Hepatocellular carcinoma （HCC） is a common malignant tumor with a high mortality rate， an insidious onset， and complex pathological mechanisms. In the tumor microenvironment， tumor-promoting immune cells protect tumor cells from immune attacks， while dysfunction of anti-tumor immune cells causes the inhibition of immune response， thereby leading to the continuous deterioration of cancer. In recent years， traditional Chinese medicine has shown good efficacy in the treatment of HCC， and it can inhibit the proliferation and metastasis of cancer cells by regulating immune cells. By analyzing related articles in China and globally， this article summarizes how immune cells affect the progression of HCC through the immunosuppressive pathway and how traditional Chinese medicine exerts an anti-HCC effect by regulating immune cells， in order to provide theoretical basis and reference for optimizing the treatment of HCC.

Objective: To explore glymphatic impairment in pediatric refractory epilepsy (RE) using multi-parameter magnetic resonance imaging (MRI), assess its relationship with white-matter (WM) abnormalities and clinical indicators, and preliminarily evaluate the performance of multi-parameter MRI in discriminating RE from drug-sensitive epilepsy (DSE). Materials and Methods: We retrospectively included 70 patients with DSE (mean age, 9.7 ± 3.5 years; male:female, 37:33) and 26 patients with RE (9.0 ± 2.9 years; male:female, 12:14). The diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index as well as fractional anisotropy (FA), mean diffusivity (MD), and nodal efficiency values were measured and compared between patients with RE and DSE. With sex and age as covariables, differences in the FA and MD values were analyzed using tract-based spatial statistics, and nodal efficiency was analyzed using a linear model. Pearson’s partial correlation was analyzed. Receiver operating characteristic (ROC) curves were used to evaluate the discrimination performance of the MRI-based machine-learning models through five-fold cross-validation. Results: In the RE group, FA decreased and MD increased in comparison with the corresponding values in the DSE group, and these differences mainly involved the callosum, right and left corona radiata, inferior and superior longitudinal fasciculus, and posterior thalamic radiation (threshold-free cluster enhancement, P < 0.05). The RE group also showed reduced nodal efficiency, which mainly involved the limbic system, default mode network, and visual network (false discovery rate, P < 0.05), and significantly lower DTI-ALPS index (F = 2.0, P = 0.049). The DTI-ALPS index was positively correlated with FA (0.25 ≤ r ≤ 0.32) and nodal efficiency (0.22 ≤ r ≤ 0.37), and was negatively correlated with the MD (-0.24 ≤ r≤ -0.34) and seizure frequency (r = -0.47). A machine-learning model combining DTI-ALPS, FA, MD, and nodal efficiency achieved a cross-validated ROC curve area of 0.83 (sensitivity, 78.2%; specificity, 84.8%). Conclusion Pediatric patients with RE showed impaired glymphatic function in comparison with patients with DSE, which was correlated with WM abnormalities and seizure frequency. Multi-parameter MRI may be feasible for distinguishing RE from DSE.

Objective: To explore glymphatic impairment in pediatric refractory epilepsy (RE) using multi-parameter magnetic resonance imaging (MRI), assess its relationship with white-matter (WM) abnormalities and clinical indicators, and preliminarily evaluate the performance of multi-parameter MRI in discriminating RE from drug-sensitive epilepsy (DSE). Materials and Methods: We retrospectively included 70 patients with DSE (mean age, 9.7 ± 3.5 years; male:female, 37:33) and 26 patients with RE (9.0 ± 2.9 years; male:female, 12:14). The diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index as well as fractional anisotropy (FA), mean diffusivity (MD), and nodal efficiency values were measured and compared between patients with RE and DSE. With sex and age as covariables, differences in the FA and MD values were analyzed using tract-based spatial statistics, and nodal efficiency was analyzed using a linear model. Pearson’s partial correlation was analyzed. Receiver operating characteristic (ROC) curves were used to evaluate the discrimination performance of the MRI-based machine-learning models through five-fold cross-validation. Results: In the RE group, FA decreased and MD increased in comparison with the corresponding values in the DSE group, and these differences mainly involved the callosum, right and left corona radiata, inferior and superior longitudinal fasciculus, and posterior thalamic radiation (threshold-free cluster enhancement, P < 0.05). The RE group also showed reduced nodal efficiency, which mainly involved the limbic system, default mode network, and visual network (false discovery rate, P < 0.05), and significantly lower DTI-ALPS index (F = 2.0, P = 0.049). The DTI-ALPS index was positively correlated with FA (0.25 ≤ r ≤ 0.32) and nodal efficiency (0.22 ≤ r ≤ 0.37), and was negatively correlated with the MD (-0.24 ≤ r≤ -0.34) and seizure frequency (r = -0.47). A machine-learning model combining DTI-ALPS, FA, MD, and nodal efficiency achieved a cross-validated ROC curve area of 0.83 (sensitivity, 78.2%; specificity, 84.8%). Conclusion Pediatric patients with RE showed impaired glymphatic function in comparison with patients with DSE, which was correlated with WM abnormalities and seizure frequency. Multi-parameter MRI may be feasible for distinguishing RE from DSE.

Objective: To explore glymphatic impairment in pediatric refractory epilepsy (RE) using multi-parameter magnetic resonance imaging (MRI), assess its relationship with white-matter (WM) abnormalities and clinical indicators, and preliminarily evaluate the performance of multi-parameter MRI in discriminating RE from drug-sensitive epilepsy (DSE). Materials and Methods: We retrospectively included 70 patients with DSE (mean age, 9.7 ± 3.5 years; male:female, 37:33) and 26 patients with RE (9.0 ± 2.9 years; male:female, 12:14). The diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index as well as fractional anisotropy (FA), mean diffusivity (MD), and nodal efficiency values were measured and compared between patients with RE and DSE. With sex and age as covariables, differences in the FA and MD values were analyzed using tract-based spatial statistics, and nodal efficiency was analyzed using a linear model. Pearson’s partial correlation was analyzed. Receiver operating characteristic (ROC) curves were used to evaluate the discrimination performance of the MRI-based machine-learning models through five-fold cross-validation. Results: In the RE group, FA decreased and MD increased in comparison with the corresponding values in the DSE group, and these differences mainly involved the callosum, right and left corona radiata, inferior and superior longitudinal fasciculus, and posterior thalamic radiation (threshold-free cluster enhancement, P < 0.05). The RE group also showed reduced nodal efficiency, which mainly involved the limbic system, default mode network, and visual network (false discovery rate, P < 0.05), and significantly lower DTI-ALPS index (F = 2.0, P = 0.049). The DTI-ALPS index was positively correlated with FA (0.25 ≤ r ≤ 0.32) and nodal efficiency (0.22 ≤ r ≤ 0.37), and was negatively correlated with the MD (-0.24 ≤ r≤ -0.34) and seizure frequency (r = -0.47). A machine-learning model combining DTI-ALPS, FA, MD, and nodal efficiency achieved a cross-validated ROC curve area of 0.83 (sensitivity, 78.2%; specificity, 84.8%). Conclusion Pediatric patients with RE showed impaired glymphatic function in comparison with patients with DSE, which was correlated with WM abnormalities and seizure frequency. Multi-parameter MRI may be feasible for distinguishing RE from DSE.

BACKGROUND: Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. METHODS: This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. RESULTS: Eighty-two patients were assigned to variant ( n  = 42) and wild type groups ( n  = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUC tau ) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. CONCLUSION: ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. REGISTRATION NCT04410965, https://clinicaltrials.gov .
Humans ; Crotonates/adverse effects* ; Toluidines/adverse effects* ; Nitriles ; Hydroxybutyrates ; Female ; Male ; Adult ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics* ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/genetics* ; Prospective Studies ; Young Adult ; Neoplasm Proteins/genetics* ; East Asian People

Objective: To explore glymphatic impairment in pediatric refractory epilepsy (RE) using multi-parameter magnetic resonance imaging (MRI), assess its relationship with white-matter (WM) abnormalities and clinical indicators, and preliminarily evaluate the performance of multi-parameter MRI in discriminating RE from drug-sensitive epilepsy (DSE). Materials and Methods: We retrospectively included 70 patients with DSE (mean age, 9.7 ± 3.5 years; male:female, 37:33) and 26 patients with RE (9.0 ± 2.9 years; male:female, 12:14). The diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index as well as fractional anisotropy (FA), mean diffusivity (MD), and nodal efficiency values were measured and compared between patients with RE and DSE. With sex and age as covariables, differences in the FA and MD values were analyzed using tract-based spatial statistics, and nodal efficiency was analyzed using a linear model. Pearson’s partial correlation was analyzed. Receiver operating characteristic (ROC) curves were used to evaluate the discrimination performance of the MRI-based machine-learning models through five-fold cross-validation. Results: In the RE group, FA decreased and MD increased in comparison with the corresponding values in the DSE group, and these differences mainly involved the callosum, right and left corona radiata, inferior and superior longitudinal fasciculus, and posterior thalamic radiation (threshold-free cluster enhancement, P < 0.05). The RE group also showed reduced nodal efficiency, which mainly involved the limbic system, default mode network, and visual network (false discovery rate, P < 0.05), and significantly lower DTI-ALPS index (F = 2.0, P = 0.049). The DTI-ALPS index was positively correlated with FA (0.25 ≤ r ≤ 0.32) and nodal efficiency (0.22 ≤ r ≤ 0.37), and was negatively correlated with the MD (-0.24 ≤ r≤ -0.34) and seizure frequency (r = -0.47). A machine-learning model combining DTI-ALPS, FA, MD, and nodal efficiency achieved a cross-validated ROC curve area of 0.83 (sensitivity, 78.2%; specificity, 84.8%). Conclusion Pediatric patients with RE showed impaired glymphatic function in comparison with patients with DSE, which was correlated with WM abnormalities and seizure frequency. Multi-parameter MRI may be feasible for distinguishing RE from DSE.

Objective: To explore glymphatic impairment in pediatric refractory epilepsy (RE) using multi-parameter magnetic resonance imaging (MRI), assess its relationship with white-matter (WM) abnormalities and clinical indicators, and preliminarily evaluate the performance of multi-parameter MRI in discriminating RE from drug-sensitive epilepsy (DSE). Materials and Methods: We retrospectively included 70 patients with DSE (mean age, 9.7 ± 3.5 years; male:female, 37:33) and 26 patients with RE (9.0 ± 2.9 years; male:female, 12:14). The diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index as well as fractional anisotropy (FA), mean diffusivity (MD), and nodal efficiency values were measured and compared between patients with RE and DSE. With sex and age as covariables, differences in the FA and MD values were analyzed using tract-based spatial statistics, and nodal efficiency was analyzed using a linear model. Pearson’s partial correlation was analyzed. Receiver operating characteristic (ROC) curves were used to evaluate the discrimination performance of the MRI-based machine-learning models through five-fold cross-validation. Results: In the RE group, FA decreased and MD increased in comparison with the corresponding values in the DSE group, and these differences mainly involved the callosum, right and left corona radiata, inferior and superior longitudinal fasciculus, and posterior thalamic radiation (threshold-free cluster enhancement, P < 0.05). The RE group also showed reduced nodal efficiency, which mainly involved the limbic system, default mode network, and visual network (false discovery rate, P < 0.05), and significantly lower DTI-ALPS index (F = 2.0, P = 0.049). The DTI-ALPS index was positively correlated with FA (0.25 ≤ r ≤ 0.32) and nodal efficiency (0.22 ≤ r ≤ 0.37), and was negatively correlated with the MD (-0.24 ≤ r≤ -0.34) and seizure frequency (r = -0.47). A machine-learning model combining DTI-ALPS, FA, MD, and nodal efficiency achieved a cross-validated ROC curve area of 0.83 (sensitivity, 78.2%; specificity, 84.8%). Conclusion Pediatric patients with RE showed impaired glymphatic function in comparison with patients with DSE, which was correlated with WM abnormalities and seizure frequency. Multi-parameter MRI may be feasible for distinguishing RE from DSE.

ObjectiveTo investigate the triglyceride-glucose (TyG) index and the level of serum homocysteine (Hcy) in association with the incidence of stroke in type 2 diabetes mellitus (T2DM) patients. MethodsBased on the chronic disease risk factor surveillance cohort in Pudong New Area, Shanghai, excluding those with stroke in baseline survey, T2DM patients who joined the cohort from January 2016 to October 2020 were selected as the research subjects. During the follow-up period, a total of 318 new-onset ischemic stroke patients were selected as the case group, and a total of 318 individuals matched by gender without stroke were selected as the control group. The Cox proportional hazards regression model was used to adjust for confounding factors and explore the serum TyG index and the Hcy biochemical indicator in association with the risk of stroke. ResultsThe Cox proportional hazards regression results showed that after adjusting for confounding factors, the risk of stroke in T2DM patients with 10 μmol·L⁻¹-¹ and Hcy>15 μmol·L⁻¹ was 1.532 times (95%CI: 1.017‒2.309 times, P=0.041) and 1.738 times (95%CI: 1.119‒2.699 times, P=0.014) higher respectively, compared to T2DM patients with Hcy≤10 μmol·L⁻¹. T2DM patients with TyG>9.074 had 1.396 times higher risk of stroke (95%CI: 1.091‒1.787, P=0.008) compared to those with TyG≤9.074. The study found that urea and α1-antitrypsin (α1-AT) were independent risk factors for the incidence of stroke in T2DM patients. For every unit increase in urea andα1-AT, the risk of stroke in T2DM patients increased by 233.6% (HR=3.336, 95%CI: 1.588‒7.009, P=0.001) and 11.3% (HR=1.113, 95%CI: 1.028‒1.205, P=0.008), respectively. Cumulative risk curves showed that Hcy>10 μmol·L⁻¹ and TyG>9.074 accelerated the time to stroke occurrence in T2DM patients. ConclusionElevated levels of Hcy>10 μmol·L⁻¹ and a higher TyG index are risk factors for stroke in T2DM patients. Effective interventions for Hcy and TyG should be conducted for diabetic patients to reduce the incidence of stroke.

Objective To investigate the antibacterial activity of the antifungal peptide Mt6-21DLeu derived from Musca domestica against Acinetobacter baumannii (AB) and unravel its underlying mechanisms, so as to provide insights into development of novel agents against AB. Methods The minimum inhibitory concentrations (MICs) of Mt6-21DLeu, M. domestica-derived antifungal peptide-1 (MAF-1A), and polymyxin B were determined against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and AB using the broth microdilution assay, and the antibacterial activity of Mt6-21DLeu and polymyxin B was dynamically assessed against AB over 24 hours with time-kill curves. The inhibitory effects of Mt6-21DLeu and polymyxin B on biofilm formation in AB at concentrations of 1/4 × MIC, 1/2 × MIC and MIC, and the eradication effects of Mt6-21DLeu and polymyxin B on mature biofilms in AB at concentrations of MIC, 2 × MIC, and 4 × MIC were evaluated using crystal violet staining. Structural changes in the cell membrane of AB were observed 3 hours post-exposure to Mt6-21DLeu at concentrations of MIC and 2 × MIC using scanning electron microscopy, and alterations in the cell membrane permeability of AB were analyzed 3 hours post-treatment with Mt6-21DLeu at concentrations of MIC and 2 × MIC by means of fluorescence microscopy and propidium iodide (PI) staining. Intracellular reactive oxygen species (ROS) levels in AB were measured 3 hours post-treatment with Mt6-21DLeu at concentrations of MIC, 2 × MIC, and 4 × MIC using flow cytometry. The survival of Caenorhabditis elegans exposed to Mt6-21DLeu at concentrations of MIC, 2 × MIC, and 4 × MIC was monitored for 7 consecutive days, and survival curves were plotted to evaluate the in vivo toxicity of Mt6-21DLeu. In addition, C. elegans infected with AB and treated with Mt6-21DLeu at a concentration of 4 × MIC served as the treatment group, and uninfected C. elegans served as the control group, while infected but untreated C. elegans served as the infection group. The in vivo antibacterial efficacy of Mt6-21DLeu at a concentration of 4 × MIC was evaluated by comparing the survival curves and bacterial load among the three groups. Results The MICs of MAF-1A were all >128 μg/mL against S. aureus, B. subtilis, E. coli, K. pneumoniae, P. aeruginosa, and AB. In contrast, the MICs of Mt6-21DLeu were >128, 32, 8, 8, 16, and 4 μg/mL against these strains, respectively, and the MIC of Mt6-21DLeu against AB was close to that of polymyxin B (2 μg/mL). Time-kill curve analysis showed that both Mt6-21DLeu at concentrations of MIC and 2 × MIC and polymyxin B at a concentration of MIC inhibited AB growth over the 24-hour study period. The biofilm biomass in AB was (52.38 ± 6.92)%, (40.88 ± 9.17)% and (14.77 ± 6.00)% post-exposure with Mt6-21DLeu at concentrations of 1/4 × MIC, 1/2 × MIC and MIC, (61.58 ± 7.35)%, (47.42 ± 5.51)% and (20.85 ± 10.48)% post-treatment with polymyxin B at concentrations of 1/4 × MIC, 1/2 × MIC and MIC, and (100.00 ± 15.92)% in the control group (only bacterial suspension), respectively (F = 68.38, P < 0.001), and pairwise comparisons indicated that Mt6-21DLeu and polymyxin B at all concentrations significantly inhibited biofilm formation as compared to the control group (all P values < 0.001). The mature biofilm biomass in AB was (73.44 ± 11.41)%, (72.56 ± 13.08)% and (49.65 ± 9.23)% post-exposure to Mt6-21DLeu at concentrations of MIC, 2 × MIC, and 4 × MIC, (84.38 ± 8.60)%, (72.31 ± 9.63)% and (58.85 ± 4.96)% post-treatment with polymyxin B at concentrations of MIC, 2 × MIC, and 4 × MIC, and (100.00 ± 6.36)% in the control group (F = 35.63, P < 0.001), and pairwise comparisons revealed that Mt6-21DLeu at all concentrations significantly eradicated biofilm biomass (all P values < 0.05); however, polymyxin B showed no clear-cut eradication effect at a concentration of MIC (P > 0.05). Scanning electron microscopy revealed pore formation and content leakage in the cell membrane of AB 3 hours post-treatment with Mt6-21DLeu at concentrations of MIC and 2 × MIC. Fluorescence microscopy showed that the proportions of PI-stained AB were (24.79 ± 11.51)% and (68.44 ± 15.80)% post-treatment with Mt6-21DLeu at concentrations of MIC and 2 × MIC, and (0.96 ± 0.94)% in the phosphate-buffered saline (PBS) treatment group (F = 105.90, P < 0.001), with the highest proportion of PI-stained AB seen post-treatment with Mt6-21DLeu at a concentration of 2 × MIC (P < 0.05). Flow cytometry revealed that the relative intracellular ROS levels in AB were (652.00 ± 141.90), (694.33 ± 14.19), and (974.33 ± 160.02) 3 hours post-treatment with Mt6-21DLeu at concentrations of MIC, 2 × MIC and 4 × MIC, and (403.67 ± 86.56) in the PBS treatment group, respectively (F = 12.27, P < 0.05), with the highest intracellular ROS level measured following treatment with Mt6-21DLeu at a concentration of 4 × MIC (P < 0.05). Survival curve analysis revealed that Mt6-21DLeu posed no impact on C. elegans survival at concentrations of MIC (χ² = 0.02, P > 0.05), 2 × MIC (χ² = 0.06, P > 0.05) or 4 × MIC (χ² = 0.16, P > 0.05), and there was a significant difference in the survival period of C. elegans among the control group, the infection group, and the treatment group (χ² = 82.66, P < 0.05), with a significantly longer survival period in the treatment group than in the infection group (χ² = 45.00, P < 0.05). In addition, the log-transformed bacterial colony counts in C. elegans were (0.00 ± 0.00), (5.46 ± 0.03), and (3.91 ± 0.47) CFU/mL in the control group, the infection group, and the treatment group, respectively (F = 324.80, P < 0.001), and the log-transformed bacterial colony counts in C. elegans were significantly lower in the treatment group than in the infection group (P < 0.05). Conclusions Mt6-21DLeu exerts potent antibacterial effects through disrupting the cell membrane integrity of AB and promoting intracellular ROS accumulation in AB, and exhibits promising potential for treatment of AB infections both in vivo and in vitro, which may serve as a candidate drug molecule against multidrug-resistant AB infections.

A primary hallmark of pathological cardiac hypertrophy is excess protein synthesis due to enhanced translational activity. However, regulatory mechanisms at the translational level under cardiac stress remain poorly understood. Here we examined the translational regulations in a mouse cardiac hypertrophy model induced by transaortic constriction (TAC) and explored the conservative networks versus the translatome pattern in human dilated cardiomyopathy (DCM). The results showed that the heart weight to body weight ratio was significantly elevated, and the ejection fraction and fractional shortening significantly decreased 8 weeks after TAC. Puromycin incorporation assay showed that TAC significantly increased protein synthesis rate in the left ventricle. RNA-seq revealed 1,632 differentially expressed genes showing functional enrichment in pathways including extracellular matrix remodeling, metabolic processes, and signaling cascades associated with pathological cardiomyocyte growth. When combined with ribosome profiling analysis, we revealed that translation efficiency (TE) of 1,495 genes was enhanced, while the TE of 933 genes was inhibited following TAC. In DCM patients, 1,354 genes were upregulated versus 1,213 genes were downregulated at the translation level. Although the majority of the genes were not shared between mouse and human, we identified 93 genes, including Nos3, Kcnj8, Adcy4, Itpr1, Fasn, Scd1, etc., with highly conserved translational regulations. These genes were remarkably associated with myocardial function, signal transduction, and energy metabolism, particularly related to cGMP-PKG signaling and fatty acid metabolism. Motif analysis revealed enriched regulatory elements in the 5' untranslated regions (5'UTRs) of transcripts with differential TE, which exhibited strong cross-species sequence conservation. Our study revealed novel regulatory mechanisms at the translational level in cardiac hypertrophy and identified conserved translation-sensitive targets with potential applications to treat cardiac hypertrophy and heart failure in the clinic.
Animals ; Humans ; Cardiomegaly/physiopathology* ; Ribosomes/physiology* ; Protein Biosynthesis/physiology* ; Mice ; Cardiomyopathy, Dilated/genetics* ; Ribosome Profiling