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Importance: Host immune dysregulation is associated with initiation and development of osteosarcoma. In addition, immunotherapy for osteosarcomas requires some knowledge of the immune state of patients., Objective: To perform an immunogenomic landscape analysis based on The Cancer Genome Atlas (TCGA) project, which provides osteosarcoma samples with clinical information., Design, Setting, and Participants: This genetic association study was conducted from July 20, 2020, to September 20, 2020, as a secondary analysis of public data. Cox regression and risk score analyses were used to construct signatures of immune-related genes (IRGs) in 84 patients with osteosarcoma from TCGA with corresponding clinical information. Patients were divided into high- and low-risk groups with 42 individuals in each group according to their risk scores. Data were analyzed from July 20 to September 20, 2020., Main Outcomes and Measures: Differentially expressed genes (DEGs) were analyzed between groups, and potential molecular mechanisms, expression regulation, and immune cell infiltration were also explored using bioinformation methods. A prognostic model based on independent risk factors selected from multivariate Cox hazard ratio regression was established to estimate 1-year overall survival., Results: In this genetic association study based on 84 samples from patients with osteosarcoma from TCGA (mean [SD] age, 15.0 [4.8] years; 47 [56.0%] men; mean [SD] follow-up time, 4.1 [2.8] years), a total of 14 survival-associated IRGs were identified. Patients assigned to the high-risk group had worse survival than patients from the low-risk group (1 death [2.4%] vs 26 deaths [61.9%%]; P < .001). The protein digestion and absorption pathway was one of the associated pathways in the functional enrichment analysis (gene ratio, 2:8; P < .001). The prognostic model based on metastases at diagnosis and risk score performed well in 1-year overall survival estimations (area under the curve, 0.947; 95% CI, 0.832-0.972). The risk score was correlated with immune cell infiltration (B cells: r = 0.331; P = .002; macrophages: r = 0.410; P < .001; CD8 T cells: r = 0.230; P = .04)., Conclusions and Relevance: This genetic association study developed a prognostic modeling tool for osteosarcoma based on IRG expression profiles, which could result in improved survival rates through more individualized therapies. Further research on IRG expression profiles could provide potential targets for future studies on immune treatment for osteosarcoma.

Purpose: Osteosarcoma is a malignant musculoskeletal tumor with early metastasis and a poor prognosis, especially in adolescents. Ganoderma lucidum (Leyss. Ex Fr.) Karst (G. lucidum), a traditional East Asian medicine, has been reported to play a critical role in antitumor and immunomodulatory activity. The aim of this study was to investigate the effects and molecular mechanisms of water extract of sporoderm-broken spores of G. lucidum (BSGWE) on osteosarcoma PD-L1 (programmed cell death-ligand 1) transcriptional regulation, efficacy enhancement, and side effect remission., Methods: The antitumor effects on cell proliferation of BSGWE in osteosarcoma cells were detected by apoptosis flow cytometry, and the migration ability of HOS and K7M2 cells were evaluated by cell scratch assay. Potential signaling regulation of PD-L1 was detected by western blotting. To confirm the signaling pathway of BSGWE-related PD-L1 downregulation, a pho-STAT3 turnover experiment was carried out. Colivelin was administered as a pho-STAT3 activator to rescue the BSGWE-induced PD-L1 inhibition. To further study in vivo signaling, in a Balb/c osteosarcoma allograft model, tumor volume was measured using an in vivo bioluminescence imaging system. The body weight curve and tumor volume curve were analyzed to reveal the remission effects of BSGWE on PD-L1 antibody-related body weight loss and its immunomodulatory effects on the osteosarcoma and spleen. The PD-L1 expression level and expression of related transcription-factor pho-STAT3 in tumor cells and spleens were assessed by IHC analysis., Results: BSGWE suppressed the proliferation and migration of osteosarcoma cells in vitro via induction of apoptosis. In addition, BSGWE downregulated PD-L1 expression and related STAT3 (signal transducers and activators of transcription) phosphorylation levels in a dose-dependent manner. Western blotting and qRT-PCR assay revealed that BSGWE downregulated PD-L1 expression by inhibiting STAT3 phosphorylation. A turnover experiment showed that colivelin administration could rescue PD-L1 inhibition via pho-STAT3 activation. BSGWE not only downregulated PD-L1 expression via the STAT3 pathway in an allograft Balb/c mouse model, but also relieved complications including weight loss and spleen atrophy in a mouse monoclonal antibody therapy model on the basis of its traditional advantages in immune enhancement., Conclusion: BSGWE downregulated PD-L1 expression via pho-STAT3 inhibition of protein and RNA levels. BSGWE enhanced PD-L1 antibody efficacy via phosphorylated STAT3 downregulation in vitro and in vivo. BSGWE also relieved complications of weight loss and spleen atrophy in a murine allograft osteosarcoma immune checkpoint blockade therapy model., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background/aims: MicroRNAs (miRNAs) are a class of small noncoding RNAs that regulate gene expression by repressing translation or cleaving RNA transcripts in a sequence-specific manner. Downregulated microRNAs and their roles in cancer development have attracted much attention. A growing body of evidence showed that microRNA-133a (miR-133a) has inhibitory effects on cell proliferation, migration, invasion, and metastasis of osteosarcoma., Methods: MiR-133a expression in human osteosarcoma cell lines and human normal osteoblastic cell line hFOB was investigated by real-time PCR (RT-PCR). The role of miR-133a in human osteosarcoma growth and invasion was assessed in cell lines in vitro and in vivo. Then, luciferase reporter assay validated IGF-1R as a downstream and functional target of miR-133a, and functional studies revealed that the anti-tumor effect of miR-133a was probably due to targeting and repressing of IGF-1R expression., Results: MiR-133a was lower expressed in human osteosarcoma cell lines than human normal osteoblastic cell line hFOB and its effect on inhibiting proliferation, invasion and metastasis is mediated by its direct interaction with the IGF-1R. Furthermore, the tumour-suppressive function of miR-133a probably contributed to inhibiting the activation AKT and ERK signaling pathway., Conclusion: MiR-133a suppresses osteosarcoma progression and metastasis by targeting IGF-1R in human osteosarcoma cells, providing a novel candidate prognostic factor and a potential anti-metastasis therapeutic target in osteosarcoma., (© 2016 The Author(s) Published by S. Karger AG, Basel.)

Gold nanorods (GNRs) are intensively explored for the application in cancer therapy, which has motivated the development of photothermal therapy (PTT) multifunctional nanoplatforms based on GNRs to cure osteosarcoma (OS). However, the major limitations include the toxicity of surface protectants of GNRs, unsatisfactory targeting therapy, and the resistant effects of photothermal-induced autophagy, so the risk of relapse and metastasis of OS increase. In the present study, the GNR multifunctional nanoplatforms were designed and synthesized to deliver transcription factor EB (TFEB)-siRNA–targeting autophagy; then, the resistance of autophagy to PTT and the pH-sensitive cell-penetrating membrane peptide (CPP) was weakened, which could improve the tumor-targeting ability of the GNR nanoplatforms and realize an efficient synergistic effect for tumor treatment. Meanwhile, it is worth noting that the GNR nanoplatform groups have anti-lung metastasis of OS. This study provides a new reference to improve the efficacy of OS clinically. [ABSTRACT FROM AUTHOR]