Methotrexate exacerbates tumor progression in a murine model of chronic myeloid leukemia

ABSTRACT Expression of drug-resistant forms of dihydrofolate reductase (DHFR) in hematopoietic cells confers substantial resistance of animals to antifolate administration. In this study, we tested whether the chemoprotection conferred by expression of the tyrosine-22 variant DHFR could be used for more effective therapy of the 32Dp210 murine model of chronic myeloid leukemia (CML). 32Dp210 tumor cells were found to be sensitive to methotrexate (MTX) in vitro, whereas cells expressing the tyrosine-22 DHFR gene were protected from MTX at up to micromolar concentrations. MTX administered at low dose (2 mg/kg/day) did not protect normal C3H-He/J mice from 32Dp210 tumor infused intravenously, with drug toxicity limiting the administration of higher doses. Animals engrafted with transgenic tyrosine-22 DHFR marrow were protected from greater MTX doses (up to 6 mg/kg/day). However, the increased doses of MTX afforded by drug-resistance gene expression surprisingly resulted in decreased survival of the transplanted tumor-bearing animals, with increased levels of tumor detected in peripheral blood. This apparent exacerbation of tumor progression by MTX was not observed in DHFR transgenic mice in which all cells and tissues contain the drugresistance gene. This suggests that increased tumor progression in MTX-administered animals resulted from MTX sensitivity of a nonhematopoietic host component, thus allowing tumor expansion. We conclude that MTX exacerbates tumor progression in the 32Dp210 model of CML, and that based on this model alternate DHFR inhibitors combined with drug-resistant DHFR or other chemotherapeutic agent/drug-resistance gene combinations may be required for the application of drugresistance gene expression to the treatment of CML

System size dependence of cluster properties from two-particle angular correlations in Cu+Cu and Au+Au collisions at sNN\sqrt{s_{_{NN}}} = 200 GeV

We present results on two-particle angular correlations in Cu+Cu and Au+Au collisions at a center of mass energy per nucleon pair of 200 GeV over a broad range of pseudorapidity ($\eta$) and azimuthal angle ($\phi$) as a function of collision centrality. The PHOBOS detector at RHIC has a uniquely-large angular coverage for inclusive charged particles, which allows for the study of correlations on both long- and short-range scales. A complex two-dimensional correlation structure in $\Delta \eta$ and $\Delta \phi$ emerges, which is interpreted in the context of a cluster model. The effective cluster size and decay width are extracted from the two-particle pseudorapidity correlation functions. The effective cluster size found in semi-central Cu+Cu and Au+Au collisions is comparable to that found in proton-proton collisions but a non-trivial decrease of the size with increasing centrality is observed. Moreover, a comparison between results from Cu+Cu and Au+Au collisions shows an interesting scaling of the effective cluster size with the measured fraction of total cross section (which is related to the ratio of the impact parameter to the nuclear radius, $b/2R$), suggesting a geometric origin. Further analysis for pairs from restricted azimuthal regions shows that the effective cluster size at $\Delta\phi \sim 180^{\circ}$ drops more rapidly toward central collisions than the size at $\Delta\phi \sim 0^{\circ}$. The effect of limited $\eta$ acceptance on the cluster parameters is also addressed, and a correction is applied to present cluster parameters for full $\eta$ coverage, leading to much larger effective cluster sizes and widths than previously noted in the literature. These results should provide insight into the hot and dense medium created in heavy ion collisions.Comment: 9 pages, 8 figures, Published in Phys. Rev.

ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA

The cytosolic antiviral innate immune sensor RIG-I distinguishes 5' tri- or diphosphate containing viral double-stranded (ds) RNA from self-RNA by an incompletely understood mechanism that involves ATP hydrolysis by RIG-I's RNA translocase domain. Recently discovered mutations in ATPase motifs can lead to the multi-system disorder Singleton-Merten Syndrome (SMS) and increased interferon levels, suggesting misregulated signaling by RIG-I. Here we report that SMS mutations phenocopy a mutation that allows ATP binding but prevents hydrolysis. ATPase deficient RIG-I constitutively signals through endogenous RNA and co-purifies with self-RNA even from virus infected cells. Biochemical studies and cryo-electron microscopy identify a 60S ribosomal expansion segment as a dominant self-RNA that is stably bound by ATPase deficient RIG-I. ATP hydrolysis displaces wild-type RIG-I from this self-RNA but not from 5' triphosphate dsRNA. Our results indicate that ATP-hydrolysis prevents recognition of self-RNA and suggest that SMS mutations lead to unintentional signaling through prolonged RNA binding

ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA

The cytosolic antiviral innate immune sensor RIG-I distinguishes 5' tri- or diphosphate containing viral double-stranded (ds) RNA from self-RNA by an incompletely understood mechanism that involves ATP hydrolysis by RIG-I's RNA translocase domain. Recently discovered mutations in ATPase motifs can lead to the multi-system disorder Singleton-Merten Syndrome (SMS) and increased interferon levels, suggesting misregulated signaling by RIG-I. Here we report that SMS mutations phenocopy a mutation that allows ATP binding but prevents hydrolysis. ATPase deficient RIG-I constitutively signals through endogenous RNA and co-purifies with self-RNA even from virus infected cells. Biochemical studies and cryo-electron microscopy identify a 60S ribosomal expansion segment as a dominant self-RNA that is stably bound by ATPase deficient RIG-I. ATP hydrolysis displaces wild-type RIG-I from this self-RNA but not from 5' triphosphate dsRNA. Our results indicate that ATP-hydrolysis prevents recognition of self-RNA and suggest that SMS mutations lead to unintentional signaling through prolonged RNA binding

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Nucleon-Gold Collisions at 200 AGeV Using Tagged d+Au Interactions in PHOBOS

Forward calorimetry in the PHOBOS detector has been used to study charged hadron production in d+Au, p+Au and n+Au collisions at sqrt(s_nn) = 200 GeV. The forward proton calorimeter detectors are described and a procedure for determining collision centrality with these detectors is detailed. The deposition of energy by deuteron spectator nucleons in the forward calorimeters is used to identify p+Au and n+Au collisions in the data. A weighted combination of the yield of p+Au and n+Au is constructed to build a reference for Au+Au collisions that better matches the isospin composition of the gold nucleus. The p_T and centrality dependence of the yield of this improved reference system is found to match that of d+Au. The shape of the charged particle transverse momentum distribution is observed to extrapolate smoothly from pbar+p to central d+Au as a function of the charged particle pseudorapidity density. The asymmetry of positively- and negatively-charged hadron production in p+Au is compared to that of n+Au. No significant asymmetry is observed at mid-rapidity. These studies augment recent results from experiments at the LHC and RHIC facilities to give a more complete description of particle production in p+A and d+A collisions, essential for the understanding the medium produced in high energy nucleus-nucleus collisions.Comment: 17 pages, 18 figure

Search for new physics in events with same-sign dileptons and jets in pp collisions at √s = 8 TeV

A search for new physics is performed based on events with jets and a pair of isolated, same-sign leptons. The results are obtained using a sample of proton-proton collision data collected by the CMS experiment at a centre-of-mass energy of 8 TeV at the LHC, corresponding to an integrated luminosity of 19.5 fb[superscript −1]. In order to be sensitive to a wide variety of possible signals beyond the standard model, multiple search regions defined by the missing transverse energy, the hadronic energy, the number of jets and b-quark jets, and the transverse momenta of the leptons in the events are considered. No excess above the standard model background expectation is observed and constraints are set on a number of models for new physics, as well as on the same-sign top-quark pair and quadruple-top-quark production cross sections. Information on event selection efficiencies is also provided, so that the results can be used to confront an even broader class of new physics models.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Search for physics beyond the standard model in events with two leptons, jets, and missing transverse momentum in pp collisions at √s = 8 TeV

A search is presented for physics beyond the standard model in final states with two opposite-sign same-flavor leptons, jets, and missing transverse momentum. The data sample corresponds to an integrated luminosity of 19.4 fb[superscript −1] of proton-proton collisions at √s = 8 TeV collected with the CMS detector at the CERN LHC in 2012. The analysis focuses on searches for a kinematic edge in the invariant mass distribution of the oppositesign same-flavor lepton pair and for final states with an on-shell Z boson. The observations are consistent with expectations from standard model processes and are interpreted in terms of upper limits on the production of supersymmetric particles.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Experimental Study of the Shortest Reset Word of Random Automata

In this paper we describe an approach to finding the shortest reset word of a finite synchronizing automaton by using a SAT solver. We use this approach to perform an experimental study of the length of the shortest reset word of a finite synchronizing automaton. The largest automata we considered had 100 states. The results of the experiments allow us to formulate a hypothesis that the length of the shortest reset word of a random finite automaton with $n$ states and 2 input letters with high probability is sublinear with respect to $n$ and can be estimated as $1.95 n^{0.55}.