Children's Hospital Oakland Research Institute (CHORI) is a biomedical research institute affiliated with California’s pediatric medical center, UCSF Benioff Children's Hospital Oakland. CHORI is based in Oakland, California, and operates a 100,000-square-foot (9,300 m2) biomedical research facility that houses 300 staff members. It includes eight research centers that conduct focused research on cancer, critical care medicine, genetics, immunobiology and vaccine development, blood and marrow transplantation and cellular therapies, nutrition and metabolism, prevention of obesity, cardiovascular disease and diabetes, sickle cell disease and thalassemia. The National Institutes of Health is CHORI's primary funding source.
Necrobiotic xanthogranuloma (NXG) represents a rare granulomatous skin disease characterized by IFN-gamma-activated macrophages with limited treatment options. This study shows that metformin not only suppresses IFN-gamma-induced macrophage activation, but also induced clinical remission in a patient with NXG. These findings highlight metformin as a promising candidate for therapeutic repurposing in NXG.
BACKGROUND:Personalised management of cystic fibrosis (CF) lung disease in the era of CF transmembrane conductance regulator (CFTR) modulator therapy will require novel approaches to assess treatment response and monitor longitudinal progression. METHODS:We evaluated the heterogeneity of short-term response to elexacaftor-tezacaftor-ivacaftor (ETI) using 129Xe MRI, multiple breath washout (MBW) and spirometry. For CFTR modulator-naïve people ≥6 years old starting commercial ETI, we measured same-day 129XeMRI ventilation defect per cent (VDP), lung clearance index (LCI), forced expiratory volume in 1 s (FEV1) and CF Questionnaire-Revised respiratory-domain (CFQ-R(R)) at pre-ETI baseline and up to 4 months post-ETI. Baseline versus follow-up measures were compared using Wilcoxon-signed-rank tests with r effect size coefficients. Abnormal follow-up measures determined using z-scores and upper/lower limits of normal; correlations evaluated using Spearman ρ coefficients. RESULTS:VDP, FEV1, LCI and CFQ-R(R) significantly improved in the total group (n=40; all p<0.001, r=0.69, r=0.79, r=0.70, r=0.77) and both ≥12-year-old subgroups (n=15 FEV1<80%, p=0.005/r=0.69, p<0.001/r=0.87, p=0.004/r=0.70, p<0.001/r=0.88; n=17 FEV1≥80%, p=0.003/r=0.54, p=0.003/r=0.74, p=0.01/r=0.56, p=0.006/r=0.73). VDP (p=0.008/r=0.89), LCI (p=0.03/r=0.83) and percent-predicted FEV1 (p=0.03/r=0.83) significantly improved in the 6-11-year-old subgroup, with VDP having the greatest effect size in children. VDP remained abnormal at follow-up in 21 participants with normal FEV1, whereas LCI was abnormal in 12. Baseline VDP (ρ=0.39/p=0.01) and LCI (ρ=0.43/p=0.008) were significantly correlated with the change in CFQ-R(R). CONCLUSION:Though all outcome measures showed a positive response, response to ETI was heterogeneous between individuals and between 129XeMRI, MBW and spirometry. Leveraging the rich information provided by multimodal tools will be critical to understanding the nature of CF lung disease and measuring response to future therapies in the era of CFTR modulators.
Glucose homeostasis is tightly controlled by hormones secreted from pancreatic islets. The most abundant cell type in islets is the β-cell, which secretes insulin in response to nutritional stimuli. We previously reported that the adverse metabolic effects of high-dose dioxin exposure in mice are regulated by the aryl hydrocarbon receptor (AHR) specifically in β-cells. Additionally, fetal exposure to low-dose dioxin reduced β-cell area in female mice at birth; however, the role of AHR in β-cell development has not been explored. To characterize the AHR pathway in developing human β-cells, we differentiated human embryonic stem cells (hESCs) into "islet-like" cell clusters (SC-islets) in vitro and treated cells with vehicle or dioxin for 24 hours at key stages of differentiation. Dioxin exposure robustly upregulated AHR gene targets (CYP1A1, AHRR) at all stages of differentiation but only had modest effects on markers of islet development and maturity. We next generated an AHR knockout (KO) hESC line and found that basal CYP1A1 expression was profoundly suppressed in AHR-KO cells compared to parental cells at all stages of differentiation. Key markers of developing and mature pancreatic islets were largely unaffected by AHR deletion; however, G6PC2 was consistently downregulated in SC-islets from AHR-KO cells compared to parental cells. Interestingly, AHR-KO SC-islets also showed modestly increased insulin secretion relative to the parental line, suggesting a role for AHR in islet development. This novel AHR-KO cell line will allow for deeper investigation into the impact of AHR on the development of human islets and other cell lineages.
Ingestion of button batteries poses an acute life-threatening injury risk, particularly for small children. The Canadian Surveillance System for Poison Information reported 1021 single-substance button-battery ingestion cases from 2020 to 2023, and the British Columbia Drug and Poison Information Centre (DPIC) managed 548 unintentional ingestion cases from 2013 to 2023. Nearly all the DPIC cases required hospital admission for X-ray imaging, and seven patients required surgical removal of the battery from the esophagus. Our findings support developing product warning labels and enforcing child-resistant battery packaging and compartments on consumer products.
Recent endeavors to optimize the efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) treatment have focused on locating individualized stimulation targets using functional connectivity derived from functional Magnetic Resonance Imaging (fMRI) scans. Practically, this approach involves three main stages: target definition, target localization, and treatment. As of now, each stage is typically conducted while participants are "at rest", meaning they are not performing a task or being presented with a stimulus. While growing evidence suggests that the effects of TMS are sensitive to the state of the brain at the time of stimulation, brain state has largely been overlooked during the first two stages (target definition and localization). Here, we consider the potential importance of brain state at each stage of individualized rTMS, reviewing the relevant (and interdisciplinary) literature, and providing some exploratory example cross-state analyses. We also explore how manipulating and constraining brain state with tasks or movie-watching may provide opportunities to improve the reliability of individualized rTMS targets.
