Imatinib Reverses Doxorubicin Resistance by Affecting Activation of STAT3-Dependent NF-κB and HSP27/p38/AKT Pathways and by Inhibiting ABCB1

Despite advances in cancer detection and prevention, a diagnosis of metastatic disease remains a death sentence due to the fact that many cancers are either resistant to chemotherapy (conventional or targeted) or develop resistance during treatment, and residual chemoresistant cells are highly metastatic. Metastatic cancer cells resist the effects of chemotherapeutic agents by upregulating drug transporters, which efflux the drugs, and by activating proliferation and survival signaling pathways. Previously, we found that c-Abl and Arg non-receptor tyrosine kinases are activated in breast cancer, melanoma, and glioblastoma cells, and promote cancer progression. In this report, we demonstrate that the c-Abl/Arg inhibitor, imatinib (imatinib mesylate, STI571, Gleevec), reverses intrinsic and acquired resistance to the anthracycline, doxorubicin, by inducing G2/M arrest and promoting apoptosis in cancer cells expressing highly active c-Abl and Arg. Significantly, imatinib prevents intrinsic resistance by promoting doxorubicin-mediated NF-κB/p65 nuclear localization and repression of NF-κB targets in a STAT3-dependent manner, and by preventing activation of a novel STAT3/HSP27/p38/Akt survival pathway. In contrast, imatinib prevents acquired resistance by inhibiting upregulation of the ABC drug transporter, ABCB1, directly inhibiting ABCB1 function, and abrogating survival signaling. Thus, imatinib inhibits multiple novel chemoresistance pathways, which indicates that it may be effective in reversing intrinsic and acquired resistance in cancers containing highly active c-Abl and Arg, a critical step in effectively treating metastatic disease. Furthermore, since imatinib converts a master survival regulator, NF-κB, from a pro-survival into a pro-apoptotic factor, our data suggest that NF-κB inhibitors may be ineffective in sensitizing tumors containing activated c-Abl/Arg to anthracyclines, and instead might antagonize anthracycline-induced apoptosis

Neighborhoods of trees in circular orderings

In phylogenetics, a common strategy used to construct an evolutionary tree for a set of species X is to search in the space of all such trees for one that optimizes some given score function (such as the minimum evolution, parsimony or likelihood score). As this can be computationally intensive, it was recently proposed to restrict such searches to the set of all those trees that are compatible with some circular ordering of the set X. To inform the design of efficient algorithms to perform such searches, it is therefore of interest to find bounds for the number of trees compatible with a fixed ordering in the neighborhood of a tree that is determined by certain tree operations commonly used to search for trees: the nearest neighbor interchange (nni), the subtree prune and regraft (spr) and the tree bisection and reconnection (tbr) operations. We show that the size of such a neighborhood of a binary tree associated with the nni operation is independent of the tree’s topology, but that this is not the case for the spr and tbr operations. We also give tight upper and lower bounds for the size of the neighborhood of a binary tree for the spr and tbr operations and characterize those trees for which these bounds are attained

Orientational phase transitions in the hexagonal phase of a diblock copolymer melt under shear flow

We generalize the earlier theory by Fredrickson [J. Rheol. v.38, 1045 (1994)] to study the orientational behaviour of the hexagonal phase of diblock copolymer melt subjected to steady shear flow. We use symmetry arguments to show that the orientational ordering in the hexagonal phase is a much weaker effect than in the lamellae. We predict the parallel orientation to be stable at low and the perpendicular orientation at high shear rates. Our analysis reproduces the experimental results by Tepe et al. [Macromolecules v.28, 3008 (1995)] and explains the difficulties in experimental observation of the different orientations in the hexagonal phase.Comment: 21 pages, 6 eps figures, submitted to Physical Review

Durability of Treatment Effect Using a Drug-Coated Balloon for Femoropopliteal Lesions

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Search for non-relativistic Magnetic Monopoles with IceCube

The IceCube Neutrino Observatory is a large Cherenkov detector instrumenting $1\,\mathrm{km}^3$ of Antarctic ice. The detector can be used to search for signatures of particle physics beyond the Standard Model. Here, we describe the search for non-relativistic, magnetic monopoles as remnants of the GUT (Grand Unified Theory) era shortly after the Big Bang. These monopoles may catalyze the decay of nucleons via the Rubakov-Callan effect with a cross section suggested to be in the range of $10^{-27}\,\mathrm{cm^2}$ to $10^{-21}\,\mathrm{cm^2}$. In IceCube, the Cherenkov light from nucleon decays along the monopole trajectory would produce a characteristic hit pattern. This paper presents the results of an analysis of first data taken from May 2011 until May 2012 with a dedicated slow-particle trigger for DeepCore, a subdetector of IceCube. A second analysis provides better sensitivity for the brightest non-relativistic monopoles using data taken from May 2009 until May 2010. In both analyses no monopole signal was observed. For catalysis cross sections of $10^{-22}\,(10^{-24})\,\mathrm{cm^2}$ the flux of non-relativistic GUT monopoles is constrained up to a level of $\Phi_{90} \le 10^{-18}\,(10^{-17})\,\mathrm{cm^{-2}s^{-1}sr^{-1}}$ at a 90% confidence level, which is three orders of magnitude below the Parker bound. The limits assume a dominant decay of the proton into a positron and a neutral pion. These results improve the current best experimental limits by one to two orders of magnitude, for a wide range of assumed speeds and catalysis cross sections.Comment: 20 pages, 20 figure

Deuteron and antideuteron production in Au+Au collisions at sqrt(s_NN)=200 GeV

The production of deuterons and antideuterons in the transverse momentum range 1.1 < p_T < 4.3 GeV/c at mid-rapidity in Au + Au collisions at sqrt(s_NN)=200 GeV has been studied by the PHENIX experiment at RHIC. A coalescence analysis comparing the deuteron and antideuteron spectra with those of protons and antiprotons, has been performed. The coalescence probability is equal for both deuterons and antideuterons and increases as a function of p_T, which is consistent with an expanding collision zone. Comparing (anti)proton yields p_bar/p = 0.73 +/- 0.01, with (anti)deuteron yields: d_bar/d = 0.47 +/- 0.03, we estimate that n_bar/n = 0.64 +/- 0.04.Comment: 326 authors, 6 pages text, 5 figures, 1 Table. Submitted to PRL. 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

Mid-Rapidity Direct-Photon Production in p+p Collisions at sqrt(s) = 200 GeV

A measurement of direct photons in p+p collisions at sqrt(s)=200 GeV is presented. A photon excess above background from pi^0 --> gamma+gamma, eta --> gamma+gamma, and other decays is observed in the transverse momentum range 5.5 < p_T < 7 GeV/c. The result is compared to a next-to-leading-order perturbative QCD calculation. Within errors, good agreement is found between the QCD calculation and the measured result.Comment: 330 authors, 7 pages text, RevTeX, 2 figures, 2 tables. Submitted to Physical Review 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

Suppressed pi^0 Production at Large Transverse Momentum in Central Au+Au Collisions at sqrt(s_NN) = 200 GeV

Transverse momentum spectra of neutral pions in the range 1 < p_T < 10 GeV/c have been measured at mid-rapidity by the PHENIX experiment at RHIC in Au+Au collisions at sqrt(s_NN) = 200 GeV. The pi^0 multiplicity in central reactions is significantly below the yields measured at the same sqrt(s_NN) in peripheral Au+Au and p+p reactions scaled by the number of nucleon-nucleon collisions. For the most central bin, the suppression factor is ~2.5 at p_T = 2 GeV/c and increases to ~4-5 at p_T ~= 4 GeV/c. At larger p_T, the suppression remains constant within errors. The deficit is already apparent in semi-peripheral reactions and increases smoothly with centrality.Comment: 326 authors, 6 pages text, RevTeX, 3 figures, 2 tables. Submitted to PRL. 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

Scaling properties of proton and anti-proton production in sqrt(s_NN) = 200 GeV Au + Au collisions

We report on the yield of protons and anti-protons, as a function of centrality and transverse momentum, in Au+Au collisions at sqrt(s_NN) = 200 GeV measured at mid-rapidity by the PHENIX experiment at RHIC. In central collisions at intermediate transverse momenta (1.5 < p_T < 4.5 GeV/c) a significant fraction of all produced particles are protons and anti-protons. They show a centrality-scaling behavior different from that of pions. The p-bar/pion and p/pion ratios are enhanced compared to peripheral Au+Au, p+p, and electron+positron collisions. This enhancement is limited to p_T < 5 GeV/c as deduced from the ratio of charged hadrons to pi^0 measured in the range 1.5 < p_T < 9 GeV/c.Comment: 325 authors, 6 pages text, 4 figures, RevTeX 4. Minor changes to text and figures to meet PRL length restrictions; no changes to figures; resubmitted to PRL. 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

J/Psi Production in Au-Au Collisions at sqrt(s_NN) = 200 GeV at the Relativistic Heavy Ion Collider

First results on charm quarkonia production in heavy ion collisions at the Relativistic Heavy Ion Collider (RHIC) are presented. The yield of J/Psi's measured in the PHENIX experiment via electron-positron decay pairs at mid-rapidity for Au-Au reactions at sqrt(s_NN) = 200 GeV are analyzed as a function of collision centrality. For this analysis we have studied 49.3 million minimum bias Au-Au reactions. We present the J/Psi invariant yield dN/dy for peripheral and mid-central reactions. For the most central collisions where we observe no signal above background, we quote 90% confidence level upper limits. We compare these results with our J/Psi measurement from proton-proton reactions at the same energy. We find that our measurements are not consistent with models that predict strong enhancement relative to binary collision scaling.Comment: 325 authors, 11 pages text, 6 figures, 4 tables, RevTeX 4. Accepted for publication as a regular article in Physical Review C. This version has minor changes to respond to referee suggestions. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are publicly available at http://www.phenix.bnl.gov/papers.htm