ER-PM Junctions on GABAergic Interneurons Are Organized by Neuregulin 2/VAP Interactions and Regulated by NMDA Receptors.

Neuregulins (NRGs) signal via ErbB receptors to regulate neural development, excitability, synaptic and network activity, and behaviors relevant to psychiatric disorders. Bidirectional signaling between NRG2/ErbB4 and NMDA receptors is thought to homeostatically regulate GABAergic interneurons in response to increased excitatory neurotransmission or elevated extracellular glutamate levels. Unprocessed proNRG2 forms discrete clusters on cell bodies and proximal dendrites that colocalize with the potassium channel Kv2.1 at specialized endoplasmic reticulum-plasma membrane (ER-PM) junctions, and NMDA receptor activation triggers rapid dissociation from ER-PM junctions and ectodomain shedding by ADAM10. Here, we elucidate the mechanistic basis of proNRG2 clustering at ER-PM junctions and its regulation by NMDA receptors. Importantly, we demonstrate that proNRG2 promotes the formation of ER-PM junctions by directly binding the ER-resident membrane tether VAP, like Kv2.1. The proNRG2 intracellular domain harbors two non-canonical, low-affinity sites that cooperatively mediate VAP binding. One of these is a cryptic and phosphorylation-dependent VAP binding motif that is dephosphorylated following NMDA receptor activation, thus revealing how excitatory neurotransmission promotes the dissociation of proNRG2 from ER-PM junctions. Therefore, proNRG2 and Kv2.1 can independently function as VAP-dependent organizers of neuronal ER-PM junctions. Based on these and prior studies, we propose that proNRG2 and Kv2.1 serve as co-regulated downstream effectors of NMDA receptors to homeostatically regulate GABAergic interneurons.

Motor Learning and Physical Exercise in Adaptive Myelination and Remyelination.

The idea that myelination is driven by both intrinsic and extrinsic cues has gained much traction in recent years. Studies have demonstrated that myelination occurs in an intrinsic manner during early development and continues through adulthood in an activity-dependent manner called adaptive myelination. Motor learning, the gradual acquisition of a specific novel motor skill, promotes adaptive myelination in both the healthy and demyelinated central nervous system (CNS). On the other hand, exercise, a physical activity that involves planned, structured and repetitive bodily movements that expend energy and benefits one's fitness, promotes remyelination in pathology, but it is less clear whether it promotes adaptive myelination in healthy subjects. Studies on these topics have also investigated whether the timing of motor learning or physical exercise is important for successful addition of myelin. Here we review our current understanding of the relationship of motor skill learning and physical exercise on myelination.

Gender, Productivity, and Philanthropic Fundraising in Academic Oncology.

BACKGROUND: Philanthropic donations are important funding sources in academic oncology but may be vulnerable to implicit or explicit biases toward women. However, the influence of gender on donations has not been assessed quantitatively. METHODS: We queried a large academic cancer center's development database for donations over 10 years to the sundry funds of medical and radiation oncologists. Types of donations and total amounts for medical oncologists and radiation oncologists hired prior to April 1, 2018 (allowing ≥2 years on faculty prior to query), were obtained. We also obtained publicly available data on physician/academic rank, gender, specialty, disease site, and Hirsch-index (h-index), a metric of productivity. RESULTS: We identified 127 physicians: 64% men and 36% women. Median h-index was higher for men (31; range, 1-100) than women (17; range, 3-77; P=.003). Men were also more likely to have spent more time at the institution (median, 15 years; range, 2-43 years) than women (median, 12.5 years; range, 3-22 years; P=.025). Those receiving donations were significantly more likely to be men (70% vs 30%; P=.034). Men received significantly higher median amounts ($259,474; range, $0-$29,507,784) versus women ($37,485; range, $0-$7,483,726; P=.019). On multivariable analysis, only h-index and senior academic rank were associated with donation receipt, and only h-index with donation amount. CONCLUSIONS: We found significant gender disparities in receipt of philanthropic donations on unadjusted analyses. However, on multivariable analyses, only productivity and rank were significantly associated with donations, suggesting gender disparities in productivity and promotions may contribute to these differences.

Chimeric Antigen Receptor T-Cell Therapy.

Patients with relapsed or refractory (R/R) cancers have a poor prognosis and limited treatment options. The recent approval of 2 chimeric antigen receptor (CAR) autologous T-cell products for R/R B-cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma treatment is setting the stage for what is possible in other diseases. However, there are important factors that must be considered, including patient selection, toxicity management, and costs associated with CAR T-cell therapy. To begin to address these issues, NCCN organized a task force consisting of a multidisciplinary panel of experts in oncology, cancer center administration, and health policy, which met for the first time in March 2018. This report describes the current state of CAR T-cell therapy and future strategies that should be considered as the application of this novel immunotherapy expands and evolves.

Ten trends transforming cancer care and their effects on space planning for academic medical centers.

OBJECTIVE: This article aims to define the major trends currently affecting space needs for academic medical center (AMC) cancer centers. It will distinguish between the trends that promote the concentration of services with those that promote decentralization as well as identify opportunities for achieving greater effectiveness in cancer care space planning. BACKGROUND: Changes in cancer care-higher survival rates, increased clinical trials, new technology, and changing practice models-increasingly fill hospitals' and clinicians' schedules and strain clinical space resources. Conflicts among these trends are concentrating some services and dispersing others. As a result, AMCs must expand and renovate intelligently to continue providing state-of-the-art, compassionate care. CONCLUSIONS: Although the typical AMC cancer center can expect to utilize more space than it would have 10 years ago, a deeper understanding of the cancer center enterprise can lead to opportunities for more effectively using available facility resources. Each AMC must determine for itself the appropriate balance of patient volume, clinical activity, and services between its main hospital campus and satellite branches. As well, space allocation should be flexible, as care trends, medical technology, and the provider's own priorities shift over time. The goal isn't necessarily more space-it's better space.

Massachusetts general hospital: improving patient access to the breast oncology clinic.

As part of Massachusetts General Hospital's overall quality improvement program, the Massachusetts General Hospital Breast Oncology Program participated in the NCCN Breast Cancer Outcomes Database Opportunities for Improvement Program. A review of concordance to breast oncology quality measures revealed that a small proportion of patients with breast cancer started chemotherapy more than 120 days after diagnosis. Therefore, the research team designed a quality improvement project to increase the percentage of concordance with the ASCO quality measure that requires time to treatment of less than 120 days and to decrease the number weeks from last definitive surgery to first adjuvant chemotherapy by 2014. A multipronged approach of improvements was used: to systems and infrastructure, communication among providers, and recruitment of additional staff as needed. This article describes the project and future initiatives to further improve the quality of breast cancer care at the institution.

NCCN molecular testing white paper: effectiveness, efficiency, and reimbursement.

Personalized medicine in oncology is maturing and evolving rapidly, and the use of molecular biomarkers in clinical decision-making is growing. This raises important issues regarding the safe, effective, and efficient deployment of molecular tests to guide appropriate care, specifically regarding laboratory-developed tests and companion diagnostics. In May 2011, NCCN assembled a work group composed of thought leaders from NCCN Member Institutions and other organizations to identify challenges and provide guidance regarding molecular testing in oncology and its corresponding utility from clinical, scientific, and coverage policy standpoints. The NCCN Molecular Testing Work Group identified challenges surrounding molecular testing, including health care provider knowledge, determining clinical utility, coding and billing for molecular tests, maintaining clinical and analytic validity of molecular tests, efficient use of specimens, and building clinical evidence.