Objective: To investigate the effect of sirtuin 2(SIRT2) on the proliferation and migration of cardiac fibroblasts(CFs)in C57BL/6 mice under angiotensin II(Ang Ⅱ) stimulation. Methods : The hearts were taken from 1 to 2 days C57BL/6 milk mice. After cutting and digesting, CFs were extracted by different adhesion centrifugation. After CFs attachment, the cells were cultured under control medium and Ang Ⅱ(100 nmol/L) medium and treated using OE-SIRT2 plasmid to overexpression the SIRT2 gene. RT-qPCR was used to detect mRNA expression of SIRT2 proliferating cell nuclear antigen(PCNA), periostin(POSTN)and type Ⅰ collagen procollagen A1(Col1A1), Western blot assay was used to measure the protein expression levels of SIRT2, PCNA, POSTN and Col1A1, CCK-8 assay and EdU assay were used to evaluate CFs proliferation rate, Transwell experiment was used to assess CFs migration activity. Results: Compared with control group, Ang Ⅱ stimulation led to down-regulation of SIRT2 expression in CFs, increased collagen expression, and promoted CFs proliferation and migration. The expression of SIRT2 was up regulated in CFs treated with OE-SIRT2 plasmid under Ang Ⅱ stimulation, Col1A1, POSTN and PCNA expression was down regulated, and CFs proliferation and migration ability decreased. Conclusion Overexpression of SIRT2 can inhibit the proliferation and migration of CFs under Ang Ⅱ stimulation, indicating that SIRT2 may be a key regulatory point in the onset and progression of cardiac fibrosis.

Objective:To investigate the prognostic value of 18F-FDG PET/CT-based habitat radiomics combined with stacking ensemble learning model in overall survival (OS) of patients with hepatocellular carcinoma (HCC). Methods:A total of 136 HCC patients (114 males, 22 females, age (55.3±10.4) years) who underwent 18F-FDG PET/CT before treatment between January 2018 and January 2023 were retrospectively analyzed. Eighty-five cases from Tianjin First Central Hospital and 51 cases from Tianjin Medical University Cancer Institute and Hospital were used as a training cohort and an external validation cohort, respectively. The tumor volume of interest (VOI) was delineated on PET and CT images, and a total of 4 habitats were segmented by using the Otsu algorithm, including PET high ∩ CT low, PET low ∩ CT low, PET high ∩ CT high, and PET low ∩ CT high. After the feature selection, a total of 36 stacking ensemble learning models were established, and the optimal model was selected based on the calculated concordance index (C-index). Moreover, a combined model was developed by integrating the optimal model with clinical information. The predictive efficacy of those models was assessed by time-dependent ROC curves. Results:The model based on PET high ∩ CT high habitat radiomics features with multilayer perceptron (MLP) classifier had the highest C-index (0.770) in the external validation cohort, and it was regarded as the optimal radiomics model. The combined model incorporating this model with clinical information achieved an improved C-index of 0.815 in the external validation cohort. The combined model outperformed the other models for OS prediction, with a time-dependent AUC of 0.919, 0.900, and 0.862 in predicting the 1-year, 2-year, and 3-year OS, respectively. Conclusions:18F-FDG PET/CT-based habitat analysis outperforms traditional radiomics in OS prediction for HCC patients. By integrating the optimal habitat model with the clinical model, the combined model is able to improve the predictive efficacy.

Pseudohypoaldosteronism type Ⅰ(PHA Ⅰ)is a rare inherited disease,mainly caused by the deficiency of the aldosterone receptor or by reduced or absent binding between aldosterone and its receptor.It typically manifests as neonatal hyponatremia,hyperkalaemia,metabolic acidosis,accompanied by dehydration,vomiting,weight loss,and even shock.PHA Ⅰ is classified into renal-type with mutations in the salt corticosteroid receptor and multi-organ with mutations in any of the three subunits of the epithelial sodium channel(α,β or γ).The renal-type,which is inherited in an autosomal dominant manner,is caused by mutations in the aldosterone receptor with an isolated nephrogenic salt-loss syndrome,and the clinical symptoms are milder compared with those of the multi-organ type,which may improve with age.However,severity varies among individuals depending on the degree of salt loss,and if not treated in time,it may lead to shock due to repeated dehydration or even cardiac arrest due to high potassium.Currently,domestic studies have found that the human salt corticosteroid receptor is encoded by the NR3C2 gene,which is located between the regions of 4q31.1 and 4q31.2.This case reports a child with nephrogenic PHA Ⅰ due to a new-onset variant of the NR3C2(4q31.22)gene,who had chromosomal anomalies in the fetus and demonstrated high blood pressure,high blood potassium and low sodium after birth.The diagnosis of renal neonatal PHA Ⅰ was confirmed by the presence of a microdeletion of NR3C2 gene(4q31.22 region)in the child,which was demonstrated by a genome-wide chromosomal assay and accompanied by a significant elevation of the plasma aldosterone level(>2 000 pg/mL),and by the presence of a microdeletion of NR3C2 gene(4q31.22 region)in the child.Electrolyte disorders were corrected after oral administration of concentrated sodium chloride,and the condition remained stable at the 1-month follow-up.

Aim To investigate the effect of N6-methy-ladenosine(m6A)demethylase ALKBH5 on the prolif-eration and migration of cardiac fibroblasts(CFs)in-duced by high glucose.Methods Primary CFs were isolated from neonatal mouse hearts and identified u-sing optical and confocal microscopy.Cell activation was induced using a high-glucose medium(33 mmol·L-1 glucose).An ALKBH5 overexpression model was established by transfecting CFs with an ALKBH5 ex-pression vector in a high-glucose medium.The expres-sion of ALKBH5 in CFs was assessed through immuno-fluorescence staining,Western blot and RT-qPCR.Changes in m6A levels were evaluated using Dot blot a-nalysis.Additionally,Alterations in the expression of proliferating cell nuclear antigen(PCNA)and collagenⅠ,a pivotal fibrosis indicator,were measured using Western blot.The proliferation and migration ability of CFs were assessed through EdU staining and Transwell migration assay,respectively.Results Following treatment with high glucose,the expression of ALKBH5 in CFs notably decreased,while m6A level increased.This was accompanied by a significant increase in the expression of the proliferation marker PCNA and the fi-brosis marker collagen Ⅰ.Additionally,there was a sig-nificant improvement in the ability of proliferation and migration.Overexpression of ALKBH5 resulted in a significant decrease in the expressions of PCNA and collagen Ⅰ,leading to the inhibition of both proliferation and migration in CFs.Conclusion Overexpression of ALKBH5 suppresses the expression of PCNA and colla-gen Ⅰ,consequently reducing the proliferation and mi-gration of CFs,potentially through m6A methylation modification.

Aim To investigate the effect of N6-methy-ladenosine(m6A)demethylase ALKBH5 on the prolif-eration and migration of cardiac fibroblasts(CFs)in-duced by high glucose.Methods Primary CFs were isolated from neonatal mouse hearts and identified u-sing optical and confocal microscopy.Cell activation was induced using a high-glucose medium(33 mmol·L-1 glucose).An ALKBH5 overexpression model was established by transfecting CFs with an ALKBH5 ex-pression vector in a high-glucose medium.The expres-sion of ALKBH5 in CFs was assessed through immuno-fluorescence staining,Western blot and RT-qPCR.Changes in m6A levels were evaluated using Dot blot a-nalysis.Additionally,Alterations in the expression of proliferating cell nuclear antigen(PCNA)and collagenⅠ,a pivotal fibrosis indicator,were measured using Western blot.The proliferation and migration ability of CFs were assessed through EdU staining and Transwell migration assay,respectively.Results Following treatment with high glucose,the expression of ALKBH5 in CFs notably decreased,while m6A level increased.This was accompanied by a significant increase in the expression of the proliferation marker PCNA and the fi-brosis marker collagen Ⅰ.Additionally,there was a sig-nificant improvement in the ability of proliferation and migration.Overexpression of ALKBH5 resulted in a significant decrease in the expressions of PCNA and collagen Ⅰ,leading to the inhibition of both proliferation and migration in CFs.Conclusion Overexpression of ALKBH5 suppresses the expression of PCNA and colla-gen Ⅰ,consequently reducing the proliferation and mi-gration of CFs,potentially through m6A methylation modification.

Pseudohypoaldosteronism type Ⅰ(PHA Ⅰ)is a rare inherited disease,mainly caused by the deficiency of the aldosterone receptor or by reduced or absent binding between aldosterone and its receptor.It typically manifests as neonatal hyponatremia,hyperkalaemia,metabolic acidosis,accompanied by dehydration,vomiting,weight loss,and even shock.PHA Ⅰ is classified into renal-type with mutations in the salt corticosteroid receptor and multi-organ with mutations in any of the three subunits of the epithelial sodium channel(α,β or γ).The renal-type,which is inherited in an autosomal dominant manner,is caused by mutations in the aldosterone receptor with an isolated nephrogenic salt-loss syndrome,and the clinical symptoms are milder compared with those of the multi-organ type,which may improve with age.However,severity varies among individuals depending on the degree of salt loss,and if not treated in time,it may lead to shock due to repeated dehydration or even cardiac arrest due to high potassium.Currently,domestic studies have found that the human salt corticosteroid receptor is encoded by the NR3C2 gene,which is located between the regions of 4q31.1 and 4q31.2.This case reports a child with nephrogenic PHA Ⅰ due to a new-onset variant of the NR3C2(4q31.22)gene,who had chromosomal anomalies in the fetus and demonstrated high blood pressure,high blood potassium and low sodium after birth.The diagnosis of renal neonatal PHA Ⅰ was confirmed by the presence of a microdeletion of NR3C2 gene(4q31.22 region)in the child,which was demonstrated by a genome-wide chromosomal assay and accompanied by a significant elevation of the plasma aldosterone level(>2 000 pg/mL),and by the presence of a microdeletion of NR3C2 gene(4q31.22 region)in the child.Electrolyte disorders were corrected after oral administration of concentrated sodium chloride,and the condition remained stable at the 1-month follow-up.

Objective:To investigate the prognostic value of 18F-FDG PET/CT-based habitat radiomics combined with stacking ensemble learning model in overall survival (OS) of patients with hepatocellular carcinoma (HCC). Methods:A total of 136 HCC patients (114 males, 22 females, age (55.3±10.4) years) who underwent 18F-FDG PET/CT before treatment between January 2018 and January 2023 were retrospectively analyzed. Eighty-five cases from Tianjin First Central Hospital and 51 cases from Tianjin Medical University Cancer Institute and Hospital were used as a training cohort and an external validation cohort, respectively. The tumor volume of interest (VOI) was delineated on PET and CT images, and a total of 4 habitats were segmented by using the Otsu algorithm, including PET high ∩ CT low, PET low ∩ CT low, PET high ∩ CT high, and PET low ∩ CT high. After the feature selection, a total of 36 stacking ensemble learning models were established, and the optimal model was selected based on the calculated concordance index (C-index). Moreover, a combined model was developed by integrating the optimal model with clinical information. The predictive efficacy of those models was assessed by time-dependent ROC curves. Results:The model based on PET high ∩ CT high habitat radiomics features with multilayer perceptron (MLP) classifier had the highest C-index (0.770) in the external validation cohort, and it was regarded as the optimal radiomics model. The combined model incorporating this model with clinical information achieved an improved C-index of 0.815 in the external validation cohort. The combined model outperformed the other models for OS prediction, with a time-dependent AUC of 0.919, 0.900, and 0.862 in predicting the 1-year, 2-year, and 3-year OS, respectively. Conclusions:18F-FDG PET/CT-based habitat analysis outperforms traditional radiomics in OS prediction for HCC patients. By integrating the optimal habitat model with the clinical model, the combined model is able to improve the predictive efficacy.

The development of treatment of severe acute pancreatitis (SAP) has gone through a dramatic transformation from radical surgery to conservative treatment, and now to a multidisciplinary comprehensive diagnosis and treatment model which combines minimally invasive and open surgery. Due to the complexity, rapid progression, and significantly individual differences, some patients of SAP may experience surgical emergencies such as gastrointestinal fistula, severe abdominal infection, massive bleeding, abdominal compartment syndrome, and severe biliary system complications. Conservative treatment has little effect and often requires decisive surgical rescue to potentially save the patients′ lives. Based on clinical practice and the latest literature, the authors introduce the concept of surgical rescue into the treatment of SAP for the first time, in order to explain the strategies of surgical rescue in the SAP disease process and the key points of implemen-ting surgical rescue in different situations, and to provide personal insights on how to improve the success rate of surgical rescue for further improving the overall cure rate of SAP.

Objective:The effect of bone marrow soluble B cell maturation antigen (sBCMA) expression on the efficacy and side effects of chimeric antigen receptor (CAR) -modified T-cell-targeting B cell maturation antigen (BCMA) in patients with multiple myeloma (MM) .Methods:This study involved 29 patients with relapsed or refractory MM (RRMM) who received humanized anti-BCMA CAR-T cell clinical trials from January 2018 to December 2021. The expression of sBCMA in bone marrow before and after anti-BCMA CAR-T cell treatment was detected by flow cytometry and compared.Results:①Two months after BCMA CAR-T cell treatment, 20 patients (68.97%) achieved an overall response (OR), whereas nine patients had stable disease (SD) or miner emission (MR). ②The expression of sBCMA in the bone marrow of 20 patients with OR was higher before treatment than after [26 926 (18 215, 32 488) ng/L vs 9 968 (6 634, 11 459) ng/L; P<0.001]; no significant difference was observed in patients with MR and SD [41 187 (33 816, 47 046) ng/L vs. 33 954 (31 569, 36 256) ng/L; P=0.145]; sBCMA expression in patients with OR before CAR-T cell treatment was lower than in patients with MR and SD ( P=0.005). ③No significant linear correlation was found between the peak value of CAR-T cells and sBCMA expression in the bone marrow of all 29 patients with RRMM ( R2=0.035, P=0.330). ④No significant difference in sBCMA expression was found between grades 0-1 CRS group (13 patients) and grades 2-4 CRS group [16 patients; 32 045 (18 742, 40 801) ng/L vs 29 102 (24 679, 38 776) ng/L, P=0.879], nor between grade 0 ICANS group (22 patients) and grade 1-3 ICANS group [seven patients; 30 073 (19 375, 40 065) ng/L vs 33 816 (22 933, 43 459) ng/L, P=0.763]. Conclusion:sBCMA expression in the bone marrow is related to the efficacy of BCMA CAR-T cell therapy in patients with RRMM, but is not significantly correlated with the severity of adverse events. It may serve as a predictive biomarker for the efficacy of BCMA CAR-T cell therapy in these patients.

Objective To explore the mechanism of'homotherapy for heteropathy'Zhigancao Decoction in the treatment of coronary heart disease arrhythmia and pulmonary fibrosis by network pharmacology and molecular docking technology.Methods All the active components of Zhigancao Decoction were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP)and Herbal Compendium(HERB).The SwissTargetPrediction database was used to predict the targets.Cytoscape software was used to construct the drugs-targets network diagram and network topology analysis was performed to obtain the core drug targets.The disease targets of coronary heart disease,arrhythmia and pulmonary fibrosis were obtained in GeneCards and OMIM databases,and the intersection targets of Chinese medicine and disease were obtained by Venny software.The intersection targets were imported into the STRING online database to construct a protein-protein interaction network,and the data were imported into Cytoscape software for visualization and screening of core targets.Gene ontology(GO)function enrichment analysis and kyto encyclo-pedia of genes and genomes(KEGG)pathway enrichment analysis were performed on the intersection targets using the Metascape database.Molecular docking verification and heat map visualization were performed on the core intersection target and the core drug target through the CB-DOCK2 online platform.Results A total of 137 active components of Zhigancao Decoction were screened out,and 848 corresponding drug targets were obtained by removing repeated values.A total of 9 962 targets of coronary heart disease,5 735 targets of arrhythmia and 7 722 targets of pulmonary fibrosis were obtained.A total of 362 drug-disease intersection targets were obtained by Venny platform processing.The potential core targets with higher degree values were GAPDH,IL-6,ALB,STAT3,TNF,MMP-9 and so on by network topology analysis.GO functional enrichment analysis showed that the main biological processes(BP)involved in Zhigancao Decoction'homotherapy for heteropathy'were the response to hormones,the positive regulation of circulatory system process,phosphorus metabolism process,the response to exogenous stimulation,and the response to organic matter,the main cellular components(CC)include lipid rafts,receptor complexes,cytoplasmic perinuclear regions,dendrites,membrane sides,etc.,the main molecular functions(MF)include protein kinase activity,kinase binding,protein homopolymerization activity,nuclear receptor activity,heme binding,etc..KEGG pathway enrichment analysis showed that the main signaling pathways involved in Zhigancao Decoction'homotherapy for heteropathy'were lipid and atherosclerosis,calcium signaling pathway,cAMP signaling pathway,insulin resistance,cGMP-PKG signaling pathway,JAK-STAT signaling pathway,NF-κB signaling pathway,etc..The results of molecular docking suggested that there was a good binding activity between the main active component targets of Zhigancao Decoction and the core targets of'homotherapy for heteropathy'.Conclusion Zhigancao Decoction mainly regulates JAK-STAT,NF-κB,cAMP and other signaling pathways,acts on IL-6,STAT3,TNF,MMP-9 and other gene targets,and exerts the effect of'homotherapy for heteropathy'on coronary heart disease arrhythmia and pulmonary fibrosis.