Aspirin inhibits adipogenesis of tendon stem cells and lipids accumulation in rat injury tendon through regulating PTEN/PI3K/AKT signalling.

Tendon injury repairs are big challenges in sports medicine, and fatty infiltration after tendon injury is very common and hampers tendon injury healing process. Tendon stem cells (TSCs), as precursors of tendon cells, have shown promising effect on injury tendon repair for their tenogenesis and tendon extracellular matrix formation. Adipocytes and lipids accumulation is a landmark event in pathological process of tendon injury, and this may induce tendon rupture in clinical practice. Based on this, it is important to inhibit TSCs adipogenesis and lipids infiltration to restore structure and function of injury tendon. Aspirin, as the representative of non-steroidal anti-inflammatory drugs (NSAIDs), has been widely used in tendon injury for its anti-inflammatory and analgesic actions, but effect of aspirin on TSCs adipogenesis and fatty infiltration is still unclear. Under adipogenesis conditions, TSCs were treated with concentration gradient of aspirin. Oil red O staining was performed to observe changes of lipids accumulation. Next, we used RNA sequencing to compare profile changes of gene expression between induction group and aspirin-treated group. Then, we verified the effect of filtrated signalling on TSCs adipogenesis. At last, we established rat tendon injury model and compared changes of biomechanical properties after aspirin treatment. The results showed that aspirin decreased lipids accumulation in injury tendon and inhibited TSCs adipogenesis. RNA sequencing filtrated PTEN/PI3K/AKT signalling as our target. After adding the signalling activators of VO-Ohpic and IGF-1, inhibited adipogenesis of TSCs was reversed. Still, aspirin promoted maximum loading, ultimate stress and breaking elongation of injury tendon. In conclusion, by down-regulating PTEN/PI3K/AKT signalling, aspirin inhibited adipogenesis of TSCs and fatty infiltration in injury tendon, promoted biomechanical properties and decreased rupture risk of injury tendon. All these provided new therapeutic potential and medicine evidence of aspirin in treating tendon injury and tendinopathy.

Obesity enhances the response to neoadjuvant anti-PD1 therapy in oral tongue squamous cell carcinoma.

OBJECTIVES: Previous studies have demonstrated that obesity may impact the efficacy of anti-PD1 therapy, but the underlying mechanism remains unclear. In this study, our objective was to determine the prognostic value of obesity in patients with oral tongue squamous cell carcinoma (OTSCC) treated with pembrolizumab and establish a subtype based on fatty acid metabolism-related genes (FAMRGs) for immunotherapy. MATERIALS AND METHODS: We enrolled a total of 56 patients with OTSCC who underwent neoadjuvant anti-PD1 therapy. Univariate and multivariate Cox regression analyses, Kaplan-Meier survival analysis, and immunohistochemistry staining were performed. Additionally, we acquired the gene expression profiles of pan-cancer samples and conducted GSEA and KEGG pathway analysis. Moreover, data from TCGA, MSigDB, UALCAN, GEPIA and TIMER were utilized to construct the FAMRGs subtype. RESULTS: Our findings indicate that high Body Mass Index (BMI) was significantly associated with improved PFS (HR = 0.015; 95% CI, 0.001 to 0.477; p = 0.015), potentially attributed to increased infiltration of PD1 + T cells. A total of 91 differentially expressed FAMRGs were identified between the response and non-response groups in pan-cancer patients treated with immunotherapy. Of these, 6 hub FAMRGs (ACSL5, PLA2G2D, PROCA1, IL4I1, UBE2L6 and PSME1) were found to affect PD-1 expression and T cell infiltration in HNSCC, which may impact the efficacy of anti-PD1 therapy. CONCLUSION: This study demonstrates that obesity serves as a robust prognostic predictor for patients with OTSCC undergoing neoadjuvant anti-PD1 therapy. Furthermore, the expression of 6 hub FAMRGs (ACSL5, PLA2G2D, PROCA1, IL4I1, UBE2L6 and PSME1) plays a pivotal role in the context of anti-PD1 therapy and deserves further investigation.

Prognostic risk factor of major salivary gland carcinomas and survival prediction model based on random survival forests.

Salivary gland malignancies are rare and are often acompanied by poor prognoses. So, identifying the populations with risk factors and timely intervention to avoid disease progression is significant. This study provides an effective prediction model to screen the target patients and is helpful to construct a cost-effective follow-up strategy. We enrolled 249 patients diagnosed with salivary gland tumors and analyzed prognostic risk factors using Cox proportional hazard univariable and multivariable regression models. The patients' data were split into training and validation sets on a 7:3 ratio, and the random survival forest (RSF) model was established using the training sets and validated using the validation sets. The maximally selected rank statistics method was used to determine a cut point value corresponding to the most significant relation with survival. Univariable Cox regression suggested age, smoking, alcohol consumption, untreated, neural invasion, capsular invasion, skin invasion, tumors larger than 4 cm, advanced T and N stage, distant metastasis, and non-mucous cell carcinoma were risk factors for poor prognosis, and multivariable analysis suggested that female, aging, smoking, untreated, and non-mucous cell carcinoma were risk factors. The time-dependent ROC curve showed the AUC of the RSF prediction model on 1-, 2-, and 3-year survival were 0.696, 0.779, and 0.765 respectively in the validation sets. Log-rank tests suggested that the cut point 7.42 risk score calculated from the RSF was most effective in dividing patients with significantly different prognoses. The prediction model based on the RSF could effectively screen patients with poor prognoses.

[Circular RNA expression pattern and competing endogenous RNA network involved in rotator cuff tendinopathy].

OBJECTIVE: To detect the differentially expressed circular RNA (circRNA) in rotator cuff tendinopathy and analyze the potential molecular mechanism of these parental genes. METHODS: Ten supraspinatus tendons donated from patients who underwent tendon repair surgery between June 2018 and June 2019 were used for RNA-sequence. All rotator cuff tendinopathy and normal tendon samples were confirmed by MRI, histological staining, and observation by arthroscopy. All pathological tendons were matched with tendon samples for patients' age, gender, body mass index, and Bonar score. The bioinformatic analysis was performed based on the differentially expressed circRNA and their parental genes, including gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and competing endogenous RNA (ceRNA) network construction. RESULTS: There were 94 differentially expressed circRNAs, including 31 up-regulated and 63 down-regulated, detected between the rotator cuff tendinopathy and normal tendon samples with |log2 fold change (FC)| >2, P<0.05. GO analysis showed that the genes were mostly enriched in response to cyclic adenosine monophosphate (cAMP). KEGG pathway analysis showed that the most genes were enriched in extracellular matrix-receptor interaction, protein digestion and absorption, cell cycle, and nuclear factor κB signaling pathway. ceRNA networks showed the interactions among circRNAs, mRNAs, and miRNAs. And circRNA.8951-has-miR-6089-DNMT3B was the most sum max energy. CONCLUSION: This bioinformatic study reveals several potential therapeutic targets for rotator cuff tendinopathy, which paves the way to better treatment and prevention of this disorder.