THE IMPORT DEMAND FOR U.S. BURLEY TOBACCO IN EUROPEAN MARKETS

International Relations/Trade,

Small molecule activation of apurinic/apyrimidinic endonuclease 1 reduces DNA damage induced by cisplatin in cultured sensory neurons

Although chemotherapy-induced peripheral neuropathy (CIPN) affects approximately 5-60% of cancer patients, there are currently no treatments available in part due to the fact that the underlying causes of CIPN are not well understood. One contributing factor in CIPN may be persistence of DNA lesions resulting from treatment with platinum-based agents such as cisplatin. In support of this hypothesis, overexpression of the base excision repair (BER) enzyme, apurinic/apyrimidinic endonuclease 1 (APE1), reduces DNA damage and protects cultured sensory neurons treated with cisplatin. Here, we address stimulation of APE1's endonuclease through a small molecule, nicorandil, as a means of mimicking the beneficial effects observed for overexpression of APE1. Nicorandil, was identified through high-throughput screening of small molecule libraries and found to stimulate APE1 endonuclease activity by increasing catalytic efficiency approximately 2-fold. This stimulation is primarily due to an increase in kcat. To prevent metabolism of nicorandil, an approved drug in Europe for the treatment of angina, cultured sensory neurons were pretreated with nicorandil and daidzin, an aldehyde dehydrogenase 2 inhibitor, resulting in decreased DNA damage but not altered transmitter release by cisplatin. This finding suggests that activation of APE1 by nicorandil in cisplatin-treated cultured sensory neurons does not imbalance the BER pathway in contrast to overexpression of the kinetically faster R177A APE1. Taken together, our results suggest that APE1 activators can be used to reduce DNA damage induced by cisplatin in cultured sensory neurons, although further studies will be required to fully assess their protective effects

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

Antinociceptive Effects of Spinal Manipulative Therapy on Nociceptive Behavior of Adult Rats during the Formalin Test

Optimizing pain relief resulting from spinal manipulative therapies, including low velocity variable amplitude spinal manipulation (LVVA-SM), requires determining their mechanisms. Pain models that incorporate simulated spinal manipulative therapy treatments are needed for these studies. The antinociceptive effects of a single LVVA-SM treatment on rat nociceptive behavior during the commonly used formalin test were investigated. Dilute formalin was injected subcutaneously into a plantar hindpaw. Licking behavior was video-recorded for 5 minutes. Ten minutes of LVVA-SM at 20° flexion was administered with a custom-made device at the lumbar (L5) vertebra of isoflurane-anesthetized experimental rats (n=12) beginning 10 minutes after formalin injection. Hindpaw licking was video-recorded for 60 minutes beginning 5 minutes after LVVA-SM. Control rats (n=12) underwent the same methods except for LVVA-SM. The mean times spent licking the formalin-injected hindpaw of both groups 1–5 minutes after injection were not different. The mean licking time during the first 20 minutes post-LVVA-SM of experimental rats was significantly less than that of control rats (P<0.001). The mean licking times of both groups during the second and third 20 minutes post-LVVA-SM were not different. Administration of LVVA-SM had a short-term, remote antinociceptive effect similar to clinical findings. Therefore, mechanistic investigations using this experimental approach are warranted

A survey for pulsating subdwarf B stars with the Nordic Optical Telescope

A search programme for pulsating subdwarf B stars was conducted with the Nordic Optical Telescope on La Palma over 59 nights between 1999 and 2009. The purpose of the programme was to significantly extend the number of rapidly pulsating sdB stars to better understand the properties of this new group of variable compact stars. Candidates were selected initially from the HS and HE surveys, but were supplemented with additional objects from other surveys. Short sequences of time-series photometry were made on the candidates to determine the presence of rapid pulsations. In total twenty new pulsators were found in this survey, most of which have already been published and some extensively studied. We present four new short period pulsators, bringing the total of such pulsators up to 49. We also give limits on pulsation amplitudes for 285 objects with no obvious periodic variations, summarise the results of the survey, and provide improved physical parameters on the composite pulsators for which only preliminary estimates were published earlier.Comment: 17 pages, accepted for publication in A&

Using Microstructure Observations to Quantify Fracture Properties and Improve Reservoir Simulations

The research for this project, funded by the U.S. Department of Energy, provides new technology to understand and successfully characterize, predict, and simulate reservoir-scale fractures. Such fractures have worldwide importance because of their influence on successful extraction of resources. For example, many conventional U.S. reservoirs yield about one-third of the oil originally in place, but some estimates suggest that reservoirs with naturally occurring fractures yield only about 10 percent of their reserves. This is a serious technical and financial challenge for producers of reservoirs containing natural fractures. Most fractures are below the limits of seismic resolution or detection and are difficult or impossible to characterize adequately using currently available well test, full-diameter core, or geophysical well log technology; this is because large fractures are intrinsically difficult to sample with conventional wellbore sampling methods owing to their wide spacing. Consequently, fractured reservoirs have been intractable to describe and interpret effectively, impeding accurate reservoir description and simulation. Accurate characterization of reservoir fractures, however, still holds great potential for improving production by increasing the efficiency of exploration and recovery processes.Bureau of Economic Geolog