Inference of Developmental Hierarchy and Functional States of Exhausted T Cells from Epigenetic Profiles with Deep Learning.

Exhausted T cells are a key component of immune cells that play a crucial role in the immune response against cancer and influence the efficacy of immunotherapy. Accurate assessment and measurement of T-cell exhaustion (TEX) are critical for understanding the heterogeneity of TEX in the tumor microenvironment (TME) and tailoring individualized immunotherapeutic strategies. In this study, we introduced DeepEpiTEX, a novel computational framework based on deep neural networks, for inferring the developmental hierarchy and functional states of exhausted T cells in the TME from epigenetic profiles. DeepEpiTEX was trained using various modalities of epigenetic data, including DNA methylation data, microRNA expression data, and long non-coding RNA expression data from 30 bulk solid cancer types in the TCGA pan-cancer cohort, and identified five optimal TEX subsets with significant survival differences across the majority of cancer types. The performance of DeepEpiTEX was further evaluated and validated in external multi-center and multi-type cancer cohorts, consistently demonstrating its generalizability and applicability in different experimental settings. In addition, we discovered the potential relationship between TEX subsets identified by DeepEpiTEX and the response to immune checkpoint blockade therapy, indicating that individuals with immune-favorable TEX subsets may experience the greatest benefits. In conclusion, our study sheds light on the role of epigenetic regulation in TEX and provides a powerful and promising tool for categorizing TEX in different disease settings.

Genetic Insights into the Association and Causality Between Blood Metabolites and Alzheimer's Disease.

Background: Alzheimer's disease (AD) is an increasing public health concern with the aging of the global population. Understanding the genetic correlation and potential causal relationships between blood metabolites and AD may provide important insights into the metabolic dysregulation underlying this neurodegenerative disorder. Objective: The aim of this study was to investigate the causal relationship between blood metabolites and AD using Mendelian randomization (MR) analysis. Methods: Association data were obtained from three large-scale genome-wide association studies of 486 blood metabolites (N = 7,824), AD (71,880 cases and 383,378 controls), early-onset AD (N = 303,760), and late-onset AD (N = 307,112). Causal associations between blood metabolites and AD were assessed using inverse variance weighting (IVW), MR-Egger, and weighted median methods. Bidirectional two-sample MR analysis was used to identify causal blood metabolites. MR-PRESSO, MR-Egger, and Cochran-Q were used to quantify instrumental variable heterogeneity and horizontal pleiotropy. Results: Using MR and sensitivity analysis, we identified 40 blood metabolites with potential causal associations with AD. After applying false discovery rate (FDR) correction, two metabolites, gamma-glutamylphenylalanine (OR = 1.15, 95% CI: 1.06-1.24, p = 3.88×10-4, q = 0.09) and X-11317 (OR = 1.16, 95% CI: 1.08-1.26, p = 1.14×10-4, q = 0.05), retained significant associations with AD. Reverse MR analysis indicated no significant causal effect of AD on blood metabolites. No significant instrumental variable heterogeneity or horizontal pleiotropy was found. Conclusions: This two-sample MR study provides compelling evidence for a potential causal relationship between blood metabolic dysregulation and susceptibility to AD. Further investigation of the biological relevance of the identified metabolites to AD and additional supporting evidence is warranted.

Deep learning identifies a T-cell exhaustion-dependent transcriptional signature for predicting clinical outcomes and response to immune checkpoint blockade.

Immune checkpoint blockade (ICB) therapies have brought unprecedented advances in cancer treatment, but responses are limited to a fraction of patients. Therefore, sustained and substantial efforts are required to advance clinical and translational investigation on managing patients receiving ICB. In this study, we investigated the dynamic changes in molecular profiles of T-cell exhaustion (TEX) during ICB treatment using single-cell and bulk transcriptome analysis, and demonstrated distinct exhaustion molecular profiles associated with ICB response. By applying an ensemble deep-learning computational framework, we identified an ICB-associated transcriptional signature consisting of 16 TEX-related genes, termed ITGs. Incorporating 16 ITGs into a machine-learning model called MLTIP achieved reliable predictive power for clinical ICB response with an average AUC of 0.778, and overall survival (pooled HR = 0.093, 95% CI, 0.031-0.28, P < 0.001) across multiple ICB-treated cohorts. Furthermore, the MLTIP consistently demonstrated superior predictive performance compared to other well-established markers and signatures, with an average increase in AUC of 21.5%. In summary, our results highlight the potential of this TEX-dependent transcriptional signature as a tool for precise patient stratification and personalized immunotherapy, with clinical translation in precision medicine.

Analysis of Dynamics of Recurrent Epidemics: Periodic or Non-periodic.

The periodic behaviors and non-periodic behaviors of recurrent epidemic are discussed by building an SIS model with disease age structure and infectious delay. We formulate the model as an abstract non-densely defined Cauchy problem and derive the conditions for the existence of Hopf bifurcation under the condition where endemic equilibrium is unstable. It implies that the recurrent epidemics will switch between periodic behavior and non-periodic behavior as the parameter values changing when the disease persists in population. The numerical examples are provided to illustrate our theoretical results.

Cellular uptake mechanism and clearance kinetics of fluorescence-labeled glycyrrhetinic acid and glycyrrhetinic acid-modified liposome in hepatocellular carcinoma cells.

Glycyrrhetinic acid (GA) is a natural pentacyclic triterpene derivative that exerts significant effects in the suppression of liver cancer. The receptors of GA on liver cells and hepatocellular carcinoma (HCC) cells have drawn broad attention. The effects of GA might depend on its transport into and out of cells. However, the question has not been previously addressed despite its obvious and fundamental importance. In this paper, GA and GA-modified liposome (GA-Lip) were labeled with fluorescein isothiocyanate (FITC) or coumarin 6 (Cou6) using chemical or pharmaceutical techniques. The transport courses of FITC-GA and GA-Cou6-Lip were studied in HepG2 cells in vitro. We found that the fluorescence labeled GA and GA-Lip uptake and clearance were time-dependent. FITC-GA uptake involved passive diffusion and active transport, and the receptors were in the cytomembrane proteins. GA-Cou6-Lip uptake was mediated by caveolae-dependent endocytosis. In addition, FITC-GA and GA-Cou6-Lip clearance of the HCC cells fitted exponential decay and second-order processes, respectively. These findings provide new insights into the anti-HCC actions of GA.

Patient-specific instrumentation does not improve accuracy in total knee arthroplasty.

Patient-specific instrumentation (PSI) has been introduced as a tool to increase the accuracy of total knee arthroplasty (TKA) compared with conventional instrumentation (CLI). However, previous studies have shown inconsistent results. The authors conducted a meta-analysis to compare the performance of PSI to CLI in TKA. PubMed, EMBASE, and Cochrane Central Register of Controlled Trials electronic databases were systematically searched to identify eligible trials published between 2000 and March 2014. Two reviewers independently assessed methodological quality according to the Cochrane Handbook. Subgroup analyses were performed based on the different study designs (randomized, controlled trial [RCT] vs non-randomized, controlled trial [non-RCT]), preoperative magnetic resonance imaging vs computed tomography, and systems of PSI to explore the source of heterogeneity. Fourteen studies (7 RCTs and 7 non-RCTs) involving 1906 patients were included. There were no statistical differences with respect to the outliers of mechanical axis, coronal femoral component, sagittal femoral component, femoral component rotation, operative time, blood loss, and length of hospital stay between PSI and CLI groups. The number of outliers in coronal tibial components (odds ratio, 2.29; 95% confidence interval, 1.20 to 4.35; P=.01) and sagittal tibial components (odds ratio, 1.67; 95% confidence interval, 1.16 to 2.42; P<.01) was significantly lower in the CLI group than in the PSI group. Based on the numbers available, the use of PSI compared with CLI was not likely to improve the accuracy of component alignment and treatment effects of TKA. Further high-quality RCTs are warranted to confirm the authors' results.

Does immobilization after arthroscopic rotator cuff repair increase tendon healing? A systematic review and meta-analysis.

INTRODUCTION: To determine whether immobilization after arthroscopic rotator cuff repair improved tendon healing compared with early passive motion. MATERIALS AND METHODS: A systematic electronic literature search was conducted to identify randomized controlled trials (RCTs) comparing early passive motion with immobilization after arthroscopic rotator cuff repair. The primary outcome assessed was tendon healing in the repaired cuff. Secondary outcome measures were range of motion (ROM) and American Shoulder and Elbow Surgeons (ASES) shoulder scale, Simple Shoulder Test (SST), Constant, and visual analog scale (VAS) for pain scores. Pooled analyses were performed using a random effects model to obtain summary estimates of treatment effect with 95% confidence intervals. Heterogeneity among included studies was quantified. RESULTS: Three RCTs examining 265 patients were included. Meta-analysis revealed no significant difference in tendon healing in the repaired cuff between the early-motion and immobilization groups. A significant difference in external rotation at 6 months postoperatively favored early motion over immobilization, but no significant difference was observed at 1 year postoperatively. In one study, Constant scores were slightly higher in the early-motion group than in the immobilization group. Two studies found no significant difference in ASES, SST, or VAS score between groups. CONCLUSION: We found no evidence that immobilization after arthroscopic rotator cuff repair was superior to early-motion rehabilitation in terms of tendon healing or clinical outcome. Patients in the early-motion group may recover ROM more rapidly. LEVEL OF EVIDENCE: Level II; systematic review of levels I and II studies.

[Effectiveness of cervical disc replacement for cervical myelopathy].

OBJECTIVE: To evaluate the effectiveness of cervical disc replacement for cervical myelopathy. METHODS: Between October 2006 and October 2008, 20 patients (26 segments) with cervical myelopathy underwent single-level (14 segments) or bi-level (6 segments) cervical disc replacement. There were 8 males and 12 females with an average age of 46 years (range, 26-65 years). The disease duration ranged 2-18 months (mean, 7 months). The effectiveness was evaluated using visual analogue scale (VAS) score, cervical range of motion (ROM), and the Odom et al. criteria. Heterotopic ossification (HO), osteophyte formation, and prosthesis loosening were observed. RESULTS: All incisions healed by first intention, with no severe complication. Twenty patients were followed up 30-48 months (mean, 34 months). At 28 months after operation, according to Odom et al, criteria, the results were excellent in 17 cases and good in 3 cases. The VAS scores of the neck, shoulder, and upper limb were significantly improved when compared with preoperative scores (P < 0.05). At 30 months after operation, X-ray films showed that 20 replaced segments were mobile and ROM was (10.6 +/- 4.5) degrees, showing no significant difference (P > 0.05) when compared with that of upper adjacent segment (10.8 +/- 3.7) degrees and lower adjacent segment (7.5 +/- 4.2) degrees. HO occurred in 10 cases (13 segments). No displacement, subsidence, or loosening occurred except 1 case of retrodisplacement of the prosthesis. CONCLUSION: Cervical disc replacement can obtain good effectiveness. It can maintain normal cervical ROM and physiological curvature. But it needs further long-term follow-up to evaluate the function and the influence on the adjacent segments.

[Problems and solutions in minimally invasive process of posterior discectomy for lumbar disc herniation].

OBJECTIVE: To analyze the problems and complications of posterior discectomy for lumbar disc herniation. METHODS: From January 2005 to June 2010, 497 patients with lumbar disc herniation were treated by posterior discectomy, which data were analyzed retrospectively. There were 395 males and 102 females,ranging in age from 20 to 78 years with an average of 43.7 years. Among them, 405 cases were in single gap, 86 cases were in double gaps and 6 cases were in three gaps. The complication of operation and solution was analyzed. RESULTS: The mean operative time was 70 min (from 45 to 210 min), and the mean hospitalization was 10 d (from 5 to 20 d). Forty-seven cases suffered operative complications. There were 16 cases of wrong location of segments (14 cases occurred in operation and 2 occurred after operation), 15 cases of less alleviation or aggravation of nerve symptoms (12 cases were poor alleviation and 3 cases were aggravation), 10 cases of urinary retention, 5 cases of cerebrospinal fluid leakage and 1 case of infection. CONCLUSION: Minimally invasive process of posterior discectomy in treating lumbar disc herniation may complicate with many problems. The operative effects can be improved and the complication can be decreased if the ability of location is improved,surgical indications is correct and the operation is exactly performed.