RESUMO
Glioblastoma (GBM) as the most common and aggressive brain tumor is characterized by genetic heterogeneity, invasiveness, radio-/chemoresistance, and occurrence of GBM stem-like cells. The metalloprotease-disintegrin ADAM8 is highly expressed in GBM tumor and immune cells and correlates with poor survival. In GBM, ADAM8 affects intracellular kinase signaling and increases expression levels of osteopontin/SPP1 and matrix metalloproteinase 9 (MMP9) by an unknown mechanism. Here we explored whether microRNA (miRNA) expression levels could be regulators of MMP9 expression in GBM cells expressing ADAM8. Initially, we identified several miRNAs as dysregulated in ADAM8-deficient U87 GBM cells. Among these, the tumor suppressor miR-181a-5p was significantly upregulated in ADAM8 knockout clones. By inhibiting kinase signaling, we found that ADAM8 downregulates expression of miR-181a-5p via activation of signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) signaling suggesting an ADAM8-dependent silencing of miR-181a-5p. In turn, mimic miR-181a-5p transfection caused decreased cell proliferation and lower MMP9 expression in GBM cells. Furthermore, miR-181a-5p was detected in GBM cell-derived extracellular vesicles (EVs) as well as patient serum-derived EVs. We identified miR-181a-5p downregulating MMP9 expression via targeting the MAPK pathway. Analysis of patient tissue samples (n=22) revealed that in GBM, miR-181a-5p is strongly downregulated compared to ADAM8 and MMP9 mRNA expression, even in localized tumor areas. Taken together, we provide evidence for a functional axis involving ADAM8/miR-181a-5p/MAPK/MMP9 in GBM tumor cells.
RESUMO
OBJECTIVE: We prospectively investigated how to integrate indocyanine green (ICG) angiography in an augmented reality (AR) setting for aneurysm surgery. METHODS: In 20 patients with a total of 22 aneurysms, the head-up display of the operating microscope (Kinevo900) was used for AR. ICG-AR was established directly by the head-up display superimposing the ICG angiography as green live video overlay. In addition, the reconstructed outline of the three-dimensional (3D) vessel architecture was visualized by AR applying intraoperative low-dose computed tomography (vessel-AR). RESULTS: In all patients, ICG-AR and vessel-AR were successfully implemented. The flow in the vessels could be observed directly in the white light view of the microscope oculars without being distracted from the surgical site by looking on separate screens. This factor enabled also surgical manipulation during ICG angiography. In parallel, AR additionally visualized the 3D vessel architecture, enhancing the understanding of the 3D anatomy (target registration error, 0.71 ± 0.21 mm; intraoperative low-dose computed tomography effective dose, 42.7 µSv). Linear (n = 28; range, 1-8.5 mm) and rotational (n = 3; range, 2.9°-14.4°) navigation adjustments performed in 18 of 20 patients resulted in a close matching of the vessel-AR outline with the real vessel situation after preparation, compensating for shifting. CONCLUSIONS: ICG-AR could be successfully implemented. It facilitated surgical manipulation and flow interpretation during ICG angiography because it could be observed directly while looking through the microscope oculars in white light instead of being distracted from the surgical site while looking on separate screens. Additional AR visualizing the vessel architecture improved understanding of 3D anatomy for preparation and clipping.