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Three dimensional finite element models of cam-type FAI with alpha angles of 60°, 70°, 80°, and 90° were created to investigate the cartilage contact mechanics in daily activities. Intra-articular cartilage contact pressures during routine daily activities were assessed and cross-compared with a normal control hip. Alpha angles and hip range of motion were found to have a combined influence on the cartilage contact mechanics in hips with cam-type FAI, thereby resulting in abnormally high pressures and driving the cartilage damage. In particular, alpha angles of 80° or greater contribute to substantial pressure increase under certain types of daily activities. [ABSTRACT FROM AUTHOR]

Objective: Precancerous lesions of gastric cancer (PLGC) are key pathological stages in the transformation of gastric "inflammation-cancer", and timely and effective intervention at this stage is of great importance in the prevention and treatment of gastric cancer. Zhiwei Fuwei Pills (ZWFW), as a traditional Chinese medicine formulation, has been proven to have good clinical efficacy in the treatment of PLGC, but its specific mechanism of action has not been fully explained. Thus, this study validated the efficacy and explored the potential mechanisms of ZWFW in treating PLGC by integrating network pharmacology analyses and experimental verification., Methods: The TCMSP database was used to obtain the active ingredients of ZWFW and their corresponding targets, and the GeneCards database was used to retrieve PLGC-related targets. The intersecting targets between ZWFW and PLGC were obtained through mapping, and protein-protein interaction (PPI) networks and "drug-active ingredient-target" networks were constructed by using Cytoscape software. The DAVID database was used for GO functional enrichment analysis and KEGG pathway enrichment analysis. AutoDockTools software was used for molecular docking of key active ingredients and key targets. In order to verify the analysis results of network pharmacology, TEM and H&E were used to observe the effects of different dosage groups of ZWFW on gastric mucosal microvasculature in PLGC rats. Subsequently, the ELISA, IF, IHC, RT-PCR and western blot were used to detected the expression levels of relevant targets in the tissues, so as to verify the potential mechanism of ZWFW in intervening PLGC., Results: After the screening, 258 effective active ingredients and 325 targets were obtained, and 1294 disease-related targets were determined, resulting in 139 intersection targets through mapping. The KEGG enrichment results showed that PI3K/Akt and HIF-1 signaling pathway might play important roles in the treatment mechanism of PLGC. The molecular docking results showed that active ingredients of ZWFW all had a strong affinity and stable structure with key targets, including AKT1 and VEGF. In vivo experiments confirmed that ZWFW could improve gastric mucosal microvascular abnormalities in PLGC, effectively intervene in gastric mucosal pathological grading. Meanwhile, compared with the model group, this formulation could reduce the expression levels of PI3K, Akt, mTOR, HIF-1α, and VEGF in gastric mucosa, showing a dose-effect relationship., Conclusion: ZWFW can intervene in the neovascularization and pathological evolution of PLGC, and this mechanism of action may be achieved by inhibiting abnormal activation of the PI3K/Akt/mTOR/HIF-1α/VEGF signaling pathway., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Most guidelines recommend the use of nonsteroidal anti-inflammatory drugs (NSAIDs), duloxetine, and tramadol for the nonoperative treatment of osteoarthritis (OA), but the use of them is limited by the tolerability and safety concerns. Lutikizumab is a novel anti-IL-1 α / β dual variable domain immunoglobulin that can simultaneously bind and inhibit IL-1 α and IL-1 β to relieve the pain and dysfunction symptoms. We conducted this network meta-analysis to comprehensively compare the clinical efficacy and safety of lutikizumab with other drugs recommended by guidelines., Methods: We conducted a Bayesian network and conventional meta-analyses to compare the efficacy and safety of lutikizumab with other traditional drugs. All eligible randomized clinical trials, in PubMed, CNKI, EMBASE, and Web of Science databases, from January 2000 to January 2020, were included. The Cochrane risk of the bias assessment tool was used for quality assessment. Pain relief, function improvement, and risk of adverse effects (AEs) were compared in this study., Results: 24 articles with 11858 patients were included. Duloxetine (DUL) had the largest effect for pain relief (4.76, 95% CI [2.35 to 7.17]), and selective cox-2 inhibitors (SCI) were the most efficacious treatment for physical function improvement (SMD 3.94, 95% CI [2.48 to 5.40]). Lutikizumab showed no benefit compared with placebo for both pain relief (SMD 1.11, 95% CI [-2.29 to 4.52]) and function improvement (SMD 0.992, 95% CI [-0.433 to 4.25]). Lutikizumab and all other drugs are of favorable tolerance for patients in the treatment of OA compared with placebo., Conclusions: Lutikizumab, the new anti-Interleukin-1 α / β dual variable domain immunoglobulin, showed no improvement in pain or function when compared with placebo. Selective cox-2 inhibitors and duloxetine remain the most effective and safest treatment for OA. More high-quality trials are still needed to reconfirm the findings of this study., Competing Interests: The authors declare that they do not have any competing interests., (Copyright © 2020 Ziqin Cao et al.)

Cisplatin is an effective chemotherapeutic agent for osteosarcoma (OS) and has been shown to induce endoplasmic reticulum (ER) stress-associated apoptosis in human cancer cells. Ganglioside GD2-specific antibodies can inhibit tumor cell viability without involvement of the immune system. A recent study has shown that antiGD2 monoclonal antibody (mAb) 14G2a effectively inhibits the viability and invasiveness of human OS cells. In this study, we explored the effect of anti-GD2 mAb and cisplatin alone and in combination on ER stress-associated apoptosis in osteosarcoma cells. MG-63 and Saos-2 human OS cells were treated with cisplatin and/or an-GD2 mAb 14G2a for 48 hours. Cisplatin and 14G2a dose-dependently induced apoptosis in MG-63 and Saos-2 cells. They in combination induced 70%-77% of apoptosis in MG-63 cells and 79%-85% of apoptosis in Saos-2 cells, exhibiting a synergistic effect stronger than addition of their individual effects over the control level. Showing no significant effect on the expression of protein kinase RNA-like ER kinase (PERK), cisplatin and 14G2a exhibited a marked synergistic effect on inducing phosphorylation/activation of PERK, phosphorylation/inactivation of eukaryotic translation initiation factor 2α (eIF2α), expression of CHOP, in parallel to inducing the caspase-3 activity and apoptosis in MG-63 and Saos-2 cells. The effects were abolished by lentivirus-mediated knockdown of PERK. Particularly, PERK knockdown abolished 63% and 65% of the combined apoptotic effect of cisplatin and 14G2a on MG-63 and Saos-2 cells, respectively. In conclusion, this study provides the first evidence supporting that cisplatin and 14G2a synergize to induce ER stress-associated apoptosis in human OS cells through activating the PERK ER stress pathway by synergistically inducing phosphorylation/activation of PERK. Our findings add new insights into the pharmacologic effects of anti-GD2 mAb in anticancer treatment and suggest that cisplatin plus anti-GD2 mAb could be a new effective therapeutic strategy for OS.

Accumulating evidence indicated that inhibiting the expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5 ameliorate cartilage degradation, suggesting ADAMTS-5 as an effective target for treating osteoarthritis (OA). A recent study has identified long noncoding RNA (lncRNA) HOTAIR and ADAMTS-5 as the most up-regulated lncRNA and the most upregulated gene, respectively, in human OA cartilage compared with normal cartilage. In the present study, we explored the regulatory effect of HOTAIR on the expression of ADAMTS-5 as well as the underlying mechanisms in human normal and OA articular chondrocytes. We found that human OA articular chondrocytes had significantly higher basal expression levels of HOTAIR and ADAMTS-5 than normal articular chondrocytes. Tumor necrosis factor (TNF)-α significantly enhanced the basal expression of HOTAIR and ADAMTS-5 in OA but not in normal articular chondrocytes. Lentiviral overexpression and knockdown of HOTAIR markedly increased and decreased the expression of ADAMTS-5, respectively, in OA but not in normal articular chondrocytes in the presence or absence of TNF-α. Neither overexpression/ knockdown of HOTAIR nor TNF-α showed a significant effect on the ADAMTS-5 gene promoter in OA articular chondrocytes. Although HOTAIR showed no significant effect on the stability of ADAMTS-5 mRNA in normal articular chondrocytes, HOTAIR overexpression and knockdown respectively increased and decreased the ADAMTS-5 mRNA stability in OA articular chondrocytes. TNF-α enhanced the protective effect of HOTAIR on the ADAMTS-5 mRNA stability. In conclusion, this study provides the first evidence supporting that HOTAIR strongly promotes the expression of ADAMTS-5 by increasing its mRNA stability in human OA articular chondrocytes; this effect is enhanced by TNF-α. It adds new insights into the pathogenesis of OA and suggests that HOTAIR could be a new therapeutic target for ADAMTS-5 inhibition in human OA cartilage.