BACKGROUND: T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction. METHODS: A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models. RESULTS: In vitro , blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg -1 ·day -1 ) and Rapamycin (0.1 mg·kg -1 ·day -1 ) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression. CONCLUSIONS Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.
Animals ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Interferon Regulatory Factors/metabolism* ; Heart Transplantation/methods* ; T-Lymphocytes/immunology* ; Sirolimus/therapeutic use* ; Pyridones/therapeutic use* ; Graft Survival/drug effects* ; Pyrimidinones/therapeutic use* ; Cell Proliferation/drug effects* ; Apoptosis/drug effects* ; Male ; Signal Transduction/drug effects*

Objective To explore the correlation of MET status in patients with advanced prostatic acinar adenocarcinoma with the clinical pathological parameters and prognosis. Methods The specimen from 135 patients with advanced prostatic acinar adenocarcinoma was included. The expression of c-MET protein was detected via immunohistochemistry, and MET gene amplification was assessed by fluorescence in situ hybridization. The relationships of c-MET expression and gene amplification with clinicopathological features and prognosis were analyzed. Results The positive expression rate of c-MET was 52.60% (71/135). Compared with the c-MET expression in adjacent tissues, that in tumor tissues showed lower heterogeneous expression. Among the cases, 1.71% (2/117) exhibited MET gene polyploidy, but no gene amplification was detected. Positive c-MET expression was significantly correlated with high Gleason scores and grade groups (P=0.0073). However, no significant relationship was found between c-MET expression and progression-free survival or post-treatment t-PSA levels. Conclusion c-MET protein is expressed at a relatively low level in advanced prostatic acinar adenocarcinoma, suggesting that c-MET may not be a viable target for ADC drug development in prostatic acinar adenocarcinoma.

Objective To explore the safety and effects of alpha-lipoic acid (ALA) in patients with ischemic heart failure (IHF). Methods A randomized, double-blind, placebo-controlled trial was designed (ClinicalTrial.gov registration number NCT03491969). From January 2019 to January 2023, 300 patients with IHF were enrolled in four medical centers in China, and were randomly assigned at a 1∶1 ratio to receive ALA (600 mg daily) or placebo on top of standard care for 24 months. The primary outcome was the composite outcome of hospitalization for heart failure (HF) or all-cause mortality events. The second outcome included non-fatal myocardial infarction (MI), non-fatal stroke, changes of left ventricular ejection fraction (LVEF) and 6-minute walking distance (6MWD) from baseline to 24 months after randomization. Results Finally, 138 patients of the ALA group and 139 patients of the placebo group attained the primary outcome. Hospitalization for HF or all-cause mortality events occurred in 32 patients (23.2%) of the ALA group and in 40 patients (28.8%) of the placebo group (HR＝0.753, 95%CI 0.473-1.198, P＝0.231; Figure 1A-1C). The absolute risk reduction (ARR) was 5.6%, the relative risk reduction (RRR) associated with ALA therapy was approximately 19.4% compared to placebo, corresponding to a number needed to treat (NNT) of 18 patients to prevent one event. In the secondary outcome analysis, the composite outcome of the major adverse cardiovascular events (MACE) including the hospitalization for HF, all-cause mortality events, non-fatal MI or non-fatal stroke occurred in 35 patients (25.4%) in the ALA group and 47 patients (33.8%) in the placebo group (HR＝0.685, 95%CI 0.442-1.062, P＝0.091; Figure 1D). Moreover, greater improvement in LVEF (β＝3.20, 95%CI 1.14-5.23, P＝0.002) and 6MWD (β＝31.7, 95%CI 8.3-54.7, P＝0.008) from baseline to 24 months after randomization were observed in the ALA group as compared to the placebo group. There were no differences in adverse events between the study groups. Conclusions These results show potential long-term beneficial effects of adding ALA to IHF patients. ALA could significantly improve LVEF and 6MWD compared to the placebo group in IHF patients.

Traditional Chinese medicine (TCM) represents a paradigmatic approach to personalized medicine, developed through the systematic accumulation and refinement of clinical empirical data over more than 2000 years, and now encompasses large-scale electronic medical records (EMR) and experimental molecular data. Artificial intelligence (AI) has demonstrated its utility in medicine through the development of various expert systems (e.g., MYCIN) since the 1970s. With the emergence of deep learning and large language models (LLMs), AI's potential in medicine shows considerable promise. Consequently, the integration of AI and TCM from both clinical and scientific perspectives presents a fundamental and promising research direction. This survey provides an insightful overview of TCM AI research, summarizing related research tasks from three perspectives: systems-level biological mechanism elucidation, real-world clinical evidence inference, and personalized clinical decision support. The review highlights representative AI methodologies alongside their applications in both TCM scientific inquiry and clinical practice. To critically assess the current state of the field, this work identifies major challenges and opportunities that constrain the development of robust research capabilities-particularly in the mechanistic understanding of TCM syndromes and herbal formulations, novel drug discovery, and the delivery of high-quality, patient-centered clinical care. The findings underscore that future advancements in AI-driven TCM research will rely on the development of high-quality, large-scale data repositories; the construction of comprehensive and domain-specific knowledge graphs (KGs); deeper insights into the biological mechanisms underpinning clinical efficacy; rigorous causal inference frameworks; and intelligent, personalized decision support systems.
Medicine, Chinese Traditional/methods* ; Artificial Intelligence ; Humans ; Precision Medicine ; Decision Support Systems, Clinical

To apply electrical impedance tomography (EIT) technology to assess the lung regional ventilation distribution in patients admitted to the intensive care unit (ICU) after a cardiac surgery, and to analyze its value of predicting patients' short-term prognosis.

Objective Recent studies have indicated potential anti-inflammatory effects of glucagon-like peptide-1 receptor agonists(GLP-1RAs)on asthma,which is often comorbid with type 2 diabetes mellitus(T2DM)and obesity.Therefore,we conducted a meta-analysis to assess the association between the administration of glucagon-like peptide-1(GLP-1)receptor-based agonists and the incidence of asthma in patients with T2DM and/or obesity. Methods PubMed,Web of Science,Embase,the Cochrane Central Register of Controlled Trials,and Clinicaltrial.gov were systematically searched from inception to July 2023.Randomized controlled trials(RCTs)of GLP-1 receptor-based agonists(GLP-1RA,GLP-1 based dual and triple receptor agonist)with reports of asthma events were included.Outcomes were computed as risk ratios(RR)using a fixed-effects model. Results Overall,39 RCTs with a total of 85,755 participants were included.Compared to non-GLP-1 receptor-based agonist users,a trend of reduced risk of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments,although the difference was not statistically significant[RR=0.91,95%confidence interval(CI):0.68 to 1.24].Further Subgroup analyses indicated that the use of light-molecular-weight GLP-1RAs might be associated with a reduced the risk of asthma when compared with non-users(RR=0.65,95%CI:0.43 to 0.99,P=0.043).We also performed sensitivity analyses for participant characteristics,study design,drug structure,duration of action,and drug subtypes.However,no significant associations were observed. Conclusion Compared with non-users,a modest reduction in the incidence of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments.Further investigations are warranted to assess the association between GLP-1 receptor-based agonists and the risk of asthma.

Objective:To compare the diagnostic efficacy of ultrasound and MRI in fibro-adipose vascular anomaly (FAVA).Methods:The clinical data of patients with suspected FAVA who underwent ultrasound and MRI examinations at Henan Provincial People’s Hospital from January 2011 to October 2021 were retrospectively analyzed. The imaging findings from ultrasound and MRI were analyzed, and then compared with the pathological findings. To evaluate the diagnostic efficacy of ultrasound and MRI in diagnosing FAVA by assessing sensitivity, specificity, positive predictive value, negative predictive value, and coincidence rate. Paired χ2 test (McNemar test) was used to compare the coincidence rate of ultrasound and MRI, as well as their combined diagnosis. A significance level of P < 0.05 was considered statistically significant. Results:A total of 50 patients were included in the study, comprising 24 males and 26 females, with their ages ranging from 1 to 50 years and an average age of (16.2 ± 10.5) years. Pathology confirmed 43 FAVA patients and 7 non-FAVA patients. The sensitivity, specificity, positive predictive value, negative predictive value, and coincidence rate of ultrasound in the diagnosis of FAVA were 83.7%, 71.4%, 94.7%, 41.7%, and 82.0%, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and coincidence rate of MRI in the diagnosis of FAVA were 69.8%, 85.7%, 96.8%, 31.6%, and 72.0%, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and coincidence rate of FAVA were 90.7%, 71.4%, 95.1%, 55.6%, and 88.0%, respectively. The diagnostic accuracy of ultrasound was higher than that of MRI, but the difference was not statistically significant ( χ2 = 1.41, P = 0.235). The coincidence rate of combined diagnosis was higher than that of ultrasound ( χ2= 0.71, P = 0.401) and MRI ( χ2= 4.00, P = 0.039), with a statistically significant difference. Conclusion:Both ultrasound and MRI are highly valuable in diagnosing FAVA. The combined usage of ultrasound and MRI can enhance the accuracy of preoperative FAVA diagnosis.

Objective:To compare the diagnostic efficacy of ultrasound and MRI in fibro-adipose vascular anomaly (FAVA).Methods:The clinical data of patients with suspected FAVA who underwent ultrasound and MRI examinations at Henan Provincial People’s Hospital from January 2011 to October 2021 were retrospectively analyzed. The imaging findings from ultrasound and MRI were analyzed, and then compared with the pathological findings. To evaluate the diagnostic efficacy of ultrasound and MRI in diagnosing FAVA by assessing sensitivity, specificity, positive predictive value, negative predictive value, and coincidence rate. Paired χ2 test (McNemar test) was used to compare the coincidence rate of ultrasound and MRI, as well as their combined diagnosis. A significance level of P < 0.05 was considered statistically significant. Results:A total of 50 patients were included in the study, comprising 24 males and 26 females, with their ages ranging from 1 to 50 years and an average age of (16.2 ± 10.5) years. Pathology confirmed 43 FAVA patients and 7 non-FAVA patients. The sensitivity, specificity, positive predictive value, negative predictive value, and coincidence rate of ultrasound in the diagnosis of FAVA were 83.7%, 71.4%, 94.7%, 41.7%, and 82.0%, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and coincidence rate of MRI in the diagnosis of FAVA were 69.8%, 85.7%, 96.8%, 31.6%, and 72.0%, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and coincidence rate of FAVA were 90.7%, 71.4%, 95.1%, 55.6%, and 88.0%, respectively. The diagnostic accuracy of ultrasound was higher than that of MRI, but the difference was not statistically significant ( χ2 = 1.41, P = 0.235). The coincidence rate of combined diagnosis was higher than that of ultrasound ( χ2= 0.71, P = 0.401) and MRI ( χ2= 4.00, P = 0.039), with a statistically significant difference. Conclusion:Both ultrasound and MRI are highly valuable in diagnosing FAVA. The combined usage of ultrasound and MRI can enhance the accuracy of preoperative FAVA diagnosis.

Objective To assess the value of cardiac magnetic resonance(CMR)imaging for predicting adverse left ventricular remodeling in patients with ST-segment elevation myocardial infarction(STEMI).Methods We retrospectively analyzed the clinical data and serial CMR(cine and LGE sequences)images of 86 STEMI patients within 1 week and 5 months after percutaneous coronary intervention(PCI),including 25 patients with adverse LV remodeling and 61 without adverse LV remodeling,defined as an increase of left ventricular end-systolic volume(LVESV)over 15%at the second CMR compared to the initial CMR.The CMR images were analyzed for LV volume,infarct characteristics,and global and infarct zone myocardial function.The independent predictors of adverse LV remodeling following STEMI were analyzed using univariate and multivariate Logistic regression methods.Results The initial CMR showed no significant differences in LV volume or LV ejection fraction(LVEF)between the two groups,but the infarct mass and microvascular obstructive(MVO)mass were significantly greater in adverse LV remodeling group(P<0.05).Myocardial injury and cardiac function of the patients recovered over time in both groups.At the second CMR,the patients with adverse LV remodeling showed a significantly lower LVEF,a larger left ventricular end-systolic volume index(LVESVI)and a greater extent of infarct mass(P<0.001)with lower global peak strains and strain rates in the radial,circumferential,and longitudinal directions(P<0.05),infarct zone peak strains in the 3 directions,and infarct zone peak radial and circumferential strain rates(P<0.05).The independent predictors for adverse LV remodeling following STEMI included the extent of infarct mass(AUC=0.793,95%CI:0.693-0.873;cut-off value:30.67%),radial diastolic peak strain rate(AUC=0.645,95%CI:0.534-0.745;cut-off value:0.58%),and RAAS inhibitor(AUC= 0.699,95%CI:0.590-0.793).Conclusion The extent of infarct mass,peak radial diastolic strain rate,and RAAS inhibitor are independent predictors of adverse LV remodeling following STEMI.

Objective To analyze the causal relationship of gluteal tendinitis and primary coxarthrosis with the occurrence of iliotibial band syndrome using Mendelian randomization.Methods The GWAS data of gluteal tendinitis,primary coxarthrosis and iliotibial band syndrome were screened for high correlation single-nucleotide polymorphisms(SNPs).Mendelian randomization analysis was performed using random-effects inverse variance weighting(IVW),MR-Egger regression,and weighted median method to determine whether gluteal tendinitis and primary coxarthrosis were causally related with iliotibial band syndrome.Heterogeneity test,multiple validity test and sensitivity analysis,and clinical data analysis were used to verify the reliability of the results.Results Both gluteal tendinitis[IVW:OR(95%CI)=1.32(1.03-1.68),P=0.026]and primary coxarthrosis[IVW:OR(95%CI)=1.40(1.06-1.84),P=0.017]was positively correlated with iliotibial band syndrome.Conclusion Gluteal tendinitis and primary coxarthrosis may increase the risk of iliotibial band syndrome.