A GAD1 inhibitor suppresses osteosarcoma growth through the Wnt/ß-catenin signaling pathway.

Background: As a marker of the GABAergic system, the expression of glutamate decarboxylase 1 (GAD1) is mainly restricted to the central nervous system. Emerging studies have shown that aberrant expression of GAD1 in tumor tissues may promote tumor cell growth. The role of GAD1 in the development of osteosarcoma (OS) remains unclear, so this study sought to investigate the expression status of GAD1 and the effect of its specific inhibitor 3-mercaptopropionic acid (3-MPA) on OS. Methods: The R2 database was used to analyze the relationship between the expression of GAD1 and clinical prognosis in OS patients. Immunohistochemistry was used to compare the expression profile of GAD1 between OS and matched neighboring tissues. The potential antitumor effects of 3-MPA on cell viability, colony formation and the cell cycle were examined. Moreover, the in vivo effect of 3-MPA on tumor growth was investigated using tumor-bearing nude mice. Results: The expression level of GAD1 was aberrantly upregulated in OS tissues, but almost no expression of GAD1 was found in matched neighboring tissues. Western blotting analyses showed upregulation of GAD1 in OS cells compared to human osteoblast cells. In vitro and in vivo, 3-MPA significantly suppressed the growth of OS. Regarding the mechanism, 3-MPA inhibited ß-catenin and cyclin D1 in OS cells, thereby inactivating the Wnt/ß-catenin pathway. Conclusions: OS displays increased expression of the GABAergic neuronal marker GAD1, and 3-MPA significantly reduces OS growth by inhibiting the Wnt/ß-catenin pathway.

Targeting PERK-ATF4-P21 axis enhances the sensitivity of osteosarcoma HOS cells to Mppα-PDT.

Osteosarcoma (OS) is the most prevalent type of malignant bone tumor in adolescents. The overall survival of OS patients has reached a plateau recently. Thus, there is an urgent need to develop approaches to improve the sensitivity of OS to therapies. Pyropheophorbide-α methyl ester-mediated photodynamic therapy (MPPα-PDT) is a new type of tumor therapy, and elucidating its mechanism is helpful to improve its anti-tumor efficacy. Here, we investigated how PERK signaling promotes the human OS (HOS) cell survival induced by MPPα-PDT, as overcoming this may enhance sensitivity to MPPα-PDT. We found that MPPα-PDT combined with PERK inhibitor GSK2656157 enhanced HOS cell apoptosis by suppressing autophagy and p21. Autophagy inhibition and p21 depletion enhanced cell death, indicating pro-survival effects in MPPα-PDT. Notably, p21 was found to be an effector of the PERK-Atf4 pathway, which could positively regulate autophagy mediated by MPPα-PDT. In conclusion, we found that the combination of MPPα-PDT and GSK2656157 enhanced apoptosis in HOS cells by inhibiting autophagy. Mechanistically, this autophagy is p21-dependent and can be suppressed by GSK2656157, thereby enhancing sensitivity to MPPα-PDT.

LncRNA DGCR5-encoded polypeptide RIP aggravates SONFH by repressing nuclear localization of ß-catenin in BMSCs.

The differentiation fate of bone marrow mesenchymal stem cells (BMSCs) affects the progression of steroid-induced osteonecrosis of the femoral head (SONFH). We find that lncRNA DGCR5 encodes a 102-amino acid polypeptide, RIP (Rac1 inactivated peptide), which promotes the adipogenic differentiation of BMSCs and aggravates the progression of SONFH. RIP, instead of lncRNA DGCR5, binds to the N-terminal motif of RAC1, and inactivates the RAC1/PAK1 cascade, resulting in decreased Ser675 phosphorylation of ß-catenin. Ultimately, the nuclear localization of ß-catenin decreases, and the differentiation balance of BMSCs tilts toward the adipogenesis lineage. In the femoral head of rats, overexpression of RIP causes trabecular bone disorder and adipocyte accumulation, which can be rescued by overexpressing RAC1. This finding expands the regulatory role of lncRNAs in BMSCs and suggests RIP as a potential therapeutic target.

Comparison of clinical outcomes of arthroscopic rotator cuff repair utilizing suture-bridge procedures with or without medial knots: a meta-analysis.

PURPOSE: This investigation aimed to compare the medical efficacy of the knotted and knotless suture-bridge procedures in rotator cuff repair. METHODS: The Pubmed, Embase, and Cochrane Library datasets were searched for all available publications comparing the medical results of arthroscopic rotator cuff repairs utilizing knotted or knotless suture-bridge procedures. Two researchers utilized Newcastle-Ottawa Scale and Cochrane risk-of-bias tool to evaluate the included studies. Employing Revman 5.3 software, meta-analysis was conducted following the PRISMA reporting guideline. RESULTS: Eleven investigations with 1083 patients were considered suitable for the final meta-analysis. 522 individuals were assigned to the knotted group, whereas 561 were assigned to the knotless group. No statistical difference was found between the knotted and knotless groups, regarding VAS score (WMD, 0.17; 95% CI, - 0.10 to 0.44; P = 0.21); Constant score (WMD, -1.50; 95% CI, - 3.52 to 0.52; P = 0.14); American Shoulder and Elbow Surgeons Shoulder (WMD, -2.02; 95% CI, - 4.53 to 0.49; P = 0.11); University of California Los Angeles score (WMD, -0.13; 95% CI, - 0.89 to 0.63; P = 0.73); ROM of flexion (WMD, 1.57; 95% CI, - 2.11 to 5.60; P = 0.37), abduction (WMD, 1.08; 95% CI, - 4.53 to 6.70; P = 0.71) and external rotation (WMD, 1.90; 95% CI, - 1.36 to 5.16; P = 0.25); re-tear rate (OR, 0.74; 95% CI, 0.50 to 1.08; P = 0.12), and medical complications (OR, 0.90; 95% CI, 0.37 to 2.20; P = 0.82). CONCLUSION: For arthroscopic rotator cuff repairs, there were no statistical differences in medical results among knotted and knotless suture-bridge procedures. Overall, both techniques showed excellent clinical outcomes and could be safely utilized to treat rotator cuff injuries.

Detection of inguinal lymph nodes is promising for the diagnosis of periprosthetic joint infection.

Background: Localized inguinal lymphadenopathy often represents lower extremity pathogen infection, while normalized lymphadenopathy is associated with infection regression. We hypothesized that inguinal lymph nodes (LNs) were enlarged in Periprosthetic Joint Infection (PJI) patients and that normalized inguinal LNs would be a promising way to determine the timing of reimplantation. Methods: We prospectively enrolled 176 patients undergoing primary and revision hip or knee arthroplasty. All patients underwent ultrasound examination of inguinal LNs preoperatively. The diagnostic value of inguinal LNs in PJI was evaluated by the receiver operating characteristic (ROC) curve. Results: The median level of inguinal LNs was 26mm in the revision for PJI group compared with 12 mm in the aseptic revision group (p< 0.0001). The size of the inguinal LNs well distinguishes PJI from aseptic failure (AUC= 0.978) compare with ESR (AUC= 0.707) and CRP (AUC= 0.760). A size of 19mm was determined as the optimal threshold value of the inguinal LNs for the diagnosis of PJI, with a sensitivity of 92% and specificity of 96%. Conclusion: Ultrasonic analysis of inguinal LNs is a valuable piece of evidence for the diagnosis of PJI and evaluation of persistent infection.

Survival and complications of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in patients with intra-abdominal malignancies: A meta-analysis of randomized controlled trials.

Background: Peritoneal metastasis (PM) is an advanced stage of intra-abdominal malignancy with a very poor prognosis. In recent years, hyperthermic intraperitoneal chemotherapy (HIPEC) combined with cytoreductive surgery (CRS) has been utilized as an active treatment in the prevention and treatment of PM, with encouraging results. However, compared with CRS alone, the results of the CRS plus HIPEC strategy in the treatment of patients with intra-abdominal malignancies are still controversial. This study sought to determine the impact of HIPEC + CRS on patient survival and adverse events (AEs) by reviewing randomized controlled trials (RCTs) for all types of intra-abdominal malignancies. Methods: A PubMed, Embase, Cochrane Library, Web of Science and Clinical Trials.gov search extracted all RCTs until 12 October 2022, examining the CRS + HIPEC vs. CRS alone strategies in the treatment of various types of intra-abdominal malignancies. The outcomes included overall survival (OS), disease-free survival (DFS), relapse-free survival (RFS), progression-free survival (PFS) and AEs. The dichotomous data were pooled and reported as odds ratios (ORs) with 95% confidence intervals (CIs). The survival outcome data were pooled using hazard ratios (HRs) and corresponding 95% CIs. The Cochrane Collaboration's Risk of Bias Tool was used to assess the risk of bias in the included studies. Results: A total of 12 RCTs were included in this meta-analysis, including 873 patients in the CRS + HIPEC group and 878 patients in the CRS alone group. The studies included 3 (617 patients) on colorectal cancer, 4 (416 patients) on gastric cancer, and 5 (718 patients) on ovarian cancer. Our analysis showed no difference in OS between the CRS + HIPEC and CRS alone groups (HR: 0.79, 95% CI 0.62-1.01). Subgroup analysis showed that CRS + HIPEC improved the OS of gastric cancer patients (HR: 0.49, 95% CI 0.32-0.76) compared with CRS alone. However, CRS + HIPEC did not significantly improve the OS of colorectal cancer (HR: 1.06, 95% CI 0.81-1.38) and ovarian cancer (HR: 0.82, 95% CI 0.62-1.07) patients. In addition, there was no significant difference in DFS/RFS (HR: 0.78, 95% CI 0.57-1.07) or PFS (HR: 1.03, 95% CI 0.77-1.38) between the two groups. Compared with CRS alone, CRS with HIPEC had greater nephrotoxicity (OR: 0.45, 95% CI 0.21-0.98), while other AEs did not differ significantly between the two groups. Conclusion: Our results suggest that CRS + HIPEC may improve OS in gastric cancer patients compared with CRS alone, but we did not observe a benefit for DFS/RFS. For patients with ovarian and colorectal cancers, our results suggest that HIPEC + CRS does not appear to improve survival outcomes. In addition, CRS + HIPEC has higher nephrotoxicity than CRS alone. More evidence from RCTs is needed to evaluate whether the use of CRS + HIPEC is an appropriate option.