Faculty Bibliography

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by insulin deficiency, and patients with diabetes have an increased risk of bone fracture and significantly impaired fracture healing. Proinflammatory cytokine tumor necrosis factor-alpha is significantly upregulated in diabetic fractures and is believed to underlie delayed fracture healing commonly observed in diabetes. Our previous genetic screen for the binding partners of progranulin (PGRN), a growth factor-like molecule that induces chondrogenesis, led to the identification of tumor necrosis factor receptors (TNFRs) as the PGRN-binding receptors. In this study, we employed several in vivo models to ascertain whether PGRN has therapeutic effects in diabetic fracture healing. Here, we report that deletion of PGRN significantly delayed bone fracture healing and aggravated inflammation in the fracture models of mice with T1DM. In contrast, recombinant PGRN effectively promoted diabetic fracture healing by inhibiting inflammation and enhancing chondrogenesis. In addition, both TNFR1 proinflammatory and TNFR2 anti-inflammatory signaling pathways are involved in PGRN-stimulated diabetic fracture healing. Collectively, these findings illuminate a novel understanding concerning the role of PGRN in diabetic fracture healing and may have an application in the development of novel therapeutic intervention strategies for diabetic and other types of impaired fracture healing.

PURPOSE/OBJECTIVE:Genetically engineered mouse models of sporadic cancers are critical for studying tumor biology and for preclinical testing of therapeutics. We present an MRI-based pipeline designed to produce high resolution, quantitative information about tumor progression and response to novel therapies in mouse models of medulloblastoma (MB). METHODS:Sporadic MB was modeled in mice by inducing expression of an activated form of the Smoothened gene (aSmo) in a small number of cerebellar granule cell precursors. aSmo mice were imaged and analyzed at defined time-points using a 3D manganese-enhanced MRI-based pipeline optimized for high-throughput. RESULTS:A semi-automated segmentation protocol was established that estimates tumor volume in a time-frame compatible with a high-throughput pipeline. Both an empirical, volume-based classifier and a linear discriminant analysis-based classifier were tested to distinguish progressing from nonprogressing lesions at early stages of tumorigenesis. Tumor centroids measured at early stages revealed that there is a very specific location of the probable origin of the aSmo MB tumors. The efficacy of the manganese-enhanced MRI pipeline was demonstrated with a small-scale experimental drug trial designed to reduce the number of tumor associated macrophages and microglia. CONCLUSION/CONCLUSIONS:Our results revealed a high level of heterogeneity between tumors within and between aSmo MB models, indicating that meaningful studies of sporadic tumor progression and response to therapy could not be conducted without an imaging-based pipeline approach.

PURPOSE/OBJECTIVE:To investigate the effect of a change in USMLE Step 1 timing on Step 2 Clinical Knowledge (CK) scores, the effect of lag-time on Step 2 CK performance, and the relationship of incoming MCAT score to Step 2 CK performance pre- and post-change. METHOD/METHODS:Four LCME-accredited schools that moved Step 1 after core clerkships between academic years 2008-2009 and 2017-2018 were analyzed in a pre-post format. Standard t-tests were used to examine the change in Step 2 CK scores pre- and post-change. Tests of differences in proportions were used to evaluate whether Step 2 CK failure rates differed between curricular change groups. Linear regressions were used to examine the relationships between Step 2 CK performance, lag-time and incoming MCAT score, and curricular change group. RESULTS:Step 2 CK performance did not change significantly (P = .20). Failure rates remained highly consistent (pre-change: 1.83%, post-change: 1.79%). The regression indicated that lag-time had a significant effect on Step 2 CK performance, with scores declining with increasing lag-time. The regression yielded small but significant interaction effects between MCAT and Step 2 CK scores. Students with lower incoming MCATs tended to perform better on Step 2 CK when Step 1 was after clerkships. CONCLUSIONS:Moving Step 1 after core clerkships appears to have had no significant impact on Step 2 CK scores or failure rates, supporting the argument that such a change is noninferior to the traditional model. Students with lower MCAT scores benefit most from the change.

The gastrointestinal (GI) tract renews frequently to sustain nutrient digestion and absorption in the face of consistent tissue stress. In many species, proliferative intestinal stem cells (ISCs) are responsible for the repair of the damage arising from chemical and mechanical aspects of food breakdown and exposure to pathogens. As the cellular source of all mature cell types of the intestinal epithelium throughout adulthood, ISCs hold tremendous therapeutic potential for understanding and treating GI disease in humans. This review focuses on recent advances in our understanding of ISC identity, behavior, and regulation during homeostasis and injury-induced repair, as revealed by two major animal models used to study regeneration of the small intestine: Drosophila melanogaster and Mus musculus. We emphasize recent findings from Drosophila that are likely to translate to the mammalian GI system, as well as challenging topics in mouse ISC biology that may be ideally suited for investigation in flies. For context, we begin by reviewing major physiological similarities and distinctions between the Drosophila midgut and mouse small intestine.

Reduction of caloric intake delays and prevents age-associated diseases and extends the life span in many organisms. It may be that these benefits are due to positive effects of caloric restriction on stem cell function. We use the planarian model Schmidtea mediterranea, an immortal animal that adapts to long periods of starvation by shrinking in size, to investigate the effects of starvation on telomere length. We show that the longest telomeres are a general signature of planarian adult stem cells. We also observe that starvation leads to an enrichment of stem cells with the longest telomeres and that this enrichment is dependent on mTOR signaling. We propose that one important effect of starvation for the rejuvenation of the adult stem cell pool is through increasing the median telomere length in somatic stem cells. Such a mechanism has broad implications for how dietary effects on aging are mediated at the whole-organism level.

Social skills intervention is an evidence-based practice for enhancing communication and interpersonal skills in individuals with autism spectrum disorder (ASD). Participation in the Program for the Education and Enrichment of Relational Skills (PEERS®), a manualized social skills intervention for adolescents with ASD, is associated with improved social skills and peer interactions, as well as decreased autism symptoms. Participation in PEERS® has also been linked to increased parent self-efficacy and decreased family chaos. The present study examined parenting stress in the context of PEERS®. Following participation in PEERS®, parents reported lower levels of parenting stress associated with adolescent mood and social isolation. These findings provide further evidence of the family-wide benefits of adolescent-focused social skills intervention.

Translating advances in cancer research to clinical applications requires better insight into the metabolism of normal cells and tumour cells in vivo. Much effort has focused on understanding how glycolysis and oxidative phosphorylation (OxPhos) support proliferation, while their impact on other aspects of development and tumourigenesis remain largely unexplored. We found that inhibition of OxPhos in neural stem cells (NSCs) or tumours in the Drosophila brain not only decreases proliferation, but also affects many different aspects of stem cell behaviour. In NSCs, OxPhos dysfunction leads to a protracted G₁/S-phase and results in delayed temporal patterning and reduced neuronal diversity. As a consequence, NSCs fail to undergo terminal differentiation, leading to prolonged neurogenesis into adulthood. Similarly, in brain tumours inhibition of OxPhos slows proliferation and prevents differentiation, resulting in reduced tumour heterogeneity. Thus, in vivo, highly proliferative stem cells and tumour cells require OxPhos for efficient growth and generation of diversity.