RESUMO
Ewing sarcoma (ES) is an aggressive cancer diagnosed in adolescents and young adults. The fusion oncoprotein (EWSR1::FLI1) that drives Ewing sarcoma is known to downregulate TGFBR2 expression (part of the TGFß receptor). Because TGFBR2 is downregulated, it was thought that TGFß likely plays an inconsequential role in Ewing biology. However, the expression of TGFß in the Ewing tumor immune microenvironment (TIME) and functional impact of TGFß in the TIME remains largely unknown given the historical lack of immunocompetent preclinical models. Here, we use single-cell RNAseq analysis of human Ewing tumors to show that immune cells, such as NK cells, are the largest source of TGFß production in human Ewing tumors. We develop a humanized (immunocompetent) mouse model of ES and demonstrate distinct TME signatures and metastatic potential in these models as compared to tumors developed in immunodeficient mice. Using this humanized model, we study the effect of TGFß inhibition on the Ewing TME during radiation therapy, a treatment that both enhances TGFß activation and is used to treat aggressive ES. Utilizing a trivalent ligand TGFß TRAP to inhibit TGFß, we demonstrate that in combination with radiation, TGFß inhibition both increases ES immune cell infiltration and decreases lung metastatic burden in vivo . The culmination of these data demonstrates the value of humanized models to address immunobiologic preclinical questions in Ewing sarcoma and suggests TGFß inhibition as a promising intervention during radiation therapy to promote metastatic tumor control.
RESUMO
The current study explores the effect of demographics on serum cortisol expression in a study group of 52 individuals to improve the current serum reference ranges to produce personalized expression profiles consequently increasing clinical confidence in the diagnosis. The serum cortisol concentration was inspected against demographical data like age, sex, and body mass index and showed an association with age and sex. The serum cortisol values also indicated a positive association with chronic illnesses however this finding requires a more focused study for establishment. Additionally, saliva samples are also collected from the same study group at the same time through drool and an absorbent sponge and correlated with serum values to draw an alternative route of serological testing. Salivary cortisol from drool showed a linear correlation with Pearson's correlation coefficients of 0.71 and 0.72 with serum cortisol and with saliva samples collected using a porous sponge respectively. Overall, the study shows the role of demographics in shaping the reference ranges for cortisol, suggesting a path for developing personalized diagnostics. The study also highlights the efficacy of saliva as an alternative to serum cortisol to facilitate cortisol measurement for efficient stress management.