Glioblastomas are the most prevalent and lethal primary brain tumor and are comprised of hierarchies with selfrenewing cancer stem cells (CSCs) at the apex. Like neural stem cells (NSCs), CSCs reside in functional niches that provide essential cues to maintain the cellular hierarchy. Bone morphogenetic proteins (BMPs) instruct NSCs to adopt an astrocyte fate and are proposed as anti-CSC therapies to induce differentiation, but, paradoxically, tumors express high levels of BMPs. Here we demonstrate that the BMP antagonist Gremlin1 is specifically expressed by CSCs as protection from endogenous BMPs. Gremlin1 colocalizes with CSCs in vitro and in vivo. Furthermore, Gremlin1 blocks prodifferentiation effects of BMPs, and overexpression of Gremlin1 in non-CSCs decreases their endogenous BMP signaling to promote stem-like features. Consequently, Gremlin1-overexpressing cells display increased growth and tumor formation abilities. Targeting Gremlin1 in CSCs results in impaired growth and self-renewal. Transcriptional profiling demonstrated that Gremlin1 effects were associated with inhibition of p21, a key CSC signaling node. This study establishes CSC-derived Gremlin1 as a driving force in maintaining glioblastoma tumor proliferation and glioblastoma hierarchies through the modulation of endogenous prodifferentiation signals.

Introduction: Simulation-based medical education allows learners to refine and maintain clinical skills especially for high-stake situations such as trauma resuscitation. Despite the primary and secondary survey being its foundation, literature shows poor adherence with overall rates as low as 13%. This study evaluates the impact of rapid cycle deliberate practice (RCDP) on primary and secondary survey skill retention. We hypothesized that RCDP-trained surgery residents will have real-world clinical improvement in their survey completion in pediatric trauma resuscitations. Methods: We developed an RCDP trauma resuscitation curriculum. Videos of trauma resuscitations before and after curriculum implementation were scored by 2 blinded reviewers using a modified Pediatric Trauma Assessment Scoring Tool. Actual trauma care by residents who had received the curriculum (study group) was compared with care provided by residents who had not received the curriculum (precurriculum historical control group and a concurrent control group who provided care without receiving the curriculum). Results: One hundred eighty-eight videos were scored with 98 in study group, 33 in concurrent control group, and 57 in historical control group. There was a significant improvement in primary survey performance between study group and historical control group (P < 0.001), but no difference between study group and concurrent control group. There was a significant improvement between study group and 2 control groups in secondary survey performance (both P < 0.001). Conclusions: The RCDP curriculum led to significant improvement in surgical residents' trauma survey performance and had clinical impact on actual patients, which is rare in pediatric trauma simulation literature.

Background Optimal performance of the primary and secondary survey is the foundation of Advance Trauma Life Support care. Despite its importance, not all primary surveys completed at level 1 pediatric trauma centers are performed according to established guidelines (Gala et al., Pediatr Emerg Care 32:756–762, 2016, Carter et al., Resuscitation 84:66–71, 2013). We hypothesize that rapid cycle deliberate practice (RCDP) will improve surgical residents’ confidence in performing the primary and secondary survey. Methods We developed a curriculum to teach surgical interns the principles of performing the primary and secondary survey using RCDP. Surveys distributed after each session assessed the impact of the curriculum on learner confidence and perception that this curriculum would benefit patient care. Questions were scored on a 5-point Likert scale. Sixteen surgical interns participated during intern orientation and 100% of the participants completed the post curriculum survey. Results Thirteen (81%) of participants agreed or strongly agreed that the simulation would impact future performance in the pediatric trauma bay. The curriculum also significantly improved the confidence of our learners to perform trauma surveys (p < 0.001). Conclusion This curriculum improves the confidence of junior surgical residents in learning the primary and secondary survey. Most learners enjoyed the session and felt that the curriculum would positively impact their performance.