ARID1A suppresses R-loop-mediated STING-type I interferon pathway activation of anti-tumor immunity.

Clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to immune checkpoint blockade (ICB) in several solid tumor types independent of microsatellite instability. We show that ARID1A loss in murine models is sufficient to induce anti-tumor immune phenotypes observed in ARID1A mutant human cancers, including increased CD8+ T cell infiltration and cytolytic activity. ARID1A-deficient cancers upregulated an interferon (IFN) gene expression signature, the ARID1A-IFN signature, associated with increased R-loops and cytosolic single-stranded DNA (ssDNA). Overexpression of the R-loop resolving enzyme, RNASEH2B, or cytosolic DNase, TREX1, in ARID1A-deficient cells prevented cytosolic ssDNA accumulation and ARID1A-IFN gene upregulation. Further, the ARID1A-IFN signature and anti-tumor immunity were driven by STING-dependent type I IFN signaling, which was required for improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings define a molecular mechanism underlying anti-tumor immunity in ARID1A mutant cancers.

Collaboration between distinct SWI/SNF chromatin remodeling complexes directs enhancer selection and activation of macrophage inflammatory genes.

Macrophages elicit immune responses to pathogens through induction of inflammatory genes. Here, we examined the role of three variants of the SWI/SNF nucleosome remodeling complex-cBAF, ncBAF, and PBAF-in the macrophage response to bacterial endotoxin (lipid A). All three SWI/SNF variants were prebound in macrophages and retargeted to genomic sites undergoing changes in chromatin accessibility following stimulation. Cooperative binding of all three variants associated with de novo chromatin opening and latent enhancer activation. Isolated binding of ncBAF and PBAF, in contrast, associated with activation and repression of active enhancers, respectively. Chemical and genetic perturbations of variant-specific subunits revealed pathway-specific regulation in the activation of lipid A response genes, corresponding to requirement for cBAF and ncBAF in inflammatory and interferon-stimulated gene (ISG) activation, respectively, consistent with differential engagement of SWI/SNF variants by signal-responsive transcription factors. Thus, functional diversity among SWI/SNF variants enables increased regulatory control of innate immune transcriptional programs, with potential for specific therapeutic targeting.

Glycaemic patterns during breastfeeding with postpartum use of closed-loop insulin delivery in women with type 1 diabetes.

AIMS/HYPOTHESIS: This study aimed to describe the relationship between breastfeeding episodes and maternal glucose levels, and to assess whether this differs with closed-loop vs open-loop (sensor-augmented pump) insulin therapy. METHODS: Infant-feeding diaries were collected at 6 weeks, 12 weeks and 24 weeks postpartum in a trial of postpartum closed-loop use in 18 women with type 1 diabetes. Continuous glucose monitoring (CGM) data were used to identify maternal glucose patterns within the 3 h of breastfeeding episodes. Generalised mixed models adjusted for breastfeeding episodes in the same woman, repeat breastfeeding episodes, carbohydrate intake, infant age at time of feeding and early pregnancy HbA1c. This was a secondary analysis of data collected during a randomised trial (ClinicalTrials.gov registration no. NCT04420728). RESULTS: CGM glucose remained above 3.9 mmol/l in the 3 h post-breastfeeding for 93% (397/427) of breastfeeding episodes. There was an overall decrease in glucose at nighttime within 3 h of breastfeeding (1.1 mmol l-1 h-1 decrease on average; p=0.009). A decrease in nighttime glucose was observed with open-loop therapy (1.2 ± 0.5 mmol/l) but was blunted with closed-loop therapy (0.4 ± 0.3 mmol/l; p<0.01, open-loop vs closed-loop). CONCLUSIONS/INTERPRETATION: There is a small decrease in glucose after nighttime breastfeeding that usually does not result in maternal hypoglycaemia; this appears to be blunted with the use of closed-loop therapy.

Assessment of insulin dose changes in pediatric patients with type 1 diabetes mellitus starting on continuous subcutaneous insulin infusion.

Objective: To assess change in total daily dose (TDD) of insulin following a switch from subcutaneous (SC) injections to continuous subcutaneous insulin infusion (CSII) in pediatric patients with type 1 diabetes (T1D). Secondary objectives were to determine the change in %basal insulin, insulin to carbohydrate (I:C) ratios, insulin sensitivity factor (ISF), and HbA1c/IDAA1c. Methods: A retrospective chart review of patients < 18 years of age who transitioned from SC to CSII at the Alberta Children's Hospital (Calgary, Alberta, Canada) between January 2019 and March 2022. Results: There was an increase of 0.04 units/kg/day in TDD from baseline vs 1-3 months later (p = 0.04, 95 % confidence interval (CI) [0.002, 0.072]). When stratified by age, a similar increase in TDD was observed in age 5-12 years only (p = 0.05, 95 % CI [0.0006, 0.8236]). There was a decrease in overall %basal insulin by 3 (44 % of TDD at baseline vs 41 % of TDD on CSII). (p = 0.02, 95 % CI [-5.5, -0.4]). No strengthening was seen in I:C ratios from baseline vs 1-3 months later. There was a significant strengthening of I:C ratios at all meals in the basal bolus group from 1-3 weeks to 1-3 months post-CSII; overall strengthening of ISF at both time points; and an overall HbA1c decrease -0.30 (p < 0.0001, CI [-0.45, -0.15]). Each extra year with diabetes was associated with a decrease in HbA1c by 0.07 % (p = 0.006). Conclusions: TDD of insulin was not found to be decreased post CSII initiation and patient characteristics should be considered when changing from SC to CSII. HbA1c was significantly improved post CSII.

Reported barriers to physical activity and the role of built environment among overweight and obese youth attending a Canadian pediatric weight management clinic.

Objective: To assess activity levels and role of the built environment among overweight and obese youth referred to a pediatric weight management clinic. Design: A cross-sectional study using a caregiver-administered survey was completed from October 2017 to February 2018. Results: The study analyzed 210 surveys. Participants were 52 % male and average age was 11.6 years (3-18 years). Of those surveyed, 73 % of respondents reported ≥ 2 h of average daily screen time in the past 3 months, and 74 % of children partook in < 60 min of daily physical activity of any intensity. The most common location for physical activity was a recreational facility. The least common was nearby green spaces. Moreover, 77 % of caregivers felt that their child did not engage in enough physical activity, and the most common cited barrier was motivation. The built environment, however, was not cited as a barrier to active living as 90 % of caregivers reported their community was safe, and greater than 80 % of caregivers agreed their community was aesthetically beautiful, well connected with good infrastructure. The majority of commonly used spaces were located within 2 km of their home, however, it was uncommon for children to walk or bike to them. Conclusion: Overweight and obese children referred to our clinic are not meeting national recommendations for physical activity and screen time. The built environment does not appear to be a large contributing factor to decreased physical activity in this population and the most common reason cited for lack of physical activity was motivation.