Acidic microenvironment plays a key role in human melanoma progression through a sustained exosome mediated transfer of clinically relevant metastatic molecules

Background: Microenvironment cues involved in melanoma progression are largely unknown. Melanoma is highly influenced in its aggressive phenotype by the changes it determinates in its microenvironment, such as pH decrease, in turn influencing cancer cell invasiveness, progression and tissue remodelling through an abundant secretion of exosomes, dictating cancer strategy to the whole host. A role of exosomes in driving melanoma progression under microenvironmental acidity was never described. Methods: We studied four differently staged human melanoma lines, reflecting melanoma progression, under microenvironmental acidic pHs pressure ranging between pH 6.0-6.7. To estimate exosome secretion as a function of tumor stage and environmental pH, we applied a technique to generate native fluorescent exosomes characterized by vesicles integrity, size, density, markers expression, and quantifiable by direct FACS analysis. Functional roles of exosomes were tested in migration and invasion tests. Then we performed a comparative proteomic analysis of acid versus control exosomes to elucidate a specific signature involved in melanoma progression. Results: We found that metastatic melanoma secretes a higher exosome amount than primary melanoma, and that acidic pH increases exosome secretion when melanoma is in an intermediate stage, i.e. metastatic non-invasive. We were thus able to show that acidic pH influences the intercellular cross-talk mediated by exosomes. In fact when exposed to exosomes produced in an acidic medium, pH naïve melanoma cells acquire migratory and invasive capacities likely due to transfer of metastatic exosomal proteins, favoring cell motility and angiogenesis. A Prognoscan-based meta-analysis study of proteins enriched in acidic exosomes, identified 11 genes (HRAS, GANAB, CFL2, HSP90B1, HSP90AB1, GSN, HSPA1L, NRAS, HSPA5, TIMP3, HYOU1), significantly correlating with poor prognosis, whose high expression was in part confirmed in bioptic samples of lymph node metastases. Conclusions: A crucial step of melanoma progression does occur at melanoma intermediate -stage, when extracellular acidic pH induces an abundant release and intra-tumoral uptake of exosomes. Such exosomes are endowed with pro-invasive molecules of clinical relevance, which may provide a signature of melanoma advancement

Trust in the public sector: Is there any evidence for a long-term decline?

Concerns with declining public trust in government have become a permanent element of the contemporary political discourse. This concern also extends to levels of citizens’ trust in the public administration and public services. Trust is said to be declining, and this decline is generally seen as detrimental to public service delivery. In this article, we examine the main elements in this discussion, review the existing international survey data and summarise the main findings for OECD countries. Citizens’ trust in the public sector is found to fluctuate, and the data generally do not show consistently declining levels of trust. Furthermore, in some countries there simply is insufficient data to come to any conclusions at all about time trends in citizen trust in the public sector. Points for practitioners This article summarises some of the survey material on citizens’ trust in the public administration. It allows practitioners to compare trends in public trust in their country across time and space. The findings lead us to reject the hypothesis of a universal decline of trust in the public sector. The article warns against using opinion poll results without considering context. The long-term and comparative perspective on citizens’ trust in the public sector is all too often absent from the policy discourse that is frequently based on assumptions and ad-hoc approaches

Production of π0 and η mesons in Cu+Au collisions at sNN =200 GeV

Production of π0 and η mesons has been measured at midrapidity in Cu+Au collisions at sNN=200GeV. Measurements were performed in π0(η)→γγ decay channel in the 1(2)-20GeV/c transverse momentum range. A strong suppression is observed for π0 and η meson production at high transverse momentum in central Cu+Au collisions relative to the p+p results scaled by the number of nucleon-nucleon collisions. In central collisions the suppression is similar to Au+Au with comparable nuclear overlap. The η/π0 ratio measured as a function of transverse momentum is consistent with mT-scaling parametrization down to pT=2GeV/c, its asymptotic value is constant and consistent with Au+Au and p+p and does not show any significant dependence on collision centrality. Similar results were obtained in hadron-hadron, hadron-nucleus, and nucleus-nucleus collisions as well as in e+e- collisions in a range of collision energies sNN=3-1800 GeV. This suggests that the quark-gluon-plasma medium produced in Cu+Cu collisions either does not affect the jet fragmentation into light mesons or it affects the π0 and η the same way

Cross Section and Transverse Single-Spin Asymmetry of η\eta Mesons in p↑+pp^{\uparrow}+p Collisions at s=200\sqrt{s}=200 GeV at Forward Rapidity

We present a measurement of the cross section and transverse single-spin asymmetry ($A_N$) for $\eta$ mesons at large pseudorapidity from $\sqrt{s}=200$~GeV $p^{\uparrow}+p$ collisions. The measured cross section for $0.5<p_T<5.0$~GeV/$c$ and $3.0<|\eta|<3.8$ is well described by a next-to-leading-order perturbative-quantum-chromodynamics calculation. The asymmetries $A_N$ have been measured as a function of Feynman-$x$ ($x_F$) from $0.2<|x_{F}|<0.7$, as well as transverse momentum ($p_T$) from $1.0<p_T<4.5$~GeV/$c$. The asymmetry averaged over positive $x_F$ is $\langle{A_{N}}\rangle=0.061{\pm}0.014$. The results are consistent with prior transverse single-spin measurements of forward $\eta$ and $\pi^{0}$ mesons at various energies in overlapping $x_F$ ranges. Comparison of different particle species can help to determine the origin of the large observed asymmetries in $p^{\uparrow}+p$ collisions.Comment: 484 authors, 13 pages, 11 figures, 4 tables, 2008 data. v2 is version accepted by Phys. Rev. D. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be)publicly available at http://www.phenix.bnl.gov/papers.htm

Single electron yields from semileptonic charm and bottom hadron decays in Au++Au collisions at sNN=200\sqrt{s_{NN}}=200 GeV

The PHENIX Collaboration at the Relativistic Heavy Ion Collider has measured open heavy-flavor production in minimum bias Au$+$Au collisions at $\sqrt{s_{_{NN}}}=200$ GeV via the yields of electrons from semileptonic decays of charm and bottom hadrons. Previous heavy-flavor electron measurements indicated substantial modification in the momentum distribution of the parent heavy quarks due to the quark-gluon plasma created in these collisions. For the first time, using the PHENIX silicon vertex detector to measure precision displaced tracking, the relative contributions from charm and bottom hadrons to these electrons as a function of transverse momentum are measured in Au$+$Au collisions. We compare the fraction of electrons from bottom hadrons to previously published results extracted from electron-hadron correlations in $p$$+$$p$ collisions at $\sqrt{s_{_{NN}}}=200$ GeV and find the fractions to be similar within the large uncertainties on both measurements for $p_T>4$ GeV/$c$. We use the bottom electron fractions in Au$+$Au and $p$$+$$p$ along with the previously measured heavy flavor electron $R_{AA}$ to calculate the $R_{AA}$ for electrons from charm and bottom hadron decays separately. We find that electrons from bottom hadron decays are less suppressed than those from charm for the region $3<p_T<4$ GeV/$c$.Comment: 432 authors, 33 pages, 23 figures, 2 tables, 2011 data. v2 is version accepted for publication by Phys. Rev. C. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Medium modification of jet fragmentation in Au+Au collisions at sqrt(s_NN)=200 GeV measured in direct photon-hadron correlations

The jet fragmentation function is measured with direct photon-hadron correlations in p+p and Au+Au collisions at sqrt(s_NN)=200 GeV. The p_T of the photon is an excellent approximation to the initial p_T of the jet and the ratio z_T=p_T^h/p_T^\gamma is used as a proxy for the jet fragmentation function. A statistical subtraction is used to extract the direct photon-hadron yields in Au+Au collisions while a photon isolation cut is applied in p+p. I_ AA, the ratio of jet fragment yield in Au+Au to that in p+p, indicates modification of the jet fragmentation function. Suppression, most likely due to energy loss in the medium, is seen at high z_T. The fragment yield at low z_T is enhanced at large angles. Such a trend is expected from redistribution of the lost energy into increased production of low-momentum particles.Comment: 562 authors, 70 insitutions, 8 pages, and 3 figures. Submitted to Phys. Rev. Lett. v2 has minor changes to improve clarity. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

L\'evy-stable two-pion Bose-Einstein correlations in sNN=200\sqrt{s_{_{NN}}}=200 GeV Au++Au collisions

We present a detailed measurement of charged two-pion correlation functions in 0%-30% centrality $\sqrt{s_{_{NN}}}=200$ GeV Au$+$Au collisions by the PHENIX experiment at the Relativistic Heavy Ion Collider. The data are well described by Bose-Einstein correlation functions stemming from L\'evy-stable source distributions. Using a fine transverse momentum binning, we extract the correlation strength parameter $\lambda$, the L\'evy index of stability $\alpha$ and the L\'evy length scale parameter $R$ as a function of average transverse mass of the pair $m_T$. We find that the positively and the negatively charged pion pairs yield consistent results, and their correlation functions are represented, within uncertainties, by the same L\'evy-stable source functions. The $\lambda(m_T)$ measurements indicate a decrease of the strength of the correlations at low $m_T$. The L\'evy length scale parameter $R(m_T)$ decreases with increasing $m_T$, following a hydrodynamically predicted type of scaling behavior. The values of the L\'evy index of stability $\alpha$ are found to be significantly lower than the Gaussian case of $\alpha=2$, but also significantly larger than the conjectured value that may characterize the critical point of a second-order quark-hadron phase transition.Comment: 448 authors, 25 pages, 11 figures, 4 tables, 2010 data. v2 is version accepted for publication in Phys. Rev. C. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm