The immature and dysfunctional vascular network within solid tumors poses a substantial obstacle to immunotherapy because it creates a hypoxic tumor microenvironment that actively limits immune cell ...infiltration. The molecular basis underpinning this vascular dysfunction is not fully understood. Using genome-scale receptor array technology, we showed here that insulin-like growth factor binding protein 7 (IGFBP7) interacts with its receptor CD93, and we subsequently demonstrated that this interaction contributes to abnormal tumor vasculature. Both CD93 and IGFBP7 were up-regulated in tumor-associated endothelial cells. IGFBP7 interacted with CD93 via a domain different from multimerin-2, the known ligand for CD93. In two mouse tumor models, blockade of the CD93/IGFBP7 interaction by monoclonal antibodies promoted vascular maturation to reduce leakage, leading to reduced tumor hypoxia and increased tumor perfusion. CD93 blockade in mice increased drug delivery, resulting in an improved antitumor response to gemcitabine or fluorouracil. Blockade of the CD93 pathway triggered a substantial increase in intratumoral effector T cells, thereby sensitizing mouse tumors to immune checkpoint therapy. Last, analysis of samples from patients with cancer under anti-programmed death 1/programmed death-ligand 1 treatment revealed that overexpression of the IGFBP7/CD93 pathway was associated with poor response to therapy. Thus, our study identified a molecular interaction involved in tumor vascular dysfunction and revealed an approach to promote a favorable tumor microenvironment for therapeutic intervention.
Abstract
We describe an image-based method that uses two radio criteria, compactness, and spectral index, to identify promising pulsar candidates among Fermi Large Area Telescope (LAT) unassociated ...sources. These criteria are applied to those radio sources from the Giant Metrewave Radio Telescope all-sky survey at 150 MHz (TGSS ADR1) found within the error ellipses of unassociated sources from the 3FGL catalogue and a preliminary source list based on 7 yr of LAT data. After follow-up interferometric observations to identify extended or variable sources, a list of 16 compact, steep-spectrum candidates is generated. An ongoing search for pulsations in these candidates, in gamma rays and radio, has found 6 ms pulsars and one normal pulsar. A comparison of this method with existing selection criteria based on gamma-ray spectral and variability properties suggests that the pulsar discovery space using Fermi may be larger than previously thought. Radio imaging is a hitherto underutilized source selection method that can be used, as with other multiwavelength techniques, in the search for Fermi pulsars.
Using the Parkes Radio Telescope, we have carried out deep observations of 11 unassociated gamma-ray sources. Periodicity searches of these data have discovered two millisecond pulsars, PSR ...J1103−5403 (1FGL J1103.9−5355) and PSR J2241−5236 (1FGL J2241.9−5236), and a long-period pulsar, PSR J1604−44 (1FGL J1604.7−4443). In addition, we searched for but did not detect any radio pulsations from six gamma-ray pulsars discovered by the Fermi satellite to a level of ∼0.04 mJy (for pulsars with a 10 per cent duty cycle).
The timing of the millisecond pulsar PSR J1103−5403 has shown that its position is 9 arcmin from the centroid of the gamma-ray source. Since these observations were carried out, independent evidence has shown that 1FGL J1103.9−5355 is associated with the flat spectrum radio source PKS 1101−536. It appears certain that the pulsar is not associated with the gamma-ray source, despite the seemingly low probability of a chance detection of a radio millisecond pulsar. We consider that PSR J1604−44 is a chance discovery of a weak, long-period pulsar and is unlikely to be associated with 1FGL J1604.7−4443. PSR J2241−5236 has a spin period of 2.2 ms and orbits a very low mass companion with a 3.5-h orbital period. The relatively high flux density and low dispersion measure of PSR J2241−5236 make it an excellent candidate for high precision timing experiments. The gamma rays of 1FGL J2241.9−5236 have a spectrum that is well modelled by a power law with an exponential cut-off, and phase binning with the radio ephemeris results in a multipeaked gamma-ray pulse profile. Observations with Chandra have identified a coincident X-ray source within 0.1 arcsec of the position of the pulsar obtained by radio timing.
The regularity of pulsar emissions becomes apparent once we reference the pulses' times of arrivals to the inertial rest frame of the solar system. It follows that errors in the determination of ...Earth's position with respect to the solar system barycenter can appear as a time-correlated bias in pulsar-timing residual time series, affecting the searches for low-frequency gravitational waves performed with pulsar-timing arrays. Indeed, recent array data sets yield different gravitational-wave background upper limits and detection statistics when analyzed with different solar system ephemerides. Crucially, the ephemerides do not generally provide usable error representations. In this article, we describe the motivation, construction, and application of a physical model of solar system ephemeris uncertainties, which focuses on the degrees of freedom (Jupiter's orbital elements) most relevant to gravitational-wave searches with pulsar-timing arrays. This model, BayesEphem, was used to derive ephemeris-robust results in NANOGrav's 11 yr stochastic-background search, and it provides a foundation for future searches by NANOGrav and other consortia. The analysis and simulations reported here suggest that ephemeris modeling reduces the gravitational-wave sensitivity of the 11 yr data set and that this degeneracy will vanish with improved ephemerides and with pulsar-timing data sets that extend well beyond a single Jovian orbital period.
ABSTRACT
We present a catalog of high-energy gamma-ray sources detected by the Large Area
Telescope (LAT), the primary science instrument on the
Fermi Gamma-ray
Space Telescope (Fermi)
, during the ...first 11 months of the science
phase of the mission, which began on 2008 August 4. The First
Fermi
-LAT catalog (1FGL) contains 1451 sources detected and
characterized in the 100 MeV to 100 GeV range. Source detection was based on the
average flux over the 11 month period, and the threshold likelihood Test
Statistic is 25, corresponding to a significance of just over 4σ. The 1FGL
catalog includes source location regions, defined in terms of elliptical fits to
the 95% confidence regions and power-law spectral fits as well as flux
measurements in five energy bands for each source. In addition, monthly light
curves are provided. Using a protocol defined before launch we have tested for
several populations of gamma-ray sources among the sources in the catalog. For
individual LAT-detected sources we provide firm identifications or plausible
associations with sources in other astronomical catalogs. Identifications are
based on correlated variability with counterparts at other wavelengths, or on
spin or orbital periodicity. For the catalogs and association criteria that we
have selected, 630 of the sources are unassociated. Care was taken to
characterize the sensitivity of the results to the model of interstellar diffuse
gamma-ray emission used to model the bright foreground, with the result that 161
sources at low Galactic latitudes and toward bright local interstellar clouds
are flagged as having properties that are strongly dependent on the model or as
potentially being due to incorrectly modeled structure in the Galactic diffuse
emission.
ABSTRACT We report on radio timing and multiwavelength observations of the 4.66 ms redback pulsar J1048+2339, which was discovered in an Arecibo search targeting the Fermi-Large Area Telescope source ...3FGL J1048.6+2338. Two years of timing allowed us to derive precise astrometric and orbital parameters for the pulsar. PSR J1048+2339 is in a 6 hr binary and exhibits radio eclipses over half the orbital period and rapid orbital period variations. The companion has a minimum mass of 0.3 M , and we have identified a V ∼ 20 variable optical counterpart in data from several surveys. The phasing of its ∼1 mag modulation at the orbital period suggests highly efficient and asymmetric heating by the pulsar wind, which may be due to an intrabinary shock that is distorted near the companion, or to the companion's magnetic field channeling the pulsar wind to specific locations on its surface. We also present gamma-ray spectral analysis of the source and preliminary results from searches for gamma-ray pulsations using the radio ephemeris.
Abstract We have searched for radio pulsations toward 49 Fermi Large Area Telescope (LAT) 1FGL Catalog γ -ray sources using the Green Bank Telescope at 350 MHz. We detected 18 millisecond pulsars ...(MSPs) in blind searches of the data; 10 of these were discoveries unique to our survey. 16 are binaries, with eight having short orbital periods P B < 1 day. No radio pulsations from young pulsars were detected, although three targets are coincident with apparently radio-quiet γ -ray pulsars discovered in LAT data. Here, we give an overview of the survey and present radio and γ -ray timing results for the 10 MSPs discovered. These include the only isolated MSP discovered in our survey and six short- P B binary MSPs. Of these, three have very-low-mass companions ( M c ≪ 0.1 M ⊙ ) and hence belong to the class of black widow pulsars. Two have more massive, nondegenerate companions with extensive radio eclipses and orbitally modulated X-ray emission consistent with the redback class. Significant γ -ray pulsations have been detected from nine of the discoveries. This survey and similar efforts suggest that the majority of Galactic γ -ray sources at high Galactic latitudes are either MSPs or relatively nearby nonrecycled pulsars, with the latter having on average a much smaller radio/ γ -ray beaming ratio as compared to MSPs. It also confirms that past surveys suffered from an observational bias against finding short- P B MSP systems.
The frequency dependence of radio pulse arrival times provides a probe of structures in the intervening media. Demorest et al. was the first to show a short-term (∼100-200 days) reduction in the ...electron content along the line of sight to PSR J1713+0747 in data from 2008 (approximately MJD 54750) based on an apparent dip in the dispersion measure of the pulsar. We report on a similar event in 2016 (approximately MJD 57510), with average residual pulse-arrival times −3.0, −1.3, and −0.7 s at 820, 1400, and 2300 MHz, respectively. Timing analyses indicate possible departures from the standard −2 dispersive-delay dependence. We discuss and rule out a wide variety of potential interpretations. We find the likeliest scenario to be lensing of the radio emission by some structure in the interstellar medium, which causes multiple frequency-dependent pulse arrival-time delays.
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