Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme in humans, and a current and promising inhibition target for the development of new chemosensitizing agents due to its ability to remove DNA damage caused by topoisomerase 1 (Top1) poisons such as topotecan and irinotecan. Herein, we report our work on the synthesis and characterization of new Tdp1 inhibitors that combine the arylcoumarin (neoflavonoid) and monoterpenoid moieties. Our results showed that they are potent Tdp1 inhibitors with IC50 values in the submicromolar range. In vivo experiments with mice revealed that compound 3ba (IC50 0.62 µM) induced a significant increase in the antitumor effect of topotecan on the Krebs-2 ascites tumor model. Our results further strengthen the argument that Tdp1 is a druggable target with the potential to be developed into a clinically-potent adjunct therapy in conjunction with Top1 poisons

Azimuthal anisotropy in Au+Au collisions at sqrtsNN = 200 GeV

The results from the STAR Collaboration on directed flow (v_1), elliptic flow (v_2), and the fourth harmonic (v_4) in the anisotropic azimuthal distribution of particles from Au+Au collisions at sqrtsNN = 200 GeV are summarized and compared with results from other experiments and theoretical models. Results for identified particles are presented and fit with a Blast Wave model. Different anisotropic flow analysis methods are compared and nonflow effects are extracted from the data. For v_2, scaling with the number of constituent quarks and parton coalescence is discussed. For v_4, scaling with v_2^2 and quark coalescence is discussed.Comment: 26 pages. As accepted by Phys. Rev. C. Text rearranged, figures modified, but data the same. However, in Fig. 35 the hydro calculations are corrected in this version. The data tables are available at http://www.star.bnl.gov/central/publications/ by searching for "flow" and then this pape

Cancer Genomics Identifies Regulatory Gene Networks Associated with the Transition from Dysplasia to Advanced Lung Adenocarcinomas Induced by c-Raf-1

Background: Lung cancer is a leading cause of cancer morbidity. To improve an understanding of molecular causes of disease a transgenic mouse model was investigated where targeted expression of the serine threonine kinase c-Raf to respiratory epithelium induced initialy dysplasia and subsequently adenocarcinomas. This enables dissection of genetic events associated with precancerous and cancerous lesions. Methodology/Principal Findings: By laser microdissection cancer cell populations were harvested and subjected to whole genome expression analyses. Overall 473 and 541 genes were significantly regulated, when cancer versus transgenic and non-transgenic cells were compared, giving rise to three distinct and one common regulatory gene network. At advanced stages of tumor growth predominately repression of gene expression was observed, but genes previously shown to be upregulated in dysplasia were also up-regulated in solid tumors. Regulation of developmental programs as well as epithelial mesenchymal and mesenchymal endothelial transition was a hall mark of adenocarcinomas. Additionaly, genes coding for cell adhesion, i.e. the integrins and the tight and gap junction proteins were repressed, whereas ligands for receptor tyrosine kinase such as epi- and amphiregulin were up-regulated. Notably, Vegfr- 2 and its ligand Vegfd, as well as Notch and Wnt signalling cascades were regulated as were glycosylases that influence cellular recognition. Other regulated signalling molecules included guanine exchange factors that play a role in an activation of the MAP kinases while several tumor suppressors i.e. Mcc, Hey1, Fat3, Armcx1 and Reck were significantly repressed. Finally, probable molecular switches forcing dysplastic cells into malignantly transformed cells could be identified. Conclusions/Significance: This study provides insight into molecular pertubations allowing dysplasia to progress further to adenocarcinoma induced by exaggerted c-Raf kinase activity

Azimuthal Charged-Particle Correlations and Possible Local Strong Parity Violation

Parity-odd domains, corresponding to nontrivial topological solutions of the QCD vacuum, might be created during relativistic heavy-ion collisions. These domains are predicted to lead to charge separation of quarks along the system’s orbital momentum axis. We investigate a three-particle azimuthal correlator which is a P even observable, but directly sensitive to the charge separation effect. We report measurements of charged hadrons near center-of-mass rapidity with this observable in Au+Au and Cu+Cu collisions at √sNN=200  GeV using the STAR detector. A signal consistent with several expectations from the theory is detected. We discuss possible contributions from other effects that are not related to parity violation

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Incident energy dependence of p(t) correlations at relativistic energies

Journals published by the American Physical Society can be found at http://publish.aps.org/We present results for two-particle transverse momentum correlations, , as a function of event centrality for Au+Au collisions at root SNN = 20, 62, 130, and 200 GeV at the BNL Relativistic Heavy Ion Collider. We observe correlations decreasing with centrality that are similar at all four incident energies. The correlations multiplied by the multiplicity density increase with incident energy, and the centrality dependence may show evidence of processes such as thermalization, jet production, or the saturation of transverse flow. The square root of the correlations divided by the event-wise average transverse momentum per event shows little or no beam energy dependence and generally agrees with previous measurements made at the CERN Super Proton Synchrotron

Multistrange baryon elliptic flow in Au plus Au collisions at root(NN)-N-S=200 GeV

We report on the first measurement of elliptic flow nu(2)(p(T)) of multistrange baryons Xi(-)+Xi(+) and Omega(-)+Omega(+) in heavy-ion collisions. In minimum-bias Au+Au collisions at root s(NN)=200 GeV, a significant amount of elliptic flow, comparable to other nonstrange baryons, is observed for multistrange baryons which are expected to be particularly sensitive to the dynamics of the partonic stage of heavy-ion collisions. The p(T) dependence of nu(2) of the multistrange baryons confirms the number of constituent quark scaling previously observed for lighter hadrons. These results support the idea that a substantial fraction of the observed collective motion is developed at the early partonic stage in ultrarelativistic nuclear collisions at the Relativistic Heavy Ion Collider

Open charm yields in d+Au collisions at root s(NN)=200 GeV

Midrapidity open charm spectra from direct reconstruction of D-0((D) over bar (0))-->K(-/+)pi(+/-) in d(+)Au collisions and indirect electron-positron measurements via charm semileptonic decays in p+p and d+Au collisions at roots(NN)=200 GeV are reported. The D-0((D) over bar (0)) spectrum covers a transverse momentum (p(T)) range of 0.1< p(T) < 3 GeV/c, whereas the electron spectra cover a range of 1< p(T) < 4 GeV/c. The electron spectra show approximate binary collision scaling between p+p and d+Au collisions. From these two independent analyses, the differential cross section per nucleon-nucleon binary interaction at midrapidity for open charm production from d+Au collisions at BNL RHIC is dsigma(c)((c)) over bar (NN)/dy=0.30+/-0.04(stat)+/-0.09(syst) mb. The results are compared to theoretical calculations. Implications for charmonium results in A+A collisions are discussed

Effect of complex oxide promoters and Pd on activity and stability of Ni/YSZ (ScSZ) cermets as anode materials for IT SOFC

Effect of fluorite-like or perovskite-like complex oxide promoters, Pd and Cu on the performance of Ni/8YSZ and Ni/ScCeSZ anode materials in CH4 steam reforming (SR) or selective oxidation (SO) by O-2 into syngas was studied. The spatial distribution of dopants in composites before and after contact with the reaction feed, features of components mutual interaction and forms of deposited coke were controlled by TEM combined with EDX analysis. The lattice oxygen mobility and reactivity were estimated by CH4 and H-2 temperature-programmed reduction (TPR), and the amount of deposited carbon after operation in the feed with stoichiometric H2O/CH4 ratio was estimated by the temperature-programmed oxidation. Promoters decrease the amount of deposited coke, while doping by Pd or Cu ensures also a good and stable performance at moderate (similar to 550 degrees C) temperatures required for the intermediate-temperature solid oxide fuel cells (IT SOFC) operation. (c) 2007 Elsevier B.V. All rights reserved.</p