Research Grants Program Office

Introduction

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Conclusions

These data show the differentially expressed genes (DEG) from HCC38 breast cancer cell line chronically exposed to nicotine versus vehicle control. Additional data is also provided from dynamic trajectory analysis, identifying the most dynamic genes due to chronic nicotine treatment. To produce this dataset, we first performed single cell RNA sequencing from HCC38 cells chronically treated with vehicle or nicotine, followed by scanpy analysis to yield 6 discrete cell clusters at conservative resolution. We then evaluated differential gene expression between chronic nicotine and control cells for each individual cluster or in the whole sample using PyDESeq2. For dynamic trajectory analysis, Velocyto (0.6) was used to estimate the spliced and unspliced counts for each gene between chronic nicotine-treated cells and vehicle, allowing computation of gene velocities. These data are useful for analysing the expression of individual genes or gene velocities either in the whole sample or in the different clusters identified. Since the HCC38 cell line used in these experiments is heterogeneous, including cells with features of stem-like, luminal progenitor-like and more differentiated cells, this dataset allows examination of the conserved as well as disparate gene expression effects of nicotine in different breast cancer cell types. Our dataset has a great potential for re-use given the recent surge in interest surrounding the role tobacco-use plays in breast cancer progression.

Introduction

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Conclusions

Smoking plays an underappreciated role in breast cancer progression, increasing recurrence and mortality in patients. Here, we show that S100A8/A9 innate immune signaling is a molecular mechanism that identifies smoking-related breast cancers and underlies their enhanced malignancy. In contrast to acute exposure, chronic nicotine increased tumorigenicity and reprogrammed breast cancer cells to express innate immune response genes. This required the α7 nicotinic acetylcholine receptor, which elicited dynamic changes in cell differentiation, proliferation, and expression of secreted cytokines, such as S100A8 and S100A9, as assessed by unbiased scRNA-seq. Indeed, pharmacologic or genetic inhibition of S100A8/A9-RAGE receptor signaling blocked nicotine's tumor-promoting effects. We also discovered Syntaphilin (SNPH) as an S100A8/A9-dependent gene enriched specifically in estrogen receptor-negative (ER^-) cancers from former smokers, linking this response to patient disease. Together, our findings describe a new α7 nAChR-S100A8/A9-Syntaphilin immune signaling module that drives nicotine-induced tumor progression and distinguishes smoking-related patient disease as a distinct subset of aggressive breast cancers.

Objective: Distinctive stressors facing pregnant and postpartum individuals during the COVID-19 pandemic may have affected their emergency department (ED) care-seeking for behavioral health concerns and violence victimization. We tested whether the incidence of postpartum behavioral health and assault injury ED visits differed for individuals according to their months of postpartum pandemic exposure. Methods: We used statewide, longitudinally linked hospital and ED administrative claims data from California to classify all individuals with hospital deliveries between January 1, 2016, and December 31, 2020, according to their months of postpartum pandemic exposure. Outcomes comprised 12-month incidence of any ED visit for a psychiatric disorder, drug use disorder/overdose, alcohol use disorder/intoxication, or assault injury, defined using International Classification of Diseases-Clinical Modification, version 10 codes. Risk ratios compared the incidence of each outcome among people with 1-12 months of postpartum pandemic exposure to those with 0 months of exposure. Results: Compared to people with 0 months of postpartum pandemic exposure (n = 1,163,215), delivering people with 1-12 month' exposure (range: n = 26,836 to n = 273,561) were approximately equally likely to have a postpartum ED visit for a psychiatric disorder, drug use disorder, or alcohol use disorder, after adjusting for demographic differences (most p > 0.10). The incidence of assault injury was significantly lower among delivering individuals with 11 or 12 months of pandemic exposure (RR_adj = 0.70 and 0.91, respectively; both p < 0.01) compared to those with 0 months. Conclusions: Contrary to expectations, the pandemic did not appear to have affected ED utilization for most behavioral health conditions among postpartum individuals, but assault injury ED visits declined.

Progenitors of intraepithelial T cells (IELps) migrate from the thymus to the intestines after birth where they develop into unconventional TCRγδ and TCRαβ lymphocytes in a process of extrathymic lymphopoiesis within cryptopatches. Mechanisms of IELp migration have remained unclear. Here we show that thymic IELps express the somatostatin receptor SSTR2, which contributes to their homing to the gut. IELp homing is Sstr2 dependent and correlates with neonatal induction of Sst encoding somatostatin in neuroendocrine and lamina propria stromal cells. The SSTR2 ligands somatostatin and cortistatin attract IELps in chemotaxis assays and somatostatin triggers IELp binding to the mucosal vascular addressin MAdCAM1. T cell transduction with Sstr2 confers homing to the neonatal colon. Human fetal thymic IELp-like cells express SSTR2 and intestinal stromal cells express SST at the time of initial T cell population, suggesting conserved mechanisms of progenitor seeding of the developing intestines. These results reveal an unexpected role for the SSTR2-somatostatin axis in early immune system development and describe a new role for a small peptide hormone G-protein-coupled receptor in developmental lymphocyte trafficking.

With the many negative health consequences of cigarette smoking, quitting is known to improve health in multiple domains. Using positron emission tomography/computed tomography (PET/CT) scanning, our group previously demonstrated that smokers have lower levels than nonsmokers of translocator protein binding both acutely and following overnight abstinence. Here, we sought to determine the effects of longer smoking abstinence on this marker of gliosis for microglia and astroglia, as well as explore associations between the marker and smoking-related symptoms. This observational study was performed in an academic VA medical centre. Fifty-nine generally healthy Veterans who were either nonsmokers (n = 15) or smokers (n = 44) participated in the study. Participants completed an intake visit to evaluate for inclusion/exclusion criteria, [¹⁸F]FEPPA PET/CT scanning and a structural magnetic resonance imaging scan. Smokers were alternately assigned either to smoke to satiety (n = 24) before scanning or undergo three nights of continuous abstinence prior to scanning using contingency management (n = 20 completed this protocol and scanning). The smoker satiety group had a significantly lower mean whole brain (WB) standardized uptake value (SUV) for [¹⁸F]FEPPA binding than both the nonsmoking (-15.3%) and abstinent smoker (-12.3%) groups. The nonsmoking control and abstinent smoker groups had mean WB SUVs that were not significantly different from one another (3.0% group difference). In an exploratory analysis, a significant inverse relationship was found between WB SUVs and mood ratings for smokers, indicating that higher levels of TSPO binding were associated with worse mood. The central findings here support previous studies demonstrating lower levels of the marker for gliosis in satiated smokers and imply normalization with elimination of cigarette smoke constituents from the body, although other explanations for study results (e.g., alterations in radioligand delivery or clearance of radioligand by cigarette smoke constituents) are possible. These findings may represent a previously unknown health benefit of quitting smoking.

Background

Objective

Methods

Results

Conclusion

Background

Methods

Results

Conclusion

To explore the hypothesis that differential exposures to estrogen active chemicals may contribute to regional disparities in cancer incidence, a comprehensive targeted and nontargeted analysis was conducted over two seasons (2020) for drinking water samples from 120 households served by 8 public water systems (4 with historically elevated breast cancer incidence) and from 15 brands of retail water. All samples were analyzed using gas and liquid chromatography with high-resolution mass spectrometry and a bioassay for estrogen receptor agonism. Target compounds included disinfection byproducts, per- and polyfluoroalkyl substances (PFAS), trace elements, and compounds selected for their possible relation to breast cancer. Over 7500 GC and LC nontargeted molecular features passed all quality control filters in each sampling season and were prioritized for identification if they were related to measured estrogen receptor agonism or were present at higher levels in areas with high breast cancer incidence (n = 1036). Benzothiazole-2-sulfonic acid, acetyl tributyl citrate, and diphenyl sulfone were among the prioritized and confirmed nontarget compounds. Nine polycyclic aromatic hydrocarbons and two ketone derivatives displayed significant negative correlations with estrogen receptor agonism. Many prioritized compounds remained unidentified, as 84.4% of the LC features and 77.5% of the GC features could not be annotated with high confidence.