Diverse small molecule inhibitors of human apurinic/apyrimidinic endonuclease APE1 identified from a screen of a large public collection.

The major human apurinic/apyrimidinic endonuclease APE1 plays a pivotal role in the repair of base damage via participation in the DNA base excision repair (BER) pathway. Increased activity of APE1, often observed in tumor cells, is thought to contribute to resistance to various anticancer drugs, whereas down-regulation of APE1 sensitizes cells to DNA damaging agents. Thus, inhibiting APE1 repair endonuclease function in cancer cells is considered a promising strategy to overcome therapeutic agent resistance. Despite ongoing efforts, inhibitors of APE1 with adequate drug-like properties have yet to be discovered. Using a kinetic fluorescence assay, we conducted a fully-automated high-throughput screen (HTS) of the NIH Molecular Libraries Small Molecule Repository (MLSMR), as well as additional public collections, with each compound tested as a 7-concentration series in a 4 µL reaction volume. Actives identified from the screen were subjected to a panel of confirmatory and counterscreen tests. Several active molecules were identified that inhibited APE1 in two independent assay formats and exhibited potentiation of the genotoxic effect of methyl methanesulfonate with a concomitant increase in AP sites, a hallmark of intracellular APE1 inhibition; a number of these chemotypes could be good starting points for further medicinal chemistry optimization. To our knowledge, this represents the largest-scale HTS to identify inhibitors of APE1, and provides a key first step in the development of novel agents targeting BER for cancer treatment

Interface-resolved direct numerical simulations of sediment transport in a turbulent oscillatory boundary layer

The flow within an oscillatory boundary layer, which approximates the flow generated by propagating sea waves of small amplitude close to the bottom, is simulated numerically by integrating the Navier-Stokes and continuity equations. The bottom is made up of spherical particles, free to move, which mimic sediment grains. The approach allows one to fully resolve the flow around the particles and to evaluate the forces and torques that the fluid exerts on their surface. Then, the dynamics of sediments is explicitly computed by means of the Newton-Euler equations. For the smallest value of the flow Reynolds number presently simulated, the flow regime turns out to fall in the intermittently turbulent regime such that turbulence appears when the free-stream velocity is close to its largest value but the flow recovers a laminar-like behaviour during the remaining phases of the cycle. For the largest value of the Reynolds number, turbulence is significant during almost the whole flow cycle. The evaluation of the sediment transport rate allows one to estimate the reliability of the empirical predictors commonly used to estimate the amount of sediments transported by sea waves. For large values of the Shields parameter, the sediment flow rate during the accelerating phases does not differ from that observed during the decelerating phases. However, for relatively small values of the Shields parameter, the amount of moving particles depends not only on the bottom shear stress but also on flow acceleration. Moreover, the numerical results provide information on the role that turbulent eddies have on sediment dynamics

Tactical decisions in the operative treatment of advanced and urgent cases of colorectal cancer

The authors reviewed retrospectively the patients treated in the Clinic of Surgery for colorectal cancer (CRC) during a five-year period (2008-2012). The main purpose was to consider the different tactical decisions for operative treatment in complicated, advanced and urgent cases. There were a total of 706 operated patients who were analyzed according to their age, gender, stage of disease, planned and urgent operative interventions, presence of concomitant diseases, performed operative procedures and mortality rate. The principles of assessment of every different case and those for making decisions for operative tactics and kind of intervention were described. The performed different operations in complicated, advanced and urgent patients were analyzed, too. Conclusions concerning the obtained results and their comparison with literature data available as well as concerning the benefits of differentiated tactical approach to every individual case with CRC were drawn

Cotton fabric: a natural matrix suitable for controlled release systems

The possibility to use cotton as a matrix for controlled release systems was studied by covalently attaching a model compound, specifically the reactive dye Remazol Brilliant Blue R to its surface. Afterwards the fabric was coated with a commercial cellulase. The release of the dye, obtained by the hydrolysis of cotton fibres in sweat buffer, was monitored. The reducing sugars concentration increased for both fabrics (with and without the dye covalently fixed) while the increase in the absorbance was only attained for the dyed cotton, as expected. These results confirm the viability of using cotton as a natural matrix for controlled released systems while presenting a promising approach to immobilize covalently other substances in cotton garments, like fragrances, which could be released by the action of human sweat

Prototype performance evaluation of multimedia service components

This paper deals with a formal approach for decomposition and description of multimedia service components and their performance analysis. Our approach is based on the Temporal Logic of Actions (TLA) specifications. A TLA based specification of multimedia components is transformed into process prototypes described with the SPIMS (SICS Protocol Implementation Measurement System) application language. The multimedia component prototype derived in this way is then evaluated with the SPIMS tool for different QoS parameters. The proposed approach using TLA based specifications, transformations in SPIMS application prototypes, and performance analysis provides the background for an computer based system for test specification and performance analysis which is currently under development. We present and discuss practical test scenarios derived from the proposed method for performance analysis of the Audio-Visual Communication (AVC)component of the Joint-Viewing and Tele-Operation Service (JVTOS). The multimedia test scenarios shown use the TCP/IP and XTP protocols on top of FORE ATM networks

Fragment-based discovery of a regulatory site in thioredoxin glutathione reductase acting as "doorstop" for NADPH entry

Members of the FAD/NAD-linked reductase family are recognized as crucial targets in drug development for cancers, inflammatory disorders, and infectious diseases. However, individual FAD/NAD reductases are difficult to inhibit in a selective manner with off target inhibition reducing usefulness of identified compounds. Thioredoxin glutathione reductase (TGR), a high molecular weight thioredoxin reductase-like enzyme, has emerged as a promising drug target for the treatment of schistosomiasis, a parasitosis afflicting more than 200 million people. Taking advantage of small molecules selected from a high-throughput screen and using X-ray crystallography, functional assays, and docking studies, we identify a critical secondary site of the enzyme. Compounds binding at this site interfere with well-known and conserved conformational changes associated with NADPH reduction, acting as a doorstop for cofactor entry. They selectivity inhibit TGR from Schistosoma mansoni and are active against parasites in culture. Since many members of the FAD/NAD-linked reductase family have similar catalytic mechanisms the unique mechanism of inhibition identified in this study for TGR broadly opens new routes to selectively inhibit homologous enzymes of central importance in numerous diseases

Blue lasing at room temperature in high quality factor GaN/AlInN microdisks with InGaN quantum wells

The authors report on the achievement of optically pumped III-V nitride blue microdisk lasers operating at room temperature. Controlled wet chemical etching of an AlInN interlayer lattice matched to GaN allows forming inverted cone pedestals. Whispering gallery modes are observed in the photoluminescence spectra of InGaN∕GaN quantum wells embedded in the GaN microdisks. Typical quality factors of several thousands are found (Q>4000). Laser action at ∼420nm is achieved under pulsed excitation at room temperature for a peak power density of 400kW/cm2. The lasing emission linewidth is down to 0.033nm