Development, Implementation and Assessment of a Comprehensive Strategic Plan in a School of Pharmacy.

Objective. To develop, implement and assess a strategic plan and its process within a school of pharmacy. Methods. The process for developing the strategic plan included five phases: designing and scanning by a planning committee; divergent thinking with input from key internal and external stakeholders who shared their vision for the school; convergent planning in which faculty members helped to prioritize the clusters, goals, and metrics that had been identified; refining ideas into strategies; and assessment, during which metrics were aligned with assessment plans and data were collected and analyzed. Results. The completed strategic plan had five broad strategies, 20 specific goals, and 90 associated metrics. The plan was implemented with engagement by all major stakeholders in the program. Reallocation of existing resources and generation of new resources were key in making progress. The assessment, which was conducted three years after implementation of the strategic plan, found that each strategy had affected the school's mission to provide an exemplary educational experience for students and to advance the institution. Conclusion. The strategic plan provided direction and focus to meet the challenges of continuing to advance the school. The keys for success in strategic planning are having a well-defined process, involving all faculty members and other key stakeholders, implementing the plan, and routinely assessing progress in meeting the strategic goals.

An evaluation of a human stem cell line to identify risk of developmental neurotoxicity with antiepileptic drugs.

Determination of the impact of a drug on human brain development relies instead on surrogate animal studies. Here we have exploited the human stem cell line, TERA2.cl.SP12 to differentiate into neurons and addressed their value as an in vitro model to evaluate the risk of developmental neurotoxicity with antiepileptic drugs (AEDs). The effects of four AEDs were investigated on cell viability, cell cycle and neural differentiation. Exposure to either phenobarbital (10-1000 µM), valproic acid (10-1000 µM), lamotrigine (1-100 µM) or carbamazepine (1-100 µM) for 3 days reduced viability in non-differentiating cells only at the highest concentrations tested. Viability was also reduced with lower concentrations of all AEDs in cells undergoing neural differentiation. Valproic acid and carbamazepine increased DNA fragmentation and reduced cell cycle progression. 3 days exposure at the start of neural differentiation to phenobarbital, valproic acid or lamotrigine also significantly reduced the proportion of stem cells that subsequently differentiated into neurons at 15 days in vitro. The two control agents tested, ciprofloxacin and perfluorooctanoic acid had no impact on neurogenesis in vitro. These new data show that modelling neurogenesis in vitro using a human stem cell line may be a powerful method to predict risks of developmental neurotoxicity in vivo with psychotropic drugs.

AKT-induced tamoxifen resistance is overturned by RRM2 inhibition.

UNLABELLED: Acquired tamoxifen resistance develops in the majority of hormone-responsive breast cancers and frequently involves overexpression of the PI3K/AKT axis. Here, breast cancer cells with elevated endogenous AKT or overexpression of activated AKT exhibited tamoxifen-stimulated cell proliferation and enhanced cell motility. To gain mechanistic insight on AKT-induced endocrine resistance, gene expression profiling was performed to determine the transcripts that are differentially expressed post-tamoxifen therapy under conditions of AKT overexpression. Consistent with the biologic outcome, many of these transcripts function in cell proliferation and cell motility networks and were quantitatively validated in a larger panel of breast cancer cells. Moreover, ribonucleotide reductase M2 (RRM2) was revealed as a key contributor to AKT-induced tamoxifen resistance. Inhibition of RRM2 by RNA interference (RNAi)-mediated approaches significantly reversed the tamoxifen-resistant cell growth, inhibited cell motility, and activated DNA damage and proapoptotic pathways. In addition, treatment of tamoxifen-resistant breast cancer cells with the small molecule RRM inhibitor didox significantly reduced in vitro and in vivo growth. Thus, AKT-expressing breast cancer cells upregulate RRM2 expression, leading to increased DNA repair and protection from tamoxifen-induced apoptosis. IMPLICATIONS: These findings identify RRM2 as an AKT-regulated gene, which plays a role in tamoxifen resistance and may prove to be a novel target for effective diagnostic and preventative strategies.

2-Aminoethoxydiphenyl borate perturbs hormone-sensitive calcium stores and blocks store-operated calcium influx pathways independent of cytoskeletal disruption in human A549 lung cancer cells.

Recent studies have identified novel actions for 2-aminoethoxydiphenyl borate (2-APB) in triggering calcium release and enhancing calcium influx induced by the depletion of intracellular calcium stores. In this study, we have examined the effects of 2-APB on the human lung adenocarcinoma A549 cell line, which we have previously shown displays a unique calcium influx response, when ER calcium stores are depleted by thapsigargin (TG) treatment. Here, we show that low concentrations of 2-APB failed to induce the rapid augmentation of TG-activated calcium influx previously reported for other cell types. We observed that store-operated calcium (SOC) channels in the A549 cell line exhibited short-term sensitivity to low doses of 2-APB, perhaps reflecting a delayed augmentation of SOC channel activity or the recruitment of 2-APB-insensitive SOC channels. In both intact and permeabilized cells, 2-APB effectively discharged a subset of A549 calcium pools corresponding to the hormone-sensitive intracellular calcium stores. The 2-APB-induced calcium release produced a long-lasting perturbation of the adenosine triphosphate (ATP)-releasable calcium pools, effectively uncoupling ATP-activated calcium release even, when stores are replenished with calcium. In contrast to previous reports, we found that disruption of either the actin or microtubule-based cytoskeleton failed to block the 2-APB-induced effects on calcium signaling in A549 cells. Our study describes novel cytoskeletal-independent effects of 2-APB on Ca2+-signaling pathways, revealing differentially sensitive Ca2+-influx pathways and long-term perturbation of hormone-sensitive Ca2+ stores.

Differential regulation of calcium homeostasis in adenocarcinoma cell line A549 and its Taxol-resistant subclone.

Drug resistance is a fundamental problem in cancer chemotherapy. Intracellular calcium concentration ([Ca2+](i)) may play a role in the development of chemoresistance. We investigated the regulatory role of [Ca2+](i) in Taxol resistance in the non-small-cell lung cancer cell line A549 and its chemoresistant subclone A549-T24. Measurement of cytosolic calcium ([Ca2+](c)) in single cells and cell populations revealed similar levels of basal calcium in the two cell lines. However, a reduced response to thapsigargin (a sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor) in A549-T24 cells compared to the parent cell line suggested a lower ER Ca2+ content in these cells. mRNA expression of SERCA2b and SERCA3, major Ca2+ pumps involved in ER Ca2+ homeostasis, did not significantly differ between the two cell lines, as revealed by RT-PCR. An altered calcium influx pathway in the Taxol-resistant cell line was observed. Modulation of the ER calcium pools using CMC (4-chloro-m-cresol) and ATP revealed lower ryanodine receptor (RyR) and IP(3) receptor (IP(3)R)-sensitive Ca2+ stores in the chemoresistant cell line. Western blot and RT-PCR studies suggested that A549-T24 cells expressed higher levels of the antiapoptotic protein Bcl-2 and the calcium-binding protein sorcin, respectively, in comparison to the parent cell line. Both of these proteins have been previously implicated in chemoresistance, in part, due to their ability to modulate[Ca2+](i). These results suggest that altered intracellular calcium homeostasis may contribute to the Taxol-resistant phenotype.

The Aggregate Demand Index: measuring the balance between pharmacist supply and demand, 1999-2001.

OBJECTIVE: To describe the development and 2-year performance of the Aggregate Demand Index (ADI) survey, a tool for longitudinally tracking the difficulty of filling open pharmacist positions throughout the United States. DESIGN: From August 1999 through July 2001, panelists completed a monthly survey on the difficulty of filling open pharmacist positions by state. Results are reported on the Web (www.pharmacymanpower.com). SETTING: Panelists estimated difficulty filling pharmacist vacancies in the community, institutional, both community and institutional, and nonpatient care pharmacy settings. PARTICIPANTS: A panel of individuals involved in the direct hiring of pharmacists. INTERVENTION: A monthly survey. MAIN OUTCOME MEASURES: Monthly indices reflecting the level of difficulty filling open pharmacy positions at the state, regional, and national levels and by pharmacy position type. Over time, these data formed a longitudinal record of the balance between the supply of and demand for pharmacists. RESULTS: Cumulative data from 50 states and the District of Columbia showed, on average, excess demand over available supply. The five states with the highest unmet demand level (i.e., where it was most difficult to fill open positions) were Minnesota, California, Wisconsin, Iowa, and Kentucky. The only states in which demand was in balance with supply were Hawaii and Rhode Island. Over 2 years, at least 92% of the U.S. population each month resided in areas where demand for pharmacists exceeded supply. The demand level in the Northeast was significantly lower than in other regions. Unmet demand was greatest for organizations with both community and institutional positions and least for organizations with primarily community positions. CONCLUSION: For the study period, the demand for pharmacists exceeded the available supply in the United States; ADI survey data indicated than open pharmacist positions were "somewhat difficult" to "difficult" to fill. Substantial but unexplained differences were noted by state, by region, and by type of pharmacy position. Other health care professions could use the ADI survey methodology to study workforce issues.