Recent calls for educational reform highlight ongoing concerns about the ability of current curricula to equip aspiring health care professionals with the skills for success. Whereas a wide range of proposed solutions attempt to address apparent deficiencies in current educational models, a growing body of literature consistently points to the need to rethink the traditional in-class, lecture-based course model. One such proposal is the flipped classroom, in which content is offloaded for students to learn on their own, and class time is dedicated to engaging students in student-centered learning activities, like problem-based learning and inquiry-oriented strategies. In 2012, the authors flipped a required first-year pharmaceutics course at the University of North Carolina Eshelman School of Pharmacy. They offloaded all lectures to self-paced online videos and used class time to engage students in active learning exercises. In this article, the authors describe the philosophy and methodology used to redesign the Basic Pharmaceutics II course and outline the research they conducted to investigate the resulting outcomes. This article is intended to serve as a guide to instructors and educational programs seeking to develop, implement, and evaluate innovative and practical strategies to transform students' learning experience. As class attendance, students' learning, and the perceived value of this model all increased following participation in the flipped classroom, the authors conclude that this approach warrants careful consideration as educators aim to enhance learning, improve outcomes, and fully equip students to address 21st-century health care needs.

Objective. To determine whether "flipping" a traditional basic pharmaceutics course delivered synchronously to 2 satellite campuses would improve student academic performance, engagement, and perception. Design. In 2012, the basic pharmaceutics course was flipped and delivered to 22 satellite students on 2 different campuses. Twenty-five condensed, recorded course lectures were placed on the course Web site for students to watch prior to class. Scheduled class periods were dedicated to participating in active-learning exercises. Students also completed 2 course projects, 3 midterm examinations, 8 graded quizzes, and a cumulative and comprehensive final examination. Assessment. Results of a survey administered at the beginning and end of the flipped course in 2012 revealed an increase in students' support for learning content prior to class and using class time for more applied learning (p50.01) and in the belief that learning key foundational content prior to coming to class greatly enhanced in-class learning (p50.001). Significantly more students preferred the flipped classroom format after completing the course (89.5%) than before completing the course (34.6%). Course evaluation responses and final examination performance did not differ significantly for 2011 when the course was taught using a traditional format and the 2012 flipped-course format. Qualitative findings suggested that the flipped classroom promoted student empowerment, development, and engagement. Conclusion. The flipped pharmacy classroom can enhance the quality of satellite students' experiences in a basic pharmaceutics course through thoughtful course design, enriched dialogue, and promotion of learner autonomy.

The ability to non-invasively monitor tumor-infiltrating T cells in vivo could provide a powerful tool to visualize and quantify tumor immune infiltrates. For non-invasive evaluations in vivo, an anti-CD3 mAb was modified with desferrioxamine (DFO) and radiolabeled with zirconium-89 (Zr-89 or 89Zr). Radiolabeled 89Zr-DFO-anti-CD3 was tested for T cell detection using positron emission tomography (PET) in both healthy mice and mice bearing syngeneic bladder cancer BBN975. In vivo PET/CT and ex vivo biodistribution demonstrated preferential accumulation and visualization of tracer in the spleen, thymus, lymph nodes, and bone marrow. In tumor bearing mice, 89Zr-DFO-anti-CD3 demonstrated an 11.5-fold increase in tumor-to-blood signal compared to isotype control. Immunological profiling demonstrated no significant change to total T cell count, but observed CD4+ T cell depletion and CD8+ T cell expansion to the central and effector memory. This was very encouraging since a high CD8+ to CD4+ T cell ratio has already been associated with better patient prognosis. Ultimately, this anti-CD3 mAb allowed for in vivo imaging of homeostatic T cell distribution, and more specifically tumor-infiltrating T cells. Future applications of this radiolabeled mAb against CD3 could include prediction and monitoring of patient response to immunotherapy.

Monoclonal antibodies (mAbs) offer promise as effective tumor targeting and drug delivery agents for cancer therapy. However, comparative biological and clinical characteristics of mAbs targeting the same tumor-associated antigen (TAA) often differ widely. This study examined the characteristics of mAbs that impact tumor targeting using a panel of mAb clones specific to the cancer-associated cell-surface receptor and cancer stem cell marker CD44. CD44 mAbs were screened for cell-surface binding, antigen affinity, internalization, and CD44-mediated tumor uptake by CD44-positive A549 cells. It was hypothesized that high-affinity, rapidly internalizing CD44 mAbs would result in high tumor uptake and prolonged tumor retention. Although high-affinity clones rapidly bound and were internalized by A549 cells in vitro, an intermediate-affinity clone demonstrated significantly greater tumor uptake and retention than high-affinity clones in vivo. Systemic exposure, rather than high antigen affinity or rapid internalization, best associated with tumor targeting of CD44 mAbs in A549 tumor-bearing mice.

The nonclinical safety profile of GS-8873, an HBV RNA transcript inhibitor was evaluated in rat and monkey 13-week toxicity studies with 8-week recovery phases. Vehicle or GS-8873 was dosed orally for 13 weeks at 2, 6, 20, and 60 mg/kg/day to Wistar Han rats and at 0.5, 1.5, 3 and 6 mg/kg/day to cynomolgus monkeys. In vitro and in vivo screening results from an analog discovered prior to GS-8873 informed the 13-week toxicology study designs. Neuroelectrophysiology and neurobehavioral evaluations were included at week 4 and 13 of the dosing and recovery phases for GS-8873. No adverse neurobehavioral effects were observed. Significant nerve conduction velocity (NCV) decreases and latency increases occurred at the high doses after 4 weeks of dosing. By week 13, dose responsive NCV reductions and latency increases worsened across all dose groups compared to controls. Some reversal occurred 8 weeks after the last dose administered, but not to vehicle control levels. A minimal, axonal degeneration was observed in rat spinal and peripheral nerves across dose groups compared to controls. No monkey nervous system microscopic findings were observed. NOAELs could not be determined for either species due to the neuroelectrophysiology findings and development was halted in the interest of safety. A retrospective risk assessment approach utilizing benchmark dose (BMD) modeling contributed 13-week NCV BMDL estimates (lower limits of the 95% confidence interval) in lieu of NOAELs. The best fitted models extrapolated NCV BMDLs for the rat caudal and monkey sural nerve at 0.3 mg/kg/day and 0.1 mg/kg/day, respectively.

The safety and efficacy of anticancer antibody-drug conjugates (ADCs) depend on the selection of tumor-targeting monoclonal antibody (mAb), linker, and drug, as well as their specific chemical arrangement and linkage chemistry. In this study, we used a heterobifunctional cross-linker to conjugate docetaxel (DX) to cetuximab (CET) or panitumumab (PAN). The resulting ADCs were investigated for their in vitro EGFR-specific cytotoxicity and in vivo anticancer activity. Reaction conditions, such as reducing agent, time, temperature, and alkylation buffer, were optimized to yield potent and stable ADCs with consistent batch-to-batch drug-to-antibody ratios (DARs). ADCs were synthesized with DARs from 0.4 to 3.0, and all retained their EGFR affinity and specificity after modification. ADCs were sensitive to cell surface wildtype EGFR expression, demonstrating more cytotoxicity in EGFR-expressing A431 and MDA-MB-231 cell lines compared to U87MG cells. A431 tumor-bearing mice treated once weekly for four weeks with 100 mg/kg cetuximab-docetaxel ADC (C-SC-DX, DAR 2.5) showed durable anticancer responses and improved overall survival compared to the same treatment regimen with 1 mg/kg DX, 100 mg/kg CET, or a combination 1 mg/kg DX and 100 mg/kg CET. New treatment options are emerging for patients with both wild-type and mutated EGFR-overexpressing cancers, and these studies highlight the potential role of EGFR-targeted ADC therapies as a promising new treatment option.

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