Silencing of SIRPα enhances the antitumor efficacy of CAR-M in solid tumors.

The potential of macrophage-mediated phagocytosis as a cancer treatment is promising. Blocking the CD47-SIRPα interaction with a CD47-specific antibody significantly enhances macrophage phagocytosis. However, concerns regarding their toxicity to nontumor cells remain substantial. Here, we engineered chimeric antigen receptor macrophages (CAR-Ms) by fusing a humanized single-chain variable fragment with FcγRIIa and integrating short hairpin RNA to silence SIRPα, thereby disrupting the CD47-SIRPα signaling pathway. These modified CAR-shSIRPα-M cells exhibited an M1-like phenotype, superior phagocytic function, substantial cytotoxic effects on HER2-positive tumor cells, and the ability to eliminate patient-derived organoids. In vivo, CAR-M cells significantly inhibited tumor growth and prolonged survival in tumor-bearing mice. Notably, CAR-shSIRPα-M cells enhanced cytotoxic T-cell infiltration into tumors, thereby enhancing the antitumor response in both the humanized immune system mouse model and immunocompetent mice. Mechanistically, SIRPα inhibition activated inflammatory pathways and the cGAS-STING signaling cascade in CAR-M cells, leading to increased production of proinflammatory cytokines, reactive oxygen species, and nitric oxide, thereby enhancing their antitumor effects. These findings underscore the potential of SIRPα inhibition as a novel strategy to increase the antitumor efficacy of CAR-M cells in cancer immunotherapy, particularly against solid tumors.

Laponite modified methacryloyl gelatin hydrogel with controlled release of vascular endothelial growth factor a for bone regeneration.

Reconstruction of bone defects has long been a major clinical challenge. Limited by the various shortcomings of conventional treatment like autologous bone grafting and inorganic substitutes, the development of novel bone repairing strategies is on top priority. Injectable biomimetic hydrogels that deliver stem cells and growth factors in a minimally invasive manner can effectively promote bone regeneration and thus represent a promising alternative. Therefore, in this study, we designed and constructed an injectable nanocomposite hydrogel co-loaded with Laponite (Lap) and vascular endothelial growth factor (VEGF) through a simplified and convenient scheme of physical co-mixing (G@Lap/VEGF). The introduced Lap not only optimized the injectability of GelMA by the electrostatic force between the nanoparticles, but also significantly delayed the release of VEGF-A. In addition, Lap promoted high expression of osteogenic biomarkers in mesenchymal stem cells (MSCs) and enhanced the matrix mineralization. Besides, VEGF-A exerted chemotactic effects recruiting endothelial progenitor cells (EPCs) and inducing neovascularization. Histological and micro-CT results demonstrated that the critical-sized calvarial bone defect lesions in the SD rats after treated with G@Lap/VEGF exhibited significant in vivo bone repairing. In conclusion, the injectable G@Lap/VEGF nanocomposite hydrogel constructed in our study is highly promising for clinical transformation and applications, providing a convenient and simplified scheme for clinical bone repairing, and contributing to the further development of the injectable biomimetic hydrogels.

Weight-adjusted waist index is a potential early predictor of degraded bone microarchitecture: A cross-sectional study of the national health and nutrition examination survey 2007-2008.

PURPOSE: This study aimed to investigate the association between weight-adjusted waist index (WWI) and trabecular bone score (TBS) and to assess the ability of WWI to identify individuals with degraded bone microarchitecture (DBMA). METHODS: This cross-sectional study included participants aged 20 and older from the National Health and Nutrition Examination Survey. Furthermore, WWI was calculated by waist circumference and body weight. In addition, linear regression models were employed to investigate the association between WWI and TBS, while logistic regression models were employed to determine the association between WWI and the risk of DBMA. Finally, the performance of WWI in identifying individuals with DBMA was using the receiver operating characteristic (ROC) curves with area under the ROC curve. RESULTS: A total of 4,179 participants with a mean age of 49.90 years were included in the final analysis. WWI was negatively associated with TBS and positively associated with an increased risk of DBMA. Furthermore, the associations between WWI and TBS, as well as DBMA risk, were stable regardless of stratification by age, sex, race, or body mass index (BMI). Moreover, WWI achieved good performances in identifying individuals with DBMA or low TBS. In addition, the combination of WWI and BMI showed better performances in identifying individuals with DBMA or low TBS than WWI or BMI alone. CONCLUSION: WWI established a negative association with TBS and a positive association with the risk of DBMA. Clinicians should be alert to the potential risk of DBMA among individuals with high WWI. Moreover, WWI, alone or in combination with BMI, has the potential to serve as an early screening strategy in identifying individuals with DBMA.

DNAJC1 facilitates glioblastoma progression by promoting extracellular matrix reorganization and macrophage infiltration.

BACKGROUND: Glioblastoma (GBM) is a high-grade and heterogeneous subtype of glioma that presents a substantial challenge to human health, characterized by a poor prognosis and low survival rates. Despite its known involvement in regulating leukemia and melanoma, the function and mechanism of DNAJC1 in GBM remain poorly understood. METHODS: Utilizing data from the TCGA, CGGA, and GEO databases, we investigated the expression pattern of DNAJC1 and its correlation with clinical characteristics in GBM specimens. Loss-of-function experiments were conducted to explore the impact of DNAJC1 on GBM cell lines, with co-culture experiments assessing macrophage infiltration and functional marker expression. RESULTS: Our analysis demonstrated frequent overexpression of DNAJC1 in GBM, significantly associated with various clinical characteristics including WHO grade, IDH status, chromosome 1p/19q codeletion, and histological type. Moreover, Kaplan‒Meier and ROC analyses revealed DNAJC1 as a negative prognostic predictor and a promising diagnostic biomarker for GBM patients. Functional studies indicated that silencing DNAJC1 impeded cell proliferation and migration, induced cell cycle arrest, and enhanced apoptosis. Mechanistically, DNAJC1 was implicated in stimulating extracellular matrix reorganization, triggering the epithelial-mesenchymal transition (EMT) process, and initiating immunosuppressive macrophage infiltration. CONCLUSIONS: Our findings underscore the pivotal role of DNAJC1 in GBM pathogenesis, suggesting its potential as a diagnostic and therapeutic target for this challenging disease.

The role of ST3GAL4 in glioma malignancy, macrophage infiltration, and prognostic outcomes.

Background: Glioma, a prevalent malignancy of the brain and spinal cord, poses a considerable threat to human health. The association between aberrant sialic acid modification and glioma progression has been suggested, but the precise mechanism is still elusive. ST3GAL4, a sialoglycosyltransferase, is implicated in increased metastatic potential and poor prognosis in various cancers; however, its specific role in glioma requires further elucidation. Methods: We evaluated ST3GAL4 expression levels and their clinical relevance using the TCGA database, and we assessed immune infiltration via the Tumor Immune Evaluation Resource (TIMER) database. In vitro experiments were performed to determine the effects of ST3GAL4 knockdown on glioma cell malignancy, with additional co-culture assays to assess its impact on macrophage phenotype. Results: ST3GAL4 expression was markedly elevated in glioma tissues compared to normal brain tissues, with a strong correlation to glioma patient clinical characteristics. Survival analyses and receiver operating characteristic (ROC) curves suggested that ST3GAL4 is a feasible diagnostic and prognostic biomarker for glioma. Knockdown studies revealed that ST3GAL4 inhibition reduces glioma cell line proliferation, migration, and invasion, while causing G1 phase cell cycle arrest. ST3GAL4 appears to mediate glioma progression through extracellular matrix reorganization and EMT signaling pathway activation, further contributing to M2 macrophage polarization and infiltration within the tumor microenvironment. Conclusion: Our research highlights the critical role of ST3GAL4 in glioma development, positioning it as a promising candidate for diagnostic and therapeutic interventions.

Electric field induced the changes in structure and function of human transforming growth factor beta receptor type I: from molecular dynamics to docking.

The transforming growth factor beta (TGF-ß) signaling pathway is believed to play essential roles in several physiological activities, including cancer. TGF-ß receptor type I (TBR-I) is a key membrane receptor protein in the TGF-ß signaling pathway, which relates to many intracellular biological effects. In recent years, cold atmospheric plasma (CAP) has been found to have promising prospects in selective anticancer therapy and has confirmed its essential role in the TGF-ß signaling pathway. However, the ambiguous effect of CAP-induced electric field (EF) on TBR-I still limits the application of CAP in clinical therapy. Molecular dynamics is applied to assess the effect of EF on the structure of the extracellular domain of TBR-I using a series of indicators and methods, and then we discuss the ligand binding ability of TBR-I. Results show that moderate EF intensities' structural restraints may contribute to the structural stability and ligand-binding ability of TBR-I, but an EF higher than 0.1 V/nm will be harmful. What's more, EF induces a change in the docking interface of TBR-I, showing the conformation and position of special sequences of residues decide the ligand binding surface. The relevant results suggest that CAP-induced EF plays a crucial role in receptor-receptor interaction and provides significant guidelines for EF-related anticancer therapy.Communicated by Ramaswamy H. Sarma.

Ultrasound-guided versus fluoroscopy-guided lumbar selective nerve root block: a retrospective comparative study.

The purpose of this study is to compare the accuracy and effectiveness of ultrasound-guided and fluoroscopy-guided lumbar selective nerve root block (SNRB), and to explore the feasibility of ultrasound-guided methods. This retrospective study included patients with lumbar radicular pain who underwent ultrasound-guided and fluoroscopy-guided selective nerve root block at Honghui Hospital Affiliated to Xi'an Jiaotong University from August 2020 to August 2022. Patients were divided into U-SNRB group and F-SNRB group according to ultrasound-guided or fluoroscopy-guided selective nerve root block. There were 43 patients in U-SNRB group and 20 patients in F-SNRB group. The pain visual analogue scale (VAS) scores, Japanese Orthopaedic Association (JOA) scores, related indexes and complications were recorded and compared between the two groups before, 30 min, 1 month and 6 months after block. To evaluate the feasibility, accuracy and effectiveness of ultrasound-guided selective nerve root block. There were no complications in the process of selective nerve root block in both groups. The operating time and the times of closing needle angle adjustment in U-SNRB group were better than those in F-SNRB group, and the difference was statistically significant (P < 0.05). The VAS score and JOA score of patients in the two groups were significantly improved 30 min after block, 1 month and 6 months after block, and the difference was statistically significant (P < 0.05). There was no significant difference between the two groups (P > 0.05). The accuracy of ultrasound-guided selective nerve root block and the degree of pain relief of patients were similar to those of fluoroscopy guidance, but the operation time and needle angle adjustment times were significantly less than that of fluoroscopy, and could effectively reduce radiation exposure. Therefore, it can be used as a better way to guide for choice.

[Effectiveness of one-stage posterior eggshell osteotomy and long-segment pedicle screw fixation for ankylosing spondylitis kyphosis combined with acute thoracolumbar vertebral fracture].

Objective: To explore the safety and effectiveness of one-stage posterior eggshell osteotomy and long-segment pedicle screw fixation in the treatment of ankylosing spondylitis kyphosis combined with acute thoracolumbar vertebral fracture. Methods: A clinical data of 20 patients with ankylosing spondylitis kyphosis combined with acute thoracolumbar spine fracture, who were treated with one-stage posterior eggshell osteotomy and long-segment pedicle screw fixation between April 2016 and January 2022, was retrospectively analyzed. Among them, 16 cases were male and 4 cases were female; their ages ranged from 32 to 68 years, with an average of 45.9 years. The causes of injury included 10 cases of sprain, 8 cases of fall, and 2 cases of falling from height. The time from injury to operation ranged from 1 to 12 days, with an average of 7.1 days. The injured segment was T 11 in 2 cases, T 12 in 2 cases, L 1 in 6 cases, and L 2 in 10 cases. X-ray film and CT showed that the patients had characteristic imaging manifestations of ankylosing spondylitis, and the fracture lines were involved in the anterior, middle, and posterior columns and accompanied by different degrees of kyphosis and vertebral compression; and MRI showed that 12 patients had different degrees of nerve injuries. The operation time, intraoperative bleeding, intra- and post-operative complications were recorded. The visual analogue scale (VAS) score and Oswestry disability index (ODI) were used to evaluate the low back pain and quality of life, and the American spinal cord injury association (ASIA) classification was used to evaluate the neurological function. X-ray films were taken, and local Cobb angle (LCA) and sagittal vertical axis (SVA) were measured to evaluate the correction of the kyphosis. Results: All operations were successfully completed and the operation time ranged from 127 to 254 minutes (mean, 176.3 minutes). The amount of intraoperative bleeding ranged from 400 to 950 mL (mean, 722.5 mL). One case of dural sac tear occurred during operation, and no cerebrospinal fluid leakage occurred after repair, and the rest of the patients did not suffer from neurological and vascular injuries, cerebrospinal fluid leakage, and other related complications during operation. All incisions healed by first intention without infection or fat liquefaction. All patients were followed up 8-16 months (mean, 12.5 months). The VAS score, ODI, LCA, and SVA at 3 days after operation and last follow-up significantly improved when compared with those before operation ( P<0.05), and the difference between 3 days after operation and last follow-up was not significant ( P>0.05). The ASIA grading of neurological function at last follow-up also significantly improved when compared with that before operation ( P<0.05), including 17 cases of grade E and 3 cases of grade D. At last follow-up, all bone grafts achieved bone fusion, and no complications such as loosening, breaking of internal fixation, and pseudoarthrosis occurred. Conclusion: One-stage posterior eggshell osteotomy and long-segment pedicle screw fixation is an effective surgical procedure for ankylosing spondylitis kyphosis combined with acute thoracolumbar vertebral fracture. It can significantly relieve patients' clinical symptoms and to some extent, alleviate the local kyphotic deformity.

Assistive diagnostic indicators for infections related to lumbar posterior interbody fusion internal fixation: platelet count and mean platelet volume.

BACKGROUND: The most severe complication after posterior single-segment lumbar interbody fusion and internal fixation (PIFIF) surgery for degenerative lumbar diseases is deep surgical site infection (DSSI). Preoperatively diagnosing such complications proves to be challenging. Platelets, as acute-phase reactants, undergo changes in response to infections and inflammation. This study aims to assess whether platelet indices can further aid in the diagnosis of DSSI. METHODS: A single-center retrospective study was conducted from January 2016 to February 2021 at Xi'an Jiaotong University-Affiliated Honghui Hospital, involving 83 patients who underwent revision surgery after PIFIF due to lumbar degenerative diseases. Among them, 24 patients were diagnosed with DSSI based on combined bacterial culture and imaging data. Preoperative complete serological indicators including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and platelet count and mean platelet volume ratio (P/M ratio) were analyzed using receiver operating characteristic (ROC) curve analysis to determine cutoff values, sensitivity, and specificity. This was done to further assess the ability of these serological indicators to identify the occurrence of DSSI after PIFIF. RESULTS: There were no significant differences in baseline demographic characteristics between the two patient groups (P > 0.05). The P/M ratio was 13.54 ± 5.05 in the aseptic revision group, while it was 19.21 ± 6.30 in the DSSI revision patients, showing a significant difference (P < 0.001). ROC curve analysis revealed that the optimal cutoff value for the P/M ratio was 17.50, with a sensitivity of 58.3% and a specificity of 78.6%. The areas under the curve (AUC) for ESR, CRP, and P/M ratio were 0.797, 0.845, and 0.756, respectively. The negative predictive value (NPV) was 87.04%, 89.47%, and 82.45%, respectively; the positive predictive value (PPV) was 58.62%, 69.23%, and 53.84%, respectively, for ESR, CRP, and P/M ratio, respectively. When P/M ratio is used in combination with ESR and CRP, the AUC is 0.887, with a sensitivity of 95.4%, specificity of 67.8%, NPV of 97.56%, PPV of 54.76%. The diagnostic performance of the model for evaluating DSSI is significantly improved compared to using ESR and CRP alone (P < 0.05). CONCLUSION: Platelets and their related serum biomarkers are closely associated with DSSI. The P/M ratio can serve as a reliable test for screening DSSI and is worth considering for inclusion in the assessment of patients at risk of developing DSSI after potential PIFIF surgery.

KDELR2 as a diagnostic and prognostic biomarker of bladder urothelial carcinoma and its correlation with immune infiltration.

KDELR2 has been reported as a promotive factor for the genesis and progression of several malignancies. However, it is uncertain how it affects bladder urothelial carcinoma (BLCA). Using data extracted from online databases, an enhanced expression of KDELR2 in BLCA tissues was verified. Overexpression of KDELR2 was correlated with advanced clinicopathologic characteristics and unfavourable prognosis of BLCA. Receiver operating characteristic analysis highlighted the potential diagnostic value of KDELR2. Univariate and multivariate logistic regression analyses further revealed the predictive effect of KDELR2 for the prognosis of BLCA. KDELR2 was primarily enriched in biological functions related to organization of the extracellular matrix. TIMER, ssGSEA and GEPIA analyses suggested that KDELR2 expression is positively related to the infiltration of macrophages, Th2 cells and neutrophils. Finally, knocking-down of KDELR2 in T24 cells resulted in reduced proliferation, migration and macrophages recruitment. These results suggest that KDELR2 overexpression is an indicator for poor prognosis of BLCA and it has the potential to be employed as an immunotherapy target for BLCA.

A Novel Technology for 3D-Printing Artificial Vertebral Bodies for Treating Lumbar Spine Adrenal Pheochromocytoma Metastases: A Case Report and Review of the Literature.

BACKGROUND: Pheochromocytoma is an adrenal medullary neuroendocrine tumor that rarely metastasizes to the spine. Currently, its specific treatment methods still present challenges. CASE DESCRIPTION: A 41-year-old male patient who underwent left total adrenalectomy due to pheochromocytoma 3 years ago presented with lower back pain, accompanied by numbness and decreased muscle strength in both legs, as well as decreased sensation. Abnormal transmittance of the L3 vertebral body could be seen on anterior-posterior and lateral lumbar X-rays, irregular bone destruction of the L3 vertebral body was found on CT, and an MRI scan showed that the tumor was located within the L3 vertebral body, protruding into the spinal canal and compressing the epidural sac. No recurrence was found in the abdomen. Preoperatively, perform local embolization of the blood vessels supplying the tumor. First, the L2-3 intervertebral disc, L3-4 intervertebral disc and L3 vertebral body were removed using an anterior approach, the whole tumor was removed, and some of the vertebrae were taken for pathological examination and replaced with a 3D-printed prosthesis. Then, four pedicle screws were placed in the bilateral pedicles of L2 and L4 using the posterior approach, pre-bent connecting rods were installed to replace the bone cortex of the lamina and articular process followed by bone graft fusion of the interlaminar and facet joints. The postoperative results were satisfactory, and there were no perioperative complications. CONCLUSION: Lumbar pheochromocytoma metastasis is rare, difficult to treat, and should be considered in spinal metastases' differential diagnoses so early diagnosis can be made based on medical history and imaging. Preoperative local vascular imaging and embolization of the blood supply vessels were performed. After total en-bloc spondylectomy of the tumor during surgery, a prosthesis was implanted and combined with pedicle screw fixation to reconstruct spinal biomechanical stability, achieving satisfactory results. Therefore, 3D printed artificial vertebral bodies are a good choice for treating adrenal pheochromocytoma lumbar metastasis. The key to successful treatment is close interdisciplinary collaboration in formulating rigorous comprehensive perioperative plans.

M1 polarization enhances the antitumor activity of chimeric antigen receptor macrophages in solid tumors.

BACKGROUND: Chimeric antigen receptor macrophage (CAR-M) therapy is a novel cancer immunotherapy approach that integrates CAR structure and macrophage functions. CAR-M therapy has shown unique and impressive antitumor effects in immunotherapy for solid tumors. However, the polarization state of macrophages can affect the antitumor effect of CAR-M. We hypothesized that the antitumor activity of CAR-Ms may be further improved after inducing M1-type polarization. METHODS: In this report, we constructed a novel HER2-targeting CAR-M, which was composed of humanized anti-HER2 scFv, CD28 hinge region and FcγRI transmembrane domain and intracellular domain. Phagocytosis, tumor-killing capacities, and cytokine release of CAR-Ms were detected with or without M1-polarization pretreatment. Several syngeneic tumor models were used to monitor the in vivo antitumor activity of M1-polarized CAR-Ms. RESULTS: After polarization with LPS combined with interferon-γ in vitro, we found that the phagocytic and tumor-killing capacities of CAR-Ms against target cells were significantly enhanced. The expression of costimulatory molecules and proinflammatory cytokines was also significantly increased after polarization. By establishing several syngeneic tumor models in vivo, we also demonstrated that infusing polarized M1-type CAR-Ms could effectively suppress tumor progression and prolong the survival of tumor-bearing mice with enhanced cytotoxicity. CONCLUSIONS: We demonstrated that our novel CAR-M can effectively eliminate HER2-positive tumor cells both in vitro and in vivo, and M1 polarization significantly enhanced the antitumor ability of CAR-M, resulting in a stronger therapeutic effect in solid cancer immunotherapy.

Necroptosis of nucleus pulposus cells involved in intervertebral disc degeneration through MyD88 signaling.

Background context: Low back pain, affecting nearly 40% of adults, mainly results from intervertebral disc degeneration (IVDD), while the pathogenesis of IVDD is still not fully elucidated. Recently, some researches have revealed that necroptosis, a programmed necrosis, participated in the progression of IVDD, nevertheless, the underlying mechanism remains unclear. Purpose: To study the mechanism of necroptosis of Nucleus Pulposus (NP) cells in IVDD, focusing on the role of MyD88 signaling. Study design: The expression and co-localization of necroptotic indicators and MyD88 were examined in vivo, and MyD88 inhibitor was applied to determine the role of MyD88 signaling in necroptosis of NP cells in vitro. Methods: Human disc specimens were collected from patients receiving diskectomy for lumbar disc herniation (LDH) or traumatic lumbar fractures after MRI scanning. According to the Pfirrmann grades, they were divided into normal (Grades 1, 2) and degenerated groups (4, 5). Tissue slides were prepared for immunofluorescence to assess the co-localization of necroptotic indicators (RIP3, MLKL, p-MLKL) and MyD88 histologically. The combination of TNFα, LPS and Z-VAD-FMK was applied to induce necroptosis of NP cells. Level of ATP, reactive oxygen species (ROS), live-cell staining and electron microscope study were employed to study the role of MyD88 signaling in necroptosis of NP cells. Results: In vivo, the increased expression and co-localization of necroptotic indicators (RIP3, MLKL, p-MLKL) and MyD88 were found in NP cells of degenerated disc, while very l low fluorescence intensity in tissue of traumatic lumbar fractures. In vitro, the MyD88 inhibitor effectively rescued the necroptosis of NP cells, accompanied by increased viability, ATP level, and decreased ROS level. The effect of MyD88 inhibition on necroptosis of NP cells was further confirmed by ultrastructure of mitochondria shown by Transmission Electron Microscope (TEM). Conclusion: Our results indicated that the involvement of MyD88 signaling in the necroptosis of NP cells in IVDD, which will replenish the pathogenesis of IVDD and provide a novel potential therapeutic target for IVDD.

Exosomes derived from olfactory ensheathing cells provided neuroprotection for spinal cord injury by switching the phenotype of macrophages/microglia.

Transplantation of olfactory ensheathing cells (OECs) has been demonstrated to be beneficial for spinal cord injury (SCI) by modulating neuroinflammation, supporting neuronal survival and promoting angiogenesis. Besides OECs, the conditioned medium (CM) from OECs has also been proved to have therapeutic effects for SCI, indicating that the bioactive substances secreted by OECs are essential for its protective effects. Nevertheless, there is still little information regarding the underlying mechanisms. Considering that exosomes are crucial for intercellular communication and could be secreted by different types of cells, we speculated that the therapeutic potential of OECs for SCI might be partially based on their exosomes. To examine whether OECs could secret exosomes, we isolated exosomes by polyethylene glycol-based method, and identified them by electron microscopy study, nanoparticle tracking analysis (NTA) and western blotting. In view of phagocytic ability of microglia and its distinct roles in microenvironment regulation after SCI, we then focused the effects of OECs-derived exosomes (OECs-Exo) on microglial phenotypic regulation. We found that the extracted OECs-Exo could be engulfed by microglia and partially reverse the LPS-induced pro-inflammatory polarization through inhibiting NF-κB and c-Jun signaling pathways in vitro. Furthermore, OECs-Exo were found to inhibit the polarization of pro-inflammatory macrophages/microglia while increased the numbers of anti-inflammatory cells after SCI. Considering that the neuronal injury is closely related to the activation state of macrophages/microglia, co-culture of microglia and neurons were performed. Neuronal death induced by LPS-treated microglia could be significantly alleviated when microglia treated by LPS plus OECs-Exo in vitro. After SCI, NeuN-immunostaining and axonal tract-tracing were performed to assess neuronal survival and axon preservation. Our data showed that the OECs-Exo promoted the neuronal survival and axon preservation, and facilitated functional recovery after SCI. Our findings provide a promising therapeutic strategy for SCI based on exosome-immunomodulation.

Surgical treatment of the lower cervical brucellosis with osteoporosis in the northwest region of China: review of 22 cases.

OBJECTIVE: To analyze the surgical treatment of patients with cervical brucellosis with osteoporosis over a 4-year period in Northwest China. METHODS: From 2013 to 2018, 22 patients (12 males and 10 females) with lower cervical spine brucellosis (C3-C7) underwent anterior lesion debridement, decompression, bone grafting and internal fixation combined with posterior bone graft fusion and internal fixation (ADDF+PIF). The follow-up period averaged 37.4 months (ranging from 24 to 57 months). RESULTS: Involvement of 1 vertebra was observed in 3 patients, involvement of 3 vertebrae was observed in 9 patients, and involvement of 3 vertebrae was observed in 10 patients. Before surgery, 1 patient had Frankel grade B, 2 had grade C, 9 had grade D, and 10 had grade E. In the final follow-up, 12 patients had neurological deficits, 10 patients improved by one grade, 6 patients improved by two grades, and the neurological status of 6 patients remained unchanged. In all cases, it was observed that bone fusion required 6.8 months on average. The kyphosis Cobb angle was enhanced from an average of 11.5° preoperatively (range 0°-24°) to 0.13° postoperatively (range 1°-5°), and there was no vital loss of correction in the follow-up. CONCLUSIONS: ADDF+PIF is an effective and safe treatment for patients with lower cervical brucellosis with osteoporosis.

MYC inhibition reprograms tumor immune microenvironment by recruiting T lymphocytes and activating the CD40/CD40L system in osteosarcoma.

The efficacy of immune checkpoint blockade (ICB) therapy depends on sufficient infiltration and activation of primed tumor-specific cytotoxic T lymphocytes (CTLs) in the tumor microenvironment. However, many tumor types, including osteosarcoma, mainly display immune-desert or immune-excluded phenotypes, which are characterized by a lack of tumor-infiltrating lymphocytes and a poor response to ICB monotherapy. Thus, novel therapeutic strategies are urgently needed to surmount these obstacles. In this study, we found that the expression of the c-Myc oncogene is negatively correlated with the T cell infiltration rate in osteosarcoma. Pharmacological inhibition of c-Myc with JQ-1 significantly reduced tumor burden and improved overall survival in an immunocompetent syngeneic murine model of osteosarcoma (K7M2). A mechanistic study revealed that JQ-1 administration dramatically reprogrammed the tumor immune microenvironment (TIME) within K7M2 tumors. On the one hand, JQ-1 can promote T cell trafficking into tumors by increasing the expression and secretion of T cell-recruiting chemokines. On the other hand, JQ-1 is capable of facilitating crosstalk between antigen-presenting dendritic cells and T cells through the CD40/CD40L costimulatory pathway, leading to activation of tumor-specific CTLs. Combined treatment with anti-PD-1 antibody and JQ-1 resulted in more pronounced tumor regression than either monotherapy, showing an obvious synergistic effect. These findings uncover for the first time that c-Myc inhibition can promote T cell infiltration and activation in osteosarcoma in multiple ways, delivering a one-two punch for modulating TIME. The present work also provides the basis for establishing c-Myc inhibitor and ICB coadministration as a novel therapeutic regimen for patients with osteosarcoma.

Psychometric Properties of the Chinese Version of the Sarcopenia and Quality of Life, a Quality of Life Questionnaire Specific for Sarcopenia.

A quality of life questionnaire specific to sarcopenia (SarQoL®) was successfully developed. There is a huge demand for translation and validation in Chinese. The aim of this study was to translate the SarQoL® into Chinese and investigate its psychometric properties. The translation and cross-cultural adaptation process recommended by the developers of the initial questionnaire was followed. A total of 159 participants were investigated. The translation process consists of five steps: (1) two bilinguals independently translate initial English to Chinese; (2) synthesize the two translations into one; (3) backward translations; (4) expert committee review and (5) test of the pre-final version. The validation consists of three parts: (1) validity (discriminative power, construct validity); (2) reliability (internal consistency, test-retest reliability) and (3) floor and ceiling effects. There was no difficulty in translation process. Regarding the validity, good discriminant validity {quality of life for sarcopenic subjects [35.56 (29.73-42.70)] vs. non-sarcopenic ones [73.22 (60.09-82.90)], p < 0.001} and consistent construct validity [high correlations (spearman's r) of SarQoL® with generic Short Form-36 version 2 questionnaire (0.250 to 0.824) and EuroQoL-5-Dimension questionnaire (- 0.114 to - 0.823)] were found in SarQoL®. Regarding reliability, high internal consistency (Cronbach's alpha coefficient was 0.867) and excellent test-retest reliability (intraclass coefficient correlation was 0.997, 95% CI 0.994-0.998) were found. No ceiling/floor effect was reflected. A valid SarQoL® questionnaire is now available for Chinese population. It can provide a better understanding of the sarcopenia disease burden and serve as a therapeutic outcome indicator in research.