Fragment-Based Discovery of Bromodomain Inhibitors Part 2: Optimization of Phenylisoxazole Sulfonamides

Bromodomains are epigenetic reader modules that regulate gene transcription through their recognition of acetyl-lysine modified histone tails. Inhibitors of this protein–protein interaction have the potential to modulate multiple diseases as demonstrated by the profound anti-inflammatory and antiproliferative effects of a recently disclosed class of BET compounds. While these compounds were discovered using phenotypic assays, here we present a highly efficient alternative approach to find new chemical templates, exploiting the abundant structural knowledge that exists for this target class. A phenyl dimethyl isoxazole chemotype resulting from a focused fragment screen has been rapidly optimized through structure-based design, leading to a sulfonamide series showing anti-inflammatory activity in cellular assays. This proof-of-principle experiment demonstrates the tractability of the BET family and bromodomain target class to fragment-based hit discovery and structure-based lead optimization

Convergence angles for full veneer crown preparation completed by undergraduate students in a dental teaching hospital

Objectives: To determine the degree of taper and the average angle of convergence (AOC) accomplished for full veneer/coverage crowns (FVC) by supervised undergraduate students at a dental teaching hospital. Methods One hundred and twenty-five stone dies of FVC preparations (25 full-metal [FMCs] and 100 metal-ceramic [MCCs]), prepared by dental students were included in this study. To measure AOC, standardised buccal and mesial photographs were taken when dies were mounted onto a custom silicone jig after careful positioning. 2D digital analysis software (ImageJ) was used to calculate the average mesio-distal (MD), bucco-lingual (BL) and overall AOC for each die. Differences between groups were tested for significance at 95% confidence using t-tests and analysis of variance (ANOVA). Findings were compared to the recommended 6°–15° range. Results: The average AOC was 24.2° ± 11.95°. As few as one-in-four preparations (26.4%, n = 33) complied with the recommended standards. The MD plane (24.7° ± 15.53°) was more tapered than the BL plane (23.0° ± 13.84°) (p >0.05) and FMCs preparations (34.7° ± 15.10°) more than MCCs (21.6° ± 9.38°) (p <0.001). Molars (31.6° ± 12.56°) had the greatest AOC, followed by premolars (20.7° ± 7.81°), canines (19.4° ± 6.37°) and incisors (17.0° ± 9.62°) (p <0.001). Additionally, mandibular teeth (28.8° ± 13.76°) exhibited a greater AOC than those in the maxilla (21.7° ± 10.08°) (p <0.05). Conclusion: The findings of this study suggest that within a dental school teaching environment, crown preparations completed by undergraduate students are over-tapered. Tooth type, inter and intra-arch position and crown material significantly impact taper, with mandibular molar FMCs displaying the greatest AOC. Contemporary dental school teaching should help support students in this important aspect of their clinical training

Intensive care unit scoring systems outperform emergency department scoring systems for mortality prediction in critically ill patients: a prospective cohort study

BACKGROUND: Multiple scoring systems have been developed for both the intensive care unit (ICU) and the emergency department (ED) to risk stratify patients and predict mortality. However, it remains unclear whether the additional data needed to compute ICU scores improves mortality prediction for critically ill patients compared to the simpler ED scores. METHODS: We studied a prospective observational cohort of 227 critically ill patients admitted to the ICU directly from the ED at an academic, tertiary care medical center. We compared Acute Physiology and Chronic Health Evaluation (APACHE) II, APACHE III, Simplified Acute Physiology Score (SAPS) II, Modified Early Warning Score (MEWS), Rapid Emergency Medicine Score (REMS), Prince of Wales Emergency Department Score (PEDS), and a pre-hospital critical illness prediction score developed by Seymour et al. (JAMA 2010, 304(7):747–754). The primary endpoint was 60-day mortality. We compared the receiver operating characteristic (ROC) curves of the different scores and their calibration using the Hosmer-Lemeshow goodness-of-fit test and visual assessment. RESULTS: The ICU scores outperformed the ED scores with higher area under the curve (AUC) values (p = 0.01). There were no differences in discrimination among the ED-based scoring systems (AUC 0.698 to 0.742; p = 0.45) or among the ICU-based scoring systems (AUC 0.779 to 0.799; p = 0.60). With the exception of the Seymour score, the ED-based scoring systems did not discriminate as well as the best-performing ICU-based scoring system, APACHE III (p = 0.005 to 0.01 for comparison of ED scores to APACHE III). The Seymour score had a superior AUC to other ED scores and, despite a lower AUC than all the ICU scores, was not significantly different than APACHE III (p = 0.09). When data from the first 24 h in the ICU was used to calculate the ED scores, the AUC for the ED scores improved numerically, but this improvement was not statistically significant. All scores had acceptable calibration. CONCLUSIONS: In contrast to prior studies of patients based in the emergency department, ICU scores outperformed ED scores in critically ill patients admitted from the emergency department. This difference in performance seemed to be primarily due to the complexity of the scores rather than the time window from which the data was derived