ObjectiveTo explore the mechanism of action of Paeoniae Radix Rubra and Aconiti Lateralis Radix Praeparata （CSFZ） in the treatment of acute-on-chronic liver failure （ACLF） through network pharmacology， molecular docking， and animal experiments. MethodsNetwork pharmacology was used to identify potential targets and related signaling pathways for the treatment of ACLF with CSFZ. Molecular docking was used to examine the binding activity of the core components with corresponding key targets. An ACLF rat model was established by subcutaneous and tail vein injections of bovine serum albumin combined with lipopolysaccharide （LPS） + D-galactosamine （D-GalN） intraperitoneal injection. A normal control group （NC）， a model group， a CSFZ group （CSFZ， 5.85 g·kg^-1）， and a hepatocyte growth-promoting granule group （HGFG， 4.05 g·kg^-1） were set up in this study. Pathological changes in rat liver tissue were observed using hematoxylin and eosin （HE） and Masson staining. Enzyme-linked immunosorbent assay （ELISA） was used to detect the expression levels of interleukin-6 （IL-6）， B-cell lymphoma-2 （Bcl-2）， Caspase-3， and albumin （ALB）. Real-time quantitative polymerase chain reaction （Real-time PCR） and Western blot were used to measure the mRNA and protein expression levels of phosphoinositide 3-kinase （PI3K）， protein kinase B （Akt）， phosphorylated PI3K （p-PI3K）， and phosphorylated Akt （p-Akt）. ResultsNetwork pharmacology screening identified 49 active ingredients of CSFZ， 103 action targets， and 3 317 targets related to ACLF. Among these， 74 targets overlapped with CSFZ drug targets. Key nodes in the protein-protein interaction （PPI） network included Akt1， tumor necrosis factor （TNF）， IL-6， Bcl-2， and Caspase-3. Gene Ontology （GO） functional analysis and Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment analysis identified multiple signaling pathways， with the PI3K/Akt signaling pathway being the most frequent. Molecular docking showed that the core components of the drug exhibited good binding activity with the corresponding key targets. Animal experiments confirmed that CSFZ significantly improved liver tissue pathological damage in ACLF rats， reduced the release of inflammatory factors and liver cell apoptosis， and upregulated the expression levels of the PI3K/Akt signaling pathway. ConclusionThrough network pharmacology， molecular docking， and in vivo experiments， this study confirms the effect of CSFZ in reducing liver cell inflammatory damage and inhibiting liver cell apoptosis. The specific mechanism may be related to its involvement in regulating the PI3K/Akt signaling pathway.

To investigate the clinical features and peripheral blood immune cell subsets ofelderly (≥60 years old) onset rheumatoid arthritis (EORA) patients.

Background and Aims:Microsatellite-stable(MSS)colorectal cancer(CRC)generally exhibits poor responsiveness to immune checkpoint inhibitors(ICIs),and effective immunotherapy strategies remain lacking.Anti-angiogenic agents such as bevacizumab(BEV)can improve the tumor immune microenvironment and act synergistically with ICIs.This multicenter real-world study compared the efficacy of different immunotherapy-based combination regimens in patients with MSS/MSI-L/pMMR advanced CRC,aiming to identify the optimal treatment strategy.Methods:A total of 100 patients with MSS/MSI-L/pMMR advanced CRC who received systemic treatment between November 2019 and February 2025 at four tertiary hospitals in Hunan,China,were retrospectively enrolled.Patients were classified into six treatment groups:chemotherapy alone,chemotherapy+targeted therapy,immunotherapy alone,immunotherapy+chemotherapy,immunotherapy+targeted therapy,and immunotherapy+chemotherapy+targeted therapy.The primary endpoints were overall survival(OS)and progression-free survival(PFS),while secondary endpoints were objective response rate(ORR)and disease control rate(DCR).Additionally,among patients receiving immunotherapy,subgroup analysis was performed according to BEV administration.Results:Among all 100 patients,the immunotherapy+chemotherapy+targeted therapy group achieved the highest ORR(32.0%)and DCR(76.0%)and was the only regimen yielding a complete response(CR).Compared with chemotherapy or immunotherapy alone,the triplet regimen significantly improved OS(P<0.05);although PFS improvement did not reach statistical significance,a clear late-stage separation of survival curves was observed.In the immunotherapy subgroup,BEV-containing regimens achieved markedly better outcomes than non-BEV regimens,with DCR of 75.0%vs.48.8%,median OS of 18.9 vs.11.5 months,and median PFS of 13.8 vs.7.2 months(all P<0.001).Cox regression analysis showed that compared with chemotherapy alone,the triplet regimen significantly reduced the risk of death(HR=0.11)and disease progression(HR=0.25)(both P=0.002).Vascular invasion was identified as an adverse prognostic factor for PFS(HR=3.0,P=0.007).Conclusion:This multicenter real-world study demonstrated that combining immunotherapy with chemotherapy and targeted therapy significantly improves DCR and survival outcomes in patients with MSS/MSI-L/pMMR advanced CRC,with BEV-containing triplet regimens providing the most pronounced benefit.BEV may enhance immune responsiveness by modulating the tumor microenvironment and promoting effector T-cell infiltration,offering a promising therapeutic direction for"immune-cold"CRC.Prospective randomized studies are warranted to further validate its clinical value and define appropriate patient populations.

Decreased exercise tolerance is a common clinical issue in children with congenital heart disease (CHD), significantly impacting their long-term quality of life and increasing the risk of adverse cardiovascular events.However, due to the complexity of CHD, the diversity of assessment methods, and the limitations in equipment accessibility, standardized protocols for evaluating and intervening in exercise tolerance are still lacking.In order to provide a basis for improving exercise tolerance in children with CHD, the latest domestic and international research on the assessment and intervention of exercise tolerance in children with CHD was systematically summarized.The applicability, advantages, and limitations of existing methods, including cardiopulmonary exercise testing, the 6-minute walk test, and smart wearable devices in clinical practice were discussed.Furthermore, the effectiveness of various intervention strategies (such as exercise training, nutritional management, surgical correction, and pharmacological treatment) in improving exercise tolerance was analyzed.

Background and Aims:Microsatellite-stable(MSS)colorectal cancer(CRC)generally exhibits poor responsiveness to immune checkpoint inhibitors(ICIs),and effective immunotherapy strategies remain lacking.Anti-angiogenic agents such as bevacizumab(BEV)can improve the tumor immune microenvironment and act synergistically with ICIs.This multicenter real-world study compared the efficacy of different immunotherapy-based combination regimens in patients with MSS/MSI-L/pMMR advanced CRC,aiming to identify the optimal treatment strategy.Methods:A total of 100 patients with MSS/MSI-L/pMMR advanced CRC who received systemic treatment between November 2019 and February 2025 at four tertiary hospitals in Hunan,China,were retrospectively enrolled.Patients were classified into six treatment groups:chemotherapy alone,chemotherapy+targeted therapy,immunotherapy alone,immunotherapy+chemotherapy,immunotherapy+targeted therapy,and immunotherapy+chemotherapy+targeted therapy.The primary endpoints were overall survival(OS)and progression-free survival(PFS),while secondary endpoints were objective response rate(ORR)and disease control rate(DCR).Additionally,among patients receiving immunotherapy,subgroup analysis was performed according to BEV administration.Results:Among all 100 patients,the immunotherapy+chemotherapy+targeted therapy group achieved the highest ORR(32.0%)and DCR(76.0%)and was the only regimen yielding a complete response(CR).Compared with chemotherapy or immunotherapy alone,the triplet regimen significantly improved OS(P<0.05);although PFS improvement did not reach statistical significance,a clear late-stage separation of survival curves was observed.In the immunotherapy subgroup,BEV-containing regimens achieved markedly better outcomes than non-BEV regimens,with DCR of 75.0%vs.48.8%,median OS of 18.9 vs.11.5 months,and median PFS of 13.8 vs.7.2 months(all P<0.001).Cox regression analysis showed that compared with chemotherapy alone,the triplet regimen significantly reduced the risk of death(HR=0.11)and disease progression(HR=0.25)(both P=0.002).Vascular invasion was identified as an adverse prognostic factor for PFS(HR=3.0,P=0.007).Conclusion:This multicenter real-world study demonstrated that combining immunotherapy with chemotherapy and targeted therapy significantly improves DCR and survival outcomes in patients with MSS/MSI-L/pMMR advanced CRC,with BEV-containing triplet regimens providing the most pronounced benefit.BEV may enhance immune responsiveness by modulating the tumor microenvironment and promoting effector T-cell infiltration,offering a promising therapeutic direction for"immune-cold"CRC.Prospective randomized studies are warranted to further validate its clinical value and define appropriate patient populations.

Decreased exercise tolerance is a common clinical issue in children with congenital heart disease (CHD), significantly impacting their long-term quality of life and increasing the risk of adverse cardiovascular events.However, due to the complexity of CHD, the diversity of assessment methods, and the limitations in equipment accessibility, standardized protocols for evaluating and intervening in exercise tolerance are still lacking.In order to provide a basis for improving exercise tolerance in children with CHD, the latest domestic and international research on the assessment and intervention of exercise tolerance in children with CHD was systematically summarized.The applicability, advantages, and limitations of existing methods, including cardiopulmonary exercise testing, the 6-minute walk test, and smart wearable devices in clinical practice were discussed.Furthermore, the effectiveness of various intervention strategies (such as exercise training, nutritional management, surgical correction, and pharmacological treatment) in improving exercise tolerance was analyzed.

[Objective] To investigate the functional differences and potential effects of chromatin spatial structure in patients with normal karyotype and complex karyotype multiple myeloma. [Methods] High-throughput chromosome conformational capture (Hi-C) analysis was performed on plasma cells of 1 case with 1q21 complex karyotype and 1 case with normal karyotype multiple myeloma, and the differences in three-dimensional genome structure between the two patients were analyzed, and the transcriptome characteristics of plasma cells were combined to investigate the differential features through gene functional enrichment. [Results] A/B switch occurred in 36% of the chromatin compartments in two cases, and 1 041 genes in patient with complex karyotype had B/A switch. About 3 500 topological association domains (TADs) were identified in each sample, and there was no significant difference. The number of loops identified in complex karyotype sample was 1 069, which was 1/6 of the normal sample, and there were significant differences in the number of three different types of loops, which to some extent reflected the loss of genome stability. Transcriptome analysis showed significant differences in expression profiles between the two patients, and a total of 6 150 differentially expressed genes (3 303 up-regulated genes and 2 847 down-regulated genes) were identified. [Conclusion] Compared with patient with normal karyotype, patient with 1q21 complex karyotype multiple myeloma exhibit significant changes in the spatial structure of plasma cell chromatin at different levels, which leads to changes in gene expression and activation of pathways related to cancer progression.

Objective:To analyze clinical characteristics of acromegaly patients who have discordant growth hormone(GH) or insulin-like growth factor-1(IGF-1) levels and evaluate impact of different GH cut-offs on discordance rate.Methods:A retrospective analysis was conducted on data from 66 acromegaly patients treated at Nanjing Drum Tower Hospital from November 2017 to March 2023. Patients were categorized based on the nadir GH(GHn) and IGF-1 levels at the last follow-up into four groups: controlled, high GH, high IGF-1, and active. Clinical and metabolic parameters were compared across these groups, and impact of different GHn and fasting growth hormone(GHf) cut-offs on discordance rate was evaluated.Results:No statistically significant differences were observed among groups in age, duration of follow-up, imaging characteristics(all P>0.05). High IGF-1 group had higher fasting insulin and homeostasis model assessment for β cell function compared to controlled and high GH group(all P<0.05), while these parameters did not differ between high GH and controlled group. High IGF-1 group had higher carboxy-terminal cross-linked telopeptide of type 1 collagen, osteocalcin and procollagen type 1 N-terminal propeptide compared to controlled and high GH group, but differences were not statistically significant(all P>0.05). These parameters also did not differ between high GH and controlled group. Discordance rate was not significantly different when GHn cut-offs was 1.0 μg/L or 0.4 μg/L(30.3% vs 21.3%, P=0.146). Compared to 2.5 μg/L, discordance rate was lower when GHf cut-off was 1.0 μg/L(39.4% vs 24.3%, P=0.041). Conclusion:The discordance rate in treated acromegaly patients during follow-up is approximately 30%. Different GH measurement timings and cut-offs significantly impact discordance rate. Patients with normal GH and elevated IGF-1 levels are at potential risk of active disease, and require closer follow-up. This study provides a valuable reference for treatment of patients with discordant GH and IGF-1 levels.

Objective:To identify the clinical and pathological characteristics of adrenocortical carcinoma(ACC) with hypercortisolism and analyze the prognostic factors.Methods:Clinical data of ACC patients between January 2003 and December 2022 from Nanjing Drum Tower Hospital were collected retrospectively. Clinical and pathological characteristics were compared between ACC patients with hypercortisolism and nonfunctional ACCs. Kaplan-Meier method was used for survival analyses and Cox regression models were performed to analyze prognostic factors for ACC patients.Results:In 61 cases of ACC patients, the average age was (49.33±16.32) years. After a median follow-up of 77 months(95% CI 47.49-106.51 months), median overall survival and progression-free survival were 50 months(95% CI 20.44-79.56 months) and 29 months(95% CI 22.87-35.13 months), respectively. Among 36 patients with complete endocrinologic evaluations, 19(52.77%) were diagnosed with hypercortisolism. Compared with nonfunctional ACC, patients with hypercortisolism had more hypokalemia(42.11% vs 6.25%, P=0.022), capsular invasion(68.42% vs 25.00%, P=0.018), and distant metastases(73.68% vs 25.00%, P=0.007). Median overall survival and progression-free survival were significantly shorter than nonfunctional ACC(overall survival: 39 months vs 67 months, P=0.009; progression-free survival: 30 months vs 51 months, P=0.040) as well. Multivariate Cox regression analyses indicated that Ki67 index( HR=1.078, P=0.024) was an independent risk factor for overall survival. Hypercortisolism( HR=71.112, P=0.006), Ki67 index( HR=1.345, P=0.003), adjuvant therapy( HR=176.652, P=0.012), and operation( HR=0.020, P=0.003), were associated with disease progression. Conclusion:ACC accompanied by hypercortisolism is more prone to invasion and distant metastasis, resulting in shorter survival. Hypercortisolism is an independent prognostic factor for ACC patients.

Objective:To explore the pathological characteristics of adrenal masses based on various tumor diameter and unenhanced computed tomography(CT) attenuation value, and evaluate the value of the two parameters in the assessment of the benign and malignant nature of adrenal masses.Methods:The data of 1 367 patients who underwent adrenalectomy in Nanjing Drum Tower Hospital from January 2017 to October 2022 were retrospectively collected. The adrenal masses were divided into four groups according to tumor diameter and unenhanced CT attenuation value, and the clinical and histopathological characteristics of the four groups were compared respectively. Logistic regression was used to analyze the correlation between tumor diameter, non-contrast CT attenuation value and malignant adrenal masses, and receiver operating characteristic(ROC) curve was used to assess the diagnostic value of both in benign and malignant adrenal masses.Results:The proportion of adrenocortical carcinoma and other malignant tumors increased with the rise of tumor diameter or unenhanced CT attenuation value. After adjusting for age and gender, tumor diameter( OR=1.624, 95% CI 1.464-1.803, P<0.001) and unenhanced CT attenuation value( OR=1.108, 95% CI 1.079-1.138, P<0.001) were predictors of malignant adrenal masses. The tumor diameter and unenhanced CT attenuation value in diagnosing malignant adrenal masses had area under the ROC curve(AUC) of 0.838 and 0.892, respectively. With the optimal cut-off values of >3.4 cm and >30 HU, the sensitivity was 75.5% and 83.7%, and the specificity was 80.5% and 84.4%, respectively. The combination of tumor diameter >3.4 cm and unenhanced CT attenuation value >20 HU had an AUC of 0.927, with a sensitivity of 71.4% and a specificity of 90.1% in diagnosing malignant adrenal masses. Conclusions:Tumor diameter and unenhanced CT attenuation value has important significance in the differential diagnosis of benign and malignant adrenal masses. A combination of tumor diameter (>3.4 cm) and unenhanced CT attenuation value (>20 HU) demonstrates best diagnostic efficiency. Clinical application of this combined index can effectively diagnose malignant adrenal masses while avoiding unnecessary investigations or surgery.