Discovery of macrocyclic inhibitors of apurinic/apyrimidinic endonuclease 1

Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential base excision repair enzyme that is upregulated in a number of cancers, contributes to resistance of tumors treated with DNA-alkylating or -oxidizing agents, and has recently been identified as an important therapeutic target. In this work, we identified hot spots for binding of small organic molecules experimentally in high resolution crystal structures of APE1 and computationally through the use of FTMAP analysis (http://ftmap.bu.edu/). Guided by these hot spots, a library of drug-like macrocycles was docked and then screened for inhibition of APE1 endonuclease activity. In an iterative process, hot-spot-guided docking, characterization of inhibition of APE1 endonuclease, and cytotoxicity of cancer cells were used to design next generation macrocycles. To assess target selectivity in cells, selected macrocycles were analyzed for modulation of DNA damage. Taken together, our studies suggest that macrocycles represent a promising class of compounds for inhibition of APE1 in cancer cells.This work was supported by grants from the National Institutes of Health (Grant R01CA205166 to M.R.K. and M.M.G. and Grant R01CA167291 to M.R.K.) and by the Earl and Betty Herr Professor in Pediatric Oncology Research, Jeff Gordon Children's Foundation, and the Riley Children's Foundation (M.R.K.). Work at the BU-CMD (J.A.P., L.E.B., R.T.) is supported by the National Institutes of Health, Grant R24 GM111625. D.B. and S.V. were supported by the National Institutes of Health, Grant R35 GM118078. (R35 GM118078 - National Institutes of Health; R01CA205166 - National Institutes of Health; R01CA167291 - National Institutes of Health; R24 GM111625 - National Institutes of Health; Earl and Betty Herr Professor in Pediatric Oncology Research; Jeff Gordon Children's Foundation; Riley Children's Foundation)Accepted manuscriptSupporting documentatio

Cosmological CMBR dipole in open universes ?

The observed CMBR dipole is generally interpreted as a Doppler effect arising from the motion of the Earth relative to the CMBR frame. An alternative interpretation, proposed in the last years, is that the dipole results from ultra-large scale isocurvature perturbations. We examine this idea in the context of open cosmologies and show that the isocurvature interpretation is not valid in an open universe, unless it is extremely close to a flat universe, $|\Omega_0 -1|< 10^{-4}$.Comment: 26 pages, Latex, 6 figures, to appear in Phys. Rev.

Strike point splitting induced by the application of magnetic perturbations on MAST

Divertor strike point splitting induced by resonant magnetic perturbations (RMPs) has been observed on MAST for a variety of RMP configurations in a plasma scenario with Ip=750kA where those configurations all have similar resonant components. Complementary measurements have been obtained with divertor Langmuir probes and an infrared camera. Clear splitting consistently appears in this scenario only in the even configuration of the perturbation coils, similarly to the density pump-out. These results present a challenge for models of plasma response to RMPs.Comment: 9 pages, 4 figures, submitted to the proceedings of the 20th Conference on Plasma Surface Interactions, to be published in the Journal of Nuclear Material

Effects of 60 MeV protons and 250 kV X-rays on cell viability

Particle radiotherapy such as the one using proton beams, provides a successful treatment approach in many cancer types. However, the cellular and molecular mechanisms by which proton irradiation induces cell death, particularly in a human peripheral blood lymphocyte model has not been examined in detail. Comparative studies of the biological effects, such as cell death, of particle therapy versus conventional X-rays treatment are of utmost importance. Here, we compared the viability of human peripheral blood lymphocyte following in vitro irradiation with protons (therapeutic 60 MeV proton beam) and photon beam (250 kV, X-rays), by applying separate doses within the range of 0.3-4.0 Gy. Cell viability was assessed 1 and 4 h after irradiation with protons and X-rays by the FITC-Annexin V labelling procedure (Apoptotic & Necrotic & Healthy Cells Quantification Kit, Biotium). Results showed that irradiation with both radiation types reduced the number of viable cells in a dose-dependent manner, as assessed as a function of the duration of post-irradiation time. Protons proved more fatal to the cells treated than X-ray photons. This demonstrates a difference in cell viability after irradiation with protons and photons in a human peripheral blood lymphocyte model