Deciphering Immune Landscape Remodeling Unravels the Underlying Mechanism for Synchronized Muscle and Bone Aging.

Evidence from numerous studies has revealed the synchronous progression of aging in bone and muscle; however, little is known about the underlying mechanisms. To this end, human muscles and bones are harvested and the aging-associated transcriptional dynamics of two tissues in parallel using single-cell RNA sequencing are surveyed. A subset of lipid-associated macrophages (triggering receptor expressed on myeloid cells 2, TREM2+ Macs) is identified in both aged muscle and bone. Genes responsible for muscle dystrophy and bone loss, such as secreted phosphoprotein 1 (SPP1), are also highly expressed in TREM2+ Macs, suggesting its conserved role in aging-related features. A common transition toward pro-inflammatory phenotypes in aged CD4+ T cells across tissues is also observed, activated by the nuclear factor kappa B subunit 1 (NFKB1). CD4+ T cells in aged muscle experience Th1-like differentiation, whereas, in bone, a skewing toward Th17 cells is observed. Furthermore, these results highlight that degenerated myocytes produce BAG6-containing exosomes that can communicate with Th17 cells in the bone through its receptor natural cytotoxicity triggering receptor 3 (NCR3). This communication upregulates CD6 expression in Th17 cells, which then interact with TREM2+ Macs through CD6-ALCAM signaling, ultimately stimulating the transcription of SPP1 in TREM2+ Macs. The negative correlation between serum exosomal BCL2-associated athanogene 6 (BAG6) levels and bone mineral density further supports its role in mediating muscle and bone synchronization with aging.

Promoting postoperative recovery in patients with metastatic epidural spinal cord compression based on the concept of ERAS: a multicenter analysis of 304 patients.

BACKGROUND CONTEXT: Enhanced recovery after surgery (ERAS) has proven beneficial for patients undergoing orthopedic surgery. However, the application of ERAS in the context of metastatic epidural spinal cord compression (MESCC) remains undefined. PURPOSE: This study aims to establish a medical pathway rooted in the ERAS concept, with the ultimate goal of scrutinizing its efficacy in enhancing postoperative outcomes among patients suffering from MESCC. STUDY DESIGN/SETTING: An observational cohort study. PATIENT SAMPLE: A total of 304 patients with MESCC who underwent surgery were collected between January 2016 and January 2023 at two large tertiary hospitals. OUTCOME MEASURES: Surgery-related variables, patient quality of life, and pain outcomes. Surgery-related variables in the study included surgery time, surgery site, intraoperative blood loss, and complication. METHODS: From January 2020 onwards, ERAS therapies were implemented for MESCC patients in both institutions. Thus, the ERAS cohort included 138 patients with MESCC who underwent surgery from January 2020 to January 2023, whereas the traditional cohort consisted of 166 patients with MESCC who underwent surgery from January 2016 to December 2019. Clinical baseline characteristics, surgery-related features, and surgical outcomes were collected. Patient quality of life was evaluated using the Functional Assessment of Cancer Therapy-General Scale (FACT-G), and pain outcomes were assessed using the Visual Analogue Scale (VAS). RESULTS: Comparison of baseline characteristics revealed that the two cohorts were similar (all p>.050), indicating comparable distribution of clinical characteristics. In terms of surgical outcomes, patients in the ERAS cohort exhibited lower intraoperative blood loss (p<.001), shorter postoperative hospital stays (p<.001), lower perioperative complication rates (p=.020), as well as significantly shorter time to ambulation (P<0.001), resumption of regular diet (p<.001), removal of urinary catheter (p<.001), initiation of radiation therapy (p<.001), and initiation of systemic internal therapy (p<.001) compared with patients in the traditional cohort. Regarding pain outcomes and quality of life, patients undergoing the ERAS program demonstrated significantly lower VAS scores (p<.010) and higher scores for physical (p<.001), social (p<.001), emotional (p<.001), and functional (p<.001) well-being compared with patients in the traditional cohort. CONCLUSIONS: The ERAS program, renowned for its ability to expedite postoperative recuperation, emerges as a promising approach to ameliorate the recovery process in MESCC patients. Not only does it exhibit potential in enhancing pain management outcomes, but it also holds the promise of elevating the overall quality of life for these individuals. Future investigations should delve deeper into the intricate components of the ERAS program, aiming to unravel the precise mechanisms that underlie its remarkable impact on patient outcomes.

A New Treatment Strategy for Spinal Metastasis: The "Systemic Conditions, Effectiveness of Systemic Treatment, Neurology, and Oncology" Decision Framework System.

BACKGROUND AND OBJECTIVES: Treating metastatic spinal tumors poses a significant challenge because there are currently no universally applied guidelines for managing spinal metastases. This study aims to propose a new decision framework for the 12-point epidural spinal cord compression grading system to treat patients with metastatic spinal tumors and investigate its clinical effectiveness in a multicenter analysis. METHODS: This study analyzed 940 patients with metastatic spinal tumors between December 2017 and March 2023. The study provided the clinical evidence for the systemic conditions, effectiveness of systemic treatment, neurology, and oncology (SENO) decision framework among spine metastases. The SENO decision framework was launched in January 2021 in our hospitals, classifying patients into 2 groups: The non-SENO group (n = 489) consisted of patients treated between December 2017 and January 2021, while the SENO group (n = 451) comprised patients treated from January 2021 to March 2023. RESULTS: Patients in the SENO group were more likely to receive minimally invasive surgery (67.85% vs 58.69%) and less chance of receiving spinal cord circular decompression surgery (14.41% vs 24.74%) than patients in the non-SENO group ( P < .001). Furthermore, patients in the SENO group experienced fewer perioperative complications (9.09% vs 15.34%, P = .004), incurred lower hospitalization costs ( P < .001), had shorter length of hospitalization ( P < .001), and received systematic treatments for tumors earlier ( P < .001). As a result, patients in the SENO group (329.00 [95% CI: 292.06-365.94] days) demonstrated significantly improved survival outcomes compared with those in the non-SENO group (279.00 [95% CI: 256.91-301.09], days) ( P < .001). At 3 months postdischarge, patients in the SENO group reported greater improvements in their quality of life, encompassing physical, social, emotional, and functional well-being, when compared with patients in the non-SENO group. CONCLUSION: The SENO decision framework is a promising approach for treating patients with metastatic spinal tumors.

Development of a novel 12-point grading system for evaluating epidural spinal cord compression and its clinical implications.

BACKGROUND CONTEXT: The assessment of epidural spinal cord compression (ESCC) plays a crucial role in clinical decision-making, yet the current grading system lacks reliability and requires improvements. PURPOSE: The study aims to develop a reliable grading system for evaluating ESCC and to investigate its association with the neurological status of patients. STUDY DESIGN/SETTING: A prospective cohort study. PATIENT SAMPLE: A total of 330 patients with metastatic spinal disease were included in the study. OUTCOME MEASURES: The main outcome was the neurological status evaluated using the American Spinal Injury Association (ASIA) scale. METHODS: We proposed a novel grading system, called the 12-point ESCC grading system, to evaluate ESCC based on findings from spinal magnetic resonance imaging (MRI). This new grading system consists of 12 grades, ranging from Grade 0 to 3, with higher grades indicating more severe ESCC. The detailed information about the sagittal image of the spine and the severity of spinal cord swelling was considered in this new grading system. The Spearman correlation analysis and logistic regression analysis were employed to investigate the correlation between the previous 6-point grading system and ASIA, as well as between the new 12-point ESCC grading system and ASIA. The prediction effectiveness was evaluated using the area under curve (AUC) analysis. RESULTS: Patients with higher grades in the 12-point ESCC grading system exhibited a higher likelihood of experiencing a worse neurological condition. Specifically, patients with grades 2a to 2d and 3a to 3d according to the new 12-point ESCC grading system were significantly associated with more complete paralysis (p<.001) compared with patients with grade 0. The Spearman correlation coefficient was 0.729 between the previous 6-point ESCC grading system and ASIS and 0.750 between the new 12-point ESCC grading system and ASIS. When categorizing ASIS into complete paralysis and other neurological statuses, the 6-point ESCC score yielded an AUC of 0.820, which increased to 0.860 with the new 12-point ESCC grading system. Furthermore, when ASIS was divided into normal and abnormal neurological statuses, the AUC increased from 0.889 to 0.906. Additionally, spinal cord swelling was significantly associated with more complete paralysis (p<.001) and abnormal neurological status (p<.001) based on the new 12-point ESCC grading system. CONCLUSIONS: The new 12-point ESCC grading system provides more detailed information and further improves the prediction effectiveness for evaluating neurological status compared with the previous 6-point ESCC grading system. In the new 12-point ESCC grading system, higher grades or the presence of spinal cord swelling are indicative of a worse neurological condition.

Multi-Proteomic Analysis Reveals the Effect of Protein Lactylation on Matrix and Cholesterol Metabolism in Tendinopathy.

Tendinopathy is a disease with surging prevalence. Lacking understanding of molecular mechanisms impedes the development of therapeutic approaches and agents. Lysine lactylation (Kla) is a newly discovered post-translational modification related to glycolysis. It has long been noted that manipulation of glycolysis metabolism could affect tendon cell function, tendon homeostasis, and healing process of tendon. However, protein lactylation sites in tendinopathy remain unexplored. Here, we conducted the first proteome-wide Kla analysis in tendon samples harvested from patients with rotator cuff tendinopathy (RCT), which identified 872 Kla sites across 284 proteins. Compared with normal counterparts, 136 Kla sites on 77 proteins were identified as upregulated in the pathological tendon, while 56 sites on 32 proteins were downregulated. Function enrichment analysis demonstrated that the majority of proteins with upregulated Kla levels functioned in organization of the tendon matrix and cholesterol metabolism, accompanied by lower expression levels which meant impaired cholesterol metabolism and degeneration of the tendon matrix, indicating potential cross-talk between protein lactylation and expression levels. At last, by western blotting and immunofluorescence, we verified the correlation between high lactylation and the downregulation of matrix and cholesterol-related proteins including BGN, MYL3, TPM3, and APOC3. ProteomeXchange: PXD033146.

The antibacterial activity and mechanism of imidazole chloride ionic liquids on Staphylococcus aureus.

Ionic liquids (ILs) have garnered increasing attention in the biomedical field due to their unique properties. Although significant research has been conducted in recent years, there is still a lack of understanding of the potential applications of ILs in the biomedical field and the underlying principles. To identify the antibacterial activity and mechanism of ILs on bacteria, we evaluated the antimicrobial potency of imidazole chloride ILs (CnMIMCl) on Staphylococcus aureus (S. aureus). The toxicity of ILs was positively correlated to the length of the imidazolidinyl side chain. We selected C12MIMCl to study the mechanism of S. aureus. Through the simultaneous change in the internal and external parts of S. aureus, C12MIMCl caused the death of the bacteria. The production of large amounts of reactive oxygen species (ROS) within the internal parts stimulated oxidative stress, inhibited bacterial metabolism, and led to bacterial death. The external cell membrane could be destroyed, causing the cytoplasm to flow out and the whole cell to be fragmented. The antibacterial effect of C12MIMCl on skin abscesses was further verified in vivo in mice.

Ghost messages: cell death signals spread.

Cell death is a mystery in various forms. Whichever type of cell death, this is always accompanied by active or passive molecules release. The recent years marked the renaissance of the study of these molecules showing they can signal to and communicate with recipient cells and regulate physio- or pathological events. This review summarizes the defined forms of messages cells could spread while dying, the effects of these signals on the target tissue/cells, and how these types of communications regulate physio- or pathological processes. By doing so, this review hopes to identify major unresolved questions in the field, formulate new hypothesis worthy of further investigation, and when possible, provide references for the search of novel diagnostic/therapeutics agents. Video abstract.

Mechanisms of estrogen deficiency-induced osteoporosis based on transcriptome and DNA methylation.

Osteoporosis is a disease that impacts the elderly. Low estrogen is related to changes in DNA methylation and consequent alterations in gene expression, leading to a new direction in research related to the pathophysiology of osteoporosis. We constructed an Ovariectomized (OVX) mouse model in our study, and the mouse models had osteoporosis based on the phenotype and methylation levels in the mouse's bone. Furthermore, the methylation level of the OVX mice was significantly changed compared to that of SHAM mice. Therefore, we performed genome-level analysis on the mouse model using transcriptome and Whole Genome Bisulfite Sequencing (WGBS) by combining the data of two omics and discovered that the changes in gene expression level caused by osteoporosis primarily focused on the decrease of bone and muscle development and the activation of the immune system. According to intersection analysis of methylation and transcriptome data, the differentially expressed genes and pathways are consistent with the differentially expressed methylation locations and regions. Further, the differentially expressed methylation sites were mainly concentrated in promoters, exons, and other critical functional regions of essential differentially expressed genes. This is also the primary cause of gene differential expression variations, indicating that estrogen deficiency might regulate gene expression by altering methylation modification, leading to osteoporosis. We demonstrated the clinical value of methylation modification research, and these findings would improve the current understanding of underlying molecular mechanisms of osteoporosis incidence and development and provide new ideas for early detection and treatment of osteoporosis.

Bioinspired Polysaccharide-Derived Zwitterionic Brush-like Copolymer as an Injectable Biolubricant for Arthritis Treatment.

Developing highly efficient and biocompatible biolubricants for arthritis treatment is extraordinarily demanded. Herein, inspired by the efficient lubrication of synovial joints, a paradigm that combines natural polysaccharide (chitosan) with zwitterionic poly[2-(methacryloyloxy) ethyl phosphorylcholine] (PMPC), to design a series of brush-like Chitosan-g-PMPC copolymers with highly efficient biological lubrication and good biocompatibility is presented. The Chitosan-g-PMPC copolymers are prepared via facile one-step graft polymerization in aqueous medium without using any toxic catalysts and organic solvents. The as-prepared Chitosan-g-PMPC copolymers exhibit very low coefficient of friction (µ < 0.01) on Ti6 Al4 V alloy substrate in both pure water and biological fluids. The superior lubrication is attributed primarily to the hydrated feature of PMPC side chains, interface adsorption of copolymer as well as to the hydrodynamic effect. In vivo experiments confirm that Chitosan-g-PMPC can alleviate the swelling symptom of arthritis and protect the bone and cartilage from destruction. Due to their facile preparation, distinctive lubrication properties, and good biocompatibility, Chitosan-g-PMPC copolymers represent a new type of biomimetic lubricants derived from natural biopolymer for promising arthritis treatment and artificial joint lubrication.

Preoperative embolization in the treatment of patients with metastatic epidural spinal cord compression: A retrospective analysis.

Purpose: The purpose of the study was to assess the effectiveness and safety of preoperative embolization in the treatment of patients with metastatic epidural spinal cord compression (MESCC). Methods: A retrospective analysis of 138 MESCC patients who underwent decompressive surgery and spine stabilization was performed in a large teaching hospital. Among all enrolled patients, 46 patients were treated with preoperative embolization (the embolization group), whereas 92 patients did not (the control group). Patient's baseline clinical characteristics, surgery-related characteristics, and postoperative neurological status, complications, and survival prognoses were collected and analyzed. Subgroup analysis was performed according to the degree of tumor vascularity between patients with and without preoperative embolization. Results: Patients with severe hypervascularity experienced more mean blood loss in the control group than in the embolization group, and this difference was statistically significant (P=0.02). The number of transfused packed red cells (PRC) showed a similar trend (P=0.01). However, for patients with mild and moderate hypervascularity, both blood loss and the number of PRC transfusion were comparable across the two groups. Regarding decompressive techniques, the embolization group (64.29%, 9/14) had a higher proportion of circumferential decompression in comparison to the control group (30.00%, 9/30) among patients with severe hypervascularity (P=0.03), whereas the rates were similar among patients with mild (P=0.45) and moderate (P=0.54) hypervascularity. In addition, no subgroup analysis revealed any statistically significant differences in operation time, postoperative functional recovery, postoperative complications, or survival outcome. Multivariate analysis showed that higher tumor vascularity (OR[odds ratio]=3.69, 95% CI [confident interval]: 1.30-10.43, P=0.01) and smaller extent of embolization (OR=4.16, 95% CI: 1.10-15.74, P=0.04) were significantly associated with more blood loss. Conclusions: Preoperative embolization is an effective and safe method in treating MESCC patients with severe hypervascular tumors in terms of intra-operative blood loss and surgical removal of metastatic tumors. Preoperative tumor vascularity and extent of embolization are independent risk factors for blood loss during surgery. This study implies that MESCC patients with severe hypervascular tumors should be advised to undergo preoperative embolization.