RESUMEN
FOXG1 is a transcription factor that interacts with multiple signaling pathways and modulates neuronal differentiation in the telencephalon. Dysregulation of FOXG1 expression has been previously reported in medulloblastoma. In this study, we demonstrate a regional specific expression of FOXG1 and its colocalization with Nestin expression in the premigratory mitotically active (outer) layer of the external granular layer of the cerebellum. An inverse expression of the granular precursor cell markers, Math1 and Musashi1, in the inner nonmitotic migratory layer of the external granular layer and in the internal granular layer was observed. Furthermore, modulation of FOXG1 in the medulloblastoma cell line, DAOY, was associated with the induction of neuronal differentiation markers and significant changes in multiple signaling pathways regulating cell proliferation, differentiation, survival, and apoptosis. Additionally, we observed enhanced survival in intracerebellar mice xenografts injected with DAOY cells bearing shFOXG1 constructs versus shLuciferase construct. Overall, these findings suggest that down-modulation of FOXG1 is a prerequisite for the onset of neuronal differentiation during cerebellar development and that a decrease of FOXG1 in medulloblastoma cells offers a survival advantage in mice. We propose that the disruption of signaling pathways that promote mature neuronal differentiation by overexpressed FOXG1 is a contributing event in the neoplastic transformation of cerebellar stem cells.
Asunto(s)
Transformación Celular Neoplásica/metabolismo , Neoplasias Cerebelosas/patología , Factores de Transcripción Forkhead/metabolismo , Meduloblastoma/patología , Proteínas del Tejido Nervioso/metabolismo , Células-Madre Neurales/patología , Animales , Western Blotting , Diferenciación Celular/fisiología , Transformación Celular Neoplásica/patología , Cerebelo/embriología , Modelos Animales de Enfermedad , Xenoinjertos , Humanos , Inmunohistoquímica , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Reacción en Cadena de la Polimerasa , ARN Interferente Pequeño , Transducción GenéticaRESUMEN
PURPOSE: The design and implementation of a preceptor development program involving close collaboration by the pharmacy residency program director (RPD) and members of a residency advisory committee (RAC) are described. SUMMARY: In 2011 the Nebraska Medical Center (NMC) implemented a program to foster the development of preceptors' teaching and clinical skills, as required by accreditation standards of the American Society of Health-System Pharmacists (ASHP). The RPD and RAC worked closely to define expectations of resident preceptors and a pathway for their transition from "conditional" to "primary" status. Among other program requirements, prospective (and new incoming) preceptors must (1) submit to the RAC a letter of interest in becoming a resident preceptor accompanied by an academic and professional record, (2) complete a new preceptor orientation session in which teaching concepts and principles are presented and discussed, and (3) obtain 10 preceptor education (PE) credits every two years. PE credits are earned through defined preceptor development opportunities including a teaching core and a clinical core focused on enhancing skills such as the application of therapeutic knowledge and conduct of clinical research. All preceptors are required to submit updated academic and professional records to the RAC every two years. The RAC audits 25% of preceptors to document attainment of PE credits and also conducts annual reviews of ASHP Resi-Trak summary evaluations of all preceptors and learning experiences. CONCLUSION: The NMC program may serve as a model for other institutions in planning and evaluating professional development programs to ensure that preceptors maintain the skills and knowledge necessary to provide high-quality resident training.