Structure-activity relationship studies of fostriecin, cytostatin, and key analogs, with PP1, PP2A, PP5, and( beta12-beta13)-chimeras (PP1/PP2A and PP5/PP2A), provide further insight into the inhibitory actions of fostriecin family inhibitors.

Fostriecin and cytostatin are structurally related natural inhibitors of serine/threonine phosphatases, with promising antitumor activity. The total synthesis of these antitumor agents has enabled the production of structural analogs, which are useful to explore the biological significance of features contained in the parent compounds. Here, the inhibitory activity of fostriecin, cytostatin, and 10 key structural analogs were tested in side-by-side phosphatase assays to further characterize their inhibitory activity against PP1c (Ser/Thr protein phosphatase 1 catalytic subunit), PP2Ac (Ser/Thr protein phosphatase 2A catalytic subunit), PP5c (Ser/Thr protein phosphatase 5 catalytic subunit), and chimeras of PP1 (Ser/Thr protein phosphatase 1) and PP5 (Ser/Thr protein phosphatase 5), in which key residues predicted for inhibitor contact with PP2A (Ser/Thr protein phosphatase 2A) were introduced into PP1 and PP5 using site-directed mutagenesis. The data confirm the importance of the C9-phosphate and C11-alcohol for general inhibition and further demonstrate the importance of a predicted C3 interaction with a unique cysteine (Cys(269)) in the beta12-beta13 loop of PP2A. The data also indicate that additional features beyond the unsaturated lactone contribute to inhibitory potency and selectivity. Notably, a derivative of fostriecin lacking the entire lactone subunit demonstrated marked potency and selectivity for PP2A, while having substantially reduced and similar activity against PP1 and PP1/PP2A- PP5/PP2A-chimeras that have greatly increased sensitivity to both fostriecin and cytostatin. This suggests that other features [e.g., the (Z,Z,E)-triene] also contribute to inhibitory selectivity. When considered together with previous data, these studies suggest that, despite the high structural conservation of the catalytic site in PP1, PP2A and PP5, the development of highly selective catalytic inhibitors should be feasible.

Improving Clinic Productivity through a Shared Medical Appointment.

INTRODUCTION: Physicians are increasingly challenged to balance quality health care with fewer resources and limited time. To help achieve this balance, shared medical appointments have been described. We improved clinic-wide access to care by creating a shared medical appointment for minor penile complaints and anomalies. METHODS: We implemented a shared medical appointment in April 2013. We developed an intake form to efficiently gather patient history, and a standardized presentation to discuss diagnosis, treatment options, risks and benefits. Outcomes assessed included access to care time, the rate at which patients were seen within a target of 28 days, the number of appointments scheduled and patient complaints. To control for provider availability we evaluated the number of vacation days and operating room cases for the sole pediatric urologist. Data were analyzed using the Mann-Whitney U test. RESULTS: The periods of November 2012 to March 2013 and May 2013 to September 2013 were evaluated. There was a statistically significant improvement in median (IQR) access to care, with a decrease from 26.6 days (26.4, 29.4) before to 20 days (17.1, 24.3) after implementation of the shared medical appointment (p=0.0163). The goal access to care standard was met with a median (IQR) of 81.4% (56.7, 82.8) after the shared medical appointment compared to 44.3% (25.0, 46.9) before the shared appointment (p=0.0283). After implementation of the shared medical appointment, more appointments were scheduled per month at 161 (156, 165) vs 128 (120, 130; p=0.1172). CONCLUSIONS: We successfully implemented a shared medical appointment and significantly improved our clinic productivity. This program allowed us to improve access to care by almost 1 week and to increase the overall volume of patients seen monthly.