Manganese Enhances the Osteogenic Effect of Silicon-Hydroxyapatite Nanowires by Targeting T Lymphocyte Polarization.

Biomaterials encounter considerable challenges in extensive bone defect regeneration. The amelioration of outcomes may be attainable through the orchestrated modulation of both innate and adaptive immunity. Silicon-hydroxyapatite, for instance, which solely focuses on regulating innate immunity, is inadequate for long-term bone regeneration. Herein, extra manganese (Mn)-doping is utilized for enhancing the osteogenic ability by mediating adaptive immunity. Intriguingly, Mn-doping engenders heightened recruitment of CD4+ T cells to the bone defect site, concurrently manifesting escalated T helper (Th) 2 polarization and an abatement in Th1 cell polarization. This consequential immune milieu yields a collaborative elevation of interleukin 4, secreted by Th2 cells, coupled with attenuated interferon gamma, secreted by Th1 cells. This orchestrated interplay distinctly fosters the osteogenesis of bone marrow stromal cells and effectuates consequential regeneration of the mandibular bone defect. The modulatory mechanism of Th1/Th2 balance lies primarily in the indispensable role of manganese superoxide dismutase (MnSOD) and the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK). In conclusion, this study highlights the transformative potential of Mn-doping in amplifying the osteogenic efficacy of silicon-hydroxyapatite nanowires by regulating T cell-mediated adaptive immunity via the MnSOD/AMPK pathway, thereby creating an anti-inflammatory milieu favorable for bone regeneration.

A Web-Based Prediction Tool to Improve Identification of Patients With Undersized Hamstring Tendon Autograft in Anterior Cruciate Ligament Reconstruction.

BACKGROUND: An undersized hamstring tendon (HT) autograft is significantly associated with a higher graft failure rate in anterior cruciate ligament reconstruction (ACLR) surgery. The ability to accurately predict inadequate HT graft diameter is critical, as it could assist surgeons in making better graft choices and surgical plans. PURPOSE: To develop a web-based prediction tool to better assess the size of HT autograft and to help clinicians accurately identify patients with potentially undersized HT grafts in order to make appropriate clinical decisions. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A total of 588 patients who received primary arthroscopic single-bundle ACLR surgery with gracilis tendon (GT) and semitendinosus tendon (ST) autograft were retrospectively reviewed. According to the size of 4-strand HT graft, patients were divided into diameter ≥8 mm and <8 mm groups. The least absolute shrinkage and selection operator method and logistic regression were used to identify the independent factors associated with HT graft diameter and establish the models. The prediction performance of the model was evaluated by concordance index and calibration combined with external validation. The diagnostic performance of the prediction model was assessed by sensitivity, specificity, predictive values, and likelihood ratios. Decision curve analysis was used to evaluate the clinical utility of the model. RESULTS: Among the numerous indicators, sex, weight, height, thigh length, and ST-GT diameter (measured on plane 1 of a magnetic resonance imaging scan) were identified to be highly correlated predictors that could provide satisfactory prediction performance in determining the HT graft diameter. Based on these predictors, a prediction model named the HTD model was developed with satisfactory discrimination (concordance index, 0.932) and calibration (mean absolute error, 0.039). When the probability calculated by the HTD model was >65%, the sensitivity and specificity of predicting 4-strand HT graft diameter ≥8 mm were 86.7% and 90.2%, respectively. CONCLUSION: As a useful supplementary prediction tool, the HTD model could accurately predict the diameter of HT autograft during preoperative planning.

Optimal fibular tunnel direction for anterior talofibular ligament reconstruction: 45 degrees outperforms 30 and 60 degrees.

PURPOSE: There is currently no consensus on the optimal drilling direction of the fibular bone tunnel for anterior talofibular ligament (ATFL) reconstruction, and few studies have investigated the potential injury to the peroneus longus and brevis tendons and the possibility of fibular fractures during the drilling process. The aim of this study was to assess the potential risk of drilling the tunnel from different directions and determine the most appropriate tunnel direction. The hypothesis was that drilling the tunnel in the 45-degree direction would be the safest and most suitable for the fibular tunnel. METHODS: Forty-eight fibular tunnels were drilled on fresh ankle specimens using a K-wire guide and a 5.0 mm hollow drill. Three tunnel orientations were created, parallel to the sagittal plane of the long axis of the fibula and angled 30°, 45°, and 60° to the coronal plane. The length of the fibular tunnel and the distances from the outlet of the K-wire to the peroneus longus and brevis tendons were measured. The occurrence of a fibula fracture was also observed. RESULTS: The lengths of the bone tunnels in the three groups were 32.9 ± 6.1 mm (30°), 27.2 ± 4.4 mm (45°) and 23.6 ± 4.0 mm (60°). The length of the tunnel drilled at 30° was the longest when compared with that of the tunnels drilled at 45° and 60° (all p values < 0.05). The distances from the outlet of the K-wire to the peroneus longus tendon were 3.0 ± 3.8 mm (30°), 3.8 ± 3.2 mm (45°) and 5.3 ± 1.8 mm (60°), and the distances to the peroneus brevis tendon were 4.2 ± 4.0 mm (30°), 6.1 ± 3.8 mm (45°), 7.9 ± 3.5 mm (60°). In terms of protecting the peroneus longus and brevis tendons, drilling in the 60° direction was better than drilling in the 30° and 45° directions (all p values < 0.05). The risk of injury to the peroneal longus and brevis tendons was 62.5% (30°), 31.3% (45°), and 0% (60°). Although no fibular fractures were observed in any of the three directions, drilling the bone tunnel in the 60° direction disrupted the lateral cortex of the fibula. CONCLUSION: This study shows that drilling the tunnel in the 45° direction is less likely to cause injury to the peroneus longus and brevis tendons, while ensuring that the tunnel has a sufficient length and avoiding fracturing the distal fibula. Drilling a fibular bone tunnel in a 45° direction is safer and recommended for ATFL reconstruction.

Construction of an interferon regulatory factors-related risk model for predicting prognosis, immune microenvironment and immunotherapy in clear cell renal cell carcinoma.

Background: Interferon regulatory factors (IRFs) played complex and essential roles in progression, prognosis, and immune microenvironment in clear cell renal cell carcinoma (ccRCC). The purpose of this study was to construct a novel IRFs-related risk model to predict prognosis, tumor microenvironment (TME) and immunotherapy response in ccRCC. Methods: Multi-omics analysis of IRFs in ccRCC was performed based on bulk RNA sequencing and single cell RNA sequencing data. According to the expression profiles of IRFs, the ccRCC samples were clustered by non-negative matrix factorization (NMF) algorithm. Then, least absolute shrinkage and selection operator (LASSO) and Cox regression analyses were applied to construct a risk model to predict prognosis, immune cells infiltration, immunotherapy response and targeted drug sensitivity in ccRCC. Furthermore, a nomogram comprising the risk model and clinical characteristics was established. Results: Two molecular subtypes with different prognosis, clinical characteristics and infiltration levels of immune cells were identified in ccRCC. The IRFs-related risk model was developed as an independent prognostic indicator in the TCGA-KIRC cohort and validated in the E-MTAB-1980 cohort. The overall survival of patients in the low-risk group was better than that in the high-risk group. The risk model was superior to clinical characteristics and the ClearCode34 model in predicting the prognosis. In addition, a nomogram was developed to improve the clinical utility of the risk model. Moreover, the high-risk group had higher infiltration levels of CD8+ T cell, macrophages, T follicular helper cells and T helper (Th1) cells and activity score of type I IFN response but lower infiltration levels of mast cells and activity score of type II IFN response. Cancer immunity cycle showed that the immune activity score of most steps was remarkably higher in the high-risk group. TIDE scores indicated that patients in the low-risk group were more likely responsive to immunotherapy. Patients in different risk groups showed diverse drug sensitivity to axitinib, sorafenib, gefitinib, erlotinib, dasatinib and rapamycin. Conclusions: In brief, a robust and effective risk model was developed to predict prognosis, TME characteristics and responses to immunotherapy and targeted drugs in ccRCC, which might provide new insights into personalized and precise therapeutic strategies.

Breast cancer stem cells, heterogeneity, targeting therapies and therapeutic implications.

Both hereditary and sporadic breast cancer are suggested to develop from a stem cell subcomponent retaining most key stem cell properties but with dysregulation of self-renewal pathways, which drives tumorigenic differentiation and cellular heterogeneity. Cancer stem cells (CSCs), characterized by their self-renewal and differentiation potential, have been reported to contribute to chemo-/radio-resistance and tumor initiation and to be the main reason for the failure of current therapies in breast cancer and other CSC-bearing cancers. Thus, CSC-targeted therapies, such as those inducing CSC apoptosis and differentiation, inhibiting CSC self-renewal and division, and targeting the CSC niche to combat CSC activity, are needed and may become an important component of multimodal treatment. To date, the understanding of breast cancer has been extended by advances in CSC biology, providing more accurate prognostic and predictive information upon diagnosis. Recent improvements have enhanced the prospect of targeting breast cancer stem cells (BCSCs), which has shown promise for increasing the breast cancer remission rate. However, targeted therapy for breast cancer remains challenging due to tumor heterogeneity. One major challenge is determining the CSC properties that can be exploited as therapeutic targets. Another challenge is identifying suitable BCSC biomarkers to assess the efficacy of novel BCSC-targeted therapies. This review focuses mainly on the characteristics of BCSCs and the roles of BCSCs in the formation, maintenance and recurrence of breast cancer; self-renewal signaling pathways in BCSCs; the BCSC microenvironment; potential therapeutic targets related to BCSCs; and current therapies and clinical trials targeting BCSCs.

Perioperative dexmedetomidine reduces delirium in elderly patients after non-cardiac surgery: a systematic review and meta-analysis of randomized-controlled trials.

BACKGROUND: Delirium is a frequent postoperative complication in elderly patients after non-cardiac surgery. We performed this updated meta-analysis to ascertain more precisely the efficacy of dexmedetomidine (DEX) on the incidence of postoperative delirium (POD) in elderly patients after non-cardiac surgery. METHODS: We searched PubMed, EMBASE, the Cochrane Library, Web of Science, and the Cumulative Index of Nursing and Allied Health Literature (CINAHL) from inception until February 24, 2019. In this meta-analysis, we included randomized-controlled trials comparing the effect of DEX vs normal saline (NS) or other anesthetic drugs on POD incidence in elderly (either ≥ 60 or ≥ 65 yr old) patients undergoing non-cardiac surgery. We performed subgroup analyses of the DEX dosing strategy (starting time, dose, and duration of administration, with or without loading dose) and the strategy of various control drugs. A random-effects model was used for all analyses. RESULTS: We included 11 studies involving 2,890 patients in our meta-analysis. The pooled results of these studies revealed that DEX significantly reduced the incidence of POD (relative risk [RR], 0.47; 95% confidence interval [CI], 0.38 to 0.58; P < 0.001) compared with the control group. Meanwhile, the incidences of hypotension (RR, 1.20; 95% CI, 1.04 to 1.39; P = 0.01) and bradycardia (RR, 1.33; 95% CI, 1.08 to 1.63; P = 0.007) were increased in the DEX group. Subgroup analyses revealed a decrease in POD incidence when DEX was administered intraoperatively (RR, 0.43; 95% CI, 0.33 to 0.57; P < 0.001) and postoperatively (RR, 0.38; 95% CI, 0.27 to 0.54; P < 0.001) with a loading dose (RR, 0.49; 95% CI, 0.36 to 0.69; P < 0.001) compared with NS (RR, 0.49; 95% CI, 0.37 to 0.64; P < 0.001) and other anesthetic drugs (RR, 0.40; 95% CI, 0.26 to 0.60; P < 0.001). There were significant differences in the time to extubation (standardized mean difference, -0.60; 95% CI, -1.17 to -0.03; P = 0.04) and the length of hospital stay (mean difference, -0.50 days; 95% CI, -0.97 to -0.03; P = 0.04). The amount of data for the duration of mechanical ventilation and length of intensive care unit stay were insufficient to perform a meta-analysis. CONCLUSION: Perioperative dexmedetomidine reduces the incidence of POD in elderly patients after non-cardiac surgery, but this comes at the cost of an increased incidence of hypotension and bradycardia.

Protective effect of propofol preconditioning on ischemia-reperfusion injury in human hepatocyte.

BACKGROUND: Blood reperfusion after ischemia is the main measure to restore cell function. This study was aimed to explore the effect of propofol on rat and cell models of liver ischemia-reperfusion (I/R) injury, and to investigate its possible mechanism. METHODS: Wistar rats were divided into four groups: control group, sham group, I/R group, and propofol group. Human hepatocyte HL7702 was divided into six groups: control group, I/R group and propofol (5, 10, 20 and 40 µmol/L) groups. After the animal and cell models were established, the alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA) and adenosine triphosphate (ATP) levels in liver tissues and hepatocytes were measured. Cell viability and apoptosis of hepatocytes were respectively determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry. Furthermore, the expressions of apoptosis-related proteins in hepatocytes were determined by Western blot analysis. RESULTS: ALT, AST and MDA levels were all decreased significantly, and the ATP level was increased significantly in propofol group compared with that in I/R group in both liver tissues and hepatocytes. Additionally, cell viability of hepatocytes in propofol group was higher than that in I/R group, while the percentage of apoptotic cells in propofol group was less than that in I/R group. Moreover, the expression of caspase-3 decreased and the expression of Bcl-2 increased significantly after propofol preconditioning. CONCLUSIONS: Our findings suggested that propofol preconditioning might be an effective strategy for protecting the liver from I/R injury, which might provide a scientific basis for clinical application.