Racial Variation in Breast Tumor Promoter Methylation in the Carolina Breast Cancer Study

African American (AA) women are diagnosed with more advanced breast cancers and have worse survival than white women, but a comprehensive understanding of the basis for this disparity remains unclear. Analysis of DNA methylation, an epigenetic mechanism that can regulate gene expression, could help to explain racial differences in breast tumor clinical biology and outcomes

Body Mass Index Is Associated with Gene Methylation in Estrogen Receptor-Positive Breast Tumors

Although obesity is associated with breast cancer incidence and prognosis, the underlying mechanisms are poorly understood. Identification of obesity-associated epigenetic changes in breast tissue may advance mechanistic understanding of breast cancer initiation and progression. The goal of this study, therefore, was to investigate associations between obesity and gene methylation in breast tumors

DNA methylation profiling in the Carolina Breast Cancer Study defines cancer subclasses differing in clinicopathologic characteristics and survival

Abstract Introduction Breast cancer is a heterogeneous disease, with several intrinsic subtypes differing by hormone receptor (HR) status, molecular profiles, and prognosis. However, the role of DNA methylation in breast cancer development and progression and its relationship with the intrinsic tumor subtypes are not fully understood. Methods A microarray targeting promoters of cancer-related genes was used to evaluate DNA methylation at 935 CpG sites in 517 breast tumors from the Carolina Breast Cancer Study, a population-based study of invasive breast cancer. Results Consensus clustering using methylation (β) values for the 167 most variant CpG loci defined four clusters differing most distinctly in HR status, intrinsic subtype (luminal versus basal-like), and p53 mutation status. Supervised analyses for HR status, subtype, and p53 status identified 266 differentially methylated CpG loci with considerable overlap. Genes relatively hypermethylated in HR+, luminal A, or p53 wild-type breast cancers included FABP3, FGF2, FZD9, GAS7, HDAC9, HOXA11, MME, PAX6, POMC, PTGS2, RASSF1, RBP1, and SCGB3A1, whereas those more highly methylated in HR-, basal-like, or p53 mutant tumors included BCR, C4B, DAB2IP, MEST, RARA, SEPT5, TFF1, THY1, and SERPINA5. Clustering also defined a hypermethylated luminal-enriched tumor cluster 3 that gene ontology analysis revealed to be enriched for homeobox and other developmental genes (ASCL2, DLK1, EYA4, GAS7, HOXA5, HOXA9, HOXB13, IHH, IPF1, ISL1, PAX6, TBX1, SOX1, and SOX17). Although basal-enriched cluster 2 showed worse short-term survival, the luminal-enriched cluster 3 showed worse long-term survival but was not independently prognostic in multivariate Cox proportional hazard analysis, likely due to the mostly early stage cases in this dataset. Conclusions This study demonstrates that epigenetic patterns are strongly associated with HR status, subtype, and p53 mutation status and may show heterogeneity within tumor subclass. Among HR+ breast tumors, a subset exhibiting a gene signature characterized by hypermethylation of developmental genes and poorer clinicopathologic features may have prognostic value and requires further study. Genes differentially methylated between clinically important tumor subsets have roles in differentiation, development, and tumor growth and may be critical to establishing and maintaining tumor phenotypes and clinical outcomes

Temporal and spatial variability of dissolved organic and inorganic phosphorus, and metrics of phosphorus bioavailability in an upwelling-dominated coastal system

Author Posting. © American Geophysical Union, 2005. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 110 (2005): C10S13, doi:10.1029/2004JC002837.High-frequency temporal and spatial shifts in the various dissolved P pools (total, inorganic, and organic) are linked to upwelling/relaxation events and to phytoplankton bloom dynamics in the upwelling-dominated Oregon coastal system. The presence and regulation of alkaline phosphatase activity (APA) is apparent in the bulk phytoplankton population and in studies of cell-specific APA using Enzyme Labeled Fluorescence (ELF®). Spatial and temporal variability are also evident in phytoplankton community composition and in APA. The spatial pattern of dissolved phosphorus and APA variability can be explained by bottom-controlled patterns of upwelling, and flushing times of different regions within the study area. The presence of APA in eukaryotic taxa indicates that dissolved organic phosphorus (DOP) may contribute to phytoplankton P nutrition in this system, highlighting the need for a more complete understanding of P cycling and bioavailability in the coastal ocean.KCR acknowledges WHOI for rapid-response funding that made possible participation on this first COAST cruise, and NSF-OCE grant 0119134 for support of subsequent work on these and other COAST samples

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Engendering the house A 1500-year-old Southwest Alaska ena at DIL-088

This research explores the application of a lithic use-wear and technological analysis in conjunction with a spatially driven correspondence analysis to identify activity distribution in a 1,500-year-old house floor in Southwest Alaska that may correspond with gender. Employing ethnographic accounts of Central Yup'ik households, I demonstrate that the archaeological assemblage of the Norton-tradition semi-subterranean structure HP22 exhibits similar activity patterning to a Yup'ik ena (pl: enet) or women's house. This analysis indicates that HP22 may be an early example of the gendered housing pattern that first developed in Alaska circa 1800 BP. The results demonstrate the ability to identify social patterns of ancestral groups through lithic analysis in conjunction with ethnographic examples

Does the implementation of a pediatric appendicitis pathway promoting ultrasound work outside of a children\u27s hospital?

BACKGROUND: Efficacy of care pathways for pediatric appendicitis is well established in children\u27s hospitals, but not in community Emergency Departments (EDs). METHODS: A diagnostic pathway combining the Pediatric Appendicitis Score (PAS) with selective ultrasound was implemented. The charts of 2201 pediatric patients seen at four general EDs before and after implementation were retrospectively reviewed, identifying 611 children seriously considered for appendicitis. RESULTS: There were no cases of missed appendicitis within the pathway cohort (0/72). Low-PAS children on pathway had fewer computed tomography (CT) scans (0% vs. 21%; p \u3c 0.02). Moderate-PAS patients also had a reduced CT-first rate (2.4% vs. 23%; p \u3c 0.01). However, pathway adoption in 2016 was only 24%. Correct pathway application would have avoided 58 ultrasounds and 17 CTs over three months (annual savings $281,276). CONCLUSION: A pediatric appendicitis pathway is safe, rules out low suspicion patients without imaging, and is cost effective in a general hospital setting