Identification and validation of miR-509-5p as a prognosticator for favorable survival in osteosarcoma.

Osteosarcoma (OS) is the most common primary bone cancer diagnosed in children. This study aims to explore the aberrantly expressed miRNAs that are prognostically related and to provide potential biomarkers for the prognosis prediction of OS. The miRNA profiles of OS and adjacent normal controls were obtained from 2 gene expression omnibus cohorts (i.e., GSE28423 and GSE65071). GSE39058 and Therapeutically Applicable Research to Generate Effective Treatments cohorts, which respectively contained 91 and 85 OS samples with both miRNA expression and clinical characteristics, were employed to perform survival and multivariate Cox regression analyses. Lymphocyte infiltration abundance between distinct subgroups was evaluated with the CIBERSORT algorithm and a previously proposed method. Gene set enrichment analysis was used to infer the dysregulated signaling pathways within each subgroup. Of the 31 differentially expressed miRNAs, miR-509-5p (miR-509) was the most significantly prognostic miRNA in the GSE39058 cohort and its high expression was associated with the better OS prognosis (Log-rank P = .008). In the Therapeutically Applicable Research to Generate Effective Treatments validation cohort, the association of high miR-509 expression with favorable survival was also observed (Log-rank P = .014). The results remained still significant even adjusted for clinical confounding factors in multivariate Cox regression models. Further immunology analyses demonstrated that elevated infiltration of lymphocytes, decreased infiltration of immune-suppressive cells, and immune response-related pathways were significantly enriched in patients with miR-509 high expression. Our study suggests that miR-509 may serve as a potential biomarker for evaluating OS prognosis and provides clues for tailoring OS immunotherapy strategies.

Tribbles Pseudokinase 2 Promotes the Proliferation, Migration, and Invasion of Osteosarcoma through Modulating AP4/p21 Pathway.

OBJECTIVE: At present, the efficacy of the clinical treatment of osteosarcoma is limited. We aimed to investigate the role of Tribbles pseudokinase 2 (TRIB2) in the progression of osteosarcoma and the underlying molecular mechanism. MATERIALS AND METHODS: TRIB2 expression in osteosarcoma tissues and cells was measured via western blot analysis and quantitative reverse transcription polymerase chain reaction. Mouse xenograft tumor model was established to investigate the in vivo effect of Tribbles pseudokinase 2 on the development of osteosarcoma. RESULTS: We found that TRIB2 expression was increased in osteosarcoma tissues and cell lines compared with that in tumor adjacent normal tissues and normal bone cell line. Suppressing TRIB2 expression inhibited the proliferation, migration, and invasion of osteosarcoma cells. Mechanistically, TRIB2 interacted with AP4, thereby inhibiting p21 expression at transcriptional level. In a mouse xenograft tumor model, TRIB2 overexpression promoted the growth of osteosarcoma by inhibiting p21 expression, which was reversed by AP4 silence. CONCLUSION: Therefore, targeting TRIB2 may become a potential approach for osteosarcoma treatment.

Resource Scheduling and Energy Consumption Optimization Based on Lyapunov Optimization in Fog Computing.

Delay-sensitive tasks account for an increasing proportion of all tasks on the Internet of Things (IoT). How to solve such problems has become a hot research topic. Delay-sensitive tasks scenarios include intelligent vehicles, unmanned aerial vehicles, industrial IoT, intelligent transportation, etc. More and more scenarios have delay requirements for tasks and simply reducing the delay of tasks is not enough. However, speeding up the processing speed of a task means increasing energy consumption, so we try to find a way to complete tasks on time with the lowest energy consumption. Hence, we propose a heuristic particle swarm optimization (PSO) algorithm based on a Lyapunov framework (LPSO). Since task duration and queue stability are guaranteed, a balance is achieved between the computational energy consumption of the IoT nodes, the transmission energy consumption and the fog node computing energy consumption, so that tasks can be completed with minimum energy consumption. Compared with the original PSO algorithm and the greedy algorithm, the performance of our LPSO algorithm is significantly improved.

A Novel Etomidate Analog EL-0052 Retains Potent Hypnotic Effect and Stable Hemodynamics without Suppressing Adrenocortical Function.

Etomidate is a potent and rapidly acting anesthetic with high therapeutic index (TI) and superior hemodynamic stability. However, side effect of suppressing adrenocortical function limits its clinical use. To overcome this side effect, we designed a novel etomidate analog, EL-0052, aiming to retain beneficial properties of etomidate and avoid its disadvantage of suppressing adrenocortical steroid synthesis. Results exhibited that EL-0052 enhanced GABAA receptors currents with a concentration for EC50 of 0.98 ± 0.02 µM, which was about three times more potent than etomidate (3.07 ± 1.67 µM). Similar to hypnotic potency of etomidate, EL-0052 exhibited loss of righting reflex with ED50s of 1.02 (0.93-1.20) mg/kg in rats and 0.5 (0.45-0.56) mg/kg in dogs. The TI of EL-0052 in rats was 28, which was higher than 22 of etomidate. There was no significant difference in hypnotic onset time, recovery time, and walking time between EL-0052 and etomidate in rats. Both of them had minor effects on mean arterial pressure in dogs. EL-0052 had no significant effect on adrenocortical function in dogs even at a high dose (4.3 × ED50), whereas etomidate significantly inhibited corticosteroid secretion. The inhibition of cortisol synthesis assay showed that EL-0052 had a weak inhibition on cortisol biosynthesis in human H259 cells with an IC50 of 1050 ± 100 nM, which was 2.09 ± 0.27 nM for etomidate. EL-0052 retains the favorable properties of etomidate, including potent hypnotic effect, rapid onset and recovery, stable hemodynamics, and high therapeutic index without suppression of adrenocortical function. SIGNIFICANCE STATEMENT: The novel etomidate analog EL-0052 retains the favorable properties of etomidate without suppressing adrenocortical function and provides a new strategy to optimize the structure of etomidate.

Discovery of the EL-0052 as a potential anesthetic drug.

As a γ-aminobutyric acid A receptor (GABAAR) inhibitor, etomidate fulfills several characteristics of an ideal anesthetic agent, such as rapid onset with rapid clearance and high potency, along with cardiovascular stability. Unfortunately, etomidate has been reported to inhibit CYP11B1 at hypnotic doses, which is associated with a marked increase in patient deaths due to this unexpected off-target effect. In this study, molecular docking was used to simulate the binding mode of etomidate with GABAAR and CYP11B1. Based on the in-depth analysis of the binding mode, strong electron-withdrawing group on the C4 position of the imidazole ring was introduced to reduce the charge density of the nitrogen, which is beneficial in reducing the coordination bond between the imidazole nitrogen and heme iron in CYP11B1, as well as in reducing the adrenocortical suppression. Based on the results of ADMET property prediction, MEP analysis, and molecular docking simulation, 4-fluoroetomidate (EL-0052) was designed and synthesized. In vivo studies in rats and mice confirmed that EL-0052 had the efficacy similar to etomidate, but without adrenocortical suppression. These findings suggested that EL-0052 was superior to etomidate and support the continued development of EL-0052 as a preclinical candidate as an anesthetic.