Interferon-gamma is Quintessential for NOS2 and COX2 Expression in ER - Breast Tumors that Lead to Poor Outcome.

A strong correlation between NOS2 and COX2 tumor expression and poor clinical outcomes in ER-breast cancer has been established. However, mechanisms of tumor induction of these enzymes are unclear. Analysis of The Cancer Genome Atlas (TCGA) revealed correlations between NOS2 and COX2 expression and Th1 cytokines. Herein, single cell RNAseq analysis of TNBC cells shows potent NOS2 and COX2 induction by IFNγ combined with IL1ß or TNFα. Given that IFNγ is secreted by cytolytic lymphocytes, which improve clinical outcomes, this role of IFNγpresents a dichotomy. To explore this conundrum, tumor NOS2, COX2, and CD8 + T cells were spatially analyzed in aggressive ER-, TNBC, and HER2+ breast tumors. High expression and clustering of NOS2-expressing tumor cells occurred at the tumor/stroma interface in the presence of stroma-restricted CD8 + T cells. High expression and clustering of COX2-expressing tumor cells extended into immune desert regions in the tumor core where CD8 + T cell penetration was limited or absent. Moreover, high NOS2-expressing tumor cells were proximal to areas with increased satellitosis suggestive of cell clusters with a higher metastatic potential. Further in vitro experiments revealed that IFNγ+IL1ß/TNFα increased elongation and migration of treated tumor cells. This spatial analysis of the tumor microenvironment provides important insight of distinct neighborhoods where stroma-restricted CD8 + T cells exist proximal to NOS2-expressing tumor niches that could have increased metastatic potential.

Yeast homologs of human MCUR1 regulate mitochondrial proline metabolism.

Mitochondria house evolutionarily conserved pathways of carbon and nitrogen metabolism that drive cellular energy production. Mitochondrial bioenergetics is regulated by calcium uptake through the mitochondrial calcium uniporter (MCU), a multi-protein complex whose assembly in the inner mitochondrial membrane is facilitated by the scaffold factor MCUR1. Intriguingly, many fungi that lack MCU contain MCUR1 homologs, suggesting alternate functions. Herein, we characterize Saccharomyces cerevisiae homologs Put6 and Put7 of MCUR1 as regulators of mitochondrial proline metabolism. Put6 and Put7 are tethered to the inner mitochondrial membrane in a large hetero-oligomeric complex, whose abundance is regulated by proline. Loss of this complex perturbs mitochondrial proline homeostasis and cellular redox balance. Yeast cells lacking either Put6 or Put7 exhibit a pronounced defect in proline utilization, which can be corrected by the heterologous expression of human MCUR1. Our work uncovers an unexpected role of MCUR1 homologs in mitochondrial proline metabolism.

Incidence of ocular injuries in motor vehicle crash victims with concomitant air bag deployment.

OBJECTIVE: To report the incidence of ocular and nonocular trauma in patients admitted to the Henry Ford Hospital via the emergency room since 1994 after a motor vehicle crash (MVC) with and without air bag deployment. DESIGN: A retrospective cohort study. METHODS: The Henry Ford Hospital Trauma Registry database was reviewed for patients involved in MVCs with and without air bag deployment since 1994. RESULTS: From 1994 to 1999, there were only seven air bag-related ocular injuries, representing 4.4% of all MVC-related ocular injuries. From 1997 to 1999, MVC-related ocular injuries with and without air bags represented 5.0% and 12.7%, respectively, of all MVC-related injuries. For that same period, the death rate and average Injury Severity Score for MVCs with air bag deployment were 3.4% and 10.75, compared with 8% and 14.5, respectively, for MVCs without air bag deployment. CONCLUSIONS: MVC-related ocular injuries associated with air bag deployment are rare, and the incidence of ocular injuries associated with MVCs was lower when air bags were deployed.