Enhanced protection of C57 BL/6 vs Balb/c mice to melanoma liver metastasis is mediated by NK cells

ABSTRACT The B16F10 murine melanoma cell line displays a low expression of MHC class I molecules favoring immune evasion and metastases in immunocompetent C57 BL/6 wild-type mice. Here, we generated metastases to the liver, an organ that is skewed towards immune tolerance, by intrasplenic injection of B16F10 cells in syngeneic C57 BL/6 compared to allogeneic Balb/c mice. Surprisingly, Balb/c mice, which usually display a pronounced M2 macrophage and Th2 T cell polarization, were ∼3 times more susceptible to metastasis than C57 BL/6 mice, despite a much higher M1 and Th1 T cell immune response. The anti-metastatic advantage of C57 BL/6 mice could be attributed to a more potent NK-cell mediated cytotoxicity against B16F10 cells. Our findings highlight the role of NK cells in innate anti-tumor immunity in the context of the liver – particularly against highly aggressive MHC I-deficient cancer cells. Moreover, the B16F10 model of melanoma liver metastasis is suited for developing novel therapies targeting innate NK cell related immunity in liver metastases and liver cancer

Physiological extremes of the human blood metabolome: A metabolomics analysis of highly glycolytic, oxidative, and anabolic athletes

Human metabolism is highly variable. At one end of the spectrum, defects of enzymes, transporters, and metabolic regulation result in metabolic diseases such as diabetes mellitus or inborn errors of metabolism. At the other end of the spectrum, favorable genetics and years of training combine to result in physiologically extreme forms of metabolism in athletes. Here, we investigated how the highly glycolytic metabolism of sprinters, highly oxidative metabolism of endurance athletes, and highly anabolic metabolism of natural bodybuilders affect their serum metabolome at rest and after a bout of exercise to exhaustion. We used targeted mass spectrometry-based metabolomics to measure the serum concentrations of 151 metabolites and 43 metabolite ratios or sums in 15 competitive male athletes (6 endurance athletes, 5 sprinters, and 4 natural bodybuilders) and 4 untrained control subjects at fasted rest and 5 minutes after a maximum graded bicycle test to exhaustion. The analysis of all 194 metabolite concentrations, ratios and sums revealed that natural bodybuilders and endurance athletes had overall different metabolite profiles, whereas sprinters and untrained controls were more similar. Specifically, natural bodybuilders had 1.5 to 1.8-fold higher concentrations of specific phosphatidylcholines and lower levels of branched chain amino acids than all other subjects. Endurance athletes had 1.4-fold higher levels of a metabolite ratio showing the activity of carnitine-palmitoyl-transferase I and 1.4-fold lower levels of various alkyl-acyl-phosphatidylcholines. When we compared the effect of exercise between groups, endurance athletes showed 1.3-fold higher increases of hexose and of tetradecenoylcarnitine (C14:1). In summary, physiologically extreme metabolic capacities of endurance athletes and natural bodybuilders are associated with unique blood metabolite concentrations, ratios, and sums at rest and after exercise. Our results suggest that long-term specific training, along with genetics and other athlete-specific factors systematically change metabolite concentrations at rest and after exercise

Pharmapolymers in the 21st century: Synthetic polymers in drug delivery applications

The administration of drugs, as a main challenge of pharmaceutical and medicinal applications, has certainly benefited from the application of synthetic polymers. However, despite an enormous effort to develop new materials for drug delivery applications, only few of them have entered the market due to the hurdles of regulation, production, cost efficiency and both industrial's and patients' acceptance. In this review, we summarize all these classes of synthetic polymers, which are on the market as well as the latest developments in clinical trials, and describe their application in polymer-drug conjugates, as excipients, in nano-/microscopic and macroscopic drug carriers, as polymeric coatings, or as polymeric drugs. Our intention is to create a link between the underlying chemical structures, the properties of the polymers, and their area of application, where they are often just known by their trade names or abbreviations. In addition selected types of synthetic polymers are highlighted that feature interesting properties and have the potential to make it to the market in future. (C) 2018 Elsevier B.V. All rights reserved