Histidine-Rich Glycoprotein Suppresses the S100A8/A9-Mediated Organotropic Metastasis of Melanoma Cells

The dissection of the complex multistep process of metastasis exposes vulnerabilities that could be exploited to prevent metastasis. To search for possible factors that favor metastatic outgrowth, we have been focusing on secretory S100A8/A9. A heterodimer complex of the S100A8 and S100A9 proteins, S100A8/A9 functions as a strong chemoattractant, growth factor, and immune suppressor, both promoting the cancer milieu at the cancer-onset site and cultivating remote, premetastatic cancer sites. We previously reported that melanoma cells show lung-tropic metastasis owing to the abundant expression of S100A8/A9 in the lung. In the present study, we addressed the question of why melanoma cells are not metastasized into the brain at significant levels in mice despite the marked induction of S100A8/A9 in the brain. We discovered the presence of plasma histidine-rich glycoprotein (HRG), a brain-metastasis suppression factor against S100A8/A9. Using S100A8/A9 as an affinity ligand, we searched for and purified the binding plasma proteins of S100A8/A9 and identified HRG as the major protein on mass spectrometric analysis. HRG prevents the binding of S100A8/A9 to the B16-BL6 melanoma cell surface via the formation of the S100A8/A9 complex. HRG also inhibited the S100A8/A9-induced migration and invasion of A375 melanoma cells. When we knocked down HRG in mice bearing skin melanoma, metastasis to both the brain and lungs was significantly enhanced. The clinical examination of plasma S100A8/A9 and HRG levels showed that lung cancer patients with brain metastasis had higher S100A8/A9 and lower HRG levels than nonmetastatic patients. These results suggest that the plasma protein HRG strongly protects the brain and lungs from the threat of melanoma metastasis

Functionalisation of PLLA nanofiber scaffolds using a possible cooperative effect between collagen type I and BMP-2: impact on growth and osteogenic differentiation of human mesenchymal stem cells

Mesenchymal stem cell differentiation of osteoblasts is triggered by a series of signaling processes including integrin and bone morphogenetic protein (BMP), which therefore act in a cooperative manner. The aim of this study was to analyze whether these processes can be remodeled in an artificial poly-(l)-lactide acid (PLLA) based nanofiber scaffold. Matrices composed of PLLA-collagen type I or BMP-2 incorporated PLLA-collagen type I were seeded with human mesenchymal stem cells (hMSC) and cultivated over a period of 22 days, either under growth or osteoinductive conditions. During the course of culture, gene expression of alkaline phosphatase (ALP), osteocalcin (OC) and collagen I (COL-I) as well as Smad5 and focal adhesion kinase (FAK), two signal transduction molecules involved in BMP-2 or integrin signaling were analyzed. Furthermore, calcium and collagen I deposition, as well as cell densities and proliferation, were determined using fluorescence microscopy. The incorporation of BMP-2 into PLLA-collagen type I nanofibers resulted in a decrease in diameter as well as pore sizes of the scaffold. Mesenchymal stem cells showed better adherence and a reduced proliferation on BMP-containing scaffolds. This was accompanied by an increase in gene expression of ALP, OC and COL-I. Furthermore the presence of BMP-2 resulted in an upregulation of FAK, while collagen had an impact on the gene expression of Smad5. Therefore these different strategies can be combined in order to enhance the osteoblast differentiation of hMSC on PLLA based nanofiber scaffold. By doing this, different signal transduction pathways seem to be up regulated

Measurement of the proton-air cross section with Telescope Array's Middle Drum detector and surface array in hybrid mode

In this work we are reporting on the measurement of the proton-air inelastic cross section sigma(inel)(p-air) using the Telescope Array detector. Based on the measurement of the sigma(inel)(p-air), the proton-proton cross section sigma(p-p) value is also determined at root s = 95(-8)(+5) TeV. Detecting cosmic ray events at ultrahigh energies with the Telescope Array enables us to study this fundamental parameter that we are otherwise unable to access with particle accelerators. The data used in this report are the hybrid events observed by the Middle Drum fluorescence detector together with the surface array detector collected over five years. The value of the sigma(inel)(p-air) is found to be equal to 567.0 +/- 70.5[Stat](-25)(+29)[Sys] mb. The total proton-proton cross section is subsequently inferred from Glauber formalism and the Block, Halzen and Stanev QCD inspired fit and is found to be equal to 170(-44)(+48)[Stat](-17)(+19)[Sys] mb.open20

Indications of intermediate-scale anisotropy of cosmic rays with energy greater than 57 EeV in the northern sky measured with the surface detector of the Telescope Array experiment

We have searched for intermediate-scale anisotropy in the arrival directions of ultrahigh-energy cosmic rays with energies above 57 EeV in the northern sky using data collected over a 5 yr period by the surface detector of the Telescope Array experiment. We report on a cluster of events that we call the hotspot, found by oversampling using 20?? radius circles. The hotspot has a Li-Ma statistical significance of 5.1??, and is centered at R.A. = 146.??7, decl. = 43.??2. The position of the hotspot is about 19?? off of the supergalactic plane. The probability of a cluster of events of 5.1?? significance, appearing by chance in an isotropic cosmic-ray sky, is estimated to be 3.7 ?? 10-4 (3.4??).open2

A NORTHERN SKY SURVEY FOR POINT-LIKE SOURCES OF EeV NEUTRAL PARTICLES WITH THE TELESCOPE ARRAY EXPERIMENT

We report on the search for steady point-like sources of neutral particles around 10(18) eV between 2008 and 2013 May with the scintillator SD of the Telescope Array experiment. We found overall no significant point-like excess above 0.5 EeV in the northern sky. Subsequently, we also searched for coincidence with the Fermi bright Galactic sources. No significant coincidence was found within the statistical uncertainty. Hence, we set an upper limit on the neutron flux that corresponds to an averaged flux of 0.07 km(-2) yr(-1) for E > 1 EeV in the northern sky at the 95% confidence level. This is the most stringent flux upper limit in a northern sky survey assuming point-like sources. The upper limit at the 95% confidence level on the neutron flux from Cygnus X-3 is also set to 0.2 km(-2) yr(-1) for E > 0.5 EeV. This is an order of magnitude lower than previous flux measurementsopen0

Update on the Combined Analysis of Muon Measurements from Nine Air Shower Experiments

Over the last two decades, various experiments have measured muon densities in extensive air showers over several orders of magnitude in primary energy. While some experiments observed differences in the muon densities between simulated and experimentally measured air showers, others reported no discrepancies. We will present an update of the meta-analysis of muon measurements from nine air shower experiments, covering shower energies between a few PeV and tens of EeV and muon threshold energies from a few 100 MeV to about 10GeV. In order to compare measurements from different experiments, their energy scale was cross-calibrated and the experimental data has been compared using a universal reference scale based on air shower simulations. Above 10 PeV, we find a muon excess with respect to simulations for all hadronic interaction models, which is increasing with shower energy. For EPOS-LHC and QGSJet-II.04 the significance of the slope of the increase is analyzed in detail under different assumptions of the individual experimental uncertainties