UCN-01 (7-hydroxystaurosporine) inhibits DNA repair and increases cytotoxicity in normal lymphocytes and chronic lymphocytic leukemia lymphocytes.

Elevated DNA repair processes represent resistance mechanisms to the treatment of malignancies with alkylating agents. Recently, the cell cycle checkpoint abrogator, UCN-01, was reported to inhibit nucleotide excision repair in cell-free systems. We hypothesized that if UCN-01 was combined with DNA-damaging agents, UCN-01 might inhibit the damage repair processes, thereby enhancing cytotoxicity in quiescent cells. Here, we investigated the effect of UCN-01 on DNA repair and viability of quiescent normal lymphocytes and chronic lymphocytic leukemia lymphocytes treated with UV or the cyclophosphamide prodrug 4-hydroperoxycyclophosphamide (4-HC). DNA damage repair kinetics were determined as DNA single strand breaks by the alkaline single cell gel electrophoresis (comet) assay and by [3H]thymidine incorporation. Pretreatment with UCN-01 inhibited DNA repair initiated by UV or 4-HC in normal lymphocytes as well as chronic lymphocytic leukemia lymphocytes in a concentration-dependent manner at clinically relevant levels (50-300 nM). This inhibition was demonstrated by the decreases in incision capability, DNA resynthesis, and in rejoining, suggesting that UCN-01 inhibits the multiple sites of the repair processes. The higher UCN-01 concentration (300 nM) maximized the inhibitory effects and enhanced the UV- or 4-HC-induced cytotoxicity, as determined by annexin V binding or Hoechst 33342 staining. This enhancement was not obtained by the lower concentrations that incompletely inhibited the repair, suggesting the close association between the inhibition of the repair and the enhancement of the cytotoxicity. Our findings suggest that UCN-01 may be a good candidate for combination strategies of cancer treatment

Shapes of Knotted Cyclic Polymers(Knots and soft-matter physics: Topology of polymers and related topics in physics, mathematics and biology)

この論文は国立情報学研究所の電子図書館事業により電子化されました。Momentary configurations of long polymers at thermal equilibrium usually deviate from spherical symmetry and can be better described, on average, by a prolate ellipsoid. The asphericity and nature of asphericity (or prolateness) that describe these momentary ellipsoidal shapes of a polymer are determined by specific expressions involving the three principal moments of inertia calculated for configurations of the polymer. Earlier theoretical studies and numerical simulations have established that as the length of the polymer increases, the average shape for the statistical ensemble of random configurations asymptotically approaches a characteristic universal shape that depends on the solvent quality. It has been established, however, that these universal shapes differ for linear, circular, and branched chains. We investigate here the effect of knotting on the shape of cyclic polymers modeled as random isosegmental polygons. We observe that random polygons forming different knot types reach asymptotic shapes that are distinct from the ensemble average shape. For the same chain length, more complex knots are, on average, more spherical than less complex knots. This paper is a shorter, revised version of the article Ref. [12]. For more details, see Ref. [12]

The VLA Nascent Disk And Multiplicity (VANDAM) Survey of Perseus Protostars. Resolving the Sub-Arcsecond Binary System in NGC 1333 IRAS2A

We are conducting a Jansky VLA Ka-band (8 mm and 1 cm) and C-band (4 cm and 6.4 cm) survey of all known protostars in the Perseus Molecular Cloud, providing resolution down to $\sim$0.06'' and $\sim$0.35" in Ka-band and C-band, respectively. Here we present first results from this survey that enable us to examine the source NGC 1333 IRAS2A in unprecedented detail and resolve it into a proto-binary system separated by 0.621"$\pm$0.006" ($\sim$143 AU) at 8 mm, 1 cm, and 4 cm. These 2 sources (IRAS2A VLA1 and VLA2) are likely driving the two orthogonal outflows known to originate from IRAS2A. The brighter source IRAS2A VLA1 is extended perpendicular to its outflow in the VLA data, with a deconvolved size of 0.055" ($\sim$13 AU), possibly tracing a protostellar disk. The recently reported candidate companions (IRAS2A MM2 and MM3) are not detected in either our VLA data, CARMA 1.3 mm data, or SMA 850 $\mu$m data. SMA CO ($J=3\rightarrow2$), CARMA CO ($J=2\rightarrow1$), and lower resolution CARMA CO ($J=1\rightarrow0$) observations are used to examine the outflow origins and the nature of the candidate companions to IRAS2A VLA1. The CO ($J=3\rightarrow2$) and ($J=2\rightarrow1$) data show that IRAS2A MM2 is coincident with a bright CO emission spot in the east-west outflow, and IRAS2A MM3 is within the north-south outflow. In contrast, IRAS2A VLA2 lies at the east-west outflow symmetry point. We propose that IRAS2A VLA2 is the driving source of the East-West outflow and a true companion to IRAS2A VLA1, whereas IRAS2A MM2 and MM3 may not be protostellar.Comment: Accepted to ApJ, 27 pages, 6 Figures, 2 Table

The Grizzly, January 26, 1979

Campus Life Committee to Replace SFARC • Quad Fire Brought Quickly Under Control • The Fabulous Greaseband Presents...Rock \u27N\u27 Roll Revue Tonight • Christmas Thefts Hit Women\u27s Dorms • Four-One-Four Proposed • Integrated Dining: An Interesting Proposal • Low Attendance Attracts Attention • Letters to the Editor: No static at all?; Big-name concert • Roving Reporter: Alcohol policy • Ritter Gift • Class Skiing Trips: Coming Up • Billy Joel: Isn\u27t One Elton John Enough? • Grateful Dead Rocks Spectrum • Operatic Forum • Audio Corner: Receivers • Token Tolkien • Financial aid night to be held; Meistersingers on tour; New sports editor; Gift collection received; William J. Phillip prize endowed • USGA Elections Near • Bears Sink Below .500 • Cagers Capture Only One Of Six • Flying Fish • Grapplers Groping • Girl\u27s B-Ballhttps://digitalcommons.ursinus.edu/grizzlynews/1010/thumbnail.jp

Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism

Cancer cells exhibit increased glycolysis for ATP production due, in part, to respiration injury (the Warburg effect). Because ATP generation through glycolysis is less efficient than through mitochondrial respiration, how cancer cells with this metabolic disadvantage can survive the competition with other cells and eventually develop drug resistance is a long-standing paradox. We report that mitochondrial respiration defects lead to activation of the Akt survival pathway through a novel mechanism mediated by NADH. Respiration-deficient cells (ρ-) harboring mitochondrial DNA deletion exhibit dependency on glycolysis, increased NADH, and activation of Akt, leading to drug resistance and survival advantage in hypoxia. Similarly, chemical inhibition of mitochondrial respiration and hypoxia also activates Akt. The increase in NADH caused by respiratory deficiency inactivates PTEN through a redox modification mechanism, leading to Akt activation. These findings provide a novel mechanistic insight into the Warburg effect and explain how metabolic alteration in cancer cells may gain a survival advantage and withstand therapeutic agents

An improved measurement of muon antineutrino disappearance in MINOS

We report an improved measurement of muon anti-neutrino disappearance over a distance of 735km using the MINOS detectors and the Fermilab Main Injector neutrino beam in a muon anti-neutrino enhanced configuration. From a total exposure of 2.95e20 protons on target, of which 42% have not been previously analyzed, we make the most precise measurement of the anti-neutrino "atmospheric" delta-m squared = 2.62 +0.31/-0.28 (stat.) +/- 0.09 (syst.) and constrain the anti-neutrino atmospheric mixing angle >0.75 (90%CL). These values are in agreement with those measured for muon neutrinos, removing the tension reported previously.Comment: 5 pages, 4 figures. In submission to Phys.Rev.Let

Search for the disappearance of muon antineutrinos in the NuMI neutrino beam

We report constraints on antineutrino oscillation parameters that were obtained by using the two MINOS detectors to measure the 7% muon antineutrino component of the NuMI neutrino beam. In the Far Detector, we select 130 events in the charged-current muon antineutrino sample, compared to a prediction of 136.4 ± 11.7(stat)^(+10.2)_(-8.9)(syst) events under the assumption │Δm^2│ = 2.32 X 10^(-3) eV^2, sin^2(2θ) = 1.0

Improved Search for Muon-Neutrino to Electron-Neutrino Oscillations in MINOS

We report the results of a search for ν_e appearance in a ν_μ beam in the MINOS long-baseline neutrino experiment. With an improved analysis and an increased exposure of 8.2×10^(20) protons on the NuMI target at Fermilab, we find 2sin^2(θ_(23))sin^2(2θ_(13))<0.12(0.20) at 90% confidence level for δ=0 and the normal (inverted) neutrino mass hierarchy, with a best-fit of 2sin^2(θ_(23))sin^2(2θ_(13))=0.041^(+0.047)_(-0.031)(0.079^(+0.071)_(-0.053). The θ_(13)= 0 hypothesis is disfavored by the MINOS data at the 89% confidence level