Editor's choice: Contemporary murine models in preclinical astrocytoma drug development

Despite 6 decades of research, only 3 drugs have been approved for astrocytomas, the most common malignant primary brain tumors. However, clinical drug development is accelerating with the transition from empirical, cytotoxic therapy to precision, targeted medicine. Preclinical animal model studies are critical for prioritizing drug candidates for clinical development and, ultimately, for their regulatory approval. For decades, only murine models with established tumor cell lines were available for such studies. However, these poorly represent the genomic and biological properties of human astrocytomas, and their preclinical use fails to accurately predict efficacy in clinical trials. Newer models developed over the last 2 decades, including patient-derived xenografts, genetically engineered mice, and genetically engineered cells purified from human brains, more faithfully phenocopy the genomics and biology of human astrocytomas. Harnessing the unique benefits of these models will be required to identify drug targets, define combination therapies that circumvent inherent and acquired resistance mechanisms, and develop molecular biomarkers predictive of drug response and resistance. With increasing recognition of the molecular heterogeneity of astrocytomas, employing multiple, contemporary models in preclinical drug studies promises to increase the efficiency of drug development for specific, molecularly defined subsets of tumors.     

Emerging Targets for the Management of Osteoarthritis Pain

Worldwide, osteoarthritis (OA) is one of the leading causes of chronic pain, for which adequate relief is not available. Ongoing peripheral input from the affected joint is a major factor in OA-associated pain. Therefore, this review focuses predominantly on peripheral targets emerging in the preclinical and clinical arena. Nerve growth factor is the most advanced of these targets, and its blockade has shown tremendous promise in clinical trials in knee OA. A number of different types of ion channels, including voltage-gated sodium channels and calcium channels, transient receptor potential channels, and acid-sensing ion channels, are important for neuronal excitability and play a role in pain genesis. Few channel blockers have been tested in preclinical models of OA, with varying results. Finally, we discuss some examples of G-protein coupled receptors, which may offer attractive therapeutic strategies for OA pain, including receptors for bradykinin, calcitonin gene-related peptide, and chemokines. Since many of the pathways described above can be selectively and potently targeted, they offer an exciting opportunity for pain management in OA, either systemically or locally.     

Changing Medical School IT to Support Medical Education Transformation

Problem: Many medical schools are modifying curricula to reflect the rapidly evolving health care environment, but schools struggle to provide the educational informatics technology (IT) support to make the necessary changes. Often a medical school's IT support for the education mission derives from isolated work units employing separate technologies that are not interoperable. Intervention: We launched a redesigned, tightly integrated, and novel IT infrastructure to support a completely revamped curriculum at the Vanderbilt School of Medicine. This system uses coordinated and interoperable technologies to support new instructional methods, capture students' effort, and manage feedback, allowing the monitoring of students' progress toward specific competency goals across settings and programs. Context: The new undergraduate medical education program at Vanderbilt, entitled Curriculum 2.0, is a competency-based curriculum in which the ultimate goal is medical student advancement based on performance outcomes and personal goals rather than a time-based sequence of courses. IT support was essential in the creation of Curriculum 2.0. In addition to typical learning and curriculum management functions, IT was needed to capture data in the learning workflow for analysis, as well as for informing individual and programmatic success. We aligned people, processes, and technology to provide the IT infrastructure for the organizational transformation. Outcomes: Educational IT personnel were successfully realigned to create the new IT system. The IT infrastructure enabled monitoring of student performance within each competency domain across settings and time via personal student electronic portfolios. Students use aggregated performance data, derived in real time from the portfolio, for mentor-guided performance assessment, and for creation of individual learning goals and plans. Poorly performing students were identified earlier through online communication systems that alert the appropriate instructor or coach of low quiz grades or missed learning goals. Graphical and narrative displays of a student's competency performance across courses and clinical experiences informed high-stake decisions made about student progress by the promotions committee. Similarly, graphical display of aggregate student outcomes provided education leaders with information needed to adjust and improve the curriculum. Lessons Learned: With the alignment of people, processes, and technology, educational IT can facilitate transformational steps in the training of medical students.