angiogenin

Although immune checkpoint inhibitors (ICIs) have demonstrated high efficacy against malignant tumors, immune-related adverse cardiovascular events remain a significant concern. ICI-associated myocarditis is rare but potentially fatal. Therefore, identifying biomarkers is crucial for patient selection and management during ICI therapy. This pilot study aimed to explore cytokine profiles associated with the development of ICI myocarditis and evaluate their predictive value.

This study included 16 patients treated with ICI (6 with myocarditis [myocarditis group] and 10 without myocarditis [control group]). Serum samples were collected before ICI initiation (baseline) and 2-3 weeks after the first cycle of ICI administration (before the second cycle). Semi-quantitative membrane-based cytokine array analysis was used to detect 80 human cytokines.

Serum IL-1β and IL-2 levels significantly increased, and CCL4, CXCL5, angiogenin, EGF, and IL-10 significantly decreased in both groups after ICI initiation compared to baseline. In contrast, baseline cytokine levels differed between the groups: 43 cytokines, including G-CSF, IL-6, and CXCL13, were significantly elevated, and IL-10 was decreased in the myocarditis group compared to controls. After ICI treatment, serum levels of 23 cytokines, including CXCL13, IL-6, and leptin, were significantly higher in the myocarditis group than in controls.

Cytokine profiles change dramatically at the onset of ICI-associated myocarditis. Baseline immune dysregulation and/or increased reactivity to ICI therapy may contribute to the development of myocarditis. However, further studies are required to confirm these findings.

Glioblastoma (GBM) represents a complex ecosystem characterized by numerous interactions between tumor cells and the surrounding tumor microenvironment (TME). Here, we show that WNT10A, a member of the WNT family, plays an important role in GBM growth where its influence is mediated via both autocrine and paracrine pathways thereby stimulating not only the tumor cells but also normal cell types within the tumor microenvironment (TME).

In silico analysis was performed to identify high-expressing WNT family members in GBM. Knockdown and overexpression methods were used to examine the function of WNT10A in GBM cells and in orthotopic GBM xenografts in vivo. Co-immunoprecipitation (Co-IP) was used to confirm receptor binding and chromatin immunoprecipitation (ChIP) was performed to analyze transcriptional activation of downstream genes.

WNT10A was found to be highly expressed in GBMs and its knockdown significantly suppressed GBM malignant behavior in vitro and in vivo. Co-IP assays confirmed an interaction between WNT10A and FZD1, which activated the JNK/c-Jun/FOSB signaling pathway and enhanced the transcription of FOSB. Importantly, GBM cells secreted WNT10A into the tumor microenvironment, leading to an activation of the PI3K-AKT pathway in tumor-associated macrophages (TAMs) and the JNK pathway in tumor-associated astrocytes. The latter caused a secretion of tumor-promoting cytokines IL-6, MCP-1, and angiogenin. LGK974, a PORCN inhibitor, inhibited the secretion of WNT10A to suppress the malignant GBM phenotype.

Our findings revealed that WNT10A is a critical factor in promoting GBM progression through both autocrine and paracrine mechanisms. Thus, our findings provide the foundation for WNT-targeted clinical GBM treatment.

This study aimed to examine the effects of weightlessness and microgravity, induced by parabolic flight, on specific biomarkers associated with angiogenesis, lipid homeostasis, and cardiovascular diseases, including angiogenin (ANG), angiopoietin-1 (ANGPT-1), angiopoietin-like protein 4 (ANGPTL4), heat shock protein 70 (HSP70), transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), and platelet-derived growth factor subunit AA (PDGF-AA). 14 healthy volunteers (mean age: 28.9 years; 6 females) participated in short-term sessions of weightlessness and microgravity using parabolic flights. Venous blood samples were collected at different time points (baseline, 1 h, and 24 h after parabolic flight) and frozen as serum samples. Initially, Proteome Profiler Angiogenesis Array was used to screen pooled serum samples of each time point for potential alterations of angiogenesis-associated proteins. Additionally, individual blood samples were analyzed using enzyme-linked immunosorbent assay (ELISA). Proteome Arrays revealed an overall decrease of angiogenesis-associated proteins in response to parabolic flight. On the other hand, proteins associated with lipid homeostasis, such as Leptin and TIMP-4, were significantly elevated in response to parabolic flight. Individual analysis of selected proteins solely revealed a slight increase of ANGPTL4 and HSP70 levels 1 hour post-flight, although without statistical significance (p = 0.7705). Nevertheless, 24 h after parabolic flight, ANGPTL4 concentrations in serum significantly decreased compared to the preceding time point (p = 0.0020). Similarly, HSP70 was tendentially elevated 1 h after flight (p = 0.8135), though significantly declined at the end of the experiment (BL vs. 24 h: p = 0.0435; 1 h vs. 24 h: p = 0.0031). No significant differences could be observed in ANG, ANGPT1, TGF-β1, VEGF, and PDGF-AA concentrations at any time point. The findings of this study suggest that exposure to gravitational changes, such as weightlessness and microgravity, may lead to relevant changes in angiogenesis and lipid homeostasis. The upregulation of Leptin and TIMP-4, as well as ANGPTL4 in short-term response to parabolic flight poses a risk to disturbances in lipid metabolism, potentially increasing the likelihood of cardiovascular or hepatic events. Further research is needed to better understand the impact of microgravity and weightlessness on angiogenesis and lipid metabolism to protect astronaut health during prolonged space missions.