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Background: While most cutaneous squamous cell carcinomas (cSCCs) are treatable, certain high‐risk cSCCs, such as those in recessive dystrophic epidermolysis bullosa (RDEB) patients, are particularly aggressive. Owing to repeated wounding, inflammation and unproductive healing, RDEB patients have a 68% cumulative risk of developing life‐threatening cSCCs by the age of 35, and a 70% risk of death by the age of 45. Despite aggressive treatment, cSCC represents the leading cause of premature mortality in these patients, highlighting an unmet clinical need. Increasing evidence points to a role of altered metabolism in the initiation and maintenance of cSCC, making metabolism a potential therapeutic target. Objectives: We sought to determine the feasibility of targeting tumour cell energetics as a strategy to selectively hinder the growth advantage of aggressive cSCC. Methods: We evaluated the cell energetics profiles of RDEB‐SCC cells by analysing available gene expression data against multiple gene signatures and single‐gene targets linked to metabolic reprogramming. Additionally, we employed real‐time metabolic profiling to measure glycolysis and respiration in these cells. Furthermore, we investigated the anti‐neoplastic properties of the metformin against human and murine high‐risk cSCCs in vitro and in vivo. Results: Gene expression analyses highlighted a divergence in cell energetics profiles between RDEB‐SCC and non‐malignant RDEB keratinocytes, with tumour cells demonstrating enhanced respiration and glycolysis scores. Real‐time metabolic profiling supported these data and additionally highlighted a metabolic plasticity of RDEB‐SCC cells. Against this background, metformin exerted an anti‐neoplastic potential by hampering both respiration and glycolysis, and by inhibiting proliferation in vitro. Metformin treatment in an analogous model of fast‐growing murine cSCC resulted in delayed tumour onset and slower tumour growth, translating to a 29% increase in median overall survival. Conclusions: Our data indicate that metformin exerts anti‐neoplastic properties in aggressive cSCCs that exhibit high‐risk features by interfering with respiration and glycolytic processes. [ABSTRACT FROM AUTHOR]

Gunter Almer1, Matthias Saba-Lepek2, Samih Haj-Yahya1, Eva Rohde3, Dirk Strunk4, Eleonore Fröhlich5, Ruth Prassl2, Harald Mangge11Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 2Institute of Biophysics and Nanosystems Research, Austrian Academy of Science, 3University Clinic of Blood Group Serology and Transfusion Medicine, 4University Clinic of Hematology, 5Center for Medical Research, Medical University of Graz, Graz, AustriaBackground: Adiponectin, an adipocyte-specific plasma protein, has been shown to accumulate in injured endothelial cells during development of atherosclerotic lesions. In this study, we investigated the potential of different adiponectin subfractions with special emphasis on globular adiponectin (gAd) to recognize and visualize atherosclerotic lesions.Methods: Recombinant mouse gAd and subfractions of full-length adiponectin (ie, trimeric, hexameric, and oligomeric forms) were fluorescence-labeled. Aortas of wild-type and apoprotein E-deficient mice fed a high cholesterol diet were dissected and incubated with the labeled biomarkers. Imaging was performed using confocal laser scanning microscopy.Results: Confocal laser scanning microscopic images showed that gAd binds more strongly to atherosclerotic plaques than full-length adiponectin subfractions. Further, we showed that gAd accumulates preferentially in endothelial cells and the fibrous cap area of plaques. Here we demonstrate for the first time that gAd recognizes atherosclerotic plaques on aortic sections of apoprotein E-deficient mice.Conclusion: These results suggest that gAd, in addition to its physiological properties, is also suitable as a target molecule for prospective diagnostic strategies in imaging atherosclerotic lesions.Keywords: adiponectin subfractions, atherosclerosis, fibrous cap, globular adiponectin, vascular imaging

BACKGROUND: Neonatal antibiotic use is associated with a greater risk of nosocomial infection, necrotizing enterocolitis, and mortality. It can induce drug-resistant pathogens that contribute to increased neonatal morbidity/mortality, healthcare costs, and length of stay. Prior to the antibiotic stewardship program, decisions to obtain blood cultures and empiric antibiotics for possible Early-onset Sepsis (EOS) in late preterm and term infants upon NICU admission were provider-dependent rather than algorithm-based. We aimed to decrease empiric antibiotic prescription from 70% to 56% (20% decrease) in infants ≥34 weeks gestation admitted to the NICU. METHODS: The stewardship initiative comprised the following practice changes: (1) use of the Neonatal Sepsis Risk Calculator (SRC); and (2) a 36-hour time-out for prescribed empiric antibiotics. Data was retrospectively collected and analyzed for inborn infants pre-intervention (January 2015–December 2015; n = 263) and post-intervention (August 2016–September 2017; n = 279). Data regarding compliance with the new antibiotic guideline were collected and disseminated to the team every week. Overlap between CDC guidelines and calculator recommendations were studied. RESULTS: Pre-and post-intervention outcomes were analyzed using chi-square tests. There was a significant post-intervention reduction in the rate of both antibiotic prescriptions (29.4% decline; 70.3% vs. 49.6%; p < 0.001) and sepsis evaluations (24.3% decline; 90.9% vs. 68.8%; p < 0.001). No difference (p = 0.271) in culture-positive EOS cases was observed. There was 92% overlap in blood culture recommendations and 95% overlap between antibiotic recommendations when current CDC guidelines were compared to the SRC. CONCLUSION: A significant reduction in antibiotic use and sepsis evaluations was achieved for late preterm and term infants upon NICU admission. No clinical deterioration occurred in post-intervention infants who did not receive antibiotics. There is significant overlap between CDC guidelines and SRC recommendations. [ABSTRACT FROM AUTHOR]