Despite the initial effectiveness of the tyrosine kinase inhibitor lapatinib against HER2 gene-amplified breast cancers, most patients eventually relapse after treatment, implying that tumors acquire ...mechanisms of drug resistance. To discover these mechanisms, we generated six lapatinib-resistant HER2-overexpressing human breast cancer cell lines. In cells that grew in the presence of lapatinib, HER2 autophosphorylation was undetectable, whereas active phosphoinositide-3 kinase (PI3K)-Akt and mitogen-activated protein kinase (MAPK) were maintained. To identify networks maintaining these signaling pathways, we profiled the tyrosine phosphoproteome of sensitive and resistant cells using an immunoaffinity-enriched mass spectrometry method. We found increased phosphorylation of Src family kinases (SFKs) and putative Src substrates in several resistant cell lines. Treatment of these resistant cells with Src kinase inhibitors partially blocked PI3K-Akt signaling and restored lapatinib sensitivity. Further, SFK mRNA expression was upregulated in primary HER2+ tumors treated with lapatinib. Finally, the combination of lapatinib and the Src inhibitor AZD0530 was more effective than lapatinib alone at inhibiting pAkt and growth of established HER2-positive BT-474 xenografts in athymic mice. These data suggest that increased Src kinase activity is a mechanism of lapatinib resistance and support the combination of HER2 antagonists with Src inhibitors early in the treatment of HER2+ breast cancers in order to prevent or overcome resistance to HER2 inhibitors.
We present the first catalog of TeV gamma-ray sources realized with data from the newly completed High Altitude Water Cherenkov Observatory (HAWC). It is the most sensitive wide field-of-view TeV ...telescope currently in operation, with a one-year survey sensitivity of ∼5%-10% of the flux of the Crab Nebula. With an instantaneous field of view >1.5 sr and >90% duty cycle, it continuously surveys and monitors the sky for gamma-ray energies between hundreds of GeV and tens of TeV. HAWC is located in Mexico, at a latitude of 19° N, and was completed in 2015 March. Here, we present the 2HWC catalog, which is the result of the first source search performed with the complete HAWC detector. Realized with 507 days of data, it represents the most sensitive TeV survey to date for such a large fraction of the sky. A total of 39 sources were detected, with an expected number of false detections of 0.5 due to background fluctuation. Out of these sources, 19 are new sources that are not associated with previously known TeV sources (association criteria: <0 5 away). The source list, including the position measurement, spectrum measurement, and uncertainties, is reported, then each source is briefly discussed. Of the 2HWC associated sources, 10 are reported in TeVCat as PWN or SNR: 2 as blazars and the remaining eight as unidentified.
We present a new catalog of TeV gamma-ray sources using 1523 days of data from the High-Altitude Water Cherenkov (HAWC) Observatory. The catalog represents the most sensitive survey of the northern ...gamma-ray sky at energies above several TeV, with three times the exposure compared to the previous HAWC catalog, 2HWC. We report 65 sources detected at ≥5 significance, along with the positions and spectral fits for each source. The catalog contains eight sources that have no counterpart in the 2HWC catalog, but are within 1° of previously detected TeV emitters, and 20 sources that are more than 1° away from any previously detected TeV source. Of these 20 new sources, 14 have a potential counterpart in the fourth Fermi Large Area Telescope catalog of gamma-ray sources. We also explore potential associations of 3HWC sources with pulsars in the Australia Telescope National Facility (ATNF) pulsar catalog and supernova remnants in the Galactic supernova remnant catalog.
We report on anomalously long duration (2 ms) count rate bursts following the impact of cosmic ray showers near a 7.62 cm x⊘7.62 cm LaBr3 scintillation detector at the High Altitude Water Cherenkov ...array in Mexico, previously described by Stenkin et al. (2001), and termed “neutron bursts.” The largest burst produced 198 counts within 2 ms in our LaBr3 detector. We simulate the neutron burst albedo flux (that is, secondary emissions from an extensive air shower core impacting the ground), and show that (1) the characteristic spectra and count rates are well explained by neutron absorption in the ground and (2) any cosmic ray secondary that produces neutrons, either through hadron inelastic collisions, or photoneutron production by gamma‐rays, produces the same characteristic spectra. This implies that other natural phenomena that produce downward beams of gamma‐rays, like Terrestrial gamma ray flashes, should produce a similar “neutron burst” signature from the photoneutron reactions occurring in the soil.
Plain Language Summary
When very large cosmic ray showers (CRS) impact the ground, neutrons are produced in the soil that will rattle around until they become captured by soil particles and release energetic gamma‐rays. This produces a slow explosion of particles emanating from the ground following a CRS impact, and is termed a 'neutron burst'. We present recent observations of neutron bursts from a hand held sized gamma‐ray detector at the High Altitude Water Cherenkov (HAWC) array in Mexico, that exhibit interesting spectral features (the presence of positron annihilation), and an interesting time structure (hundreds of counts within a few ms). Our simulations indicate that Terrestrial gamma‐ray flashes (TGFs, bursts of gamma‐rays associated with lightning) should also produce these neutron bursts. An implication of this work is that existing deployments of ground based TGF instruments, comprised of small gamma‐ray detectors, can additionally be used to observe signatures of large cosmic ray showers on clear days.
Key Points
We report on fairweather count rate bursts with 2 ms duration following the impact of a large cosmic ray shower near a small scintillation detector at HAWC
Simulations show that the spectra and decay time can be produced by either hadronic interactions, or photoneutron reactions from gamma‐rays
These results imply that downward TGFs could produce a similar delayed neutron signature in the soil near ground based detectors
► All-particle energy spectrum of cosmic rays between knee and ankle is not a single power law. ► Just above 1016eV the spectrum exhibits a hardening. ► Around 8×1016eV there is a knee-like feature ...in the spectrum.
The energy spectrum of cosmic rays between 1016eV and 1018eV, derived from measurements of the shower size (total number of charged particles) and the total muon number of extensive air showers by the KASCADE-Grande experiment, is described. The resulting all-particle energy spectrum exhibits strong hints for a hardening of the spectrum at approximately 2·1016eV and a significant steepening at ≈8·1016eV. These observations challenge the view that the spectrum is a single power law between knee and ankle. Possible scenarios generating such features are discussed in terms of astrophysical processes that may explain the transition region from galactic to extragalactic origin of cosmic rays.
Monocytes and macrophages express cell-surface markers indicative of their inflammatory and activation status. In this study, we investigated whether these markers are affected or correlated in ...non-obese T2D subjects, or glycemic/metabolic control variables.
Clinical data was recorded, and peripheral blood drawn from T2D patients (n = 28) and control subjects (n = 27). Isolated monocytes were evaluated by flow cytometry for the expression of CD14, CD16, and the phenotypic markers for the different states of activation spectrum, such as pro-inflammatory (M1) (HLA-DR, CD86), anti-inflammatory/pro-resolving (M2) (CD163, CD206, MERTK, PD-L1) and metabolically-activated (MMe) (CD36, ABCA-1). From a subset of individuals, monocytes-derived macrophages (MDM) were obtained and evaluated for phenotypic markers. A correlation analysis was performed between the clinical variables and the marker expression.
The frequency of CD14++CD16− monocytes was lower in T2D patients and it correlates negatively with poor control in glycemic and metabolic variables. T2D monocytes expressed lower levels of HLA-DR, CD86, PD-L1, and CD163, which correlated negatively with poor metabolic control. In MDM from T2D patients, HLA-DR, CD86 and CD163 expression was lower and it inversely correlated with deficient glycemic or metabolic control parameters.
The glycemic/metabolic control associated with T2D influences monocyte and MDM phenotypes toward an immune-suppressive phenotype.
•The frequency of classical monocytes (CM) is lower in monocytes from T2D patients.•Glycemic and metabolic control negatively correlates with CM frequencies.•In T2D, monocytes/MDM show lower M1 and M2 markers expression without changes in MMe.•Poor metabolic control influences HLA-DR, CD86, and CD163 expression (monos and MDM).
The ‘KASCADE Cosmic ray Data Centre’ is a web portal (
https://kcdc.ikp.kit.edu
), where the data of the astroparticle physics experiment KASCADE-Grande are made available for the interested public. ...The KASCADE experiment was a large-area detector for the measurement of high-energy cosmic rays via the detection of extensive air showers. The multi-detector installations KASCADE and its extension KASCADE-Grande stopped the active data acquisition in 2013 after more than 20 years of data taking. In several updates since our first release in 2013 with KCDC we provide the public measured and reconstructed parameters of more than 433 million air showers. In addition, KCDC provides meta data information and documentation to enable a user outside the community of experts to perform their own data analysis. Simulation data from three different high energy interaction models have been made available as well as a compilation of measured and published spectra from various experiments. In addition, detailed educational examples shall encourage high-school students and early stage researchers to learn about astroparticle physics, cosmic radiation as well as the handling of Big Data and about the sustainable and public provision of scientific data.
The KASCADE-Grande air shower experiment 1 consists of, among others, a large scintillator array for measurements of charged particles, Nch, and of an array of shielded scintillation counters used ...for muon counting, Nμ. KASCADE-Grande is optimized for cosmic ray measurements in the energy range 10PeV to about 2000PeV, where exploring the composition is of fundamental importance for understanding the transition from galactic to extragalactic origin of cosmic rays. Following earlier studies of the all-particle and the elemental spectra reconstructed in the knee energy range from KASCADE data 2, we have now extended these measurements to beyond 200PeV. By analysing the two-dimensional shower size spectrum Nch vs. Nμ for nearly vertical events, we reconstruct the energy spectra of different mass groups by means of unfolding methods over an energy range where the detector is fully efficient. The procedure and its results, which are derived based on the hadronic interaction model QGSJET-II-02 and which yield a strong indication for a dominance of heavy mass groups in the covered energy range and for a knee-like structure in the iron spectrum at around 80PeV, are presented. This confirms and further refines the results obtained by other analyses of KASCADE-Grande data, which already gave evidence for a knee-like structure in the heavy component of cosmic rays at about 80PeV 3.
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