Conserved transcriptional connectivity of regulatory T cells in the tumor microenvironment informs new combination cancer therapy strategies.

While regulatory T (Treg) cells are traditionally viewed as professional suppressors of antigen presenting cells and effector T cells in both autoimmunity and cancer, recent findings of distinct Treg cell functions in tissue maintenance suggest that their regulatory purview extends to a wider range of cells and is broader than previously assumed. To elucidate tumoral Treg cell 'connectivity' to diverse tumor-supporting accessory cell types, we explored immediate early changes in their single-cell transcriptomes upon punctual Treg cell depletion in experimental lung cancer and injury-induced inflammation. Before any notable T cell activation and inflammation, fibroblasts, endothelial and myeloid cells exhibited pronounced changes in their gene expression in both cancer and injury settings. Factor analysis revealed shared Treg cell-dependent gene programs, foremost, prominent upregulation of VEGF and CCR2 signaling-related genes upon Treg cell deprivation in either setting, as well as in Treg cell-poor versus Treg cell-rich human lung adenocarcinomas. Accordingly, punctual Treg cell depletion combined with short-term VEGF blockade showed markedly improved control of PD-1 blockade-resistant lung adenocarcinoma progression in mice compared to the corresponding monotherapies, highlighting a promising factor-based querying approach to elucidating new rational combination treatments of solid organ cancers.

Anatomic position determines oncogenic specificity in melanoma.

Oncogenic alterations to DNA are not transforming in all cellular contexts1,2. This may be due to pre-existing transcriptional programmes in the cell of origin. Here we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype arises on the palms of the hands, soles of the feet or under the nails3. We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAF mutations in cutaneous melanoma and enrichment for CRKL amplifications in acral melanoma. We modelled these changes in transgenic zebrafish models and found that CRKL-driven tumours formed predominantly in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that melanocytes in these acral locations may be uniquely susceptible to CRKL. RNA profiling of these fin and limb melanocytes, when compared with body melanocytes, revealed a positional identity gene programme typified by posterior HOX13 genes. This positional gene programme synergized with CRKL to amplify insulin-like growth factor (IGF) signalling and drive tumours at acral sites. Abrogation of this CRKL-driven programme eliminated the anatomic specificity of acral melanoma. These data suggest that the anatomic position of the cell of origin endows it with a unique transcriptional state that makes it susceptible to only certain oncogenic insults.

Cutting Edge: Polycomb Repressive Complex 1 Subunit Cbx4 Positively Regulates Effector Responses in CD8 T Cells.

CTL differentiation is controlled by the crosstalk of various transcription factors and epigenetic modulators. Uncovering this process is fundamental to improving immunotherapy and designing novel therapeutic approaches. In this study, we show that polycomb repressive complex 1 subunit chromobox (Cbx)4 favors effector CTL differentiation in a murine model. Cbx4 deficiency in CTLs induced a transcriptional signature of memory cells and increased the memory CTL population during acute viral infection. It has previously been shown that besides binding to H3K27me3 through its chromodomain, Cbx4 functions as a small ubiquitin-like modifier (SUMO) E3 ligase in a SUMO-interacting motifs (SIM)-dependent way. Overexpression of Cbx4 mutants in distinct domains showed that this protein regulates CTL differentiation primarily in an SIM-dependent way and partially through its chromodomain. Our data suggest a novel role of a polycomb group protein Cbx4 controlling CTL differentiation and indicated SUMOylation as a key molecular mechanism connected to chromatin modification in this process.

Type 2 diabetes and fasting glycemic traits are causal factors of frozen shoulder: a 2-sample Mendelian randomization analysis.

BACKGROUND: The causal relationship between type 2 diabetes (T2D) and frozen shoulder is unclear. This study aims to explore the genetic causal association between T2D and glycemic traits (fasting glucose [FG], fasting insulin [FI], glycated hemoglobin [HbA1c], and 2-hour postprandial glucose [2hGlu]) on frozen shoulder. METHODS: Using 2-sample Mendelian randomization (MR), we analyzed nonconfounded estimates of the effects of T2D and glycemic traits on frozen shoulder. Single-nucleotide polymorphisms (SNPs) strongly associated (P < 5 × 10-8) with exposures from genome-wide association studies (GWAS) were identified. We employed fixed effect mode inverse variance weighting (IVW-FE), random effect mode IVW (IVW-MRE), MR-Egger, and weighted median to assess the association of exposures and outcome. Sensitivity analysis was conducted to test for heterogeneity and multidirectionality bias in MR. RESULTS: We found a significant genetic causal correlation between T2D (IVW-MRE P = .007, odds ratio [OR] 1.093, 95% confidence interval [CI] 1.03-1.16), FG (IVW-FE P < .001, OR 1.455, 95% CI 1.173-1.806), and frozen shoulder, but no evidence for causal correlation between FI, HbA1c, and 2hGlu and frozen shoulder. Although there was certain heterogeneity, sensitivity analysis reveals no deviation from the MR assumptions. CONCLUSION: This study supports a genetic causal relationship between T2D and FG and frozen shoulder.

An Updated Model for the Epigenetic Regulation of Effector and Memory CD8+ T Cell Differentiation.

Naive CD8+ T cells, upon encountering their cognate Ag in vivo, clonally expand and differentiate into distinct cell fates, regulated by transcription factors and epigenetic modulators. Several models have been proposed to explain the differentiation of CTLs, although none fully recapitulate the experimental evidence. In this review article, we will summarize the latest research on the epigenetic regulation of CTL differentiation as well as provide a combined model that contemplates them.

Kdm6b Regulates the Generation of Effector CD8+ T Cells by Inducing Chromatin Accessibility in Effector-Associated Genes.

The transcriptional and epigenetic regulation of CD8+ T cell differentiation is critical for balancing pathogen eradication and long-term immunity by effector and memory CTLs, respectively. In this study, we demonstrate that the lysine demethylase 6b (Kdm6b) is essential for the proper generation and function of effector CD8+ T cells during acute infection and tumor eradication. We found that cells lacking Kdm6b (by either T cell-specific knockout mice or knockdown using short hairpin RNA strategies) show an enhanced generation of memory precursor and early effector cells upon acute viral infection in a cell-intrinsic manner. We also demonstrate that Kdm6b is indispensable for proper effector functions and tumor protection, and that memory CD8+ T cells lacking Kdm6b displayed a defective recall response. Mechanistically, we identified that Kdm6b, through induction of chromatin accessibility in key effector-associated gene loci, allows for the proper generation of effector CTLs. Our results pinpoint the essential function of Kdm6b in allowing chromatin accessibility in effector-associated genes, and identify Kdm6b as a potential target for therapeutics in diseases with dysregulated effector responses.

Remaining Useful Life Prediction of Rolling Bearings Based on Multi-scale Permutation Entropy and ISSA-LSTM.

The performance of bearings plays a pivotal role in determining the dependability and security of rotating machinery. In intricate systems demanding exceptional reliability and safety, the ability to accurately forecast fault occurrences during operation holds profound significance. Such predictions serve as invaluable guides for crafting well-considered reliability strategies and executing maintenance practices aimed at enhancing reliability. In the real operational life of bearings, fault information often gets submerged within the noise. Furthermore, employing Long Short-Term Memory (LSTM) neural networks for time series prediction necessitates the configuration of appropriate parameters. Manual parameter selection is often a time-consuming process and demands substantial prior knowledge. In order to ensure the reliability of bearing operation, this article investigates the application of three advanced techniques-Maximum Correlation Kurtosis Deconvolution (MCKD), Multi-Scale Permutation Entropy (MPE), and Long Short-Term Memory (LSTM) recurrent neural networks-for the prediction of the remaining useful life (RUL) of rolling bearings. The improved sparrow search algorithm (ISSA) is employed for configuring parameters in the Long Short-Term Memory (LSTM) network. Each technique's principles, methodologies, and applications are comprehensively reviewed, offering insights into their respective strengths and limitations. Case studies and experimental evaluations are presented to assess their performance in RUL prediction. Findings reveal that MCKD enhances fault signatures, MPE captures complexity, and LSTM excels in modeling temporal patterns. The root mean square error of the prediction results is 0.007. The fusion of these techniques offers a comprehensive approach to RUL prediction, leveraging their unique attributes for more accurate and reliable predictions.

Nickel-Catalyzed Decarbonylative Thioetherification of Carboxylic Acids with Thiols.

A nickel-catalyzed decarbonylative thioetherification of carboxylic acids with thiols was developed. Under the reaction conditions, benzoic acids, cinnamic acids, and benzyl carboxylic acids coupled with various thiols including both aromatic and aliphatic ones produce the corresponding thioethers in up to 99% yields. Moreover, this reaction was applicable to the modification of bioactive molecules such as 3-methylflavone-8-carboxylic acid, probenecid, and flufenamic acid, and the synthesis of acaricide chlorbenside. These results well demonstrated the potential synthetic value of this new reaction in organic synthesis.

Palladium-Catalyzed Decarbonylative Cyanation of Carboxylic Acids with TMSCN.

The direct decarbonylative cyanation of benzoic acids with TMSCN was achieved through palladium catalysis. By this strategy, a wide range of nitriles including those with functional groups was synthesized in good to high yields. Moreover, this reaction applied to modifying bioactive molecules such as adapalene, probenecid, telmisartan, and 3-methylflavone-8-carboxylic acid. These results demonstrate that this new reaction has potential synthetic value in organic synthesis.

Application of machine learning model to predict osteoporosis based on abdominal computed tomography images of the psoas muscle: a retrospective study.

BACKGROUND: With rapid economic development, the world's average life expectancy is increasing, leading to the increasing prevalence of osteoporosis worldwide. However, due to the complexity and high cost of dual-energy x-ray absorptiometry (DXA) examination, DXA has not been widely used to diagnose osteoporosis. In addition, studies have shown that the psoas index measured at the third lumbar spine (L3) level is closely related to bone mineral density (BMD) and has an excellent predictive effect on osteoporosis. Therefore, this study developed a variety of machine learning (ML) models based on psoas muscle tissue at the L3 level of unenhanced abdominal computed tomography (CT) to predict osteoporosis. METHODS: Medical professionals collected the CT images and the clinical characteristics data of patients over 40 years old who underwent DXA and abdominal CT examination in the Second Affiliated Hospital of Wenzhou Medical University database from January 2017 to January 2021. Using 3D Slicer software based on horizontal CT images of the L3, the specialist delineated three layers of the region of interest (ROI) along the bilateral psoas muscle edges. The PyRadiomics package in Python was used to extract the features of ROI. Then Mann-Whitney U test and the least absolute shrinkage and selection operator (LASSO) algorithm were used to reduce the dimension of the extracted features. Finally, six machine learning models, Gaussian naïve Bayes (GNB), random forest (RF), logistic regression (LR), support vector machines (SVM), Gradient boosting machine (GBM), and Extreme gradient boosting (XGBoost), were applied to train and validate these features to predict osteoporosis. RESULTS: A total of 172 participants met the inclusion and exclusion criteria for the study. 82 participants were enrolled in the osteoporosis group, and 90 were in the non-osteoporosis group. Moreover, the two groups had no significant differences in age, BMI, sex, smoking, drinking, hypertension, and diabetes. Besides, 826 radiomic features were obtained from unenhanced abdominal CT images of osteoporotic and non-osteoporotic patients. Five hundred fifty radiomic features were screened out of 826 by the Mann-Whitney U test. Finally, 16 significant radiomic features were obtained by the LASSO algorithm. These 16 radiomic features were incorporated into six traditional machine learning models (GBM, GNB, LR, RF, SVM, and XGB). All six machine learning models could predict osteoporosis well in the validation set, with the area under the receiver operating characteristic (AUROC) values greater than or equal to 0.8. GBM is more effective in predicting osteoporosis, whose AUROC was 0.86, sensitivity 0.70, specificity 0.92, and accuracy 0.81 in validation sets. CONCLUSION: We developed six machine learning models to predict osteoporosis based on psoas muscle images of abdominal CT, and the GBM model had the best predictive performance. GBM model can better help clinicians to diagnose osteoporosis and provide timely anti-osteoporosis treatment for patients. In the future, the research team will strive to include participants from multiple institutions to conduct external validation of the ML model of this study.

Tibial Tubercle-Trochlear Groove/Trochlear Width Is the Optimal Indicator for Diagnosing a Lateralized Tibial Tubercle in Recurrent Patellar Dislocation Requiring Surgical Stabilization.

PURPOSE: To identify the individualized method of quantifying lateralization of the tibial tubercle with the best diagnostic effectiveness, as evaluated by measurement repeatability using the intraclass correlation coefficient (ICC), the size of the difference between the case group and the control group, and receiver operating characteristic (ROC) curve analysis. METHODS: Patients who had undergone surgery for recurrent patellar dislocation (the case group) and patients who had no history of patellar dislocation (the control group) from January 2014 to December 2019 were included in the study. Six indices that describe lateralization of the tibial tubercle were calculated using either computed tomography (CT) or magnetic resonance imaging (MRI): tibial tubercle lateralization (TTL), tibial tubercle-trochlear groove (TT-TG) ratio, tibial tubercle-posterior cruciate ligament (TT-PCL) ratio, TT-TG index, (TT-TG)/patellar width (PW), and (TT-TG)/trochlear width (TW). Diagnostic effectiveness was evaluated by 1) intra-rater reliability (measurements on two occasions) and inter-rater reliability (measurements by two assessors) using the ICC, 2) the size of the difference between the case group and the control group, and 3) ROC curve analysis, measuring the area under the ROC curve (AUC) and the post hoc power. RESULTS: 100 knees in 88 patients who had undergone surgery for recurrent patellar dislocation and 55 knees in 53 patients who had no history of patellar dislocation were analyzed. The ICC for all the methods were higher than .75. The mean differences between the case group and the control group for TTL, TT-TG ratio, TT-PCL ratio, TT-TG index, (TT-TG)/PW, and (TT-TG)/TW were 2%, 8%, 2%, 12%, 24% and 56%, respectively. The mean differences between the case group and the control group for (TT-TG)/TW was significantly greater than those for the other methods (P < .0001, unpaired t-test). AUC of TTL, TT-TG ratio, TT-PCL ratio, TT-TG index, (TT-TG)/PW, and (TT-TG)/TW were .708, .880, .630, .814, .882, and .905. AUC of (TT-TG)/TW was significantly greater than those of TTL and TT-PCL ratio (P < .0001). The post hoc power for TT-PCL ratio, TT-TG index, (TT-TG)/PW, TT-TG ratio, (TT-TG)/TW, and TTL were 78%, 81%, 88%, 88%, 91%, and 71%, respectively. CONCLUSION: Of the six indices evaluated in this study, (TT-TG)/TW showed the greatest mean difference between the two groups, had the greatest diagnostic utility (as measured by AUC values) and had excellent inter-rater and intra-rater reliability (as measured by ICCs). Thus, it may be the best individualized index for diagnosing a lateralized tibial tubercle in patients with recurrent patellar dislocation requiring surgical stabilization compared to patients with no history of patellar dislocation. LEVEL OF EVIDENCE: Level III, diagnostic study, retrospective cohort study.

The Kinetic Reaction Mechanism of the Vibrio cholerae Sodium-dependent NADH Dehydrogenase.

The sodium-dependent NADH dehydrogenase (Na(+)-NQR) is the main ion transporter in Vibrio cholerae. Its activity is linked to the operation of the respiratory chain and is essential for the development of the pathogenic phenotype. Previous studies have described different aspects of the enzyme, including the electron transfer pathways, sodium pumping structures, cofactor and subunit composition, among others. However, the mechanism of the enzyme remains to be completely elucidated. In this work, we have studied the kinetic mechanism of Na(+)-NQR with the use of steady state kinetics and stopped flow analysis. Na(+)-NQR follows a hexa-uni ping-pong mechanism, in which NADH acts as the first substrate, reacts with the enzyme, and the oxidized NAD leaves the catalytic site. In this conformation, the enzyme is able to capture two sodium ions and transport them to the external side of the membrane. In the last step, ubiquinone is bound and reduced, and ubiquinol is released. Our data also demonstrate that the catalytic cycle involves two redox states, the three- and five-electron reduced forms. A model that gathers all available information is proposed to explain the kinetic mechanism of Na(+)-NQR. This model provides a background to understand the current structural and functional information.

[Study on the Evaluation Index of Depth of Anesthesia Awareness Based on Sample Entropy and Decision Tree].

Currently, monitoring system of awareness of the depth of anesthesia has been more and more widely used in clinical practices. The intelligent evaluation algorithm is the key technology of this type of equipment. On the basis of studies about changes of electroencephalography (EEG) features during anesthesia, a discussion about how to select reasonable EEG parameters and classification algorithm to monitor the depth of anesthesia has taken place. A scheme which combines time domain analysis, frequency domain analysis and the variability of EEG and decision tree as classifier and least squares to compute Depth of anesthesia Index (DOAI) is proposed in this paper. Using the EEG of 40 patients who underwent general anesthesia with propofol, and the classification and the score of the EEG annotated by anesthesiologist, we verified this scheme with experiments. Classification and scoring was based on a combination of modified observer assessment of alertness/sedation (MOAA/S), and the changes of EEG parameters of patients during anesthesia. Then we used the BIS index to testify the validation of the DOAI. Results showed that Pearson's correlation coefficient between the DOAI and the BIS over the test set was 0.89. It is demonstrated that the method is feasible and has good accuracy.

C-reactive protein: structure, function, regulation, and role in clinical diseases.

C-reactive protein (CRP) is a plasma protein that is evolutionarily conserved, found in both vertebrates and many invertebrates. It is a member of the pentraxin superfamily, characterized by its pentameric structure and calcium-dependent binding to ligands like phosphocholine (PC). In humans and various other species, the plasma concentration of this protein is markedly elevated during inflammatory conditions, establishing it as a prototypical acute phase protein that plays a role in innate immune responses. This feature can also be used clinically to evaluate the severity of inflammation in the organism. Human CRP (huCRP) can exhibit contrasting biological functions due to conformational transitions, while CRP in various species retains conserved protective functions in vivo. The focus of this review will be on the structural traits of CRP, the regulation of its expression, activate complement, and its function in related diseases in vivo.

Single Cell Analysis of Treatment-Resistant Prostate Cancer: Implications of Cell State Changes for Cell Surface Antigen Targeted Therapies.

Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)--a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis (TMA) on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated, but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer (SCLC) subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to novel antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types.

Personalized persuasion: Quantifying susceptibility to information exploitation in spear-phishing attacks.

Many cyberattacks begin with a malicious email message, known as spear phishing, targeted at unsuspecting victims. Although security technologies have improved significantly in recent years, spear phishing continues to be successful due to the bespoke nature of such attacks. Crafting such emails requires attackers to conduct careful research about their victims and collect personal information about them and their acquaintances. Despite the widespread nature of spear-phishing attacks, little is understood about the human factors behind them. This is particularly the case when considering the role of attack personalization on end-user vulnerability. To study spear-phishing attacks in the laboratory, we developed a simulation environment called SpearSim that simulates the tasks involved in the generation and reception of spear-phishing messages. Using SpearSim, we conducted a laboratory experiment with human subjects to study the effect of information availability and information exploitation end-user vulnerability. The results of the experiment show that end-users in the high information-availability condition were 2.97 times more vulnerable to spear-phishing attacks than those in the low information-availability condition. We found that access to more personal information about targets can result in attacks involving contextually meaningful impersonation and narratives. We discuss the implications of this research for the design of anti-phishing training solutions.

Bone marrow stimulation in arthroscopic rotator cuff repair is a cost-effective and straightforward technique to reduce retear rates: A systematic review and meta-analysis.

Background: Bone marrow stimulation (BMS) has been considered a well-established method for treating knee and ankle osteochondral lesions. Some studies have also shown that BMS can promote healing of the repaired tendon and enhance biomechanical properties during rotator cuff repair. Our purpose was to compare the clinical outcomes of arthroscopic repair rotator cuff (ARCR) with and without BMS. Methods: A systematic review with meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). PubMed, Embase, Web of Science, Google scholar, ScienceDirect, and the Cochrane Library were searched from inception to March 20, 2022. Data on retear rates, shoulder functional outcomes, visual analog score and range of motion were pooled and analyzed. Dichotomous variables were presented as odds ratios (OR), and continuous variables were presented as mean differences (MD). Meta-analyses were conducted with Review Manager 5.3. Results: Eight studies involving 674 patients were included, with mean follow-up period ranging from 12 to 36.8 months. Compared to ARCR alone, the intraoperative combination of the BMS resulted in lower retear rates (P < 0.0001), but showed similar results in Constant score (P = 0.10), University of California at Los Angeles (UCLA) score (P = 0.57), American Shoulder and Elbow Surgeons (ASES) score (P = 0.23), Disabilities of the Arm, Shoulder and Hand (DASH) score (P = 0.31), VAS (visual analog score) score (P = 0.34), and range of motion (ROM) (forward flexion, P = 0.42; external rotation, P = 0.21). After sensitivity analyses and subgroup analyses, no significant changes in statistical results were observed. Conclusion: Compared to ARCR alone, the combination of intraoperative BMS can significantly reduce the retear rates, but showed similar short-term results in functional outcomes, ROM and pain. Better clinical outcomes are anticipated in the BMS group by improving structural integrity during long-term follow-up. Currently, BMS may be a viable option in ARCR based on its straightforward and cost-effective advantages. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42022323379.

Donor-Matched Peripheral Blood-Derived Mesenchymal Stem Cells Combined With Platelet-Rich Plasma Synergistically Ameliorate Surgery-Induced Osteoarthritis in Rabbits: An In Vitro and In Vivo Study.

BACKGROUND: Osteoarthritis (OA) is a common disease that causes joint pain and disability. Stem cell therapy is emerging as a promising treatment for OA. PURPOSE: To evaluate the ability of peripheral blood-derived mesenchymal stem cells (PBMSCs) combined with donor-matched platelet-rich plasma (PRP) to treat OA in a rabbit model. STUDY DESIGN: Controlled laboratory study. METHODS: PBMSCs and donor-matched PRP were isolated and prepared from the same rabbit. PBMSCs were treated with serum-free medium, fetal bovine serum, and PRP; a series of PBMSC behaviors, including proliferation, migration, and adhesion, were compared among groups. The ability of PBMSCs or PRP alone and PBMSCs+PRP to protect chondrocytes against proinflammatory cytokine (interleukin 1ß [IL-1ß]) treatment was compared by analyzing reactive oxygen species (ROS)-scavenging ability and apoptosis. Real-time quantitative polymerase chain reaction and immunofluorescence were used to investigate the expression of extracellular matrix (ECM) metabolism genes and proteins, and Western blotting was used to explore the potential mechanism of the corresponding signaling pathway. In vivo, the effect of PBMSCs+PRP on cartilage and inflammation of the synovium was observed in a surgery-induced OA rabbit model via gross observation, histological and immunohistochemical staining, and enzyme-linked immunosorbent assay. RESULTS: Proliferation, migration, and adhesion ability were enhanced in PBMSCs treated with PRP. Moreover, compared with either PBMSCs or PRP alone, PBMSCs+PRP enhanced ROS-scavenging ability and inhibited apoptosis in IL-1ß-treated chondrocytes. PBMSCs+PRP also reversed the IL-1ß-induced degradation of collagen type 2 and aggrecan and increased expression of matrix metalloproteinase 13, and this effect was related to increased expression of ECM synthesis and decreased expression of degradation and inflammatory genes and proteins. Mechanistically, PBMSCs+PRP reduced the phosphorylation of inhibitor of nuclear factor-κBα (IκBα), which further inhibited the phosphorylation of downstream nuclear factor-κB (NF-κB) in the NF-κB signaling pathway. In vivo, compared with PBMSCs or PRP alone, intra-articular (IA) injection of PBMSCs+PRP enhanced cartilage regeneration and attenuated synovial inflammation in OA-induced rabbits. CONCLUSION: These results demonstrate that PRP could enhance biological activities, including viability, migration, and adhesion, in PBMSCs. PBMSCs+PRP could rescue ECM degeneration by inhibiting inflammatory signaling in IL-1ß-treated OA chondrocytes. In addition, IA injection of PBMSCs+PRP effectively attenuated OA progression in a surgery-induced OA rabbit model. CLINICAL RELEVANCE: PBMSCs+PRP may provide a promising treatment for knee OA, and this study can advance the related basic research.

Results of Medial Patellofemoral Ligament Reconstruction with and without Tibial Tubercle Transfer in Patellar Instability: A Systematic Review and Meta-Analysis.

The optimal surgical intervention for lateral patellar instability remains a topic of controversy despite satisfactory clinical outcomes and low re-dislocation rates reported in numerous studies following medial patellofemoral ligament reconstruction (MPFLR) with and without tibial tubercle transfer (TTT). The purpose of this systematic review and meta-analysis is to investigate the hypothesis that combining MPFLR with TTT provides reduced complication rates and improved clinical outcomes to isolated MPFLR in patients with lateral patellar instability. We conducted a comprehensive systematic review and meta-analysis of comparative trials involving MPFLR with and without TTT, sourcing data from PubMed, the Cochrane Library, Embase, and Web of Science. The primary clinical outcomes analyzed included the Kujala score, the Lysholm score, complication rates, and the Caton-Deschamps index (CDI). Random or fixed effects were used for the meta-analysis. Postoperatively, there were no significant differences observed in the Kujala and Lysholm scores between MPFLR and MPFLR + TTT (p = 0.053). At the final follow-up, the CDI had decreased 0.015 (95% CI -0.044, 0.013; p = 0.289) points in the MPFLR group, with no statistical significance. In contrast, the MPFLR + TTT group demonstrated a significant decrease of 0.207 (95% CI -0.240, -0.174; p = 0.000) points in CDI. Notably, the complication rate was higher in the MPFLR + TTT group compared to the MPFLR-only group (RR = 2.472; 95% CI 1.638, 3.731; p = 0.000). Both MPFLR and MPFLR + TTT procedures yield significant improvements in the Kujala and Lysholm scores. However, the MPFLR + TTT approach results in an apparent improvement in CDI and corrects patellar maltracking, particularly in cases involving high tibial tuberosity-trochlear groove (TT-TG) (>20 mm) or patella alta (CDI > 1.2), while MPFLR alone cannot. It is essential to consider the higher complication rate of MPFLR + TTT, which suggests that MPFLR alone may be sufficient for patients without high TT-TG or patella alta.

Tibial Tubercle-Trochlear Groove Distance Has Better Diagnostic Reliability Than Tubercle-Posterior Cruciate Ligament Distance For Predicting Patellar Instability: A Systematic Review.

OBJECTIVE: The tibial tubercle-trochlear groove (TT-TG) distance is now routinely utilized to help determine whether a realignment procedure is necessary for patients with patellar instability. The tibial tubercle-posterior cruciate ligament (TT-PCL) distance has been explored as an alternative measurement. The aim of this study is to compare the reliability of TT-TG and TT-PCL; to explore whether there is a relationship between the TT-PCL and the TT-TG distance; to determine whether there is a relationship between the TT-TG and TT-PCL distances and knee rotation; and to compare the abilities of the TT-PCL distance and the TT-TG distance with predicted patellar instability. METHOD: This systematic review was performed in accordance with PRISMA guidelines. Three databases, PubMed, EMBASE, and Cochrane Central Register of Controlled Trials, were searched from inception to September 2021 to identify clinical studies comparing TT-TG and TT-PCL distances to patellar instability. Data on patient baseline characteristics, TT-TG and TT-PCL distances, inter-observer reliability, and area under the receiver-operating characteristic curve (AUC) were recorded. The methodological quality of the studies was assessed using the quality assessment form recommended by the Agency for Healthcare Research and Quality (AHRQ). RESULT: Twenty studies were included in the final analysis, comprising 2330 knees from 2260 patients. The current study showed that TT-TG and TT-PCL have similar observer reliability. The inter- and intra-observer reliability of TT-TG ranged from 0.807 to 0.98 and 0.553 to 0.99, respectively. The inter- and intra-observer reliability of TT-PCL ranged from 0.553 to 0.99 and 0.88 to 0.981, respectively. Six studies compared the AUC for predicting patellar instability and showed that TT-TG had better predictive performance than TT-PCL. Three studies reported a correlation between TT-TG and knee rotation, but no such relationship was found for TT-PCL. Eight studies reported a weak or moderate correlation between TT-TG and TT-PCL. CONCLUSION: TT-TG and TT-PCL have similar inter- and intra-rater reliability (as measured by ICC), but TT-TG has greater discriminatory power to predict patellar instability than TT-PCL (as measured by AUC values and odds ratio). However, considering trochlear dysplasia and individual variations, future studies need to find more accurate and individualized methods to predict patellar instability.