Myeloid-derived suppressor cells: Ductile targets in disease

Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of immature myeloid cells with major regulatory functions and rise during pathological conditions, including cancer, infections and autoimmune conditions. MDSC expansion is generally linked to inflammatory processes that emerge in response to stable immunological stress, which alter both magnitude and quality of the myelopoietic output. Inability to reinstate physiological myelopoiesis would fall in an "emergency state" that perpetually reprograms myeloid cells toward suppressive functions. While differentiation and reprogramming of myeloid cells toward an immunosuppressive phenotype can be considered the result of a multistep process that originates in the bone marrow and culminates in the tumor microenvironment, the identification of its driving events may offer potential therapeutic approaches in different pathologies. Indeed, whereas expansion of MDSCs, in both murine and human tumor bearers, results in reduced immune surveillance and antitumor cytotoxicity, placing an obstacle to the effectiveness of anticancer therapies, adoptive transfer of MDSCs has shown therapeutic benefits in autoimmune disorders. Here, we describe relevant mechanisms of myeloid cell reprogramming leading to generation of suppressive MDSCs and discuss their therapeutic ductility in disease

Atmospheric Calorimetry above 1019^{19} eV: Shooting Lasers at the Pierre Auger Cosmic-Ray Observatory

The Pierre Auger Cosmic-Ray Observatory uses the earth's atmosphere as a calorimeter to measure extensive air-showers created by particles of astrophysical origin. Some of these particles carry joules of energy. At these extreme energies, test beams are not available in the conventional sense. Yet understanding the energy response of the observatory is important. For example, the propagation distance of the highest energy cosmic-rays through the cosmic microwave background radiation (CMBR) is predicted to be strong function of energy. This paper will discuss recently reported results from the observatory and the use of calibrated pulsed UV laser "test-beams" that simulate the optical signatures of ultra-high energy cosmic rays. The status of the much larger 200,000 km$^3$ companion detector planned for the northern hemisphere will also be outlined.Comment: 6 pages, 11 figures XIII International Conference on Calorimetry in High Energy Physic

Neutral-Current Atmospheric Neutrino Flux Measurement Using Neutrino-Proton Elastic Scattering in Super-Kamiokande

Recent results show that atmospheric $\nu_\mu$ oscillate with $\delta m^2 \simeq 3 \times 10^{-3}$ eV$^2$ and $\sin^2{2\theta_{atm}} \simeq 1$, and that conversion into $\nu_e$ is strongly disfavored. The Super-Kamiokande (SK) collaboration, using a combination of three techniques, reports that their data favor $\nu_\mu \to \nu_\tau$ over $\nu_\mu \to \nu_{sterile}$. This distinction is extremely important for both four-neutrino models and cosmology. We propose that neutrino-proton elastic scattering ($\nu + p \to \nu + p$) in water \v{C}erenkov detectors can also distinguish between active and sterile oscillations. This was not previously recognized as a useful channel since only about 2% of struck protons are above the \v{C}erenkov threshold. Nevertheless, in the present SK data there should be about 40 identifiable events. We show that these events have unique particle identification characteristics, point in the direction of the incoming neutrinos, and correspond to a narrow range of neutrino energies (1-3 GeV, oscillating near the horizon). This channel will be particularly important in Hyper-Kamiokande, with $\sim 40$ times higher rate. Our results have other important applications. First, for a similarly small fraction of atmospheric neutrino quasielastic events, the proton is relativistic. This uniquely selects $\nu_\mu$ (not $\bar{\nu}_\mu$) events, useful for understanding matter effects, and allows determination of the neutrino energy and direction, useful for the $L/E$ dependence of oscillations. Second, using accelerator neutrinos, both elastic and quasielastic events with relativistic protons can be seen in the K2K 1-kton near detector and MiniBooNE.Comment: 10 pages RevTeX, 8 figure

Heme catabolism by tumor-associated macrophages controls metastasis formation

Although the pathological significance of tumor-associated macrophage (TAM) heterogeneity is still poorly understood, TAM reprogramming is viewed as a promising anticancer therapy. Here we show that a distinct subset of TAMs (F4/80hiCD115hiC3aRhiCD88hi), endowed with high rates of heme catabolism by the stress-responsive enzyme heme oxygenase-1 (HO-1), plays a critical role in shaping a prometastatic tumor microenvironment favoring immunosuppression, angiogenesis and epithelial-to-mesenchymal transition. This population originates from F4/80+HO-1+ bone marrow (BM) precursors, accumulates in the blood of tumor bearers and preferentially localizes at the invasive margin through a mechanism dependent on the activation of Nrf2 and coordinated by the NF-κB1–CSF1R–C3aR axis. Inhibition of F4/80+HO-1+ TAM recruitment or myeloid-specific deletion of HO-1 blocks metastasis formation and improves anticancer immunotherapy. Relative expression of HO-1 in peripheral monocyte subsets, as well as in tumor lesions, discriminates survival among metastatic melanoma patients. Overall, these results identify a distinct cancer-induced HO-1+ myeloid subgroup as a new antimetastatic target and prognostic blood marker

Observation of TeV gamma rays from the Cygnus region with the ARGO-YBJ experiment

We report the observation of TeV gamma-rays from the Cygnus region using the ARGO-YBJ data collected from 2007 November to 2011 August. Several TeV sources are located in this region including the two bright extended MGRO J2019+37 and MGRO J2031+41. According to the Milagro data set, at 20 TeV MGRO J2019+37 is the most significant source apart from the Crab Nebula. No signal from MGRO J2019+37 is detected by the ARGO-YBJ experiment, and the derived flux upper limits at 90% confidence level for all the events above 600 GeV with medium energy of 3 TeV are lower than the Milagro flux, implying that the source might be variable and hard to be identified as a pulsar wind nebula. The only statistically significant (6.4 standard deviations) gamma-ray signal is found from MGRO J2031+41, with a flux consistent with the measurement by Milagro.Comment: 14 pages, 4 figure

Gamma ray flares from Mrk421 in 2008 observed with the ARGO-YBJ detector

In 2008 the blazar Markarian 421 entered a very active phase and was one of the brightest sources in the sky at TeV energies, showing frequent flaring episodes. Using the data of ARGO-YBJ, a full coverage air shower detector located at Yangbajing (4300 m a.s.l., Tibet, China), we monitored the source at gamma ray energies E > 0.3 TeV during the whole year. The observed flux was variable, with the strongest flares in March and June, in correlation with X-ray enhanced activity. While during specific episodes the TeV flux could be several times larger than the Crab Nebula one, the average emission from day 41 to 180 was almost twice the Crab level, with an integral flux of (3.6 +-0.6) 10^-11 photons cm^-2 s^-1 for energies E > 1 TeV, and decreased afterwards. This paper concentrates on the flares occurred in the first half of June. This period has been deeply studied from optical to 100 MeV gamma rays, and partially up to TeV energies, since the moonlight hampered the Cherenkov telescope observations during the most intense part of the emission. Our data complete these observations, with the detection of a signal with a statistical significance of 3.8 standard deviations on June 11-13, corresponding to a gamma ray flux about 6 times larger than the Crab one above 1 TeV. The reconstructed differential spectrum, corrected for the intergalactic absorption, can be represented by a power law with an index alpha = -2.1 extending up to several TeV. The spectrum slope is fully consistent with previous observations reporting a correlation between the flux and the spectral index, suggesting that this property is maintained in different epochs and characterizes the source emission processes.Comment: Accepted for publication on ApJ

Mean Interplanetary Magnetic Field Measurement Using the ARGO-YBJ Experiment

The sun blocks cosmic ray particles from outside the solar system, forming a detectable shadow in the sky map of cosmic rays detected by the ARGO-YBJ experiment in Tibet. Because the cosmic ray particles are positive charged, the magnetic field between the sun and the earth deflects them from straight trajectories and results in a shift of the shadow from the true location of the sun. Here we show that the shift measures the intensity of the field which is transported by the solar wind from the sun to the earth.Comment: 6 papges,3 figure

Highlights from the Pierre Auger Observatory

The Pierre Auger Observatory is the world's largest cosmic ray observatory. Our current exposure reaches nearly 40,000 km$^2$ str and provides us with an unprecedented quality data set. The performance and stability of the detectors and their enhancements are described. Data analyses have led to a number of major breakthroughs. Among these we discuss the energy spectrum and the searches for large-scale anisotropies. We present analyses of our X$_{max}$ data and show how it can be interpreted in terms of mass composition. We also describe some new analyses that extract mass sensitive parameters from the 100% duty cycle SD data. A coherent interpretation of all these recent results opens new directions. The consequences regarding the cosmic ray composition and the properties of UHECR sources are briefly discussed.Comment: 9 pages, 12 figures, talk given at the 33rd International Cosmic Ray Conference, Rio de Janeiro 201