Abstract Purpose During their clinical years, medical students rotate in diverse environments, each with unique factors motivating or demotivating learning. Student motivation to learn in specialised clinical settings has not been robustly described. One framework to understand motivation to learn is self‐determination theory (SDT), which posits that intrinsic motivation requires fulfilment of three innate psychological needs: competence, relatedness and autonomy. Referencing SDT, the authors aimed to understand factors influencing student motivation to learn in the specialised context of internal medicine (IM) subspecialty consult services, with the goal of optimising teaching and learning during these experiences. Method Focus groups were conducted with 12 fourth‐year medical students who had completed at least one inpatient IM subspecialty consult elective at the University of California, San Francisco, in 2020–2021. Students discussed factors that promoted and hindered their learning and motivation. The authors performed abductive thematic analysis using SDT as a sensitising framework. Results Three themes were identified and provided insight into how student motivation to learn can be supported: teaching at the appropriate level; integration into the team and workflow; and self‐directed learning and career exploration. These themes were overlaid onto the needs of SDT, demonstrating that, in specialised clinical contexts, fulfilment of the needs is interconnected. Conclusion This study provided insight into how students' innate needs can be satisfied in the learning environment of IM subspecialty consult electives, thereby promoting students' intrinsic motivation. Based on insights from the study, the authors offer recommendations for how educators can optimise student motivation to learn.
Summary Although the conductive function of the tympanic membrane (TM) is critical for hearing, it is unknown how the organ maintains cellular homeostasis. Using a combination of single-cell RNA sequencing, lineage tracing, whole-organ explant, and live-cell imaging, we demonstrate that the stem cells of the TM epidermis reside in a distinct location at the superior portion of the TM and, as progeny migrate inferiorly, Pdgfra+ fibroblasts maintain a niche supporting proliferation of committed progenitors, while keratinocytes distal from the niche differentiate. Thus, the TM has a three dimensional differentiation hierarchy of keratinocytes distinct from that at other epidermal sites. The TM represents a physiological context where, in the absence of injury, keratinocytes both transit through a proliferative committed progenitor state and exhibit directional lateral migration. This work forms a foundation for understanding common disorders of the TM and introduces a new model system for the understanding of keratinocyte biology.
Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Long-term survival of patients with AML has changed little over the past decade, necessitating the identification and validation of new AML targets. Integration of genomic approaches with small-molecule and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. Here, we identified a role for glycogen synthase kinase 3α (GSK-3α) in AML by performing 2 independent small-molecule library screens and an shRNA screen for perturbations that induced a differentiation expression signature in AML cells. GSK-3 is a serine-threonine kinase involved in diverse cellular processes, including differentiation, signal transduction, cell cycle regulation, and proliferation. We demonstrated that specific loss of GSK-3α induced differentiation in AML by multiple measurements, including induction of gene expression signatures, morphological changes, and cell surface markers consistent with myeloid maturation. GSK-3α-specific suppression also led to impaired growth and proliferation in vitro, induction of apoptosis, loss of colony formation in methylcellulose, and anti-AML activity in vivo. Although the role of GSK-3β has been well studied in cancer development, these studies support a role for GSK-3α in AML.
Drugs targeting metabolism have formed the backbone of therapy for some cancers. We sought to identify new such targets in acute myeloid leukemia (AML). The one-carbon folate pathway, specifically methylenetetrahydrofolate dehydrogenase-cyclohydrolase 2 (MTHFD2), emerged as a top candidate in our analyses. MTHFD2 is the most differentially expressed metabolic enzyme in cancer versus normal cells. Knockdown of MTHFD2 in AML cells decreased growth, induced differentiation, and impaired colony formation in primary AML blasts. In human xenograft and MLL-AF9 mouse leukemia models, MTHFD2 suppression decreased leukemia burden and prolonged survival. Based upon primary patient AML data and functional genomic screening, we determined that FLT3-ITD is a biomarker of response to MTHFD2 suppression. Mechanistically, MYC regulates the expression of MTHFD2, and MTHFD2 knockdown suppresses the TCA cycle. This study supports the therapeutic targeting of MTHFD2 in AML.
<p>PDF file - 326K, This file contains 11 supplementary figures with biochemistry, computational analysis, in vitro and in vivo studies to support the role of targeting MYCN in neuroblastoma with BETi.</p>
