Disturbed glycolipid metabolism activates CXCL13-CXCR5 axis in senescent TSCs to promote heterotopic ossification.

Heterotopic ossification (HO) occurs as a common complication after injury, while its risk factor and mechanism remain unclear, which restricts the development of pharmacological treatment. Clinical research suggests that diabetes mellitus (DM) patients are prone to developing HO in the tendon, but solid evidence and mechanical research are still needed. Here, we combined the clinical samples and the DM mice model to identify that disordered glycolipid metabolism aggravates the senescence of tendon-derived stem cells (TSCs) and promotes osteogenic differentiation. Then, combining the RNA-seq results of the aging tendon, we detected the abnormally activated autocrine CXCL13-CXCR5 axis in TSCs cultured in a high fat, high glucose (HFHG) environment and also in the aged tendon. Genetic inhibition of CXCL13 successfully alleviated HO formation in DM mice, providing a potential therapeutic target for suppressing HO formation in DM patients after trauma or surgery.

Maslinic acid alleviates intervertebral disc degeneration by inhibiting the PI3K/AKT and NF-κB signaling pathways.

Intervertebral disc degeneration (IDD) is the cause of low back pain (LBP), and recent research has suggested that inflammatory cytokines play a significant role in this process. Maslinic acid (MA), a natural compound found in olive plants ( Olea europaea), has anti-inflammatory properties, but its potential for treating IDD is unclear. The current study aims to investigate the effects of MA on TNFα-induced IDD in vitro and in other in vivo models. Our findings suggest that MA ameliorates the imbalance of the extracellular matrix (ECM) and mitigates senescence by upregulating aggrecan and collagen II levels as well as downregulating MMP and ADAMTS levels in nucleus pulposus cells (NPCs). It can also impede the progression of IDD in rats. We further find that MA significantly affects the PI3K/AKT and NF-κB pathways in TNFα-induced NPCs determined by RNA-seq and experimental verification, while the AKT agonist Sc-79 eliminates these signaling cascades. Furthermore, molecular docking simulation shows that MA directly binds to PI3K. Dysfunction of the PI3K/AKT pathway and ECM metabolism has also been confirmed in clinical specimens of degenerated nucleus pulposus. This study demonstrates that MA may hold promise as a therapeutic agent for alleviating ECM metabolism disorders and senescence to treat IDD.

Development and validation of a novel nomogram of 1-year mortality in the elderly with hip fracture: a study of the MIMIC-III database.

OBJECTIVE: Hip fracture is a prevalent condition with a significant death rate among the elderly. We sought to develop a nomogram-based survival prediction model for older patients with hip fracture. DESIGN: A retrospective case-control study. SETTING: The data from Medical Information Mart for Intensive Care III (MIMIC-III V.1.4). PARTICIPANTS: The clinical features of elderly patients with hip fracture, including basic information, comorbidities, severity score, laboratory tests and therapy, were filtered out based on the MIMIC-III V.1.4. METHODS AND MAIN OUTCOME MEASURES: All patients included in the study were from critical care and randomly divided into training and validation sets (7:3). On the basis of retrieved data, the least absolute shrinkage and selection operator (LASSO) regression and multiple logistic regression analysis were used to identify independent predictive variables of 1-year mortality, and then constructed a risk prediction nomogram. The predictive values of the nomogram model were evaluated by the concordance indexes (C-indexes), receiver operating characteristic curve, decision curve analysis (DCA) and calibration curve. RESULTS: A total of 341 elderly patients with hip fracture were included in this study; 121 cases died within 1 year. After LASSO regression and multiple logistic regression analysis, a novel nomogram contained the predictive variables of age, weight, the proportion of lymphocyte count, liver disease, malignant tumour and congestive heart failure. The constructed model proved satisfactory discrimination with C-indexes of 0.738 (95% CI 0.674 to 0.802) in the training set and 0.713 (95% CI 0.608 to 0.819) in the validation set. The calibration curve shows a good degree of fitting between the predicted and observed probabilities and the DCA confirms the model's clinical practicability. CONCLUSIONS: The novel prediction model provides personalised predictions for 1-year mortality in elderly patients with hip fractures. Compared with other hip fracture models, our nomogram is particularly suitable for predicting long-term mortality in critical patients.

ERRα contributes to HDAC6-induced chemoresistance of osteosarcoma cells.

Chemotherapy resistance is an important problem for clinical therapy of osteosarcoma (OS). The potential effects of histone deacetylases (HDACs) on OS chemoresistance are studied. The expression of HDACs in OS cells resistance to doxorubicin (Dox) and cisplatin (CDDP) is checked. Among 11 members of HDACs, levels of HDAC6 are significantly upregulated in OS cells resistance to Dox and CDDP. Inhibition of HDAC6 via its specific inhibitor ACY1215 restores chemosensitivity of OS-resistant cells. Further, HDAC6 directly binds with estrogen-related receptors alpha (ERRα) to regulate its acetylation and protein stability. Inhibition of ERRα further strengthens ACY1215-increased chemosensitivity of OS-resistant cells. Mechanistically, K129 acetylation is the key residue for HDAC6-regulated protein levels of ERRα. Collectively, we find that ERRα contributes to HDAC6-induced chemoresistance of OS cells. Inhibition of HDAC6/ERRα axis might be a potential approach to overcome chemoresistance and improve therapy efficiency for OS treatment. 1. HDAC6 was significantly upregulated in Dox and CDDP resistant OS cells; 2. Inhibition of HDAC6 can restore chemosensitivity of OS cells; 3. HDAC6 binds with ERRα at K129 to decrease its acetylation and increase protein stability; 4. ERRα contributes to HDAC6-induced chemoresistance of OS cells.

Incidence of postoperative symptomatic spinal epidural hematoma requiring surgical evacuation: a systematic review and meta-analysis.

PURPOSE: This systematic review and meta-analysis aimed to determine the incidence of symptomatic spinal epidural hematoma (SSEH) following spine surgery. METHODS: We systematically searched for all relevant articles that mentioned the incidence of SSEH following the spine surgery published in the PubMed, Embase, and Cochrane Library databases through March 2022 and manually searched the reference lists of included studies. The Newcastle-Ottawa quality assessment scale (NOS) was used to assess the quality of the included studies. A fixed-effects or random-effects model was performed to calculate the pooled incidence of the totality and subgroups based on the heterogeneity. The potential publication bias was assessed by Egger's linear regression and a funnel plot. Sensitivity analysis was also conducted. RESULTS: A total of 40 studies were included in our meta-analysis based on our inclusion and exclusion criteria. The overall pooled incidence of SSEH was 0.52% (95% CI 0.004-0.007). In the subgroup analysis, the pooled incidence of SSEH in males and females was 0.86% (95% CI 0.004-0.023) and 0.68% (95% CI 0.003-0.017). Among the different indications, a higher incidence (2.9%, 95% CI 0.006-0.084) was found in patients with deformity than degeneration (1.12%, 95% CI 0.006-0.020) and tumor (0.30%, 95% CI 0.006-0.084). For different surgical sites, the incidences of SSEH in cervical, thoracic and lumbar spine were 0.32% (95% CI 0.002-0.005), 0.84% (95% CI 0.004-0.017) and 0.63% (95% CI 0.004-0.010), respectively. The incidences of SSEH in anterior and posterior approach were 0.24% (95% CI 0.001-0.006) and 0.70% (95% CI 0.004-0.011), respectively. The pooled incidence of SSEH was five times higher with minimally invasive surgery (1.94%, 95% CI 0.009-0.043) than with open surgery (0.42%, 95% CI 0.003-0.006). Delayed onset of SSEH had a lower incidence of 0.16% (95% CI 0.001-0.002) than early onset. There were no significant variations in the incidence of SSEH between patients who received perioperative anticoagulation therapy and those who did not or did not report getting chemopreventive therapy (0.44%, 95% CI 0.006-0.084 versus 0.42%, 95% CI 0.003-0.006). CONCLUSION: We evaluated the overall incidence proportion of SSEH after spine surgery and performed stratified analysis, including sex, surgical indication, site, approach, minimally invasive surgery, and delayed onset of SSEH. Our research would be helpful for patients to be accurately informed of their risk and for spinal surgeons to estimate the probability of SSEH after spine surgery.

IGF2BP1-regulated expression of ERRα is involved in metabolic reprogramming of chemotherapy resistant osteosarcoma cells.

Doxorubicin (Dox) is the standard treatment approach for osteosarcoma (OS), while acquired drug resistance seriously attenuates its treatment efficiency. The present study aimed to investigate the potential roles of metabolic reprogramming and the related regulatory mechanism in Dox-resistant OS cells. The results showed that the ATP levels, lactate generation, glucose consumption and oxygen consumption rate were significantly increased in Dox-resistant OS cells compared with parental cells. Furthermore, the results revealed that the increased expression of estrogen-related receptor alpha (ERRα) was involved in metabolic reprogramming in chemotherapy resistant OS cells, since targeted inhibition of ERRα restored the shifting of metabolic profiles. Mechanistic analysis indicated that the mRNA stability, rather than ERRα transcription was markedly increased in chemoresistant OS cells. Therefore, it was hypothesized that the 3'-untranslated region of ERRα mRNA was methylated by N6-methyladenine, which could further recruit insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) to suppress mRNA decay and increase mRNA stability. IGF2BP1 knockdown downregulated ERRα and reversed the metabolic alteration of resistant OS cells. Additionally, the oncogenic effect of the IGF2BP1/ERRα axis on Dox-resistant OS cells was verified by in vitro and in vivo experiments. Clinical analysis also revealed that the expression levels of IGF2BP1 and ERRα were associated with the clinical progression of OS. Collectively, the current study suggested that the IGF2BP1/ERRα axis could regulate metabolic reprogramming to contribute to the chemoresistance of OS cells.