water Cherenkov (HAWC) Observatory in the energy range 10 to 500 TeV. HAWC is a ground based air-shower array deployed on the slopes of Volcan Sierra Negra in the state of Puebla, Mexico, and is sensitive to gamma rays and cosmic rays at TeV energies. The data used in this work were taken from 234 days between June 2016 to February 2017. The primary cosmic-ray energy is determined with a maximum likelihood approach using the particle density as a function of distance to the shower core. Introducing quality cuts to isolate events with shower cores landing on the array, the reconstructed energy distribution is unfolded iteratively. The measured all-particle spectrum is consistent with a broken power law with an index of $-2.49\pm0.01$ prior to a break at $(45.7\pm0.1$) TeV, followed by an index of $-2.71\pm0.01$. The spectrum also respresents a single measurement that spans the energy range between direct detection and ground based experiments. As a verification of the detector response, the energy scale and angular resolution are validated by observation of the cosmic ray Moon shadow's dependence on energy.Comment: 16 pages, 11 figures, 4 tables, submission to Physical Review

Very high energy particle acceleration powered by the jets of the microquasar SS 433

SS 433 is a binary system containing a supergiant star that is overflowing its Roche lobe with matter accreting onto a compact object (either a black hole or neutron star). Two jets of ionized matter with a bulk velocity of $\sim0.26c$ extend from the binary, perpendicular to the line of sight, and terminate inside W50, a supernova remnant that is being distorted by the jets. SS 433 differs from other microquasars in that the accretion is believed to be super-Eddington, and the luminosity of the system is $\sim10^{40}$ erg s$^{-1}$. The lobes of W50 in which the jets terminate, about 40 pc from the central source, are expected to accelerate charged particles, and indeed radio and X-ray emission consistent with electron synchrotron emission in a magnetic field have been observed. At higher energies (>100 GeV), the particle fluxes of $\gamma$ rays from X-ray hotspots around SS 433 have been reported as flux upper limits. In this energy regime, it has been unclear whether the emission is dominated by electrons that are interacting with photons from the cosmic microwave background through inverse-Compton scattering or by protons interacting with the ambient gas. Here we report TeV $\gamma$-ray observations of the SS 433/W50 system where the lobes are spatially resolved. The TeV emission is localized to structures in the lobes, far from the center of the system where the jets are formed. We have measured photon energies of at least 25 TeV, and these are certainly not Doppler boosted, because of the viewing geometry. We conclude that the emission from radio to TeV energies is consistent with a single population of electrons with energies extending to at least hundreds of TeV in a magnetic field of $\sim16$~micro-Gauss.Comment: Preprint version of Nature paper. Contacts: S. BenZvi, B. Dingus, K. Fang, C.D. Rho , H. Zhang, H. Zho

Search for very-high-energy emission from Gamma-ray Bursts using the first 18 months of data from the HAWC Gamma-ray Observatory

The High Altitude Water Cherenkov (HAWC) Gamma-ray Observatory is an extensive air shower detector operating in central Mexico, which has recently completed its first two years of full operations. If for a burst like GRB 130427A at a redshift of 0.34 and a high-energy component following a power law with index -1.66, the high-energy component is extended to higher energies with no cut-off other than from extragalactic background light attenuation, HAWC would observe gamma rays with a peak energy of $\sim$300 GeV. This paper reports the results of HAWC observations of 64 gamma-ray bursts (GRBs) detected by $\mathit{Swift}$ and $\mathit{Fermi}$, including three GRBs that were also detected by the Large Area Telescope ($\mathit{Fermi}$-LAT). An ON/OFF analysis method is employed, searching on the time scale given by the observed light curve at keV-MeV energies and also on extended time scales. For all GRBs and time scales, no statistically significant excess of counts is found and upper limits on the number of gamma rays and the gamma-ray flux are calculated. GRB 170206A, the third brightest short GRB detected by the Gamma-ray Burst Monitor on board the $\mathit{Fermi}$ satellite ($\mathit{Fermi}$-GBM) and also detected by the LAT, occurred very close to zenith. The LAT measurements can neither exclude the presence of a synchrotron self-Compton (SSC) component nor constrain its spectrum. Instead, the HAWC upper limits constrain the expected cut-off in an additional high-energy component to be less than $100~\rm{GeV}$ for reasonable assumptions about the energetics and redshift of the burst.Comment: 19 pages, 6 figures, published in Ap

Constraining the pˉ/p\bar{p}/p Ratio in TeV Cosmic Rays with Observations of the Moon Shadow by HAWC

An indirect measurement of the antiproton flux in cosmic rays is possible as the particles undergo deflection by the geomagnetic field. This effect can be measured by studying the deficit in the flux, or shadow, created by the Moon as it absorbs cosmic rays that are headed towards the Earth. The shadow is displaced from the actual position of the Moon due to geomagnetic deflection, which is a function of the energy and charge of the cosmic rays. The displacement provides a natural tool for momentum/charge discrimination that can be used to study the composition of cosmic rays. Using 33 months of data comprising more than 80 billion cosmic rays measured by the High Altitude Water Cherenkov (HAWC) observatory, we have analyzed the Moon shadow to search for TeV antiprotons in cosmic rays. We present our first upper limits on the $\bar{p}/p$ fraction, which in the absence of any direct measurements, provide the tightest available constraints of $\sim1\%$ on the antiproton fraction for energies between 1 and 10 TeV.Comment: 10 pages, 5 figures. Accepted by Physical Review