Sublingual Edaravone Dexborneol for the Treatment of Acute Ischemic Stroke: The TASTE-SL Randomized Clinical Trial.

Importance: Sublingual edaravone dexborneol, which can rapidly diffuse and be absorbed through the oral mucosa after sublingual exposure, is a multitarget brain cytoprotection composed of antioxidant and anti-inflammatory ingredients edaravone and dexborneol. Objective: To investigate the efficacy and safety of sublingual edaravone dexborneol on 90-day functional outcome in patients with acute ischemic stroke (AIS). Design, Setting, and Participants: This was a double-blind, placebo-controlled, multicenter, parallel-group, phase 3 randomized clinical trial conducted from June 28, 2021, to August 10, 2022, with 90-day follow-up. Participants were recruited from 33 centers in China. Patients randomly assigned to treatment groups were aged 18 to 80 years and had a National Institutes of Health Stroke Scale score between 6 and 20, a total motor deficit score of the upper and lower limbs of 2 or greater, a clinically diagnosed AIS symptom within 48 hours, and a modified Rankin Scale (mRS) score of 1 or less before stroke. Patients who did not meet the eligibility criteria or declined to participate were excluded. Intervention: Patients were assigned, in a 1:1 ratio, to receive sublingual edaravone dexborneol (edaravone, 30 mg; dexborneol, 6 mg) or placebo (edaravone, 0 mg; dexborneol, 60 µg) twice daily for 14 days and were followed up until 90 days. Main Outcomes and Measures: The primary efficacy outcome was the proportion of patients with mRS score of 1 or less on day 90 after randomization. Results: Of 956 patients, 42 were excluded. A total of 914 patients (median [IQR] age, 64.0 [56.0-70.0] years; 608 male [66.5%]) were randomly allocated to the edaravone dexborneol group (450 [49.2%]) or placebo group (464 [50.8%]). The edaravone dexborneol group showed a significantly higher proportion of patients experiencing good functional outcomes on day 90 after randomization compared with the placebo group (290 [64.4%] vs 254 [54.7%]; risk difference, 9.70%; 95% CI, 3.37%-16.03%; odds ratio, 1.50; 95% CI, 1.15-1.95, P = .003). The rate of adverse events was similar between the 2 groups (89.8% [405 of 450] vs 90.1% [418 of 464]). Conclusion and Relevance: Among patients with AIS within 48 hours, sublingual edaravone dexborneol could improve the proportion of those achieving a favorable functional outcome at 90 days compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04950920.

A novel polysaccharide isolated from Coriolus versicolor polarizes M2 macrophages into an M1 phenotype and reversesits immunosuppressive effect on tumor microenvironment.

Converting M2 macrophages into an M1 phenotype in the tumor microenvironment, provides a new direction for tumor treatment. Here, we further report CVPW-1, a new polysaccharide of 1.03 × 106 Da that was isolated from Coriolus versicolor. Its monosaccharide was composed of mannose, glucose, and galactose at a ratio of 1.00:8.73:1.68. The backbone of CVPW-1 was composed of (1 â†’ 3)-linked α-D-Glcp residues and (1 â†’ 3,6)-linked α-D-Glcp residues that branched at O-6. The branch consisted of (1 â†’ 6)-linked α-D-Glcp residues and (1 â†’ 4)-linked α-D-Glap, and some branches were terminated with (1→)-linked ß-D-Manp residues according to the results of HPLC, FT-IR, GC-MS, 1D and 2D NMR. Meanwhile, CVPW-1 could polarize M2 macrophages to M1 phenotypein vitro by binding to TLR4 and inducing the activation of Akt, JNK and NF-κB. This process involved reversing the functional inhibition of CD8+ T lymphocytes by inhibiting the expression of TREM2 in M2 macrophages. The in vivo experiments showed that oral administration of CVPW-1 could inhibit the growth of tumor in mice and polarize TAMs to M1 phenotype. Thus, the novel polysaccharide CVPW-1 from Coriolus versicolor might activate a variety of immune cells and then play an anti-tumor role. These results demonstrated that CVPW-1 could be developed as a potential immuno-oncology treatment reagent.

Efficacy and safety of Y-2 sublingual tablet for patients with acute ischaemic stroke: protocol of a phase III randomised double-blind placebo-controlled multicentre trial.

BACKGROUND AND PURPOSE: Clinical studies have demonstrated that edaravone dexborneol can improve the functional outcomes in patients with acute ischaemic stroke (AIS). The present clinical trial aimed at testing the efficacy and safety of Y-2 sublingual tablet on 90-day functional outcome in patients with AIS. METHODS AND DESIGN: This is a randomised, double-blind, placebo-controlled, multicentre, parallel-group trial of Y-2 sublingual tablet on patients with AIS.An estimated 914 patients at age of 18-80 years with AIS within 48 hours after symptom onset from 40 hospitals will be randomly assigned to receive Y-2 sublingual tablet or placebo for 14 days. Patients are at score 6-20 points on National Institutes of Health Stroke Scale (NIHSS) and had a modified Rankin Scale (mRS) ≤1 before this stroke, except mechanical thrombectomy and neuroprotective agents treatment. STUDY OUTCOMES: The primary outcome is the proportion of patients with mRS ≤1 on day 90 after randomisation. Secondary efficacy outcomes include mRS score on day 90, the proportion of patients with mRS ≤2 on day 90; the change of NIHSS score from baseline to day 14 and the proportion of patients with NIHSS score ≤1 at the days 14, 30 and 90. DISCUSSION: This trial will provide valuable evidence for the efficacy and safety of Y-2 sublingual table for improving 90 days the functional outcomes in patients with AIS. TRIAL REGISTRATION NUMBER: NCT04950920.

Tumor microenvironment-associated lactate metabolism regulates the prognosis and precise checkpoint immunotherapy outcomes of patients with lung adenocarcinoma.

BACKGROUND: Despite the wide clinical application of checkpoint inhibitor immunotherapy in lung adenocarcinoma, its limited benefit to patients remains puzzling to researchers. One of the mechanisms of immunotherapy resistance may be the dysregulation of lactate metabolism in the immunosuppressive tumor microenvironment (TME), which can inhibit dendritic cell maturation and prevent T-cell invasion into tumors. However, the key genes related to lactate metabolism and their influence on the immunotherapeutic effects in lung adenocarcinoma have not yet been investigated in depth. METHODS: In this study, we first surveyed the dysregulated expression of genes related to lactate metabolism in lung adenocarcinoma and then characterized their biological functions. Using machine learning methods, we constructed a lactate-associated gene signature in The Cancer Genome Atlas cohort and validated its effectiveness in predicting the prognosis and immunotherapy outcomes of patients in the Gene Expression Omnibus cohorts. RESULTS: A 7-gene signature based on the metabolomics related to lactate metabolism was found to be associated with multiple important clinical features of cancer and was an independent prognostic factor. CONCLUSIONS: These results suggest that rather than being simply a metabolic byproduct of glycolysis, lactate in the TME can affect immunotherapy outcomes. Therefore, the mechanism underlying this effect of lactate is worthy of further study.

5-Demethoxy-10'-ethoxyexotimarin F, a New Coumarin with MAO-B Inhibitory Potential from Murraya exotica L.

Rutaceae plants are known for being a rich source of coumarins. Preliminary molecular docking showed that there was no significant difference for coumarins in Clausena and Murraya, both of which had high scoring values and showed good potential inhibitory activity to the MAO-B enzyme. Overall, 32 coumarins were isolated from Murraya exotica L., including a new coumarin 5-demethoxy-10'-ethoxyexotimarin F (1). Their structures were elucidated on the basis of a comprehensive analysis of 1D and 2D NMR and HRMS spectroscopic data, and the absolute configurations were assigned via a comparison of the specific rotations and the ECD exciton coupling method. The potential of new coumarin (1) as a selective inhibitor of MAO-B was initially evaluated through molecular docking and pharmacophore studies. Compound (1) showed selectivity for the MAO-B isoenzyme and inhibitory activity in the sub-micromolar range with an IC50 value of 153.25 ± 1.58 nM (MAO-B selectivity index > 172).

Analysis of Clinical Manifestations and Imaging of COVID-19 Patients in Intensive Care.

Objective: The study aims to summarize and analyze the clinical and CT findings of severe COVID-19 patients. Methods: From February 11 to March 31, 2020, 61 COVID-19 patients in intensive care in the E1-3 ward of Tongji Hospital were analyzed retrospectively. Results: The main clinical manifestations were cough, expectoration in 56 cases (91.8%), shortness of breath, chest tightness in 48 cases (78.7%), fever in 61 cases (100%), muscle ache and weakness in 40 cases (65.6%), diarrhea or vomiting in 8 cases (13.1%), and headache in 4 cases (6.6%). After admission, the leukocyte count was normal in 40 cases (57.7%), higher in 9 cases (15.4%), and lower in 12 cases (26.9%). The lymphocyte count decreased in 53 cases (86.9%). CRP was increased in 29 cases (47.5%); PCT was increased in 15 cases (24.6%); ESR was increased in 38 cases (62.3%); D-dimer increased in 39 cases (63.9%); ALT/AST increased in 40 cases (65.6%); CK/CK-MB increased in 8 cases (13.1%); troponin I increased in 6 cases (9.8%); NT-proBNP increased in 35 cases (57.4%); IL-1 increased in 5 cases (8.2%); IL-2 receptor increased in 28 cases (45.9%); IL-6 increased in 23 cases (37.7%); IL-8 increased in 15 cases (24.6%); IL-10 increased in 12 cases (19.7%); and NTF increased in 22 cases (36.1%). The chest CT images showed that 38 cases (65.5%) of right lung lesions were more extensive than those of left lung lesions, 20 cases (34.5%) of left lung lesions were more extensive than those of right lung lesions, 42 cases (72.5%) of lower lobe lesions were more extensive than those of upper lobe lesions, 6 cases (10.3%) of upper lobe lesions were more extensive than those of lower lobe lesions, and 10 cases (17.2%) of upper and lower part lesions were roughly the same. Ground-glass opacity (GGO) was found in 12 cases (20.7%); GGO with focal consolidation in 38 cases (65.5%); small patchy edge fuzzy density increased in 24 cases (41.4%); large consolidation in 20 cases (34.5%); reticular or fibrous cord in 54 cases (93.1%); and air bronchogram in 8 cases (13.8%). Conclusions: COVID-19 patients in intensive care have no specific clinical manifestation and CT findings. However, analysis and summary of relevant data can help us assess the severity of the disease, decide the timing of treatment, and predict prognosis.

Degenerative Nucleus Pulposus Cells Derived Exosomes Promoted Cartilage Endplate Cells Apoptosis and Aggravated Intervertebral Disc Degeneration.

Intervertebral disc (IVD) degeneration is a complex multifactorial disease model, which pathogenesis has not been fully defined. There are few studies on the information interaction between nucleus pulposus (NP) cells and cartilage endplate (CEP) cells. Exosomes, as a carrier of information communication between cells, have become a research hotspot recently. The purpose of this study was to explore whether degenerative NP cells-derived exosomes promoted CEP cells apoptosis and aggravated IVD degeneration. The degenerative NP cells model was induced by TNFα. NPC exosomes were isolated from the supernatant of the NP cell culture medium. The viability of NP cells and CEP cells was examined by CCK-8 assays. The exosomes were identified by TEM, NTA, and western blot. Extracellular matrix (ECM) metabolism was measured by cellular immunofluorescence and qRT-PCR. Apoptosis was detected by flow cytometry and TUNEL. X-ray and magnetic resonance imaging (MRI), as well as hematoxylin-eosin (H&E), Safranine O-Green staining was adopted to evaluate IVD degeneration grades. TNFα had a minor impact on NPC viability but inhibited ECM synthesis and promoted ECM degradation. TNFα-NPC-Exo had less effect on CEPC proliferation but promoted CEPC apoptosis and affect ECM metabolism, inhibiting aggrecan and collagen II expression and enhancing MMP-3 expression. TNFα-NPC-Exo aggravates IVD degeneration in a rat model and promoted CEPC apoptosis. In conclusion, this study demonstrated that degenerated NPC-exosome could induce apoptosis of CEPCs, inhibit ECM synthesis, and promote ECM degradation. In addition, it was proved that degenerated NPC-exosome aggravates IVD degeneration.

Association between plasma free fatty acid levels and primary angle-closure glaucoma based on a mass spectrometry metabolomics analysis.

PURPOSE: To determine the association between plasma free fatty acid (FFA) levels and primary angle-closure glaucoma (PACG). METHODS: Free fatty acid (FFA) levels in patients with PACG (n = 181) and people without glaucoma (n = 340) were compared. Twenty-two FFAs and six lipid classes were measured using metabolomics analysis. Odds ratio (OR) of these metabolites and their 95% confidence intervals (95%CI) for PACG were obtained by logistic regression. Stepwise forward selection was performed to identify FFAs that influenced PACG risk. Areas under the curve (AUC) were applied to assess the predictive performance. Spearman's rank correlation was used to assess the relationship between ocular parameters and FFAs. RESULTS: Most FFAs in the PACG group were lower than those in the non-glaucoma group. Docosahexaenoic acid (DHA; OR for fourth quartile (Q4) vs. first quartile (Q1): 0.32 (0.16-0.66); per standard deviation (SD) increase: 0.64 (0.49-0.83); p for trend: 0.0007) and total saturated fatty acids (SFAs; OR for Q4 versus Q1: 0.27 (0.13-0.56); per SD increase: 0.65 (0.50-0.87); p for trend: 0.0004) were associated with decreased PACG risk. The AUC of the model that included DHA, total SFAs, demographic and ophthalmic factors increased from 0.8230 (0.7811-0.8649) to 0.8512 (0.8133-0.8891) (increased AUC: 0.0282 (0.0112-0.0453); p for increased AUC: 0.0012). Additionally, the cup-disc ratio had a weak negative correlation with DHA and total SFAs (DHA: r = -0.12085, p = 0.0065; total SFAs: r = -0.13318, p = 0.0024). CONCLUSIONS: Decrease in FFA levels may be related to lipid peroxidation. Docosahexaenoic acid (DHA) and total SFAs may be screening indices for PACG patients.

The role of endplate injury in intervertebral disc degeneration after vertebral augmentation in OVCF patients.

Background: Whether vertebral augmentation can induce or aggravate the degeneration of adjacent intervertebral discs remains controversial. The purpose of this study is to explore the role of endplate injury in intervertebral disc degeneration after vertebral augmentation. Methods: The imaging data of patients with single-segment osteoporotic vertebral compression fractures (OVCFs) were retrospectively analyzed. The upper and lower discs of the fractured vertebrae were defined as cranial and caudal discs, and the discs adjacent to the cranial discs were defined as control discs. According to the integrity of the cranial and caudal endplates, they were divided into an injury group and a noninjury group. At follow-up, the increase in the modified Pfirrmann score on MRI compared with the baseline grade was defined as the occurrence of a degenerative disc change (DDC). The changes in the disc height and the number of DDC cases on MRI during the follow-up in each group were analyzed. Results: A total of 56 patients with OVCFs were included in this study, with an average follow-up time of 18.8 ± 14.1 months (3-62 months). In the cranial and caudal discs, the number of DDC cases in the endplate injury group was significantly higher than that in the noninjury group (P = 0.007 and P = 0.018). However, the number of DDC cases in the whole endplate injury group (including the cranial and caudal endplates) was significantly higher than that of the whole noninjury group (P = 0.000) and the control group (P = 0.000). The number of DDC cases in the whole noninjury group was not different from that of the control group (P = 0.192). At follow-up, the disc height of the cranial and caudal endplate injury group was significantly lower than the baseline (P = 0.000 and P = 0.001), but the disc height of the noninjury group was not significantly lower than the baseline (P = 0.074 and P = 0.082). Conclusion: Endplate injury is associated with adjacent intervertebral disc degeneration in OVCF patients after vertebral augmentation. Evaluation of endplate damage before vertebral enhancement in OVCF patients has an important reference value for predicting the outcome of adjacent intervertebral discs after surgery.

Development and Verification of an Immune-Related Gene Pairs Prognostic Signature in Hepatocellular Carcinoma.

With the increasing prevalence of Hepatocellular carcinoma (HCC) and the poor prognosis of immunotherapy, reliable immune-related gene pairs (IRGPs) prognostic signature is required for personalized management and treatment of patients. Gene expression profiles and clinical information of HCC patients were obtained from the TCGA and ICGC databases. The IRGPs are constructed using immune-related genes (IRGs) with large variations. The least absolute shrinkage and selection operator (LASSO) regression analysis was used to construct IRGPs signature. The IRGPs signature was verified through the ICGC cohort. 1,309 IRGPs were constructed from 90 IRGs with high variability. We obtained 50 IRGPs that were significantly connected to the prognosis and constructed a signature that included 17 IRGPs. In the TCGA and ICGC cohorts, patients were divided into high and low-risk patients by the IRGPs signature. The overall survival time of low-risk patients is longer than that of high-risk patients. After adjustment for clinical and pathological factors, multivariate analysis showed that the IRGPs signature is an independent prognostic factor. The Receiver operating characteristic (ROC) curve confirmed the accuracy of the signature. Besides, gene set enrichment analysis (GSEA) revealed that the signature is related to immune biological processes, and the immune microenvironment status is distinct in different risk patients. The proposed IRGPs signature can effectively assess the overall survival of HCC, and provide the relationship between the signature and the reactivity of immune checkpoint therapy and the sensitivity of targeted drugs, thereby providing new ideas for the diagnosis and treatment of the disease.

LncRNA Snhg1-driven self-reinforcing regulatory network promoted cardiac regeneration and repair after myocardial infarction.

Rationale: Most current cardiac regeneration approaches result in very limited cell division and little new cardiomyocyte (CM) mass. Positive feedback loops are vital for cell division, but their role in CM regeneration remains unclear. We aimed to determine whether the lncRNA small nucleolar RNA host gene 1 Snhg1 (Snhg1) could form a positive feedback loop with c-Myc to induce cardiac regeneration. Methods: Quantitative PCR and in situ hybridization experiments were performed to determine the Snhg1 expression patterns in fetal and myocardial infarction (MI) hearts. Gain- and Loss-of-function assays were conducted to explore the effect of Snhg1 on cardiomyocyte (CM) proliferation and cardiac repair following MI. We further constructed CM-specific Snhg1 knockout mice to confirm the proliferative effect exerted by Snhg1 using CRISPR/Cas9 technology. RNA sequencing and RNA pulldown were performed to explore how Snhg1 mediated cardiac regeneration. Chromatin immunoprecipitation and luciferase reporter assays were used to demonstrate the positive feedback loop between Snhg1 and c-Myc. Results: Snhg1 expression was increased in human and mouse fetal and myocardial infarction (MI) hearts, particularly in CMs. Overexpression of Snhg1 promoted CM proliferation, angiogenesis, and inhibited CM apoptosis after myocardial infarction, which further improved post-MI cardiac function. Antagonism of Snhg1 in early postnatal mice inhibited CM proliferation and impaired cardiac repair after MI. Mechanistically, Snhg1 directly bound to phosphatase and tensin homolog (PTEN) and induced PTEN degradation, activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway to promote CM proliferation. The c-Myc protein, one of downstream targets of PI3K/AKT signaling, functioned as a transcription factor by binding to the promoter regions of Snhg1. Perturbation of the positive feedback between Snhg1 and c-Myc by mutation of the binding sequence significantly affected Snhg1-induced CM proliferation. Conclusions: Snhg1 effectively elicited CM proliferation and improved cardiac function post-MI by forming a positive feedback loop with c-Myc to sustain PI3K/Akt signaling activation, and thus may be a promising cardiac regeneration strategy in treating heart failure post-MI.

Association and histological characteristics of endplate injury and intervertebral disc degeneration in a rat model.

INTRODUCTION: The purpose of this study was to construct a rat caudal vertebral body fracture model and to analyze the association and histological characteristics of vertebral body fracture with endplate injury and adjacent intervertebral disc degeneration. MATERIALS AND METHODS: This study included 144 clean-grade male Sprague-Dawley rats, which were randomly divided into a control, middle vertebral body injury (MI), and endplate injury (EI) groups. A vertebral body fracture with or without endplate injury was developed by either drilling a hole in the middle of a rat caudal vertebral body to create a fracture with an intact endplate or drilling a hole in the vertebral body near the intervertebral disc to create a vertebral body fracture with endplate injury. The histological differences in the adjacent intervertebral discs of vertebral body fractures with or without endplate injury were detected using imaging, non-specific histological staining, immunohistochemistry and TUNEL assay. RESULTS: Imaging results revealed that the EI group showed a significant decrease in intervertebral space height and intervertebral disc T2 signal over time. Non-specific histological staining revealed that in the EI group, the intervertebral disc was degenerative. Immunohistochemistry indicated that Aggrecan and Collagen-II were decreased and inflammatory factors were increased in the EI group. The TUNEL detection found that apoptosis was significantly increased in the EI group as compared with the MI and control groups. CONCLUSION: In rat caudal vertebral body fractures, a fracture with endplate injury is more likely to induce or accelerate degeneration of adjacent intervertebral discs.

Percutaneous Vertebroplasty Versus Kyphoplasty for Thoracolumbar Osteoporotic Vertebral Compression Fractures in Patients with Distant Lumbosacral Pain.

BACKGROUND: In clinical practice, we have found that the pain caused by thoracolumbar osteoporotic vertebral compression fracture (OVCF) is sometimes not limited to the level of the fractured vertebrae but instead occurs in areas far away from the injured vertebrae, such as the lower back, area surrounding the iliac crest, or buttocks, and this type of pain is known as distant lumbosacral pain. The pathogenesis of pain in distant regions caused by thoracolumbar OVCF remains unclear. OBJECTIVES: To compare the clinical efficacy and imaging outcomes of percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP) in the treatment of distant lumbosacral pain accompanied by thoracolumbar OVCF and to explore the possible pathogenesis of distant lumbosacral pain caused by thoracolumbar OVCF. STUDY DESIGN: Retrospective study. SETTING: A university hospital spinal surgery departments. METHODS: A total of 62 patients who underwent vertebral augmentation for thoracolumbar OVCF with lumbosacral pain were included and divided into the PVP group (28 cases) and the PKP group (34 cases). The Visual Analog Scale (VAS) was used to evaluate the severity of local and distant lumbosacral pain, and the Chinese modified Oswestry Disability Index (CMODI) was used for functional assessment. The anterior vertebral height (AVH) of the fractured vertebrae and local kyphotic angle were measured on plain radiographs. The average follow-up time was 28.62 ± 8.43 months in the PVP group and 29.22 ± 9.09 months in the PKP group. RESULTS: Within the 2 groups, the VAS score of local pain, VAS score of distant lumbosacral pain, and CMODI score at 3 days postoperatively and at the last follow-up improved significantly compared with the scores before surgery. However, there was no significant difference between the 2 groups. At 3 days postoperatively and at last follow-up, the AVH and Cobb angle in the 2 groups improved significantly compared with those before surgery, but the magnitudes of AVH improvement and Cobb angle correction were significantly larger in the PKP group than in the PVP group. LIMITATIONS: First, this study is retrospective and may be prone to selection bias. Second, because of cultural and linguistic differences, the original version of the Oswestry Disability Index could not be properly understood and completed by people in mainland China. Therefore in this study, the CMODI was used, but the correlation coefficients of the CMODI within and between groups were 0.953 and 0.912, respectively. Third, a pain diagram was not used to accurately reflect the location of pain in the distant lumbosacral region. CONCLUSIONS: Both PVP and PKP can effectively alleviate pain in the distant lumbosacral region caused by thoracolumbar OVCF, and distant lumbosacral pain associated with thoracolumbar OVCF may be considered vertebrogenic referred pain.

Screening of osteoarthritis diagnostic markers based on immune-related genes and immune infiltration.

Osteoarthritis (OA) is a chronic degenerative disease of the bone and joints. Immune-related genes and immune cell infiltration are important in OA development. We analyzed immune-related genes and immune infiltrates to identify OA diagnostic markers. The datasets GSE51588, GSE55235, GSE55457, GSE82107, and GSE114007 were downloaded from the Gene Expression Omnibus database. First, R software was used to identify differentially expressed genes (DEGs) and differentially expressed immune-related genes (DEIRGs), and functional correlation analysis was conducted. Second, CIBERSORT was used to evaluate infiltration of immune cells in OA tissue. Finally, the least absolute shrinkage and selection operator logistic regression algorithm and support vector machine-recurrent feature elimination algorithm were used to screen and verify diagnostic markers of OA. A total of 711 DEGs and 270 DEIRGs were identified in this study. Functional enrichment analysis showed that the DEGs and DEIRGs are closely related to cellular calcium ion homeostasis, ion channel complexes, chemokine signaling pathways, and JAK-STAT signaling pathways. Differential analysis of immune cell infiltration showed that M1 macrophage infiltration was increased but that mast cell and neutrophil infiltration were decreased in OA samples. The machine learning algorithm cross-identified 15 biomarkers (BTC, PSMD8, TLR3, IL7, APOD, CIITA, IFIH1, CDC42, FGF9, TNFAIP3, CX3CR1, ERAP2, SEMA3D, MPO, and plasma cells). According to pass validation, all 15 biomarkers had high diagnostic efficacy (AUC > 0.7), and the diagnostic efficiency was higher when the 15 biomarkers were fitted into one variable (AUC = 0.758). We developed 15 biomarkers for OA diagnosis. The findings provide a new understanding of the molecular mechanism of OA from the perspective of immunology.

Development of Personalized Signature Based on the Immune Landscape to Predict the Prognosis of Osteosarcoma and the Response to Immunotherapy and Targeted Therapy.

As a heterogeneous and aggressive disease, osteosarcoma (OS) faces great challenges to prognosis and individualized treatment. Hence, we explore the role of immune-related genes in predicting prognosis and responsiveness to immunotherapy and targeted therapies in patients with OS based on the immunological landscape of osteosarcoma. Based on the database of the Therapeutical Applicable Research to Generate Effective Treatments (TARGET), single-sample gene set enrichment analysis (ssGSEA) was used to obtain the enrichment scores of 29 immune characteristics. A series of bioinformatics methods were performed to construct the immune-related prognostic signature (IRPS). Gene set enrichment analysis and gene set variation analysis were used to explore the biological functions of IRPS. We also analyzed the relationship between IRPS and tumor microenvironment. Lastly, the reactivity of IRPS to immune checkpoint therapy and targeted drugs was explored. The ssGSEA algorithm was used to define two immune subtypes, namely Immunity_High and Immunity_Low. Immunity_High was associated with a good prognosis and was an independent prognostic factor of OS. The IRPS containing 7 genes was constructed by the least absolute shrinkage and selection operator Cox regression. The IRPS can divide patients into low- and high-risk patients. Compared with high-risk patients, low-risk patients had a better prognosis and were positively correlated with immune cell infiltration and immune function. Low-risk patients benefited more from immunotherapy, and the sensitivity of targeted drugs in high- and low-risk groups was determined. IRPS can be used to predict the prognosis of OS patients, and provide therapeutic responsiveness to immunotherapy and targeted therapy.

Decreased plasma n6 : n3 polyunsaturated fatty acids ratio interacting with high C-peptide promotes non-alcoholic fatty liver disease in type 2 diabetes patients.

AIMS/INTRODUCTION: To explore relationships between polyunsaturated fatty acids (PUFA) and non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes, and whether insulin action has an interactive effect with PUFA on NAFLD progression. MATERIALS AND METHODS: We extracted clinical and omics data of 482 type 2 diabetes patients from a tertiary hospital consecutively from April 2018 to April 2019. NAFLD was estimated by ultrasound at admission. Plasma fasting n3 and n6 fatty acids were quantified by liquid chromatography-tandem mass spectrometry analysis. Restricted cubic spline nested in binary logistic regression was used to select the cut-off point, and estimate odds ratios and 95% confidence intervals. Additive interactions of the n6 : n3 ratio with insulin action for NAFLD were estimated using relative excess risk due to interaction, attributable proportion due to interaction and synergy index. Relative excess risk due to interaction >0, attributable proportion due to interaction >0 or synergy index >1 indicates biological interaction. Spearman correlation analysis was used to obtain partial correlation coefficients between PUFA and hallmarks of NAFLD. RESULTS: Of 482 patients, 313 were with and 169 were without NAFLD. N3 ≥800 and n6 PUFA ≥8,100 µmol/L were independently associated with increased NAFLD risk; n6 : n3 ratio ≤10 was associated with NAFLD (odds ratio 1.80, 95% confidence interval 1.20-2.71), and the effect size was amplified by high C-peptide (odds ratio 8.89, 95% confidence interval 4.48-17.7) with significant interaction. The additive interaction of the n6 : n3 ratio and fasting insulin was not significant. CONCLUSION: Decreased n6 : n3 ratio was associated with increased NAFLD risk in type 2 diabetes patients, and the effect was only significant and amplified when there was the co-presence of high C-peptide.

Interactive effects of asparagine and aspartate homeostasis with sex and age for the risk of type 2 diabetes risk.

BACKGROUND: Asparagine and aspartate homeostasis are linked with type 2 diabetes (T2D). This study aimed to explore whether asparagine and aspartate metabolism interacted with sex and age to increase the risk of T2D. METHODS: From 27 May 2015 to 3 August 2016, we consecutively retrieved 1032 T2D patients and 1522 subjects without T2D from a tertiary care hospital in Liaoning, China. Restricted cubic spline nested in the logistic regression was used to draw odds ratio curves of plasma asparagine to aspartate ratio for T2D by sex and age. Cut-off point was selected where curves went apart, indicating possible interaction. Addictive interactions of asparagine to aspartate ratio with sex or age and secondary interaction with copresence of unfavorable sex and age were further estimated using relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (S). RESULTS: Ratio of asparagine to aspartate > 1.5 was associated with elevated risk of T2D (OR 7.99, 95%CI 5.50 to 11.6), which was enhanced by female gender to 13.6, (95%CI 8.10-22.9) and by > 50 years of age to 28.7 (14.6-56.3), with significant additive interactions. There was a significant secondary-interaction of copresence of female sex and > 50 years of age with high asparagine to aspartate ratio for increased T2D risk with the OR being further increased to 34.4 (20.5-57.5). CONCLUSIONS: High asparagine to aspartate ratio was associated with markedly increased risk of T2D, which was further amplified by either female gender or > 50 years of age, and especially both.

Plasma phenylalanine and tyrosine and their interactions with diabetic nephropathy for risk of diabetic retinopathy in type 2 diabetes.

OBJECTIVE: Tight control of hyperglycemia reduces risk of diabetic retinopathy (DR), but the residual risk remains high. This study aimed to explore relationships between plasma phenylalanine and tyrosine with DR in type 2 diabetes (T2D) and interactions between the two amino acids, and their secondary interaction with renal dysfunction. RESEARCH DESIGN AND METHODS: We extracted data of 1032 patients with T2D from tertiary hospital consecutively from May 2015 to August 2016. Binary logistic regression models with restricted cubic spline were used to check potential non-linear associations and to obtain ORs and 95% CIs of variables under study. Addictive interaction was estimated using relative excess risk due to interaction, attributable proportion due to interaction and synergy index. Area under the receiver operating characteristic curve was used to check increased predictive values. RESULTS: Of 1032 patients, 162 suffered from DR. Copresence of low phenylalanine and low tyrosine increased DR risk (OR 6.01, 95% CI 1.35 to 26.8), while either of them alone did not have a significant effect with significant additive interaction. Presence of diabetic nephropathy further increased the OR of copresence of low phenylalanine and low tyrosine for DR to 25.9 (95% CI 8.71 to 76.9) with a significant additive interaction. Inclusion of phenylalanine and tyrosine in a traditional risk factor model significantly increased area under the curve from 0.81 to 0.83 (95% CI 0.80 to 0.86). CONCLUSION: Plasma low phenylalanine and low tyrosine worked independently and synergistically to increase the risk of DR in T2D. Presence of renal dysfunction further amplified the effect of copresence of low phenylalanine and low tyrosine on DR risk.

Analysis and improvement of the three-column spinal theory.

BACKGROUND: Denis and Ferguson et al.'s three-column spinal theory has been widely accepted and applied. However, this three-column theory was proposed based solely on observation and experience without thorough documented data and analysis. The aim of this study was to analyze and improve Denis and Ferguson et al.'s three-column spinal theory to propose a novel three-column concept in epidemiology, morphology and biomechanics. METHODS: A retrospective analysis of the computed tomography imaging data of patients with a diagnosis of T11-L5 vertebral fractures was conducted between February 2010 and December 2018. Three-dimensional (3D) distribution maps of fracture lines of all subjects were obtained based on 3D mapping techniques. In addition, a 25-year-old health male volunteer was recruited for the vertebral finite element force analysis. RESULTS: The present study enrolled 459 patients (age: 48 ± 11.42 years), containing a total of 521 fractured vertebrae. The fracture lines peaked in the upper and the outer third sections of the vertebra, starting from the anterior part of the vertebral pedicles in 3-D maps. Regarding flexion and extension of the spine, the last third of the vertebral body in front of the spinal canal was one main stress center in the finite element analysis. The stress on the vertebral body was greater in front of the pedicles in the lateral bending. CONCLUSION: The study reveals that the posterior one-third of the vertebral body in front of the spinal canal and the posterior one-third of the vertebral body in front of the pedicle are very different in terms of fracture characteristics and risks to spinal canal (3D maps and stress distributing graphs), therefore, they should be classified as different columns. We provide strong evidence that Su's three-column theory complies with the characteristics of vertebral physiological structure, vertebral fracture, and vertebral biomechanics.

Lumbar disc rehydration in the bridged segment using the BioFlex dynamic stabilization system: A case report and literature review.

BACKGROUND: In recent years, the mechanical concept of intervertebral disc regeneration has become more and more popular due to the increasing awareness of the importance of preservation of spine movement. Interestingly, there is increasing evidence, however, that dynamic stabilization systems may compensate non-physiological loads, limit pathological movement, normalize disc height and intradiscal pressure, and provide an adaptive environment for disc regeneration. CASE SUMMARY: The patient was a 54-year-old man, who presented with a 10-year history of mechanical back pain, which had become progressively serious and radiated into the left lower limb with numbness 3 mo prior. He had decreased muscle strength (class IV) of the left dorsal extensor and plantar flexor. Magnetic resonance imaging scans showed L3-S1 disc degeneration and L4-L5 disc herniation. Because the patient did not respond to various conservative treatments, he underwent a posterior L4-5 discectomy with fixation of the BioFlex dynamic stabilization system (Bio-Spine, Seoul, Korea). Preoperative symptoms were relieved and lumbar function was markedly improved after the operation. L4-L5 disc rehydration of instrumented segment was noted on magnetic resonance imaging at the 2-year follow-up. CONCLUSION: Rehydration of the degenerated disc in our patient indicates that the BioFlex dynamic stabilization system may promote disc regeneration. Further research is needed to provide more evidence to support lumbar disc rehydration in the bridged segment using this system.