OBJECTIVE: To establish venetoclax-resistant acute myeloid leukemia (AML) cell lines, assess the sensitivity of venetoclax-resistant cell lines to the BCL-2 protein family, and investigate their resistance mechanisms. METHODS: CCK-8 method was used to screen AML cell lines (MV4-11, MOLM13, OCI-AML2) that were relatively sensitive to venetoclax. Low concentrations of venetoclax continuously induced drug-resistance development in the cell lines. Changes in cell viability and apoptosis rate before and after resistance development were measured using the CCK-8 method and flow cytometry. BH3 profiling assay was performed to anayze the transform of mitochondrion-dependent apoptosis pathway as well as the sensitivity of resistant cell lines to BCL-2 family proteins and small molecule inhibitors. Real-time fluorescence quantitative PCR (RT-qPCR) was utilized to examine changes in the expression levels of BCL-2 protein family members in both venetoclax-resistant cell lines and multidrug-resistant patients. RESULTS: Venetoclax-resistant cell lines of MV4-11, MOLM13, and OCI-AML2 were successfully established, with IC₅₀ values exceeding 10-fold. Under the same concentration of venetoclax, the apoptosis rate of resistant cells decreased significantly (P < 0.05). BH3 profiling assay revealed that the drug-resistant cell lines showed increased sensitivity to many pro-apoptotic proteins (such as BIM,BID and NOXA). RT-qPCR showed significantly upregulated MCL1 and downregulated NOXA1 were detected in drug-resistant cell lines. Expression changes in MCL1 and NOXA1 in venetoclax-resistant patients were consistent with our established drug-resistant cell line results. CONCLUSION The venetoclax-resistant AML cell lines were successfully established through continuous induction with low concentrations of venetoclax. The venetoclax resistance resulted in alterations in the mitochondrial apoptosis pathway of the cells and an increased sensitivity of cells to pro-apoptotic proteins BIM, BID, and NOXA, which may be associated with the upregulation of MCL1 expression and downregulation of NOXA1 expression in the drug-resistant cells.
Humans ; Sulfonamides/pharmacology* ; Drug Resistance, Neoplasm ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology* ; Leukemia, Myeloid, Acute/pathology* ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; Cell Line, Tumor ; Apoptosis ; Antineoplastic Agents/pharmacology*

OBJECTIVE: To assess the efficacy of Qingda Granule (QDG) in ameliorating hypertension-induced cardiac damage and investigate the underlying mechanisms involved. METHODS: Twenty spontaneously hypertensive rats (SHRs) were used to develope a hypertension-induced cardiac damage model. Another 10 Wistar Kyoto (WKY) rats were used as normotension group. Rats were administrated intragastrically QDG [0.9 g/(kg•d)] or an equivalent volume of pure water for 8 weeks. Blood pressure, histopathological changes, cardiac function, levels of oxidative stress and inflammatory response markers were measured. Furthermore, to gain insights into the potential mechanisms underlying the protective effects of QDG against hypertension-induced cardiac injury, a network pharmacology study was conducted. Predicted results were validated by Western blot, radioimmunoassay immunohistochemistry and quantitative polymerase chain reaction, respectively. RESULTS: The administration of QDG resulted in a significant decrease in blood pressure levels in SHRs (P<0.01). Histological examinations, including hematoxylin-eosin staining and Masson trichrome staining revealed that QDG effectively attenuated hypertension-induced cardiac damage. Furthermore, echocardiography demonstrated that QDG improved hypertension-associated cardiac dysfunction. Enzyme-linked immunosorbent assay and colorimetric method indicated that QDG significantly reduced oxidative stress and inflammatory response levels in both myocardial tissue and serum (P<0.01). CONCLUSIONS Both network pharmacology and experimental investigations confirmed that QDG exerted its beneficial effects in decreasing hypertension-induced cardiac damage by regulating the angiotensin converting enzyme (ACE)/angiotensin II (Ang II)/Ang II receptor type 1 axis and ACE/Ang II/Ang II receptor type 2 axis.
Animals ; Drugs, Chinese Herbal/therapeutic use* ; Hypertension/pathology* ; Renin-Angiotensin System/drug effects* ; Rats, Inbred SHR ; Oxidative Stress/drug effects* ; Male ; Rats, Inbred WKY ; Blood Pressure/drug effects* ; Myocardium/pathology* ; Rats ; Inflammation/pathology*

Objective To analyze the gene expression characteristics of chronic rhinosinusitis with nasal polyps(CRSwNP)using bioinformatics methods,aim to investigate the potential biomarkers and their diagnostic value of CRSwNP.Methods(1)The CRSwNP Gene expression data set was downloaded from the American Gene Expression Omnibus(GEO)database.The differentially expressed genes(DEGs)between CRSwNP patients and healthy controls were screened through data analysis.Gene Ontology(GO)functional enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis were performed on the identified DEGs.Protein-protein interaction(PPI)networks were constructed utilizing the STRING database,and the key genes were identified by using the cytoHubba plugin.The"Cibersort"package was used to analyze the influence of key genes on common immune cells.(2)Thirty-two patients diagnosed with CRSwNP in the First Affiliated Hospital of Hebei North University from June 2022 to June 2023 were selected as the CRSwNP group,and 21 patients with simple deviation of nasal septum without a history of sinusitis during the same period were selected as control group.The pathological characteristics of specimens in the two groups were examined using hematoxylin-eosin(HE)staining.Immunohistochemistry and Western blotting were used to detect the expression levels of key genes in CRSwNP.The levels of key proteins in plasma were detected using ELISA,and ROC curve was used to analyze its efficacy in diagnosing CRSwNP.Results(1)Analysis of three gene expression database sets(GSE36830,GSE23552,and GSE194282)showed that there were 156 DEGs in CRSwNP.GO functional enrichment and KEGG pathway analysis indicated that the functions of the above DEGs were mostly related to immune functions.Key genes such as cytochrome b-245 β chain(CYBB)and colony-stimulating factor 1 receptor(CSF1R)were identified.(2)The results of HE staining revealed that the epithelial of CRSwNP tissue was metaplastic into stratified squamous epithelium with interstitial edema.Both immunohistochemistry and Western blotting analyses indicated that the expression levels of CYBB and CSF1R in the CRSwNP group were significantly increased compared to control group(P＜0.05).ELISA results demonstrated that CYBB[(21.20±3.00)μg/ml vs.(17.66±1.66)μg/ml,P＜0.05]and CSF1[(477.37±86.63)pg/ml vs.(370.71±66.24)pg/ml,P＜0.05]in CRSwNP group were significantly increased compare to control group.ROC curve analysis showed that plasma concentrations of CYBB and CSF1 had AUCs of 0.888(95%CI 0.802-0.974)and 0.821(95%CI 0.711-0.931)for diagnosing of CRSwNP,respectively;their combined AUC was 0.927(95%CI 0.851-1.000).Conclusions CYBB and CSF1R may be involved in the occurrence and development of CRSwNP.Plasma CYBB and CSF1 have high diagnostic value for CRSwNP.

Objective To develop a multi-modal deep learning method for automatic classification of immune-mediated glomerular diseases based on images of optical microscopy(OM),immunofluorescence microscopy(IM),and transmission electron microscopy(TEM).Methods We retrospectively collected the pathological images from 273 patients and constructed a multi-modal multi-instance model for classification of 3 immune-mediated glomerular diseases,namely immunoglobulin A nephropathy(IgAN),membranous nephropathy(MN),and lupus nephritis(LN).This model adopts an instance-level multi-instance learning(I-MIL)method to select the TEM images for multi-modal feature fusion with the OM images and IM images of the same patient.By comparing this model with unimodal and bimodal models,we explored different combinations of the 3 modalities and the optimal methods for modal feature fusion.Results The multi-modal multi-instance model combining OM,IM,and TEM images had a disease classification accuracy of(88.34±2.12)%,superior to that of the optimal unimodal model[(87.08±4.25)%]and that of the optimal bimodal model[(87.92±3.06)%].Conclusion This multi-modal multi-instance model based on OM,IM,and TEM images can achieve automatic classification of immune-mediated glomerular diseases with a good classification accuracy.

Objective To develop a multi-modal deep learning method for automatic classification of immune-mediated glomerular diseases based on images of optical microscopy(OM),immunofluorescence microscopy(IM),and transmission electron microscopy(TEM).Methods We retrospectively collected the pathological images from 273 patients and constructed a multi-modal multi-instance model for classification of 3 immune-mediated glomerular diseases,namely immunoglobulin A nephropathy(IgAN),membranous nephropathy(MN),and lupus nephritis(LN).This model adopts an instance-level multi-instance learning(I-MIL)method to select the TEM images for multi-modal feature fusion with the OM images and IM images of the same patient.By comparing this model with unimodal and bimodal models,we explored different combinations of the 3 modalities and the optimal methods for modal feature fusion.Results The multi-modal multi-instance model combining OM,IM,and TEM images had a disease classification accuracy of(88.34±2.12)%,superior to that of the optimal unimodal model[(87.08±4.25)%]and that of the optimal bimodal model[(87.92±3.06)%].Conclusion This multi-modal multi-instance model based on OM,IM,and TEM images can achieve automatic classification of immune-mediated glomerular diseases with a good classification accuracy.

Bone organoids can simulate the complex structure and function of the bone tissues, which makes them a frontier technology in organoid researches. Bone organoids show a tremendous potential of applications in bone disease modeling, bone injury repair, and medicine screening. Although advancements have been made so far in constructing bone organoids with functional structures like mineralization, bone marrow, trabecular bone, callus, woven bone, etc, the researches in this field are confronted with numerous challenges such as lack of standardized construction strategies and unified evaluation criteria, which limits their further promotion and application. To standardize researches in bone organoids, the Orthopedic Expert Committee of Geriatric Branch of Chinese Association of Gerontology and Geriatrics, the Youth Osteoporosis Group of Orthopedic Branch of Chinese Medical Association, the Osteoporosis Group of Orthopedic Surgeon Branch of Chinese Medical Doctor Association, and the Osteoporosis Committee of Shanghai Association of Integrated Traditional Chinese and Western Medicine organized related experts to formulate Expert consensus on the construction, evaluation, and application of bone organoids ( version 2024) based on an evidence-based approach. A total of 17 recommendations were put forth, aiming to standardize researches and clinical applications of bone organoids and enhance their value in scientific research and clinical practice.

Objective The aim of this study was to investigate the prospective association between physical activity (PA),independently or in conjunction with other contributing factors,and osteoporosis (OP) outcomes. Methods The Physical Activity in Osteoporosis Outcomes (PAOPO) study was a community-based cohort investigation. A structured questionnaire was used to gather the participants' sociodemographic characteristics. Bone mineral density (BMD) measurements were performed to assess OP outcomes,and the relationship between BMD and OP was evaluated within this cohort. Results From 2013 to 2014,8,471 participants aged 18 years and older were recruited from Tangshan,China's Jidong community. Based on their PA level,participants were categorized as inactive,moderately active,or very active. Men showed higher physical exercise levels than women across the activity groups. BMD was significantly higher in the very active group than in the moderately active and inactive groups. Individuals aged>50 years are at a higher risk of developing OP and osteopenia. Conclusion The PAOPO study offers promising insights into the relationship between PA and OP outcomes,encouraging the implementation of PA in preventing and managing OP.

Objective To systematically evaluate the efficacy and safety of single and bilateral lung transplantation in the treatment of end-stage chronic obstructive pulmonary disease (COPD). Methods Chinese and English databases were searched by computer, including PubMed, Web of Science, The Cochrane Library, EMbase, CNKI, Wanfang database, VIP database and CBM. Case-control studies on single lung transplantation or bilateral lung transplantation for COPD were collected from the inception to July 31, 2022. We evaluated the quality of the literature via Newcastle-Ottawa Scale (NOS). All results were analyzed using Review Manager V5.3 and STATA 17.0. Results A total of 8 studies were included covering 14076 patients, including 8326 patients in the single lung transplantation group and 5750 patients in the bilateral lung transplantation group. NOS scores were≥6 points. The results of meta-analysis showed that there was no statistical difference in the postoperative 1-year survival between the two groups (P=0.070). The 2-year survival rate (P=0.002), 3-year survival rate (P<0.001), 5-year survival rate (P<0.001), overall survival rate (P＜0.001), postoperative forced expiratory volume in one second/predicted value (P<0.001), postoperative forced vital capacity (P<0.001), and postoperative 6-minute walking distance (P=0.002) were lower or shorter than those in the bilateral lung transplantation group, the postoperative intubation time (P=0.030) was longer than that in the bilateral lung transplantation group. Bilateral lung transplantation group showed better surgical results. There was no statistical difference in the mortality, obliterative bronchiolitis, length of hospitalization, primary graft dysfunction, or postoperative adverse events (P>0.05). Conclusion Bilateral lung transplantation is associated with better long-term survival and postoperative lung function compared with single lung transplantation. In-hospital mortality and postoperative complications are similar between them.

Objective To evaluate the safety and efficacy of transcatheter arterial chemoembolization(TACE)combined with lenvatinib and camrelizumab in the treatment of advanced hepatocellular carcinoma(HCC).Methods The clinical data of a total of 63 patients with advanced HCC,who received TACE combined with lenvatinib and camrelizumab(triple therapy)or TACE combined with lenvatinib(dual therapy)at the Jingmen Municipal People's Hospital of China between April 2020 and December 2021,were retrospectively analyzed.Triple therapy group had 30 patients,and dual therapy group had 33 patients.The post-treatment tumor response,disease progression-free survival(PFS),overall survival(OS),and the incidence of adverse drug reactions were recorded.Results The median follow-up period of the two groups was 14 months(range of 4-26 months).Compared with the dual therapy group,in the triple therapy group the objective response rate(ORR)was remarkably higher(83.3%vs.57.6%,P=0.026),the disease control rate(DCR)was obviously higher(93.3%vs.69.7%,P=0.039),the median PFS was significantly longer(8.0 months vs.5.0 months,P＜0.01),and the median OS was strikingly longer(24.0 months vs.12.0 months,P=0.004).No statistically significant difference in the incidence of adverse drug reactions existed between the two groups(P＞0.05).Conclusion For the treatment of advanced HCC,TACE combined with lenvatinib and camrelizumab is clinically safe and effective.(J Intervent Radiol,2024,32:57-62)