Dexamethasone-Mediated Activation of Fibronectin Matrix Assembly Reduces Dispersal of Primary Human Glioblastoma Cells.

Despite resection and adjuvant therapy, the 5-year survival for patients with Glioblastoma multiforme (GBM) is less than 10%. This poor outcome is largely attributed to rapid tumor growth and early dispersal of cells, factors that contribute to a high recurrence rate and poor prognosis. An understanding of the cellular and molecular machinery that drive growth and dispersal is essential if we are to impact long-term survival. Our previous studies utilizing a series of immortalized GBM cell lines established a functional causation between activation of fibronectin matrix assembly (FNMA), increased tumor cohesion, and decreased dispersal. Activation of FNMA was accomplished by treatment with Dexamethasone (Dex), a drug routinely used to treat brain tumor related edema. Here, we utilize a broad range of qualitative and quantitative assays and the use of a human GBM tissue microarray and freshly-isolated primary human GBM cells grown both as conventional 2D cultures and as 3D spheroids to explore the role of Dex and FNMA in modulating various parameters that can significantly influence tumor cell dispersal. We show that the expression and processing of fibronectin in a human GBM tissue-microarray is variable, with 90% of tumors displaying some abnormality or lack in capacity to secrete fibronectin or assemble it into a matrix. We also show that low-passage primary GBM cells vary in their capacity for FNMA and that Dex treatment reactivates this process. Activation of FNMA effectively "glues" cells together and prevents cells from detaching from the primary mass. Dex treatment also significantly increases the strength of cell-ECM adhesion and decreases motility. The combination of increased cohesion and decreased motility discourages in vitro and ex vivo dispersal. By increasing cell-cell cohesion, Dex also decreases growth rate of 3D spheroids. These effects could all be reversed by an inhibitor of FNMA and by the glucocorticoid receptor antagonist, RU-486. Our results describe a new role for Dex as a suppressor of GBM dispersal and growth.

Chronic disease management: a residency-led intervention to improve outcomes in diabetic patients.

BACKGROUND: When quality improvement processes are integrated into resident education, many opportunities are created for improved outcomes in patient care. For Bethesda Family Medicine (BFM), integrating quality improvement into resident education is paramount in fulfilling the Accreditation Council for Graduate Medical Education Practice-Based Learning and Improvement core competency requirements. METHODS: A resident-developed diabetes management treatment protocol that targeted 11 evidence-based measures recommended for successful diabetes management was implemented within the BFM residency and all physician practices under its parent healthcare system. This study compares diabetes management at BFM and at 2 other family medicine practices at timepoints before and after protocol implementation. We measured hemoglobin A1c (HbA1c), low-density lipoprotein (LDL) cholesterol, and systolic blood pressure (SBP) in adult diabetics and compared patient outcomes for these measures for the first and third quarters of 2009 and 2010. RESULTS: In BFM patients, HbA1c, LDL, and SBP levels decreased, but only HbA1c improvement persisted long term. For the comparison groups, in general levels were lower than those of BFM patients but not significantly so after the first measurement period. CONCLUSIONS: A resident-led treatment protocol can improve HbA1c outcomes among residents' diabetic patients. Periodic educational interventions can enhance residents' focus on diabetes management. Residents in graduate medical education can initiate treatment protocols to improve patient care in a large healthcare system.