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.

Multi-Omics Pan-Cancer Analysis of Procollagen N-Propeptidase Gene Family of ADAMTS as Novel Biomarkers to Associate with Prognosis, Tumor Immune Microenvironment, Signaling Pathways, and Drug Sensitivities.

BACKGROUND: The extracellular matrix (ECM) modeling induced by the metalloproteinases is a vital characteristic for tumor progression. Previous studies mainly focus on the functions of two subgroups of metalloproteinases: matrix metalloproteinases (MMPs) and a disintegrin and metalloproteases (ADAMs) in tumors. The roles of another important group: the ADAMs with thrombospondin motifs (ADAMTS) remain unclear. This study aimed to perform a pan-cancer analysis of procollagen N-propeptidase subgroup of ADAMTS (PNPSA). METHODS: We systematically analyzed expression landscape, genomic variations, prognostic value, and cell expression clusters of PNPSA in pan-cancer based on the multiple integrated open databases. Besides, we also analyzed the impacts of expressions and genomic variations of PNPSA members on tumor immune microenvironment (TIME) and immune-related molecules in pan-cancer based on the immune-related open databases. The Gene Set Variation Analysis (GSVA) was performed to evaluate the associations of the whole PNPSA with prognosis, tumor indicators, TIME, and drug sensitivities. Meanwhile, the Kyoto Encyclopedia of Genes and Genomes (KEGG) was performed to reveal related signaling pathways. Finally, immunohistochemical staining was used to validate the differential analysis results. RESULTS: We found a dual prognostic role of PNPSA members in pan-cancer and they were significantly correlated with TIME and immune-related molecules. Interestingly, the copy number variations (CNVs) of all PNPSA members were revealed to be negatively correlated with NK cell infiltration in most cancers. Single-cell sequencing analysis reveals expressions of PNPSA gene family members on some specific tumor and immune cells in addition to the fibroblasts. The GSVA score was found to have some predictive value for survival status in Brain Lower Grade Glioma (LGG), Mesothelioma (MESO), and Uveal Melanoma (UVM) and to be significantly correlated with tumorigenesis-related pathways such as PI3K-Akt, AGE-RAGE, etc. The GSVA score also shows some predictive value for chemotherapy and immunotherapy efficacy in some tumors. CONCLUSIONS: PNPSA was correlated with tumor development and might be potential tumor biomarker and therapeutic target.

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.

Lamina-Lifting Suspension Modification in Bridge Crane Technique in Treatment of Severe Thoracic Ossification of the Ligamentum Flavum (TOLF).

BACKGROUND The aim of this study was to investigate the effectiveness and potential complications of combining a lamina-lifting suspension system with the bridge crane technique in treating thoracic ossification of the ligamentum flavum (TOLF) with thoracic myelopathy. MATERIAL AND METHODS A patient with severe TOLF and myelopathy was treated using a lamina-lifting suspension system combined with bridge crane technique. The brief surgical procedure involved implantation of internal fixation, separation of laminae, installation of cross-bridges, reverse lifting, and fixation of cross-bridges. The modified Japanese Orthopaedic Association (mJOA) scale, Hirabayashi recovery rate, and ASIA grade of the patient were recorded. The canal occupation ratio (COR) and spinal cord status were evaluated by imaging data. RESULTS The surgical intervention significantly enhances the patient's lower limb function, as evidenced by an increase in mJOA score from 5 preoperatively to 11 at terminal follow-up. The Hirabayashi recovery rate after surgery ranges between 25% and 50%. Additionally, ASIA classification improved to grade E. Imaging data showed that the ossification of the thoracic vertebrae had subsided, while the volume of the local spinal canal had recovered and the spinal cord injury had been completely relieved. No adverse effects or complications were observed. CONCLUSIONS The lamina-lifting suspension system preserves the benefits of bridge crane technique while also augmenting the traction of a post laminae-OLF complex (LOC) suspension, rendering it more secure and manageable. Nevertheless, further sample analysis and research are required in the future.

Causal influence of muscle weakness on cardiometabolic diseases and osteoporosis.

The causal roles of muscle weakness in cardiometabolic diseases and osteoporosis remain elusive. This two-sample Mendelian randomization (MR) study aims to explore the causal roles of muscle weakness in the risk of cardiometabolic diseases and osteoporosis. 15 single nucleotide polymorphisms (SNPs, P < 5 × 10-8) associated with muscle weakness were used as instrumental variables. Genetic predisposition to muscle weakness led to increased risk of coronary artery disease (inverse variance weighted [IVW] analysis, beta-estimate: 0.095, 95% confidence interval [CI]: 0.023 to 0.166, standard error [SE]:0.036, P-value = 0.009) and reduced risk of heart failure (weight median analysis, beta-estimate: - 0.137, 95% CI - 0.264 to - 0.009, SE:0.065, P-value = 0.036). In addition, muscle weakness may reduce the estimated bone mineral density (eBMD, weight median analysis, beta-estimate: - 0.059, 95% CI - 0.110 to - 0.008, SE:0.026, P-value = 0.023). We found no MR associations between muscle weakness and atrial fibrillation, type 2 diabetes or fracture. This study provides robust evidence that muscle weakness is causally associated with the incidence of coronary artery disease and heart failure, which may provide new insight to prevent and treat these two cardiometabolic diseases.

Functional enrichment analysis of LYSET and identification of related hub gene signatures as novel biomarkers to predict prognosis and immune infiltration status of clear cell renal cell carcinoma.

PURPOSE: The latest research shows that the lysosomal enzyme trafficking factor (LYSET) encoded by TMEM251 is a key regulator of the amino acid metabolism reprogramming (AAMR) and related pathways significantly correlate with the progression of some tumors. The purpose of this study was to explore the potential pathways of the TMEM251 in clear cell renal cell carcinoma (ccRCC) and establish related predictive models based on the hub genes in these pathways for prognosis and tumor immune microenvironment (TIME). METHODS: We obtained mRNA expression data and clinical information of ccRCC samples from The Cancer Genome Atlas (TCGA), E-MATE-1980, and immunotherapy cohorts. Single-cell sequencing data (GSE152938) were downloaded from the Gene Expression Omnibus (GEO) database. We explored biological pathways of the LYSET by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of TMEM251-coexpression genes. The correlation of LYSET-related pathways with the prognosis was conducted by Gene Set Variation Analysis (GSVA) and unsupervised cluster analysis. The least absolute shrinkage and selection operator (LASSO) and Cox regression were used to identify hub prognostic genes and construct the risk score. Immune infiltration analysis was conducted by CIBERSORTx and Tumor Immune Estimation Resource (TIMER) databases. The predictive value of the risk score and hub prognostic genes on immunotherapy responsiveness was analyzed through the tumor mutation burden (TMB) score, immune checkpoint expression, and survival analysis. Immunohistochemistry (IHC) was finally used to verify the expressions of hub prognostic genes. RESULTS: The TMEM251 was found to be significantly correlated with some AAMR pathways. AAGAB, ENTR1, SCYL2, and WDR72 in LYSET-related pathways were finally identified to construct a risk score model. Immune infiltration analysis showed that LYSET-related gene signatures significantly influenced the infiltration of some vital immune cells such as CD4 + cells, NK cells, M2 macrophages, and so on. In addition, the constructed risk score was found to be positively correlated with TMB and some common immune checkpoint expressions. Different predictive values of these signatures for Nivolumab therapy responsiveness were also uncovered in immunotherapy cohorts. Finally, based on single-cell sequencing analysis, the TMEM251 and the hub gene signatures were found to be expressed in tumor cells and some immune cells. Interestingly, IHC verification showed a potential dual role of four hub genes in ccRCC progression. CONCLUSION: The novel predictive biomarkers we built may benefit clinical decision-making for ccRCC. Our study may provide some evidence that LYSET-related gene signatures could be novel potential targets for treating ccRCC and improving immunotherapy efficacy. Our nomogram might be beneficial to clinical choices, but the results need more experimental verifications in the future.

Development and validation of a risk prediction model for cage subsidence after instrumented posterior lumbar fusion based on machine learning: a retrospective observational cohort study.

Background: Interbody cage subsidence is a common complication after instrumented posterior lumbar fusion surgery, several previous studies have shown that cage subsidence is related to multiple factors. But the current research has not combined these factors to predict the subsidence, there is a lack of an individualized and comprehensive evaluation of the risk of cage subsidence following the surgery. So we attempt to identify potential risk factors and develop a risk prediction model that can predict the possibility of subsidence by providing a Cage Subsidence Score (CSS) after surgery, and evaluate whether machine learning-related techniques can effectively predict the subsidence. Methods: This study reviewed 59 patients who underwent posterior lumbar fusion in our hospital from 2014 to 2019. They were divided into a subsidence group and a non-subsidence group according to whether the interbody fusion cage subsidence occurred during follow-up. Data were collected on the patient, including age, sex, cage segment, number of fusion segments, preoperative space height, postoperative space height, preoperative L4 lordosis Angle, postoperative L4 lordosis Angle, preoperative L5 lordosis Angle, postoperative PT, postoperative SS, postoperative PI. The conventional statistical analysis method was used to find potential risk factors that can lead to subsidence, then the results were incorporated into stepwise regression and machine learning algorithms, respectively, to build a model that could predict the subsidence. Finally the diagnostic efficiency of prediction is verified. Results: Univariate analysis showed significant differences in pre-/postoperative intervertebral disc height, postoperative L4 segment lordosis, postoperative PT, and postoperative SS between the subsidence group and the non-subsidence group (p < 0.05). The CSS was trained by stepwise regression: 2 points for postoperative disc height > 14.68 mm, 3 points for postoperative L4 segment lordosis angle >16.91°, and 4 points for postoperative PT > 22.69°. If the total score is larger than 0.5, it is the high-risk subsidence group, while less than 0.5 is low-risk. The score obtains the area under the curve (AUC) of 0.857 and 0.806 in the development and validation set, respectively. The AUC of the GBM model based on the machine learning algorithm to predict the risk in the training set is 0.971 and the validation set is 0.889. The AUC of the avNNet model reached 0.931 in the training set and 0.868 in the validation set, respectively. Conclusion: The machine learning algorithm has advantages in some indicators, and we have preliminarily established a CSS that can predict the risk of postoperative subsidence after lumbar fusion and confirmed the important application prospect of machine learning in solving practical clinical problems.

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.

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.

Causal Roles of Sleep Duration in Osteoporosis and Cardiometabolic Diseases: A Mendelian Randomization Study.

Sleep duration suggests some association with osteoporosis and cardiometabolic diseases, but it is unknown if these associations are causal or confounded. In this two-sample Mendelian randomization (MR) study, we included the largest genome-wide association studies (GWASs) associated with sleep duration and the outcome measures of osteoporosis and cardiometabolic diseases. Finally, 25 single nucleotide polymorphisms (SNPs) associated with short sleep duration and 7 SNPs associated with long sleep duration obtained the genome-wide significance (P < 5 × 10-8) and were used as instrumental variables. Genetic predisposition to short sleep duration was strongly associated with increased risk of coronary artery disease (beta-estimate: 0.199, 95% confidence interval CI: 0.081 to 0.317, standard error SE:0.060, P value = 0.001) and heart failure (beta-estimate: 0.145, 95% CI: 0.025 to 0.264, SE:0.061, P value = 0.017), which were both confirmed by the sensitivity analyses. Both short and long sleep duration may reduce the estimated bone mineral density (eBMD, beta-estimate: -0.086, 95% CI: -0.141 to -0.031, SE:0.028, P value = 0.002 for short sleep duration; beta-estimate: -0.080, 95% CI: -0.120 to -0.041, SE:0.020, P value < 0.0001 for long sleep duration). There was limited evidence of associations between sleep duration and fracture, type 2 diabetes, atrial fibrillation, fasting glucose, fasting insulin, or HbA1c. This study provides robust evidence that short sleep duration is causally associated with high risk of coronary artery disease and heart failure and suggests that short sleep duration should be avoided to prevent these two cardiovascular diseases. Short and long sleep duration show some MR association with reduced eBMD, which indicates that both short and long sleep duration may be prevented to reduce the incidence of osteoporosis.

SAR1A regulates the RhoA/YAP and autophagy signaling pathways to influence osteosarcoma invasion and metastasis.

Osteosarcoma is the most prevalent form of primary bone malignancy affecting adolescents. Secretion-associated Ras-related GTPase 1A (SAR1A) is a key regulator of endoplasmic reticulum (ER) homeostasis, but its role as a regulator of osteosarcoma metastasis has yet to be clarified. Bioinformatics analyses revealed SAR1A and RHOA to be upregulated in osteosarcoma patients, with the upregulation of these genes being associated with poor 5-year metastasis-free survival rates. In addition, the upregulation of SAR1A and RHOA in osteosarcoma was highly positively correlated. Immunohistochemical analyses additionally revealed that SAR1A levels were increased in osteosarcoma pulmonary metastases. In vitro wound healing and Transwell assays indicated that knocking down SAR1A or RHOA impaired the invasive and migratory activity of osteosarcoma cells, whereas RHOA overexpression had the opposite effect. Western blotting and immunofluorescent staining revealed the inhibition of osteosarcoma cell epithelial-mesenchymal transition following SAR1A or RHOA knockdown; RHOA overexpression had the opposite effect. Following SAR1A knockdown, phalloidin staining indicated that osteosarcoma cells showed reduced lamellipodia formation. Endoplasmic reticulum stress levels and reactive oxygen species production were enhanced following the knockdown of SAR1A, as was autophagic activity, with lung metastases being reduced in vivo after such knockdown. Knocking down SAR1A suppresses osteosarcoma cell metastasis through the RhoA/YAP, ER stress, and autophagic pathways, offering new insights into the regulation of autophagic activity in the context of osteosarcoma cell metastasis and suggesting that these pathways could be amenable to therapeutic intervention.

The Distribution Pattern of First-Line Anti-Tuberculosis Drug Concentrations between the Blood and the Vertebral Focus of Spinal Tuberculosis Patients.

BACKGROUND: Anti-tuberculosis drug concentrations are critical for the treatment of spinal tuberculosis. The distribution pattern of anti-tuberculosis drugs between the blood and the vertebral focus needs to be further explored. METHODS: A total of 31 spinal tuberculosis patients were prospectively included and then divided into a sclerotic group (15 cases) and a non-sclerotic group (16 cases) according to their preoperative CTs. All patients were treated with 2HERZ/6H2R2Z2 chemotherapy for 4 weeks before the operation. During the operation, blood, normal vertebral bone tissue, and vertebral focus tissue were obtained, processed, and sent to the pharmacology laboratory. The concentration values of four anti-tuberculosis drugs in each sample were obtained in a pharmacology laboratory. RESULTS: There was no significant difference in the concentrations of the four anti-tuberculosis drugs in the blood and the normal vertebral bone tissue between the two groups; however, there was a significant difference in the vertebral focus tissue. There existed a linear correlation of four anti-tuberculosis drug concentrations between the blood and the focus in the non-sclerotic bone group. CONCLUSIONS: The existence of sclerotic bone hinders the anti-tuberculosis drug distribution. In the absence of sclerotic bone in the vertebral focus, there exists a linear relationship of the four anti-tuberculosis drug concentrations between the blood and the vertebral focus of spinal tuberculosis patients.

A predictive scoring system for proximal junctional kyphosis after posterior internal fixation in elderly patients with chronic osteoporotic vertebral fracture: A single-center diagnostic study.

Objective: To establish a predictive scoring system for proximal junctional kyphosis (PJK) after posterior internal fixation in elderly patients with chronic osteoporotic vertebral fracture (COVF). Materials and methods: The medical records of 88 patients who were diagnosed with COVF and underwent posterior internal fixation in our hospital from January 2013 to December 2017 were retrospectively analyzed. The included patients were divided into two groups according to whether they suffered PJK after surgery, namely, the PJK group (25 cases) and non-PJK group (63 cases). The following clinical characteristics were recorded and analyzed: age, gender, body mass index (BMI), bone mineral density (BMD), smoking history, fracture segment, proximal junction angle, sagittal vertebral axis, pelvic incidence (PI)-lumbar lordosis (LL), pelvic tilt (PT), sacral slope (SS), posterior ligamentous complex (PLC) injury, upper instrumented vertebra, lower instrumented vertebra, and the number of fixed segments. The prevalence of these clinical characteristics in the PJK group was evaluated, and the scoring system was established using logistic regression analysis. The performance of the scoring system was also prospectively validated. Results: The predictive scoring system was established based on five clinical characteristics confirmed as significant predictors of PJK, namely, age > 70 years, BMI > 28 kg/m2, BMD < -3.5 SD, preoperative PI-LL > 20°, and PLC injury. PJK showed a significantly higher score than non-PJK (7.80 points vs. 2.83 points, t=9.556, P<0.001), and the optimal cutoff value for the scoring system was 5 points. The sensitivity and specificity of the scoring system for predicting postoperative PJK were 80.00% and 88.89%, respectively, in the derivation set and 75.00% and 80.00% in the validation set. Conclusion: The predictive scoring system was confirmed with satisfactory sensitivity and specificity in predicting PJK after posterior internal fixation in elderly COVF patients. The risk of postoperative PJK in patients with a score of 6-11 is high, while the score of 0-5 is low.

The mevalonate pathway promotes the metastasis of osteosarcoma by regulating YAP1 activity via RhoA.

Osteosarcoma is the most common malignant bone tumour, and the metastasis of osteosarcoma is an important cause of death. Evidence has shown that the mevalonate pathway is highly activated and is expected to be a new target for tumour therapy. In this study, we investigated the effect of mevalonate signalling on osteosarcoma metastasis and its molecular mechanism. First, we found that the key rate-limiting enzyme of mevalonate signalling, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), was highly expressed in osteosarcoma cells, and inhibition of HMGCR with simvastatin significantly inhibited the motility of 143B cells. Next, we found that YAP1 activity was significantly upregulated in osteosarcoma cells and that YAP1 knockdown inhibited the motility of 143B cells. We also found that the mevalonate pathway regulated the motility of 143B cells by modulating YAP1 phosphorylation and cellular localization. Moreover, we found that the activity of YAP1 was regulated by the mevalonate pathway by modulating the cell membrane localization of RhoA. Finally, we demonstrated that inhibition of the mevalonate pathway notably reduced the lung metastasis of 143B cells, as reflected by the decreased incidence and number of metastatic nodules and the increased survival time of the nude mice. Taken together, our findings suggest that the mevalonate pathway can promote the metastasis of osteosarcoma by activating YAP1 via RhoA. Inhibition of the mevalonate pathway may be a promising therapeutic strategy for osteosarcoma metastasis.

YAP knockdown in combination with ferroptosis induction increases the sensitivity of HOS human osteosarcoma cells to pyropheophorbide-α methyl ester-mediated photodynamic therapy.

BACKGROUND AND AIMS: This study was designed to explore the effects of Yes-associated protein (YAP) knockdown on human osteosarcoma (HOS) cell sensitivity to Pyropheophorbide-α methyl ester-mediated photodynamic therapy (MPPa-PDT), and to assess how YAP silencing in combination with treatment with the ferroptosis inducer Erastin improves HOS cell sensitivity to MPPa-PDT in an effort to better clarify the molecular mechanisms underlying these phenotypes. METHODS: At 12 h post-MPPa-PDT, Hoechst staining and flow cytometry were conducted to evaluate the apoptotic death of HOS cells. The expression of YAP in these cells at 12 h post-MPPa-PDT treatment was assessed via Western blotting and immunofluorescent staining. BODIPY581/591-C11 was used to evaluate lipid peroxidation. Following shYAP lentiviral transduction, Western blotting was conducted to assess the expression of proteins associated with proliferation, apoptosis, and ferroptosis. EdU assays and clonogenic assays were performed to analyze cellular proliferation. Erastin-treated HOS cells were used to establish a ferroptosis model. Western blotting was used to measure ferroptosis-associated protein levels following shYAP and erastin treatment, while changes in proliferation and MDA levels in each group were examined using an MDA kit. RESULTS: At 12 h post-MPPa-PDT, HOS cells exhibited apoptotic characteristics including nuclear fragmentation and pyknosis, with concomitant increases in apoptosis-associated proteins as detected via Western blotting and apoptotic induction as measured via flow cytometry. Phosphorylated YAP levels fell and non-phosphorylated YAP levels rose following such treatment. Transfection with shYAP was successful as a means of generating stable HOS cell lines, and Western blotting analyses of these cells revealed reductions in proteins associated with cellular proliferation together with the upregulation of apoptosis-related proteins.  MDA assays indicated that erastin combined with YAP knockdown enhanced the sensitivity of HOS cells to MPPa-PDT treatment. CONCLUSIONS: These data indicate that ferroptosis and YAP knockdown can enhance osteosarcoma cell sensitivity to MPPa-PDT therapy.

What Level Should Preoperative Albumin of Thoracic and Lumbar Tuberculosis Patients Be Reached: A Case-Controlled Study.

Objective: To explore the risk factors of hypoalbuminemia in patients with thoracic and lumbar tuberculosis and develop a scoring scale, according to which the patients with thoracic and lumbar tuberculosis were divided into 2 groups to, respectively calculate the perioperative albumin changes and to find out the preoperative albumin recommended value. Methods: A total of 166 patients with thoracic and lumbar tuberculosis, who underwent spinal focus debridement between January 2012 to May 2020, were identified into 2 groups: with and without postoperative hypoalbuminemia (n = 131 and n = 35, respectively), recording and analyzing clinical characteristics by multivariate analysis to establish a scoring scale. Using this scale, patients with spinal tuberculosis were divided into a high-risk group and a low-risk group, and then, calculated the average decrease of postoperative albumin in both groups. Combined with the diagnostic threshold of hypoalbuminemia, we proposed the preoperative albumin safe values of the patients with thoracic and lumbar tuberculosis. Results: A total of 131 of 166 patients experienced postoperative hypoalbuminemia after spinal focus debridement. Multivariate binary logistic regression analysis identified pulmonary tuberculosis (adjusted odds ratio = 0.270, p = 0.012), pre-operative serum albumin value (adjusted odds ratio = 0.754, p < 0.001), and operation time (adjusted odds ratio = 1.017, p = 0.002) as independent risk factors for the occurrence of postoperative hypoalbuminemia in patients with thoracic and lumbar tuberculosis. According to the OR value, the risk factors are assigned to make the scoring scale, the receiver operating characteristic (ROC) curve indicates that postoperative hypoalbuminemia rises when the score is greater than or equal to 4 points. The scoring scale is tested in the derivation set (166 patients) showed: sensitivity-51.9%, specificity-91.4%, and in the validation set (102 patients) showed: sensitivity-63.6% and specificity-86.1%. The perioperative albumin decreased value is 4.71 ± 2.66 g/L in the low-risk group and 8.99 ± 3.37 g/L in the high-risk group (p < 0.001). Conclusion: Complicated with pulmonary tuberculosis, low preoperative albumin value and long operation time can lead to postoperative hypoalbuminemia in patients with thoracic and lumbar tuberculosis. The scoring scale can effectively assist physicians to evaluate whether patients with thoracic and lumbar tuberculosis develop hypoalbuminemia after surgery. The scale is simple and reliable and has clinical guiding significance. For low-risk patients and high-risk patients, preoperative albumin values should reach 40 and 44 g/L, respectively, to effectively avoid postoperative hypoalbuminemia.

Causal associations of circulating adiponectin with cardiometabolic diseases and osteoporotic fracture.

Circulating adiponectin shows some relationships with the occurrence of cardiometabolic diseases and osteoporotic fracture, but little is known about their causal associations. This two-sample Mendelian randomization (MR) study aims to explore the causal roles of circulating adiponectin in cardiometabolic diseases and osteoporotic fracture. We used 15 single nucleotide polymorphisms associated with circulating adiponectin as the instrumental variables. Inverse variance weighted, weighted median and MR-Egger regression methods were applied to study the causal associations. The results found that high circulating adiponectin was causally associated with reduced risk of type 2 diabetes (beta-estimate: -0.030, 95% CI: -0.048 to -0.011, SE: 0.009, P-value = 0.002) and may be the risk factor of coronary artery disease (beta-estimate: 0.012, 95% CI: 0.001 to 0.023, SE: 0.006, P-value = 0.030). No causal associations were seen between circulating adiponectin and other outcomes including heart failure, atrial fibrillation, cerebral ischemia, intracerebral hemorrhage or osteoporotic fracture. This study found the potential causal roles of high circulating adiponectin in reduced risk of type 2 diabetes and increased risk of coronary artery disease, which may help prevent and treat these two diseases.

Comparison of the Effect of Different Local Analgesia Administration Methods in Percutaneous Vertebroplasty: A Retrospective Cohort Study.

Objective: Although various studies have described the methods of administering anesthesia during percutaneous vertebroplasty (PV) for treating osteoporotic vertebral compression fractures (OVCFs), there is still no consensus on the optimal treatment regimen. Therefore, this study aimed to investigate the effects of three application methods of local analgesia administration in PV for treating OVCFs. Methods: A total of 96 patients with OVCFs were reviewed and divided into three groups (A: lidocaine, B: ropivacaine, C: lidocaine + ropivacaine). The visual analog scale (VAS), blood pressure (BP), heart rate (HR), blood oxygen saturation (BOS), and surgery time were recorded during the following different points: before puncture, during the puncture, cement injection, and 4-h after surgery. Results: The mean age of the patients was 74.13 ± 7.02 years in group A, 70.47 ± 5.50 years in group B, and 73.07 ± 7.51 years in group C, without significant difference. No significant differences were found in sex, age, hospital stay, surgery time, blood loss, and cement volume of the patients. In the periods of before puncture and 4-h after surgery, the VAS in group C decreased significantly than that in the periods of the puncture, cement injection, and immediately after surgery. Overall, there were no significant differences in systolic BP, diastolic BP, HR, and BOS during the different periods among the groups except HR in the period of the puncture in group C, which was slower than that in other groups, and HR in the period of cement injection in group A, which was faster than the other two groups. A correlation was observed between the VAS and the periods of cement injection (r = 0.5358) and after surgery (r = 0.5775) in group C. Conclusion: Compared with the other two methods, the use of lidocaine in combination with ropivacaine could effectively relieve intraoperative pain, making the patients feel more comfortable and experience better recovery.

The risk factors of the postoperative poor wound healing in spinal tuberculosis patients: A single centre retrospective cohort study.

The purpose of this study is to find out the risk factors of poor wound healing (PWH) in spinal tuberculosis (STB) patients. A total of 232 STB patients who underwent debridement surgery between January 2012 to June 2020 were included in this retrospective study. The study cohort was divided into two groups according to the presence or absence of PWH. The clinical characteristics of STB patients who developed PWH were evaluated, and risk factors were found using logistic regression analysis. Of the 232 patients, 30 developed PWH. Multivariate binary logistic regression analysis showed that pulmonary tuberculosis, long operation time and low postoperative albumin level were independent risk factors for PWH in STB patients. Receiver operating characteristic curve analysis showed that the optimal cutoff value of PWH in operation time and postoperative albumin are 200 minutes and 30 g/L, respectively. Pulmonary tuberculosis, long operation time and low postoperative albumin level are independent risk factors for PWH following surgery for STB. Curing pulmonary tuberculosis, controlling operation time and supervising postoperative serum albumin may decrease the risk of PWH among STB patients.