Maternal obesity induces chronic inflammatory responses that impact the fetus/neonate during the perinatal period. Inflammation, iron regulation, and myelination are closely interconnected and disruptions in these processes may have deleterious effects on neurodevelopment. Hepcidin levels are increased in response to inflammation causing subsequent decreases in ferroportin and available iron needed for myelination. Our current studies were designed to test the hypotheses that: 1) maternal high fat diet (HFD) prior to and during pregnancy is sufficient to induce inflammation and alter iron regulation in the brain of the offspring, and 2) HFD exposure is associated with altered myelination and neurobehavioral deficits in the offspring. Our data revealed modest increases in inflammatory cytokines in the serum of dams fed HFD prior to pregnancy compared to dams fed a control diet (CD). Early increases in IL-5 and decreases in IL-10 were observed in serum at PN7 while IL-5 remained elevated at PN21 in the HFDexposed pups. At PN0, most cytokine levels in whole brain homogenates were higher in the pups born to HFD-fed dams but were not different or were lower than in pups born to CD-fed dams at PN21. Conversely, the inflammation mediated transcription factor Nurr77 remained elevated at PN21. At birth, brain hepcidin, ferroportin, and l-ferritin levels were elevated in pups born to HFD-fed dams compared to pups born to CD-fed dams. Hepcidin levels remained elevated at PN7 and PN21 while ferroportin and l-ferritin levels were lower at PN7 and were not different at PN21. Decreases in myelination in the medial cortex were observed in male but not in female pups born to maternal HFD-fed dams at PN21. These structural changes correlated with changes in behavior (novel object recognition) in at 4 months in males only. Our data indicate that maternal obesity (HFD) results in disruption of iron regulation in the brains of the offspring with structural and neurobehavioral deficits in males.
Complex wounds are common complications in hospice and palliative medicine (HPM), especially in patients with aggressive malignancies. Myiasis, or an infestation of maggots, is a rare but significant complication of such wounds. While uncommon in the United States, many HPM patients have multiple risk factors and comorbidities that increase their vulnerability to this condition. Currently, there are no standard diagnostic or treatment guidelines for wound myiasis. In addition, common management strategies may not be easily accessible in HPM settings. We present this case of a patient with malignant squamous cell carcinoma of the neck complicated by myiasis while in hospice, and our experience diagnosing and managing her infestation. We also reflect on special considerations for HPM patients when addressing the physical and psychological symptoms of wound myiasis.
Background Medical humanities courses that incorporate the visual arts traditionally require in-person instruction and visits to museums. The COVID-19 pandemic afforded medical educators a unique opportunity to implement and evaluate virtual visual arts programming. Methods A two-week, 7-module visual arts and medicine elective course for third and fourth-year medical students was conducted virtually in the Spring of 2021. The course included traditional didactic components as well as a range of hands-on creative art activities including painting, graphic medicine, photovoice, and Kintsugi (Japanese craft). Digital tools including Canvas, Google Jamboard, and Zoom facilitated student engagement. Student feedback was collected through anonymous post-course surveys. Results We successfully conducted a virtual visual arts and medicine elective which integrated hands-on creative art activities. Most students “strongly agreed” that remote instruction was sufficient to meet course objectives. However, all students also “agreed” that in-person instruction may promote more in-depth engagement with the visual arts. The hands-on creative art activities were appreciated by all students. Conclusion Visual arts-based medical humanities courses can be delivered virtually and can include hands-on creative art activities such as painting. Future visual arts and medicine courses may benefit from incorporating a range of pedagogical methodologies, digital tools, control groups, and pre−/post-course assessments.
Resistance to endocrine therapy is a common problem in patients with estrogen receptor alpha (ERα) positive breast cancer. In this study, we took a non-biased genome-wide approach to identify novel mechanisms of endocrine resistance using a clustered regularly interspaced short palindromic repeats (CRISPR) activating (CRISPRa) screen. Results from the screen identified 109 candidate resistance-associated genes, with several of these genes, such as EGFR and SRC, having been previously associated with endocrine resistance. One candidate gene that has not been previously associated with endocrine resistance is the tyrosine kinase receptor, c-KIT. We further tested for associations between c-KIT and endocrine resistance and found that c-KIT overexpressing cells proliferate more rapidly in the presence of tamoxifen compared to control cell lines. To gain deeper insight into the potential role of c-KIT signaling in tamoxifen resistance, we next performed precision nuclear run-on and sequencing (PRO-seq) analysis of c-KIT overexpressing cells to identify downstream factors that may mediate the c-KIT response. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of the overexpressed genes found that the only class of factors that was significantly induced by c-KIT was the ATP-binding cassette (ABC) transporters; specifically, ABCA1, ABCA4, and ABCG1. Interestingly, overexpression of two of these ABC transporters, ABCA1 and ABCG1, significantly correlated with worse prognosis in ERα+ breast cancer patients following endocrine therapy. We then tested for potential therapeutic effects of c-KIT inhibition on endocrine resistance and found that the c-KIT inhibitor Gleevec appears to synergize with tamoxifen to suppress MCF-7-S cell growth. Together, our findings support the hypothesis that c-KIT signaling promotes endocrine resistance via the induction of ABC transporter activity. Additionally, our studies suggest that inhibition of c-KIT signaling may represent a novel strategy for preventing or overcoming endocrine resistance in ERα+ patients.
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