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*

BACKGROUND:silencing information regulatory 1(SIRT1)regulates the function of related proteins in chondrocytes in a deacetylated manner and participates in chondrocyte proliferation and differentiation,thereby promoting cartilage defect repair. OBJECTIVE:To screen for signaling pathways with unclear action status after SIRT1 gene knockdown in chondrocytes,as well as diseases or functions that produce changes using high-throughput technology. METHODS:ATDC5 chondrocytes from mice in logarithmic growth phase were divided into two groups:the cells were transfected with SIRT1 gene knockdown negative control lentivirus in control group and SIRT1 gene knockdown lentivirus in experimental group.GeneChip? Mouse Genome 430 2.0 Array was used to detect the mRNA expression at 72 hours after transfection.Applied bioinformatics technology was also used to screen for unclear activation or inhibition signaling pathways and their related factors.Moreover,enrichment of disease or function modules was analyzed. RESULTS AND CONCLUSION:After knocking down the SIRT1 gene,there were 245 signaling pathways with unclear activation or inhibition status in the mouse ATDC5 chondrocytes.According to the ranking of-Log(P-value),we reported the factors in the top 20 signaling pathways with unclear activation or inhibition status,including IGFBP4,TGFBR1,CTGF,COL4A5,LHX2,IL1RL1,and KLF6.According to the ranking of-Log(P-value),there were significant changes in 14 disease or function modules,including cellular growth and proliferation,organism survival,cell death and survival.According to the number of differentially expressed genes,there were significant changes in three disease or function modules,including organismal injury and abnormalities,cancer,and cell death and survival.According to the comprehensive ranking of-Log(P-value)and the number of differentially expressed genes,the disease or function module related to intrinsic immune response was significantly activated.

MiR-138-5p is a microRNA that plays an important regulatory role in the pathogenesis of osteoarthritis.MiR-138-5p regulates various biological processes,including inflammation,cell apoptosis and proliferation,and matrix degradation in osteoarthritis,by modulating signaling pathways including nuclear factor-κB,Wnt/β-catenin,and phosphoinositide 3-kinase/AKT.This review summarizes the research progress regarding the mechanism of miR-138-5p in osteoarthritis.

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.

To summarize the nursing experience of a patient with schizophrenia complicated by severe neurodeptic malignant syndrome.Nursing points include:to emphasize monitoring of antipsychotic medications to detect the onset of neurodeptic malignant syndrome as early as possible;to leverage the multidisciplinary team for rapid initiation of acute phase management interventions;to combine multimodal cooling to help rewarm the patient;to implement the stepwise intervention program to promote recovery of bowel function;to emphasize family supportive therapy to restore social functioning;to continue case management by developing a multidisciplinary follow-up plan.After careful management and care by the multidisciplinary team,the patient was successfully discharged from the hospital after a total stay of 47 days.After 3 months of follow-up,the patient's daily life was basically back to normal.

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.

Autism spectrum disorder (ASD) is a range of neurodevelopmental diseases characterized by social dysfunction and stereotypic behaviors. The etiology of ASD remains largely unexplored, resulting in a diverse array of described clinical manifestations and varying degrees of severity. Currently, there are no drugs approved by a supervisory organization that can effectively treat the core symptoms of ASD. Childhood and adolescence are crucial stages for making significant achievements in ASD treatment, necessitating the development of drugs specifically for these periods. Based on the drug targets and mechanisms of action, it can be found that atypical psychotropic medications, anti-inflammatory and antioxidant medications, hormonal medications, ion channel medications, and gastrointestinal medications have shown significant improvement in treating the core symptoms of ASD in both children and adolescents. In addition, comparisons of drugs within the same category regarding efficacy and safety have been made to identify better alternatives and promote drug development. While further evaluation of the effectiveness and safety of these medications is needed, they hold great potential for widespread application in the clinical treatment of the principal symptoms of ASD.
Humans ; Autism Spectrum Disorder/drug therapy* ; Child ; Adolescent ; Psychotropic Drugs/therapeutic use* ; Antioxidants/therapeutic use* ; Anti-Inflammatory Agents/therapeutic use* ; Gastrointestinal Agents/therapeutic use*

Gyrus Cinguli ; Claustrum ; Cerebral Cortex ; Basal Ganglia ; Motor Activity ; Neural Pathways

Objective: To examine the patterning cropped and shaped mesh repair for perineal hernia after abdominoperineal excision (APE) in rectal cancer. Methods: The clinical data of 8 patients with perineal hernia after APE who accepted surgical treatment in the Department of Hepatopancreatobiliary and Hernia Surgery, the First Affiliated Hospital of Fujian Medical University from March 2017 to December 2022 were retrospectively reviewed. There were 3 males and 5 females, aged (67.6±7.2) years (range: 56 to 76 years). Eight patients developed a perineal mass at (11.3±2.9) months (range: 5 to 13 months) after APE. After surgical separation of adhesion and exposing the pelvic floor defect, a 15 cm×20 cm anti-adhesion mesh was fashioned as a three-dimensional pocket shape to fit the pelvic defect, then fixed to the promontory or sacrum and sutured to the pelvic sidewalls and the anterior peritoneum, while two side slender slings were tailored in front of the mesh and fixed on the pectineal ligament. Results: The repair of their perineal hernias went well, with an operating time of (240.6±48.8) minutes (range: 155 to 300 minutes). Five patients underwent laparotomy, 3 patients tried laparoscopic surgery first and then transferred to laparotomy combined with the perineal approach. Intraoperative bowel injury was observed in 3 patients. All patients did not have an intestinal fistula, bleeding occurred. No reoperation was performed and their preoperative symptoms improved significantly. The postoperative hospital stay was (13.5±2.9) days (range: 7 to 17 days) and two patients had postoperative ileus, which improved after conservative treatment. Two patients had a postoperative perineal hernia sac effusion, one of them underwent placement of a tube to puncture the hernia sac effusion due to infection, and continued irrigation and drainage. The postoperative follow-up was (34.8±14.0) months (range: 13 to 48 months), and 1 patient developed recurrence in the seventh postoperative month, no further surgery was performed. Conclusions: Surgical repair of the perineal hernia after APE can be preferred transabdominal approach, routine application of laparoscopy is not recommended, combined abdominoperineal approach can be considered if necessary. The perineal hernia after APE can be repaired safely and effectively using the described technique of patterning cropped and shaped mesh repair.
Male ; Female ; Humans ; Animals ; Herniorrhaphy/methods* ; Surgical Mesh ; Retrospective Studies ; Hernia, Abdominal/surgery* ; Hernia ; Rectal Neoplasms/surgery* ; Proctectomy ; Laparoscopy ; Perineum/surgery* ; Postoperative Complications ; Incisional Hernia/surgery* ; Hominidae

Objective To investigate the levels of γδ T cells and their subpopulations in bone marrow(BM)of patients with myelodysplastic syndrome(MDS),it aims to explore the immune deficiency status of BM microenvi-ronment in MDS patients.Methods BM samples were collected from MDS patients before and after treatment,as well as from normal donors.Multicolor flow cytometry was utilized to detect bone marrow γδ T cells and subpopulation levels.The changes of the T cell subsets after treatment were also analyzed.Results The levels of BM γδ T cells and follicular helper γδ T cells from MDS patients were significantly lower than those of normal donors(P<0.05).Among γδ T cells at different stages of differentiation,only the frequencies of na?ve γδ T cells from MDS patients decreased significantly(P = 0.037),and there was no significant difference observed about central memory,effector memory,and terminally differentiated γδ T cells in MDS patients compared to normal donors(P>0.05).Although there was a slight decrease in PD1+γδ T cells and an increase in TIM3+γδ T cells,these differences were not statistically significant(P>0.05).In patients who achieved a curative effect,the proportions of γδ T cells and naive γδ T cells increased significantly after treatment,and the effector memory γδ T cells decreased significantly after treatment(P<0.05).After treatment,85.71%(6/7)of MDS patients showed a decrease in γδ+TIM3+ T cell levels to varying degrees.Conclusions The levels of γδ T cells and their subpopulations in the BM microenvironment of patients with MDS exhibit varying degrees of abnormalities.However,in patients who receive effective treatment,these abnormal γδ T cells can recover.By detecting the levels of γδ T cells and subpopulations,we can gain insights into the immune deficiency status of MDS.This information might serve as an indicator to assess treatment efficacy and provide valuable insights for anti-tumor immunotherapy.