Growing our own theatre staff: Practice development and education.

Royal Bournemouth & Christchurch Hospitals NHS Foundation Trust engaged in a quality improvement project aimed at improving quality and safety in theatres. The improvements delivered were recruitment to full staffing template, reduction in agency staffing to zero, and creating a theatre coordinator role to ensure safe staffing. The Practice Education Team was increased fivefold with no extra investment as a result of these improvements. Student satisfaction results amongst ODPs and nurses have increased alongside staff morale and productivity.

Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497).

A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp3 hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated log D (clogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23a exhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23a in complex with the three-protein PRC2 complex enabled understanding of the key structural features required for optimal binding.

Discovery of novel, potent, and selective inhibitors of 3-phosphoinositide-dependent kinase (PDK1).

Analogues substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrazin-2-ylmethanone were discovered as potent and selective inhibitors of PDK1 with potential as anticancer agents. An early lead with 2-pyridine-3-ylethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3Kα through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and substituting on the 4-position of the aryl ring with a fluorine. ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring. The optimized analogues have a PDK1 Ki of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogues was assessed by the inhibition of AKT phosphorylation (T308) and by their antiproliferation activity against a number of tumor cell lines.

Soil Chemistry in a Loblolly/Longleaf Pine Forest with Interval Burning.

We examined the 30-yr cumulative effects of prescribed fires at intervals of 1, 2, 3, and 4 yr in a loblolly and longleaf pine forest in the Coastal Plain of South Carolina. The fine fraction of the forest floor (Oe + Oa horizons) contained much more carbon and nitrogen per unit area in the control plots (1.7 and 0.05 kg/m2 , respectively) than in the 1-yr burn interval plots (0.4 and 0.007 kg/m2 , respectively). Mineral soils (0-0.2 m depth) were highly variable in chemistry, and showed only slight differences across the burning treatments for nitrogen and sulfur. No trends were apparent for phosphorus in the forest floor or mineral soil; differences in acidity and extractable cations were also slight. The nutrient content of foliage was generally low, with no differences across burning intervals. Our results are consistent with earlier studies that showed the biogeochemical effects of repeated surface fires in southern pine forests are generally limited to the forest floor, with the possible exception of overall reductions in nitrogen cycling.