Using DNA-encoded libraries of fragments for hit discovery of challenging therapeutic targets.

INTRODUCTION: The effectiveness of Fragment-based drug design (FBDD) for targeting challenging therapeutic targets has been hindered by two factors: the small library size and the complexity of the fragment-to-hit optimization process. The DNA-encoded library (DEL) technology offers a compelling and robust high-throughput selection approach to potentially address these limitations. AREA COVERED: In this review, the authors propose the viewpoint that the DEL technology matches perfectly with the concept of FBDD to facilitate hit discovery. They begin by analyzing the technical limitations of FBDD from a medicinal chemistry perspective and explain why DEL may offer potential solutions to these limitations. Subsequently, they elaborate in detail on how the integration of DEL with FBDD works. In addition, they present case studies involving both de novo hit discovery and full ligand discovery, especially for challenging therapeutic targets harboring broad drug-target interfaces. EXPERT OPINION: The future of DEL-based fragment discovery may be promoted by both technical advances and application scopes. From the technical aspect, expanding the chemical diversity of DEL will be essential to achieve success in fragment-based drug discovery. From the application scope side, DEL-based fragment discovery holds promise for tackling a series of challenging targets.

Verification procedure for isocentric alignment of proton beams.

We present a technique--based on the Lutz, Winston, and Maleki test used in stereotactic linear accelerator radiosurgery--for verifying whether proton beams are being delivered within the required spatial coincidence with the gantry mechanical isocenter. Our procedure uses a proton beam that is collimated by a circular aperture at its central axis and is then intercepted by a small steel sphere rigidly supported by the patient couch. A laser tracker measurement system and a correction algorithm for couch position assures precise positioning of the steel sphere at the mechanical isocenter of the gantry. A film-based radiation dosimetry technique, chosen for the good spatial resolution it achieves, records the proton dose distribution for optical image analysis. The optical image obtained presents a circular high-dose region surrounding a lower-dose area corresponding to the proton beam absorption by the steel sphere, thereby providing a measure of the beam alignment with the mechanical isocenter. We found the self-developing Gafchromic EBT film (International Specialty Products, Wayne, NJ) and commercial Epson 10000 XL flatbed scanner (Epson America, Long Beach, CA) to be accurate and efficient tools. The positions of the gantry mechanical and proton beam isocenters, as recorded on film, were clearly identifiable within the scanning resolution used for routine alignment testing (0.17 mm per pixel). The mean displacement of the collimated proton beam from the gantry mechanical isocenter was 0.22 +/- 0.1 mm for the gantry positions tested, which was well within the maximum deviation of 0.50 mm accepted at the Proton Therapy Center in Houston.

Static load magnitude is a risk factor in the development of cumulative low back disorder.

Occupations requiring frequent periods of static lumbar flexion are known epidemiologically to be risk factors for the development of cumulative low back disorder. The impact of the load magnitude sustained during a series of short static lumbar flexions followed by an equally long rest period on the development of a cumulative low back disorder was addressed in an in vivo feline model. Static loads of 20, 40, and 60 N were applied over 10 min of flexion followed by 10-min rest sessions that were repeated six times (for a total of 2 h) while monitoring lumbar viscoelastic creep (laxity) and reflex electromyographic (EMG) activity from the multifidus muscles. Creep and EMG were also monitored over 7 h of rest following the six flexion-rest sessions. It was found that the creep developed in the 10-min flexion periods did not recover completely during the following 10 min of rest, giving rise to a large cumulative creep at the end of the work-rest session. Muscle activity demonstrated spasms during the static flexion periods as well as initial and delayed hyperexcitability during the 7-h rest period. Loads of 20 and 40 N did not result in delayed hyperexcitability, whereas loads of 60 N resulted in delayed hyperexcitability. Statistical analysis demonstrated that increased load significantly intensified the magnitude of the hyperexcitabilities (P < 0.05). Thus, repeated periods of static lumbar flexion were found to result in a transient neuromuscular disorder with an intensity directly related to the load magnitude, which should be considered a compounding risk factor.