ABSTRACT
Glioblastoma (GBM) is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment (TME). In this environment, myeloid cells, such as myeloid-derived suppressor cells (MDSCs), play a pivotal role in suppressing antitumor immunity. Lipometabolism is closely related to the function of myeloid cells. Here, our study reports that acetyl-CoA acetyltransferase 1 (ACAT1), the key enzyme of fatty acid oxidation (FAO) and ketogenesis, is significantly downregulated in the MDSCs infiltrated in GBM patients. To investigate the effects of ACAT1 on myeloid cells, we generated mice with myeloid-specific (LyzM-cre) depletion of ACAT1. The results show that these mice exhibited a remarkable accumulation of MDSCs and increased tumor progression both ectopically and orthotopically. The mechanism behind this effect is elevated secretion of C-X-C motif ligand 1 (CXCL1) of macrophages (Mφ). Overall, our findings demonstrate that ACAT1 could serve as a promising drug target for GBM by regulating the function of MDSCs in the TME.
ABSTRACT
Objective@#To analyze effect of fractured file removal from the middle third root canal on root fracture resistance using finite element analysis, which provides a theoretical basis for clinical prognosis evaluation.@*Methods@#Two finite-element models were established, the fractured file removal model (fractured file located in the middle third of root canals, followed by ultrasonic file removal and root canal preparation) and the control model (root canal preparation only), and compressive displacement dependencies on compressive force was computed and compared with experimental data for validation. The validated finite-element models were used to analyze the stress distribution differences during the initiation, propagation and completion of the crack between fractured file removal specimen and control one.@*Results@#The critical breaking force of the fractured file removal specimen was 406 N, and the finite element simulation result was 396 N. The critical breaking force of the control specimen was 502 N, and the finite element simulation result was 483 N. The position of crack initiation in the finite element simulation was basically consistent with that in the experiment. The experimental data of compressive test and the results of finite-element computation were in agreement, thus validating the finite-element model. In the process of continuous pressure, the stress distribution of the control root is relatively uniform, and the location of crack initiation and the direction of propagation have a certain unpredictability. Compared with the control root, the stress concentration on the root with fracture file removal was obvious, especially on edges, and the number of cracks are much more. Because of the thinner radicular wall, the crack propagation rate is faster too. Therefore, the overall root fracture resistant is decreased obviously.@*Conclusions@#During the fractured file removal procedure, amount of dentine removed should be minimized, and the edges and corners which caused by fractured file removal should be shaped to smooth in order to reduce the stress concentration and prevent the root from fracture.