Tumor drug resistance is an important problem in the failure of chemotherapy and targeted drug therapy, which is a complex process involving chromatin remodeling. SWI/SNF is one of the most studied ATP-dependent chromatin remodeling complexes in tumorigenesis, which plays an important role in the coordination of chromatin structural stability, gene expression, and post-translation modification. However, its mechanism in tumor drug resistance has not been systematically combed. SWI/SNF can be divided into 3 types according to its subunit composition: BAF, PBAF, and ncBAF. These 3 subtypes all contain two mutually exclusive ATPase catalytic subunits (SMARCA2 or SMARCA4), core subunits (SMARCC1 and SMARCD1), and regulatory subunits (ARID1A, PBRM1, and ACTB, etc.), which can control gene expression by regulating chromatin structure. The change of SWI/SNF complex subunits is one of the important factors of tumor drug resistance and progress. SMARCA4 and ARID1A are the most widely studied subunits in tumor drug resistance. Low expression of SMARCA4 can lead to the deletion of the transcription inhibitor of the BCL2L1 gene in mantle cell lymphoma, which will result in transcription up-regulation and significant resistance to the combination therapy of ibrutinib and venetoclax. Low expression of SMARCA4 and high expression of SMARCA2 can activate the FGFR1-pERK1/2 signaling pathway in ovarian high-grade serous carcinoma cells, which induces the overexpression of anti-apoptosis gene BCL2 and results in carboplatin resistance. SMARCA4 deletion can up-regulate epithelial-mesenchymal transition (EMT) by activating YAP1 gene expression in triple-negative breast cancer. It can also reduce the expression of Ca²⁺ channel IP3R3 in ovarian and lung cancer, resulting in the transfer of Ca²⁺ needed to induce apoptosis from endoplasmic reticulum to mitochondria damage. Thus, these two tumors are resistant to cisplatin. It has been found that verteporfin can overcome the drug resistance induced by SMARCA4 deletion. However, this inhibitor has not been applied in clinical practice. Therefore, it is a promising research direction to develop SWI/SNF ATPase targeted drugs with high oral bioavailability to treat patients with tumor resistance induced by low expression or deletion of SMARCA4. ARID1A deletion can activate the expression of ANXA1 protein in HER2+ breast cancer cells or down-regulate the expression of progesterone receptor B protein in endometrial cancer cells. The drug resistance of these two tumor cells to trastuzumab or progesterone is induced by activating AKT pathway. ARID1A deletion in ovarian cancer can increase the expression of MRP2 protein and make it resistant to carboplatin and paclitaxel. ARID1A deletion also can up-regulate the phosphorylation levels of EGFR, ErbB2, and RAF1 oncogene proteins.The ErbB and VEGF pathway are activated and EMT is increased. As a result, lung adenocarcinoma is resistant to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Although great progress has been made in the research on the mechanism of SWI/SNF complex inducing tumor drug resistance, most of the research is still at the protein level. It is necessary to comprehensively and deeply explore the detailed mechanism of drug resistance from gene, transcription, protein, and metabolite levels by using multi-omics techniques, which can provide sufficient theoretical basis for the diagnosis and treatment of poor tumor prognosis caused by mutation or abnormal expression of SWI/SNF subunits in clinical practice.

Objective To explore risk factors for cardiac valve calcification (CVC) in maintenance hemodialysis (MHD) patients and evaluate its impact on cardiovascular events and mortality. Methods Retrospective selection of 223 patients with MHD admitted to the Department of Nephrology of Jinshan Hospital, Fudan University from June 30, 2019 to June 30, 2024, and enrollment completed within one week of June 30, 2019. Patients were divided into CVC and non-CVC groups. Baseline data and 5-year follow-up data were collected. The binary logistic regression analysis was performed to explore the risk factors for CVC. Kaplan-Meier survival curve was used to analyze the survival rate of patients. Cox proportional hazard regression model was applied to evaluate the impact of CVC on the survival rates of MHD patients. Results Totally, 223 MHD patients with an average age of (58.4±13.5) years and an average dialysis duration of (64.0±55.4) months were involved. Among them, 136(61.0%) were males, 117(52.5%) were complicated with CVC. Age, dialysis duration, diabetic kidney disease (DKD), the serum corrected total calcium and phosphate, intact parathyroid hormone (iPTH), high-sensitive C-reactive protein (hsCRP), and homocysteine (Hcy) were independent related factors for CVC (P＜0.05). Both all-cause mortality (46.6% vs 28.7%) and cardiovascular mortality (33.3% vs 16.0%) were significantly higher in the CVC group than those in the non-CVC group (P＜0.01). Conclusions Age, dialysis duration, the primary disease, calcium and phosphate, and inflammation- and nutrition-related serum indicators are associated with CVC in MHD patients. CVC significantly increases mortality risk of MHD patients.

Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

OBJECTIVE: To identify prognostic genes associated with lysosome-dependent cell death (LDCD) in patients with gastric cancer (GC). METHODS: Differentially expressed genes (DEGs) were identified using The Cancer Genome Atlas - Stomach Adenocarcinoma. Weighted gene co-expression network analysis was performed to identify the key module genes associated with LDCD score. Candidate genes were identified by DEGs and key module genes. Univariate Cox regression analysis, and least absolute shrinkage and selection operator regression and multivariate Cox regression analyses were performed for the selection of prognostic genes, and risk module was established. Subsequently, key cells were identified in the single-cell dataset (GSE183904), and prognostic gene expression was analyzed. Cell proliferation and migration were assessed using the Cell Counting Kit-8 assay and the wound healing assay. RESULTS: A total of 4,465 DEGs, 95 candidate genes, and 4 prognostic genes, including C19orf59, BATF2, TNFAIP2, and TNFSF18, were identified in the analysis. Receiver operating characteristic curves indicated the excellent predictive power of the risk model. Three key cell types (B cells, chief cells, and endothelial/pericyte cells) were identified in the GSE183904 dataset. C19orf59 and TNFAIP2 exhibited predominant expression in macrophage species, whereas TNFAIP2 evolved over time in endothelial/pericyte cells and chief cells. Functional experiments confirmed that interfering with C19orf59 inhibited proliferation and migration in GC cells. CONCLUSION C19orf59, BATF2, TNFAIP2, and TNFSF18 are prognostic genes associated with LDCD in GC. Furthermore, the risk model established in this study showed robust predictive power.
Stomach Neoplasms/pathology* ; Humans ; Prognosis ; Lysosomes/physiology* ; RNA-Seq ; Cell Death ; Single-Cell Analysis ; Gene Expression Regulation, Neoplastic ; Cell Proliferation ; Single-Cell Gene Expression Analysis

Objective To investigate the recovery of plasma metabolism in asymptomatic and mild patients of coronavirus disease 2019(COVID-19)one year after recovery.Methods A total of 174 participants were recruited from the communities in Wuhan,including 80 healthy volunteers and the COVID-19 patients who had recovered for one year.According to the disease severity,the recovered COVID-19 patients were grouped as asymptomatic patients(n=80)and mild patients(n=14).The liquid chromatography mass spectrometry platform was employed to study the metabolomic characteristics of the plasma from all the participants.Results The plasma metabolites in asymptomatic patients and mild patients remained abnormal compared with those in healthy volunteers.Among the differential metabolites in asymptomatic patients and mild patients,some metabolites showed a downward trend only in mild patients,such as phosphatidylethanolamine[20∶3(5Z,8Z,11Z)/P-18∶0],sphingomyelin(d18∶1/24∶0),and cholesteryl(15∶0).The metabolic pathway involving the differential metabolites in mild patients was mainly glycerophospholipid metabolism.Conclusions Even one year after recovery,the mild COVID-19 patients still exhibit metabolic abnormalities.Hence,these patients may experience an extended period of time for recovery.
Humans ; COVID-19/metabolism* ; Metabolomics ; SARS-CoV-2 ; Metabolome ; Female ; Male ; Adult ; Middle Aged

Objective To explore the factors that affect the coordinated development of blood banks and apheresis plas-ma collection banks(hereinafter referred to as plasma banks),and explore feasible measures for the coordinated develop-ment of blood banks and plasma banks.Methods The blood information management system and blood source information management system were used to retrieve related data of blood and plasma donation from 9 cities in Shandong province from 2017 to 2021.The number of blood donors and plasma donors and the intersection of them were analyzed.The data analysis was performed using chi-square test,and a questionnaire survey was conducted to investigate the policies and information status,as well as expectations for coordinated development for blood and plasma donation.Results From 2017 to 2021,the total number of blood donors in 9 cities was higher than that of plasma donors,both have been increasing year by year,and the increase in plasma donors was significantly higher than that of blood donors(131.78%vs 23.90%,P<0.05).The inter-section proportion of blood and plasma donors had increased from 0.45%in 2017 to 1.04%in 2021,with an increase of 131.11%.Among the administrative regions where the participating blood and plasma banks located,94.2%have not re-leased relevant policy to promote the coordinated development of blood and plasma donation.The majority(63%)expected blood banks and plasma banks to be set at a distance more than 50 km apart.The top four functional requirements for the in-terconnection between blood banks and plasma banks management information system were blood test results(94.61%),ID number(87.54%),blood and plasma donation records(85.51%)and health consultation/examination results(82.15%).The top four elements of coordinated development between blood and plasma banks were policy support(96.25%),informa-tion networking(92.36%),top-level design(87.44%)and cultural construction(86.58%).Conclusion The number of donors who donate both blood(mainly whole blood)and plasma has been increasing year by year,which deserves our close attention.To achieve the coordinated development of blood donation and plasma donation,policy support is the most crucial and fundamental means.Establishment of a standard system and the share of blood and plasma donation information is neces-sary for blood informatization construction.It was critical to promote the coordinated development of blood and plasma dona-tion and ensure blood safety with improving legislation,formulating policies for coordinated development,strengthening top-level design,standardizing the publicity of blood and plasma donation and establishing the idea that blood and plasma dona-tion are equally honorable.

Objective:To compare the efficacy and safety of red light and daylight photodynamic therapy in the treatment of facial common acne.Methods:From March 2019 to November 2019, 52 patients with facial common acne who received 5-aminolevulinic acid photodynamic therapy in the Department of Dermatology, Chongqing Hospital of Traditional Chinese Medicine were enrolled, including 34 males and 18 females, aged 18-35 years, with an average age of 23.2 years. A 5% concentration of 5-aminolevulinic acid was applied to the entire face, with the right side of the face being exposed to red light for 20 minutes and the left side to daylight for 2 hours. The treatment was administered once a week for a total of 4 sessions. After the treatment, the acne remission, adverse reactions, and patient satisfaction on both sides of the face were compared.Results:Compared with before treatment, the number of inflammatory and non-inflammatory lesions on both sides of the face in the enrolled patients decreased, and there was no significant difference in the clearance rate of skin lesions between the two sides [53.7% (28/52) vs 59.1% (31/52), χ 2=0.89, P>0.05]. The overall effective rate on the red light side was 88.5% (46/52), and 82.7% (43/52) on the daylight side, with no significant difference between the two (χ 2=0.38, P>0.05). In terms of adverse reactions, mild erythema was common, and it was less on the daylight side than on the red light side [34.6% (18/52) vs 19.2% (10/52), χ 2=5.98, P<0.05]. During the treatment period, the pain score on the daylight side decreased compared to the red light side [(7.6±2.3) vs (4.1±1.3), t=13.10, P<0.001]. Overall satisfaction with the daylight side was reported in 49 cases (94.2%), and with the red light side in 37 cases (71.2%), with the daylight side being higher than the red light side, and the difference was statistically significant (χ 2=9.60, P<0.05). Conclusion:Daylight photodynamic therapy is as effective as red light photodynamic therapy for common acne, but it produces fewer adverse reactions and higher patient satisfaction.

Objective:To analyze the effects of low-dose methimazole treatment on thyroid volume and calcitonin levels in patients with hyperthyroidism.Methods:A total of 100 hyperthyroidism patients who were treated at the Mianyang Central Hospital from January to June 2019 were selected and randomly divided into a control group (50 cases) and an observation group (50 cases) using a random number table method. The control group was treated with once a day and 30 mg/dose of methimazole, while the observation group was treated with twice a day and 10 mg/dose of methimazole. Thyroid volume, and thyroid function [Thyroid growth hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone receptor antibody (TRAb)] before and after treatment in two groups of patients, the changes in serum levels of calcitonin (CT), visfatin, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were compared. The clinical efficacy of two groups were also compared.Results:The total clinical effective rate of the observation group was higher than that of the control group ( P<0.05). After treatment, the thyroid volume in the observation group was significantly smaller than that in the control group, and the CT level was significantly lower than that in the control group (all P<0.05). After treatment, the TSH level in the observation group was significantly higher than that in the control group, while the levels of FT3, FT4, and TRAb were significantly lower than those in the control group (all P<0.05). After treatment, the levels of Visfatin, TNF-α, and IL-6 in the observation group were significantly lower than those in the control group (all P<0.05). Conclusions:Low dose methimazole can improve thyroid function, reduce thyroid volume, lower body CT and inflammation levels in patients with hyperthyroidism, and has a better therapeutic effect.

To explore the inhibitory effect of tofatinib on skin fibrosis in bleomycin-induced systemic sclerosis mice and its mechanism,total of 24 Balb/c mice were recruited and divided into blank group,model group,early intervention group and late intervention group.The model group and two intervention groups were subcutaneously injected with bleomycin to induce model of systemic sclerosis,while the blank group was subcutaneously injected with normal saline.The early intervention group was given tofatinib intervention starting from the modeling process,and the late intervention group was given tofatinib intervention on the 8th day after the modeling process.HE and Masson staining were used to observe lesion tissue;ELISA was used to detect of serum level of IL-6;hydrolysis was employed to detect the hydroxyproline content;RT-PCR was used to measure the mRNA expression levels of p-JAK1,p-JAK2,p-JAK3 and p-STAT3;and Westem blot was used to detect the expression levels of p-JAK1,p-JAK2,p-JAK3,p-STAT3,type I collagen fiber and A-smooth muscle proteins.Compared with the blank group,the dermis in model group was thicker and collagen fibers were increased.After tofacatib intervention,the dermis was thinned and collagen fibers were relatively reduced.The dermis in early intervention group was thinner than that in late intervention group(P＜0.05).The level of IL-6 in late intervention group was significantly lower compared with that in model group(P＜0.05).The mRNA expressions of P-JAK2 and P-JAK3 in early intervention group were lower compared with those in model group(P＜0.05),and the protein expressions of P-JAK1,P-JAK3 and P-STAT3 in early intervention group were lower compared with those in model group(P＜0.05).The expression of P-JAK1 protein in early intervention group was lower than that in late intervention group(P＜0.05).In conclusion,tofatinib can suppress skin fibrosis in mice with systemic sclerosis by inhibiting JAK/STAT signaling pathway,and the anti-fibrosis effect of early tofatinib intervention is more obvious.

【Objective】 To establish a blood quality monitoring indicator system, in order to continuously improve blood quality and standardized management. 【Methods】 Based on the research of literature and standards, and guided by the key control points of blood collection and supply process, the blood quality monitoring indicator system was developed. Through two rounds of Delphi expert consultation, the indicator content was further revised and improved according to expert opinions after six months of trial implementation. The indicator weight was calculated by questionnaire and analytic hierarchy process. 【Results】 A blood quality monitoring indicator system covering the whole process of blood collection and supply was constructed, including five primary indicators, namely blood donation service, blood component preparation, blood testing, blood supply and quality control, as well as 72 secondary indicators, including definitions, calculation formulas, etc. Two rounds of expert consultation and two rounds of feasibility study meeting were held to revise 17 items and the weight of each indicator was obtained through the analytic hierarchy process. After partial adjustments, a blood quality monitoring indicator system was formed. 【Conclusion】 A blood quality monitoring indicator system covering the whole process of blood collection and supply has been established for the first time, which can effectively evaluate the quality management level of blood banks and coordinate blood quality control activities of blood banks in Shandong like pieces in a chess game, thus improving the standardized management level