BMSCs-derived exosomes inhibit macrophage/microglia pyroptosis by increasing autophagy through the miR-21a-5p/PELI1 axis in spinal cord injury.

Spinal cord injury (SCI) results in a diverse range of disabilities and lacks effective treatment options. In recent years, exosomes derived from bone mesenchymal stem cells (BMSCs) have emerged as a promising cell-free therapeutic approach for treating ischemic brain injury and other inflammatory conditions. Macrophage/microglial pyroptosis has been identified as a contributing factor to neuroinflammation following SCI. The therapeutic potential of BMSC-derived exosomes in macrophage/microglia pyroptosis-induced neuroinflammation, however, has to be determined. Our findings demonstrate that exosomes derived from BMSCs can enhance motor function recovery and mitigate neuroinflammation subsequent to SCI by upregulating the expression of autophagy-related proteins and inhibiting the activation of NLRP3 inflammasomes in macrophage/microglia. Moreover, miR-21a-5p is markedly increased in BMSCs-derived exosomes, and knocking down miR-21a-5p in BMSCs-derived exosomes eliminates the beneficial effects of administration; upregulation of miR-21a-5p in BMSCs-derived exosomes enhances the beneficial effects of administration. Mechanistically, miR-21a-5p positively regulates the autophagy of macrophage/microglia by reducing PELI1 expression, which in turn inhibits their pyroptosis. This research provides novel evidence that exosomes derived from BMSCs can effectively suppress macrophage/microglia pyroptosis through the miR-21a-5p/PELI1 axis-mediated autophagy pathway, ultimately facilitating functional restoration following SCI. In particular, our constructed miR-21a-5p overexpression exosomes greatly improved the efficacy of BMSCs-derived exosomes in treating spinal cord injury. These results establish a foundation for the prospective utilization of exosomes derived from BMSCs as a novel biological intervention for spinal cord injury.

Validation for the effect of intra-exposure patient motion on the assessment of radiostereometric implant migration in a tibial component phantom study.

BACKGROUND: An increasing number of radiostereometry (RSA) research studies have long-term follow-up implant migration outcomes, which show ascending curves of implant migration with occasionally decreasing migration. After scrutinizing images and RSA scenes related to the alternating curves, we suppose that intra-exposure patient motion may contribute to that. The main purposes of this in vitro study were 1) to identify whether the patient motion in different directions could result in the inaccurate assessment of implant migration, and 2) to figure out which direction(s) accounted for the alternating curves. HYPOTHESIS: It was hypothesized that the assessments of implant migration would be less precise and accurate than they could be when patient motion occurred, and such motion would contribute to the alternating curves of radiostereometric implant migration. MATERIALS AND METHODS: A customized phantom, assembled with a tibial component, was designed for simulating intra-exposure patient motion during follow-up RSA examinations. Two different Roentgen tubes were used as the current standard of radiology departments. Radiographs were acquired in a uniplanar technical arrangement. Two defined protocols were conducted: one is to simulate implant migration outcomes at post-op, the early stage (6months), and the later stage (2 to 10years) ; during the later stage, the other is to mimic patient motion by phantom motion in the medial-lateral (x), distal-proximal (y), and anterior-posterior (z) axes. RESULTS: Phantom motion could result in the inaccurate assessment of implant migration, and translations along the medial-lateral (x) axis were the most influenced by patient motion. Motion along the medial-lateral (x) axis could account for the curves with decreasing migration. DISCUSSION: Our assessments of implant migration may be less precise and accurate than they could be when intra-exposure patient motion occurs. We probably neglect the importance of 100% simultaneous exposures, and the influence of patient motion on RSA accuracy and data reliability, due to the difficulty in detecting patient (micro)motion. Electronically synchronized exposures of two paired Roentgen tubes are 100% simultaneous for image acquisition, and they are thus highly recommended for the assessment of implant migration in RSA. TYPE OF STUDY AND LEVEL OF PROOF: not applicable.

Treg cells-derived exosomes promote blood-spinal cord barrier repair and motor function recovery after spinal cord injury by delivering miR-2861.

The blood-spinal cord barrier (BSCB) is a physical barrier between the blood and the spinal cord parenchyma. Current evidence suggests that the disruption of BSCB integrity after spinal cord injury can lead to secondary injuries such as spinal cord edema and excessive inflammatory response. Regulatory T (Treg) cells are effective anti-inflammatory cells that can inhibit neuroinflammation after spinal cord injury, and their infiltration after spinal cord injury exhibits the same temporal and spatial characteristics as the automatic repair of BSCB. However, few studies have assessed the relationship between Treg cells and spinal cord injury, emphasizing BSCB integrity. This study explored whether Treg affects the recovery of BSCB after SCI and the underlying mechanism. We confirmed that spinal cord angiogenesis and Treg cell infiltration occurred simultaneously after SCI. Furthermore, we observed significant effects on BSCB repair and motor function in mice by Treg cell knockout and overexpression. Subsequently, we demonstrated the presence and function of exosomes in vitro. In addition, we found that Treg cell-derived exosomes encapsulated miR-2861, and miR-2861 regulated the expression of vascular tight junction (TJs) proteins. The luciferase reporter assay confirmed the negative regulation of IRAK1 by miR-2861, and a series of rescue experiments validated the biological function of IRAKI in regulating BSCB. In summary, we demonstrated that Treg cell-derived exosomes could package and deliver miR-2861 and regulate the expression of IRAK1 to affect BSCB integrity and motor function after SCI in mice, which provides novel insights for functional repair and limiting inflammation after SCI.

Ubiquitin-proteasome system-mediated ubiquitination modification patterns and characterization of tumor microenvironment infiltration, stemness and cellular senescence in low-grade glioma.

The Ubiquitin-proteasome system (UPS) performs a crucial role in immune activation and tumorigenesis. Nevertheless, the comprehensive role of the ubiquitin-proteasome system in the low-grade glioma (LGG) tumor microenvironment (TME) remains unknown. Ubiquitination modification patterns in LGG patients and corresponding characteristics of tumor immune traits, CSC stemness, and cellular senescence were evaluated via a comprehensive analysis of 20 ubiquitination modification regulators. For quantification of the ubiquitination modification status of individual patients, the UM-score was constructed and associated with TME characteristics, clinical features, cancer stem cell stemness, cellular senescence, prognosis, and immunotherapy efficacy. We identified that alterations in multiple ubiquitination regulators are linked to patient survival and the shaping of the tumor microenvironment. We found two different styles of ubiquitination modification in patients with low-grade glioma (immune-inflamed differentiation and immune-exclude dedifferentiation), characterized by high and low UM-score, and the two regulatory patterns of ubiquitination modification on immunity, stemness feature, and cellular senescence. We demonstrate that the UM-score could forecast the subtype of LGG, the immunologic infiltration traits, the biological process, the stemness feature, and the cellular senescence trait. Notably, the UM-score was related to immunotherapeutic efficacy, implying that modifying ubiquitination modification patterns by targeting ubiquitination modification regulators or ubiquitination modification pattern signature genes to reverse unfavorable TME properties will provide new insights into cancer immunotherapy. This research indicated that the ubiquitin-proteasome system is crucial in the formation of TME complexity and multiformity. The UM-score can determine ubiquitination modification status in individual patients, bringing about more personalized and effective immunotherapeutic tactics.

Injectable pH-responsive hydrogel for combinatorial chemoimmunotherapy tailored to the tumor microenvironment.

Although combination chemoimmunotherapy shows promising clinical results for cancer treatment, this approach is largely restricted by variable objective response rate and severe systemic adverse effects of immunotherapeutic antibody and chemotherapeutic drugs. Therefore, an in situ-formed therapeutic silk-chitosan composite scaffold is fabricated in this study to allow local release of the chemotherapeutic drug doxorubicin (DOX) and JQ1 (small molecular inhibitor used for the extraterminal protein BRD4 and bromodomain) with control release kinetics. DOX-JQ1@Gel contains a pH-degradable group that releases therapeutics in a weak acidic tumor microenvironment. The released DOX could directly kill tumor cells or lead to immunogenic cell death, thereby triggering the response of antitumor immunity. Meanwhile, chemotherapy-triggered antigen release and JQ1-mediated PD-L1 checkpoint blockade cumulatively contribute to trigger the response of antitumor immunity. Finally, the DOX-JQ1@Gel is locally injected to evaluate its synergistic cancer therapeutic effect, which is expected to improve objective response rate of immunotherapy and minimize systemic side effects.

Clinical efficacy of orthopilot navigation system versus conventional manual of total hip arthroplasty: A systematic review and meta-analysis.

BACKGROUND: To compare the clinical efficacy between Orthopilot navigation system and conventional manual surgery in total hip arthroplasty (THA). METHODS: Electronic databases were searched to identify randomized controlled trials (RCTs) investigating Orthopilot navigation system versus conventional manual in patients undergoing THA. Outcome measurements include anteversion angle, inclination angle, preoperative leg length discrepancy, postoperative leg length discrepancy and femoral offset. Statistical software Stata 12.0 was used for data-analysis. RESULTS: A total of 5 studies were finally included in this meta-analysis. The results showed that the conventional manual group have a less anteversion angle than that in Orthopilot navigation system group (weighted mean difference (WMD) = 4.67, 95% confidence interval (CI) = 3.53, 5.82, P = .000). And pooled analysis showed that the inclination angle in Orthopilot navigation group was less than that in conventional manual group (WMD = -4.19, 95% CI = -8.00, -0.37, P = .031). There was no significant difference between the preoperative leg length discrepancy and postoperative leg length discrepancy (P > .05). Orthopilot navigation system compared with conventional manual procedure was associated with decreased of femoral offset by 2.76 (WMD = -2.76, 95%CI = -3.90, -1.62, P = .000). CONCLUSION: Both Orthopilot navigation system and conventional THA result in significant improvements in patient function with similar overall complication rates and have their own edges in cup position.

A multicenter study to evaluate the safety and efficacy of a stand-alone anterior carbon I/F Cage for anterior lumbar interbody fusion: two-year results from a Food and Drug Administration investigational device exemption clinical trial.

STUDY DESIGN: Two-year prospective multicenter clinical trial. OBJECTIVE: To determine the safety and efficacy of the anterior I/F Cage in the primary treatment of single-level degenerative disc disease. SUMMARY OF BACKGROUND DATA: A carbon fiber-reinforced polymer cage was designed to replace the traditional allograft/autograft structural graft used in an anterior lumbar interbody fusion (ALIF). Although the outcomes of various types of ALIF cages have previously been reported, the safety and efficacy of the I/F cage are unknown. METHODS: Between June 2000 and June 2004, 112 patients were prospectively enrolled at 12 study sites for the current study. Efficacy was evaluated clinically and radiographically. "Patient success" was declared only when the following 4 criteria were present at final follow-up: (1) "clinical success": improvement of 15 points on Oswestry Disability Index, (2) absence of a new neurologic abnormality, (3) successful radiographic fusion, and (4) no subsequent secondary surgical intervention at 24-month follow-up. Safety was inferred by way of an objective summary of complications and adverse events, as reported at regular intervals throughout the course of the study. RESULTS: A total of 112 patients (mean age: 41.7 years) underwent a single-level ALIF procedure (L5-S1: 95 patients, L4-L5: 17 patients). The mean surgical time was 126 minutes, the mean estimated blood loss was 134 mL, and the mean duration of hospitalization was 3.3 days. There were 80 patients available for 24-month follow-up. Overall patient success was 25% (20/80). Clinical success was present in 46.3% (37/80), fusion success was 57.5% (46/80), and 87.5% of patients (70/80) avoided a subsequent secondary surgical intervention. Disc space height had significantly increased after surgery, and this increase was maintained at 2 years follow-up period. Complications and adverse events included the following: 8 infections (7.1%) (7 superficial, 1 deep), 2 vascular injuries (1.8%) (left common iliac vein), and 12 secondary surgical interventions (15%). CONCLUSION: This safety and efficacy study suggests that the anterior I/F Cage is a safe surgical option in the treatment of single-level lumbar degenerative disc disease. As a stand-alone construct, the I/F Cage yields suboptimal radiographic and clinical outcomes. Additional benefit may be gained from adjunctive posterior stabilization.

[Comparison study on therapeutic effects of anterior approach versus posterior approach in treating multilevel cervical disc herniation].

OBJECTIVE: To investigate the therapeutic effects of anterior approach set (AAS) versus posterior approach set (PAS) in treating multilevel cervical disc herniation of three or four segments. METHODS: Fifty-six cases of multilevel cervical disc herniation were retrospectively studied. Thirty-seven cases underwent anterior approach, and discectomy, selectively partial corpectomy with bone grafting and plate fixing was performed (AAS group); 19 cases underwent posterior approach, and laminectomy with lateral cervical mass plate screw fixing was performed (PAS group). RESULTS: The follow-up periods were 6 months to 4 years and 5 months, averaging 2 years and 10 months in AAS group and 1 year and 5 months to 5 years and 1 month, averaging 3 years and 8 months in PAS group. JOA functional assessment and sagittal diameter of dural sac were not statistically significant between two groups before operation (P>0.05) and were significantly larger in AAS group than in PAS group after operation (P<0.01). The improvement rate of AAS was significant higher than that of PAS (P<0.01). The number of complication in AAS were slight more than that in PAS. CONCLUSION: AAS is obviously better than PAS in the therapeutic effects. The operation of anterior decompression with bone grafting and plate fixing is an indication of multilevel cervical disc herniation of three or four segments.

Preoperative transarterial embolization of hypervascular vertebral tumor with permanent particles.

OBJECTIVE: To evaluate the safety and value of preoperative transarterial embolization of hypervascular vertebral tumors. METHODS: Sixteen patients with hypervascular vertebral tumors underwent transarterial embolization before surgery. The lesions were located between the middle cervical and lower lumbar spine. Forty-one arteries were embolized with permanent particles injected through a microcatheter, including polyvinyl alcohol (PVA) particles (150 - 500 micro m) in 25 arteries and Dextran particles (150 - 350 micro m) in 16. Of these, 31 had pieces of gelatin sponge added for proximal pedicled embolization. The criteria for judging the effectiveness of embolization were completeness of tumor removal and estimated blood loss during surgery. RESULTS: The particles were injected into the tumor feeders through superselection in 17 arteries or flow control in 24. Tumor embolization was defined as "total" in five patients, "nearly total" in eight, "subtotal" in two, and "partial" in another. There were no symptomatic complications associated with embolization. Tumors were entirely removed in all patients. The average estimated blood loss during surgery was 1510 ml (range of 200 - 6000 ml) for all 16 patients. CONCLUSION: Preoperative embolization of hypervascular vertebral tumors is safe and effective. It can make complete resection of a tumor possible and can make a previously unresectable tumor resectable. Superselection or flow control is necessary to achieve effective devascularization and to avoid complications.