Gamma secretase inhibitors (GSIs), initially developed as Alzheimer's therapies, have been repurposed as anticancer agents given their inhibition of Notch receptor cleavage. The success of GSIs in preclinical models has been ascribed to induction of cancer stem-like cell differentiation and apoptosis, while also impairing epithelial-to-mesenchymal transition and sensitizing cells to traditional chemoradiotherapies. The promise of these agents has yet to be realized in the clinic, however, as GSIs have failed to demonstrate clinical benefit in most solid tumors with the notable exceptions of CNS malignancies and desmoid tumors. Disappointing clinical performance to date reflects important questions that remain to be answered. For example, what is the net impact of these agents on antitumor immune responses, and will they require concurrent targeting of tumor-intrinsic compensatory pathways? Addressing these limitations in our current understanding of GSI mechanisms will undoubtedly facilitate their rational incorporation into combinatorial strategies and provide a valuable tool with which to combat Notch-dependent cancers. In the present review, we provide a current understanding of GSI mechanisms, discuss clinical performance to date, and suggest areas for future investigation that might maximize the utility of these agents.Implications for Practice: The performance of gamma secretase inhibitors (GSIs) in clinical trials generally has not reflected their encouraging performance in preclinical studies. This review provides a current perspective on the clinical performance of GSIs across various solid tumor types alongside putative mechanisms of antitumor activity. Through exploration of outstanding gaps in knowledge as well as reasons for success in certain cancer types, the authors identify areas for future investigation that will likely enable incorporation of GSIs into rational combinatorial strategies for superior tumor control and patient outcomes.

Many US medical schools have added a scholarly or research requirement as a potential intervention to increase the number of medical students choosing to become academic physicians and physician scientists. We designed a retrospective qualitative survey study to evaluate the impact of medical school research at the University of Alabama at Birmingham (UAB) on career choices. A survey tool was developed consisting of 74 possible questions with built-in skip patterns to customize the survey to each participant. The survey was administered using the web-based program Qualtrics to UAB School of Medicine alumni graduating between 2000 and 2014. Alumni were contacted 3 times at 2-week intervals during the year 2015, resulting in 168 completed surveys (11.5% response rate). MD/PhD graduates were excluded from the study. Most respondents completed elective research, typically for reasons relating to career advancement. 24 per cent said medical school research increased their desire for research involvement in the future, a response that positively correlated with mentorship level and publication success. Although completion of medical school research was positively correlated with current research involvement, the strongest predictor for a physician scientist career was pre-existing passion for research (p=0.008). In contrast, students motivated primarily by curricular requirement were less likely to pursue additional research opportunities. Positive medical school research experiences were associated with increased postgraduate research in our study. However, we also identified a strong relationship between current research activity and passion for research, which may predate medical school.

Objective: Patients with epithelial ovarian cancer (EOC) typically present with late‐stage disease, posing a significant challenge to treatment. Although taxane and platinum‐based chemotherapy plus surgical debulking are initially effective, EOC is marked by frequent recurrence with resistant disease. Immunotherapy represents an appealing treatment paradigm given the ability of immune cells to engage metastatic sites and impede recurrence; however, response rates to checkpoint blockade in ovarian cancer have been disappointing. Here, we tested whether class I HDAC inhibition can promote anti‐tumor T cell responses in a spontaneous and nonspontaneous murine model of EOC.Methods: We used the spontaneous Tg‐MISIIR‐Tag and nonspontaneous ID8 models of murine ovarian cancer to test this hypothesis. Whole tumor transcriptional changes were assessed using the nCounter PanCancer Mouse Immune Profiling Panel. Changes in select protein expression of regulatory and effector T cells were measured by flow cytometry.Results: We found that treatment with the class I HDAC inhibitor entinostat upregulated pathways and genes associated with CD8 T cell cytotoxic function, while downregulating myeloid derived suppressor cell chemoattractants. Suppressive capacity of regulatory T cells within tumors and associated ascites was significantly reduced, reversing the CD8‐Treg ratio.Conclusions: Our findings suggest class I HDAC inhibition can promote activation of intratumoral CD8 T cells, potentially by compromising suppressive networks within the EOC tumor microenvironment. In this manner, class I HDAC inhibition might render advanced‐stage EOC susceptible to immunotherapeutic treatment modalities.

Protein A affinity chromatography is a central part of most commercial monoclonal antibody and Fc‐fusion protein purification processes. In the last couple years an increasing number of new Protein A technologies have emerged. One of these new Protein A technologies consists of a novel, alkaline‐tolerant, Protein A ligand coupled to a macroporous polymethacrylate base matrix that has been optimized for immunoglobulin (Ig) G capture. The resin is interesting from a technology perspective because the particle size and pore distribution of the base beads are reported to have been optimized for high IgG binding and fast mass transfer, while the Protein A ligand has been engineered for enhanced alkaline tolerance. This resin was subjected to a number of technical studies including evaluating dynamic and static binding capacities, alkaline stability, Protein A leachate propensity, impurity clearance, and pressure–flow behavior. The results demonstrated similar static binding capacities as those achieved with industry standard agarose Protein A resins, but marginally lower dynamic binding capacities. Removal of impurities from the process stream, particularly host cell proteins, was molecule dependent, but in most instances matched the performance of the agarose resins. This resin was stable in 0.1 M NaOH for at least 100 h with little loss in binding capacity, with Protein A ligand leakage levels comparable to values for the agarose resins. Pressure–flow experiments in lab‐scale chromatography columns demonstrated minimal resin compression at typical manufacturing flow rates. Prediction of resin compression in manufacturing scale columns did not suggest any pressure limitations upon scale up. © 2014 American Institute of Chemical Engineers Biotechnol. Prog., 30:1125–1136, 2014