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.

Fucoidan(FUC)is a natural seaweed-derived drug.Previously,our experiments have shown that FUC can significantly inhibit the cell viability of human osteosarcoma 143B cells and induce cell death,but the mechanism remains unclear.Ferroptosis,a novel form of cell death,has emerged as an important target for tumor therapy.This study aims to investigate whether FUC induces ferroptosis of 143B cells and elucidate its underlying molecular mechanisms.CCK-8 and LDH assays result showed that FUC(10,100,400 μg/mL)significantly reduced cell viability of 143B cells and induced cell death.Calce-in-AM staining,FeRhoNox-1 staining,and C11 BODIPY 581/591 staining indicated that FUC obviously increased the levels of labile iron pool(LIP),Fe2+,and lipid reactive oxygen species(Lip ROS)in 143B cells.Chemical colorimetric analysis revealed that FUC markedly decreased intracellular Glutathi-one(GSH)contents.Real-time quantitative PCR showed that FUC dramatically reduced the mRNA lev-els of ferroptosis-related factors solute carrier family 7 member 11(SLC7A11)and glutathione peroxidase 4(GPX4),while increasing the mRNA levels of prostaglandin endoperoxide synthase 2(PTGS2)and acyl-CoA synthetase long-chain family member 4(ACSL4).Western blotting analysis demonstrated that FUC significantly reduced the protein levels of SLC7A11 and GPX4,and the ratios of p-PI3K/PI3K,p-AktSer473/Akt,and p-AktThr308/Akt,but increased the protein level of ACSL4.Immunofluorescence staining showed that FUC obviously inhibited the nuclear translocation of p-AktSer473.The ferroptosis in-hibitor ferrostatin-1(Fer-1)and iron chelator deferoxamine(DFO)remarkably suppressed cell death in-duced by FUC in 143B cells.Additionally,the PI3K/Akt pathway activator 740Y-P significantly inhibi-ted FUC-induced iron overload and lipid peroxidation in 143B cells,and restored the protein levels of SLC7A11 and GPX4.In conclusion,FUC can induce ferroptosis of 143B cells by inhibiting the PI3K/Akt signaling pathway,which may be a potential target for the prevention and treatment of osteosarcoma.

Depression is a heterogeneous mental disorder in which the interaction between genetic susceptibility and environ-mental factors plays a key role in its pathogenesis.Although the specific mechanisms of the disease still need to be thoroughly studied and elucidated,there is now a broad consensus that epi-genetic markers have a central influence on its mechanism of ac-tion.DNA methylation of brain-derived neurotrophic factor(BD-NF)is not only regarded as a promising epigenetic biomarker of pathology,but may also help predict the efficacy of antidepres-sants.In this paper we reviewed the gene structure of BDNF and its DNA methylation regulation mechanism,and also analyzed the changes of DNA methylation of this factor in depression pa-tients and animal models,aiming to provide new ideas and theo-retical support for clinical research.

Objective To address the challenges of constructing large language models for traditional Chinese medicine(TCM)classics,which are complex and expensive to fine-tune,this study explores a lightweight fine-tuning method for such models,aiming to develop a question-answering model centered on TCM classics,particularly various editions of Shang Han Lun through the ages.Methods Dataset construction involved designing prompts to guide GPT-4 in generating Q&A pairs based on Shang Han Lun and integrating them with the ShenNong_TCM_Dataset and cMedQA2 datasets.Five general-purpose large models were selected for Lora fine-tuning.The best model was chosen through evaluation,and the performance of multiple quantized versions was validated.Results After fine-tuning,the BLEU,ROUGE-1,ROUGE-2,and ROUGE-L metrics for the Qwen-7B-Chat model improved by 17.61,19.63,14.3,and 21.4,respectively,compared to the base model.Conclusion The selected model in this study is capable of effectively understanding and utilizing professional terms and concepts from TCM classics,such as Shang Han Lun,to provide accurate answers to user queries.Compared to similar models,it requires lower fine-tuning costs and computational power,contributing to the dissemination of TCM knowledge and the development of intelligent systems.

Aim To investigate the role of miR-130b-3p in regulating the USP47/NLRP3 inflammasome in airway remodeling associated with asthma and to explore its potential therapeutic value in asthma treat-ment.Methods An OVA-induced asthma mouse mod-el was established,and intervention with miR-130b-3p agomir was performed.Histological staining,quantita-tive real-time PCR,Western blot,immunofluorescence and flow cytometry were used to analyze the effects of miR-130b-3p on the expression of USP47,NLRP3,and related inflammatory factors,as well as the inflamma-some activity.Results miR-130b-3p was significantly downregulated in asthmatic mice,and its intervention significantly inhibited airway epithelial damage,inflam-matory cell infiltration,and collagen deposition.Addi-tionally,miR-130b-3p targeted USP47 and indirectly suppressed NLRP3 expression,leading to reduced in-flammasome activity and alleviated asthma-related in-flammatory responses.Conclusion miR-130b-3p re-duces asthma-related inflammatory responses by down-regulating USP47 expression and indirectly inhibiting NLRP3 inflammasome activity.

Objective:To investigate the dynamic characteristics of human papillomavirus (HPV) genomic integration during cervical lesion progression and the clinical value of HPV integration detection in stratify HPV-positive women, and to explore its molecular mechanisms in cervical carcinogenesis.Methods:A prospective cohort study was designed to enroll high-risk HPV (HR-HPV) positive women who underwent cervical cancer screening in Drum Tower Hospital Affiliated to Nanjing University Medical School and Nanjing Maternity and Child Health Care Hospital from July 2022 to July 2024. Cervical exfoliated cells samples were collected, and HPV whole genome targeted capture and high-throughput sequencing technology were used. The HPV integration patterns, host gene functional region distribution and pathway enrichment characteristics of 157 samples with different cervical lesions grades were analyzed, including 31 cases of normal cervix, 40 cases of cervical intraepithelial neoplasia (CIN) Ⅰ, 32 cases of CIN Ⅱ, 42 cases of CIN Ⅲ, and 12 cases of cervical cancer.Results:HR-HPV integration was detected in 80.2% (126/157) of the 157 HR-HPV positive samples. The incidence of HR-HPV integration in cervical cancer patients was 12/12, which was higher than that in normal women (77%, 24/31). The incidence of HPV16 integration was significantly higher in high-grade lesions, and the incidence of HPV16 integration was 43% (18/42) in CIN Ⅲ patients and 8/12 in cervical cancer patients ( P<0.001). A total of 14 438 integration events were detected in 126 samples with HPV integration. The integration sites were mainly distributed in the host intergenic region (51.0%, 7 359/14 438) and intronic region (38.1%, 5 494/14 438), and the integration frequency of viral L1 gene was the highest (28.4%, 4 498/16 781). Functional enrichment analysis showed that HPV integration-related host genes were significantly enriched in transport of small molecules,cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling pathway, and purine ribonucleotide biosynthetic process, which synergistically drove carcinogenesis through multiple mechanisms. Conclusions:HPV integration events are significantly associated with the progression of cervical lesions. HPV integrated detection based on cervical exfoliated cells is expected to optimize the current screening strategy, reduce excessive intervention of HPV positive women and facilitate their accurate triage management.

Objective To retrospectively analyze the association between metabolic factors and high-risk colorectal adenoma(CRA).Methods The medical records of patients aged 18-75 years who underwent their initial colonoscopy at Karamay Central Hospital of Xinjiang Uygur Autonomous Region from Jul 2000 to Mar 2017 were collected.The comparison between normal colonoscopy(NC)and high-risk CRA patients was conducted using an unpaired t-test,while chi-square test was used for categorical variables.Least absolute shrinkage and selection operator(LASSO)regression and Logistic regression were utilized to analyze the association between metabolic factors and high-risk CRA.Results A total of 1 798 patients meeting the inclusion and exclusion criteria were enrolled and divided into normal colonoscopy(NC)findings group(n=972)and high-risk CRA group(n=826).The high-risk CRA group exhibited significantly lower levels of high-density lipoprotein cholesterol(HDL-C)in comparison to the NC group,while uric acid and fibrosis 4(FIB-4)index levels were significantly higher than those observed in the NC group(all P<0.05).Based on LASSO regression analysis,we identified 12 variables that potentially influence the occurrence of high-risk CRA,including age,gender,smoking history,alcohol consumption history,non-alcoholic fatty liver disease(NAFLD),hypertension,coronary artery disease,hyperglycemia,hypercholesterolemia,low levels of HDL-C,elevated alanine aminotransferase,and elevated gamma-glutamyl transferase.Multivariate analysis revealed that individuals aged over 50 years,male gender,cigarette and alcohol consumption,low HDL-C levels,history of NAFLD and hypertension were identified as independent risk factors associated with high-risk CRA(P<0.05).In addition,without or with adjusting for age,sex,smoking,and drinking history,patients with a high TG/HDL-C ratio(the ratio≥2.68)had a significantly higher risk of high-risk CRA than those with a low TG/HDL-C ratio(the ratio<2.68)[odds ratios(ORs)were1.430 and 1.235 respectively,all P<0.05)].Without or with adjusting variables,the ORs for NAFLD patients with FIB-4 index>2.67 were 1.849(P=0.466)and 1.435(P=0.707),respectively.Conclusion A significant association exists between metabolic factors and high-risk CRA.Independent risk factors for high-risk CRA include older age(≥50 years),male,smoking history,alcohol consumption history,low levels of HDL-C,and a history of NAFLD and hypertension.Individuals exhibiting a TG/HDL-C ratio exceeding 2.68 manifest a significantly heightened susceptibility to the development of high-risk CRA.Therefore,elderly males with one or more aforementioned metabolic abnormalities should be considered a priority population for colorectal screening.

Fucoidan(FUC)is a natural seaweed-derived drug.Previously,our experiments have shown that FUC can significantly inhibit the cell viability of human osteosarcoma 143B cells and induce cell death,but the mechanism remains unclear.Ferroptosis,a novel form of cell death,has emerged as an important target for tumor therapy.This study aims to investigate whether FUC induces ferroptosis of 143B cells and elucidate its underlying molecular mechanisms.CCK-8 and LDH assays result showed that FUC(10,100,400 μg/mL)significantly reduced cell viability of 143B cells and induced cell death.Calce-in-AM staining,FeRhoNox-1 staining,and C11 BODIPY 581/591 staining indicated that FUC obviously increased the levels of labile iron pool(LIP),Fe2+,and lipid reactive oxygen species(Lip ROS)in 143B cells.Chemical colorimetric analysis revealed that FUC markedly decreased intracellular Glutathi-one(GSH)contents.Real-time quantitative PCR showed that FUC dramatically reduced the mRNA lev-els of ferroptosis-related factors solute carrier family 7 member 11(SLC7A11)and glutathione peroxidase 4(GPX4),while increasing the mRNA levels of prostaglandin endoperoxide synthase 2(PTGS2)and acyl-CoA synthetase long-chain family member 4(ACSL4).Western blotting analysis demonstrated that FUC significantly reduced the protein levels of SLC7A11 and GPX4,and the ratios of p-PI3K/PI3K,p-AktSer473/Akt,and p-AktThr308/Akt,but increased the protein level of ACSL4.Immunofluorescence staining showed that FUC obviously inhibited the nuclear translocation of p-AktSer473.The ferroptosis in-hibitor ferrostatin-1(Fer-1)and iron chelator deferoxamine(DFO)remarkably suppressed cell death in-duced by FUC in 143B cells.Additionally,the PI3K/Akt pathway activator 740Y-P significantly inhibi-ted FUC-induced iron overload and lipid peroxidation in 143B cells,and restored the protein levels of SLC7A11 and GPX4.In conclusion,FUC can induce ferroptosis of 143B cells by inhibiting the PI3K/Akt signaling pathway,which may be a potential target for the prevention and treatment of osteosarcoma.

Aim To investigate the role of miR-130b-3p in regulating the USP47/NLRP3 inflammasome in airway remodeling associated with asthma and to explore its potential therapeutic value in asthma treat-ment.Methods An OVA-induced asthma mouse mod-el was established,and intervention with miR-130b-3p agomir was performed.Histological staining,quantita-tive real-time PCR,Western blot,immunofluorescence and flow cytometry were used to analyze the effects of miR-130b-3p on the expression of USP47,NLRP3,and related inflammatory factors,as well as the inflamma-some activity.Results miR-130b-3p was significantly downregulated in asthmatic mice,and its intervention significantly inhibited airway epithelial damage,inflam-matory cell infiltration,and collagen deposition.Addi-tionally,miR-130b-3p targeted USP47 and indirectly suppressed NLRP3 expression,leading to reduced in-flammasome activity and alleviated asthma-related in-flammatory responses.Conclusion miR-130b-3p re-duces asthma-related inflammatory responses by down-regulating USP47 expression and indirectly inhibiting NLRP3 inflammasome activity.

Objective To analyze the occurrence and risk factors of needlestick and sharps injuries(NSIs)among oral health care workers(HCWs).Methods NSIs reported by West China Hospital of Stomatology from 2020 to 2023 were collected,and factors relevant to NSIs were analyzed.Results A total of 391 cases of NSIs were repor-ted.Only one case of injury was caused by a sterile device,while the remaining 390 cases were caused by contamina-ted devices.There were 85,107,113,and 86 cases in 2020,2021,2022,and 2023,respectively.Most NSIs oc-curred among interns(n=235,60.1％).294 cases(75.2％)of NSIs occurred among HCWs who had less than 3 years of clinical experience.The distribution of NSIs among 235 interns in different months showed that NSIs ac-counted for a relatively high proportion from April to June and July to September,and the difference was statistica-lly significant(P＜0.05).The ventral side of the left thumb was the most common site of NSIs(n=53,13.6％),followed by the ventral side of the right index finger(n=45,11.5％)and the ventral side of the left index finger(n=44,11.3％).The most common devices involved in NSIs were various types of syringe needles(n=84,21.5％),followed by various types of dental burs(n=76,19.4％)and suture needles(n=49,12.5％).Injuries mainly oc-curred during the treatment process(n=212,54.2％)and in the department of endodontics(n=86,22.0％).This study didn't find any occupational bloodborne infection case caused by NSIs.Conclusion NSIs mainly occur among inexperienced oral interns,and devices causing NSIs are related to the treatment process.