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.

Background Air pollution remains a critical public health issue, with persistent exposure to air pollutants continuing to pose significant health risks. Currently, research investigating the association between air pollution and myocardial infarction mortality in Shenzhen remains inadequate. Objective To quantitatively assess the association between air pollutants and myocardial infarction mortality in residents. Methods Based on the mortality surveillance system of Shenzhen Center for Disease Control and Prevention, we conducted a time-stratified case-crossover study of 10089 permanent residents who died from myocardial infarction in Shenzhen between 2013 and 2022. Using residential address information, we obtained individual-level exposure data for air pollutants from the China High Air Pollutants dataset and meteorological factors from the China Meteorological Administration Land Data Assimilation System. A time-stratified case-crossover study design was employed to construct a conditional logistic regression model to assess the association between short-term exposure to air pollutants and myocardial infarction mortality. The exposure-response relationship was visualized, and a comprehensive health risk assessment was performed. Results This study included a total of 10 089 cases of myocardial infarction deaths in Shenzhen. The median [interquartile range (IQR)] concentrations of fine particulate matter (PM_2.5), inhalable particulate matter (PM₁₀), sulfur dioxide (SO₂), nitrogen dioxide (NO₂), carbon monoxide (CO), and ozone (O₃) in Shenzhen from 2013 to 2022 were 24.59 (20.19) μg·m⁻³, 42.85 (28.42) μg·m⁻³, 8.53 (3.39) μg·m⁻³, 29.47 (13.56) μg·m⁻³, 0.77 (0.27) mg·m⁻³, and 86.53 (51.39) μg·m⁻³, respectively. The moving average concentrations of PM_2.5 and PM₁₀ over the current day and the previous 2 days (lag02) showed the highest risk of myocardial infarction mortality, with an odds ratio (OR) and 95% confidence interval (95%CI) of 1.004 (1.001, 1.007) and 1.004 (1.002, 1.006), respectively. At lag05, SO₂ demonstrated the strongest association with the risk of myocardial infarction mortality, with an OR (95%CI) of 1.042 (1.019, 1.065). The exposure-response relationships of PM_2.5, PM₁₀, and SO₂ with myocardial infarction mortality were approximately linear, whereas NO₂ exhibited a nonlinear relationship. At lag05, the highest risk of myocardial infarction mortality associated with NO₂ exposure was observed when the NO₂ concentration was ≤21.92 μg·m⁻³, with an OR (95% CI) of 1.024 (1.003, 1.046). The health risk assessment indicated that, using the WHO Air Quality Guidelines as the reference, the local PM_2.5 and NO₂ exposure led to an excess mortality of 398 and 298 cases, respectively. The sensitivity analysis revealed that after adjusting for O₃ and restricting the study period to 2013—2019, the effect estimates for PM_2.5, PM₁₀, NO₂, and SO₂ on myocardial infarction mortality slightly increased. Conclusion Short-term exposure to air pollutants, including PM_2.5, PM₁₀, NO₂, and SO₂, could increase the risk of myocardial infarction mortality. This study provides important scientific evidence for environmental health risk assessment and environmental management in Shenzhen.

ObjectiveTo investigate the demyelination induced by Angiostrongylus cantonensis （AC） infection in the brain of Balb/c mice and analyze the untargeted metabolomic changes in the corpus callosum， aiming to elucidate the underlying mechanisms. MethodsBalb/c mice were randomly assigned to a control group （n=6） and an infection group （n=6）. The infection group was orally administered 30 third-stage larvae of AC， while the control group received an equal volume of saline. Body weight， visual function， and behavioral scores were measured on post-infection 3， 6， 9， 12， 15， 18， and 21 days to assess neurological alterations. After 21 days， brain tissues were harvested for immunofluorescence staining， hematoxylin-eosin （HE） staining， and transmission electron microscopy to examine morphological changes in brain myelin and retina. Metabolomics analysis was performed， and differential metabolites were identified using volcano plots and heatmaps. The distribution of fold changes and bar charts were used to profile the key metabolites. These differential metabolites were then subjected to Kyoto Encyclopedia of Genes and Genomes （KEGG） pathway enrichment analysis and regulatory network analysis. ResultsOn the 9th day after AC infection， Balb/c mice showed a decline in neurological behavioral scores （P<0.05）. By day 15， visual scores decreased （P<0.05）， and by day 21， significant weight loss （P＜0.001） and mortality were observed. Concurrently， transmission electron microscopy and immunofluorescence staining revealed significant myelin damage in the corpus callosum and a marked reduction in oligodendrocytes （P<0.001）. HE staining showed severe retinal ganglion cell damage. Metabolomic analysis revealed that glycerophospholipids were the most abundant differential metabolites， with steroids and sphingolipids being relatively less abundant. Cholesteryl ester CE （20：2） was significantly upregulated （P<0.001）， while phosphatidylmethanol （18：0_18：1） was significantly downregulated （P<0.01）. KEGG enrichment and regulatory network analyses demonstrated that the differential metabolites were mainly enriched in metabolic pathways like steroid biosynthesis， bile secretion， and cholesterol metabolism， and were involved in key metabolic pathways such as sphingolipid metabolism， neural signal regulation， and glycerophospholipid metabolism. ConclusionsAC infection affects the metabolic state of mice via multiple pathways， modifying the levels of metabolites crucial for myelination and myelin stability. Demyelination may be closely linked to the disruption of these key metabolic pathways， particularly the dysregulation of cholesterol and sphingolipid metabolism， potentially playing a central role in demyelination onset. Furthermore， alterations in phospholipid metabolism and abnormal nerve signaling regulation may exacerbate myelin damage.

Objective: To investigate the reciprocal causal relationships between periodontitis and hepatobiliary diseases through Mendelian randomization (MR) analyses, to provide evidence for joint prevention and clinical decision-making in patients with concurrent periodontitis and hepatobiliary diseases. Methods: Single nucleotide polymorphisms (SNPs) were extracted from the largest genome-wide association study on periodontitis (17 353 cases, 28 210 controls) and hepatobiliary diseases within the European ancestry and used as instrumental variables (IVs). The strength of the associations was examined by calculating the F-statistic. The SNPs significantly associated with the outcome were removed by scanning on Phenoscanner platform. Bidirectional causal associations between periodontitis and hepatobiliary diseases were estimated using inverse variance weighted (IVW), MR-Egger, and Weighted Median methods. The robustness of the findings was further verified through additional sensitive MR approaches, including Cochran’s Q statistic （IVW）, Rucker’s Q statistic （MR-Egger）, MR-PRESSO and Leave-one-out analysis. Further MR analyses, utilizing other available genome-wide association studies (GWAS) on hepatobiliary diseases, were conducted to validate the results. Results: The IVW method found that periodontitis had a causal impact on acalculous cholecystitis (odds ratio = 1.277, 95% CI 1.097-1.485, P=0.002), implying an increased risk of acalculous cholecystitis associated with periodontitis, while the MR-Egger regression and Weighted Median failed to observe significant causal effects of periodontitis on acalculous cholecystitis. However, no bidirectional causal associations between periodontitis and nonalcoholic fatty liver disease, cirrhosis or liver cancer were observed using IVW, MR-Egger regression and Weighted Median. The bidirectional causal relationships were deemed unlikely to be influenced by horizontal pleiotropy. Further, the validation analysis based on alternative GWAS data suggested parallel results. Conclusions The MR analyses suggest that periodontitis may elevate the risk of acalculous cholecystitis. Further investigations, including clinical studies and mechanistic explorations, are warranted to validate these findings. However, the MR analyses do not support bidirectional causal associations between periodontitis and nonalcoholic fatty liver disease, cirrhosis or liver cancer.

BACKGROUND: The transcription factor POU2F1 regulates the expression levels of microRNAs in neoplasia. However, the miR-29b1/a cluster modulated by POU2F1 in gastric cancer (GC) remains unknown. METHODS: Gene expression in GC cells was evaluated using reverse-transcription polymerase chain reaction (PCR), western blotting, immunohistochemistry, and RNA in situ hybridization. Co-immunoprecipitation was performed to evaluate protein interactions. Transwell migration and invasion assays were performed to investigate the biological behavior of GC cells. MiR-29b1/a cluster promoter analysis and luciferase activity assay for the 3'-UTR study were performed in GC cells. In vivo tumor metastasis was evaluated in nude mice. RESULTS: POU2F1 is overexpressed in GC cell lines and binds to the miR-29b1/a cluster promoter. POU2F1 is upregulated, whereas mature miR-29b-3p and miR-29a-3p are downregulated in GC tissues. POU2F1 promotes GC metastasis by inhibiting miR-29b-3p or miR-29a-3p expression in vitro and in vivo . Furthermore, PIK3R1 and/or PIK3R3 are direct targets of miR-29b-3p and/or miR-29a-3p , and the ectopic expression of PIK3R1 or PIK3R3 reverses the suppressive effect of mature miR-29b-3p and/or miR-29a-3p on GC cell metastasis and invasion. Additionally, the interaction of PIK3R1 with PIK3R3 promotes migration and invasion, and miR-29b-3p , miR-29a-3p , PIK3R1 , and PIK3R3 regulate migration and invasion via the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in GC cells. In addition, POU2F1 , PIK3R1 , and PIK3R3 expression levels negatively correlated with miR-29b-3p and miR-29a-3p expression levels in GC tissue samples. CONCLUSIONS The POU2F1 - miR-29b-3p / miR-29a-3p-PIK3R1 / PIK3R1 signaling axis regulates tumor progression and may be a promising therapeutic target for GC.
MicroRNAs/metabolism* ; Humans ; Stomach Neoplasms/pathology* ; Cell Line, Tumor ; Cell Movement/physiology* ; Phosphatidylinositol 3-Kinases/metabolism* ; Animals ; Mice ; Octamer Transcription Factor-1/metabolism* ; Mice, Nude ; Class Ia Phosphatidylinositol 3-Kinase/metabolism* ; Neoplasm Invasiveness ; Gene Expression Regulation, Neoplastic/genetics* ; Male ; Immunohistochemistry ; Female

Testicular histology based on testicular biopsy is an important factor for determining appropriate testicular sperm extraction surgery and predicting sperm retrieval outcomes in patients with azoospermia. Therefore, we developed a deep learning (DL) model to establish the associations between testicular grayscale ultrasound images and testicular histology. We retrospectively included two-dimensional testicular grayscale ultrasound from patients with azoospermia (353 men with 4357 images between July 2017 and December 2021 in The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China) to develop a DL model. We obtained testicular histology during conventional testicular sperm extraction. Our DL model was trained based on ultrasound images or fusion data (ultrasound images fused with the corresponding testicular volume) to distinguish spermatozoa presence in pathology (SPP) and spermatozoa absence in pathology (SAP) and to classify maturation arrest (MA) and Sertoli cell-only syndrome (SCOS) in patients with SAP. Areas under the receiver operating characteristic curve (AUCs), accuracy, sensitivity, and specificity were used to analyze model performance. DL based on images achieved an AUC of 0.922 (95% confidence interval [CI]: 0.908-0.935), a sensitivity of 80.9%, a specificity of 84.6%, and an accuracy of 83.5% in predicting SPP (including normal spermatogenesis and hypospermatogenesis) and SAP (including MA and SCOS). In the identification of SCOS and MA, DL on fusion data yielded better diagnostic performance with an AUC of 0.979 (95% CI: 0.969-0.989), a sensitivity of 89.7%, a specificity of 97.1%, and an accuracy of 92.1%. Our study provides a noninvasive method to predict testicular histology for patients with azoospermia, which would avoid unnecessary testicular biopsy.
Humans ; Male ; Azoospermia/diagnostic imaging* ; Deep Learning ; Testis/pathology* ; Retrospective Studies ; Adult ; Ultrasonography/methods* ; Sperm Retrieval ; Sertoli Cell-Only Syndrome/diagnostic imaging*

The aim of this investigation was to determine the optimal storage medium for testicular hypothermic transportation and identify the ideal concentration for the application of the protective agent 5-aminolevulinic acid (5-ALA). Furthermore, this study aimed to explore the underlying mechanism of the protective effects of 5-ALA. First, we collected and stored mouse testicular fragments in different media, including Hank's balanced salt solution (HBSS; n = 5), Dulbecco's Modified Eagle Medium/Nutrient Mixture F-12 (DMEM/F12; n = 5), and alpha-minimum essential medium (αMEM; n = 5). Storage of testicular tissue in HBSS preserved the integrity of testicular morphology better than that in the DMEM/F12 group ( P < 0.05) and the αMEM group ( P < 0.01). Testicular fragments were subsequently placed in HBSS with various concentrations of 5-ALA (0 [control], 1 mmol l -1 , 2 mmol l -1 , and 5 mmol l -1 ) to determine the most effective concentration of 5-ALA. The 2 mmol l -1 5-ALA group ( n = 3) presented the highest positive rate of spermatogonial stem cells compared with those in the control, 1 mmol l -1 , and 5 mmol l -1 5-ALA groups. Finally, the tissue fragments were preserved in HBSS with control ( n = 3) and 2 mmol l -1 5-ALA ( n = 3) under low-temperature conditions. A comparative analysis was performed against fresh testes ( n = 3) to elucidate the underlying mechanism of 5-ALA. Gene set enrichment analysis (GSEA) for WikiPathways revealed that the p38 mitogen-activated protein kinase (MAPK) signaling pathway was downregulated in the 2 mmol l -1 5-ALA group compared with that in the control group (normalized enrichment score [NES] = -1.57, false discovery rate [FDR] = 0.229, and P = 0.019). In conclusion, these data suggest that using 2 mmol l -1 5-ALA in HBSS effectively protected the viability of spermatogonial stem cells upon hypothermic transportation.
Male ; Animals ; Testis/cytology* ; Aminolevulinic Acid/pharmacology* ; Mice ; Organ Preservation/methods* ; Organ Preservation Solutions/pharmacology* ; Cryopreservation/methods*

OBJECTIVES: To summarize the clinical and genetic characteristics of end-stage renal disease caused by PLCE1 gene mutations. METHODS: A retrospective analysis of the clinical and genetic features of three children from a family with PLCE1 gene mutations was conducted, along with a literature review of hereditary kidney disease cases caused by PLCE1 gene mutations. RESULTS: The proband was an 8-year-old male presenting with nephrotic syndrome stage 4 chronic kidney disease. Renal biopsy showed focal segmental glomerulosclerosis. Two years and five months after kidney transplantation, the patient had persistent negative proteinuria and normal renal function. Whole-exome sequencing identified two pathogenic heterozygous variants: c.961C>T and c.3255_3256delinsT, with c.3255_3256delinsT being a novel mutation. Family screening revealed no renal involvement in the parents, but among five siblings, one brother died at age of 4 years from end-stage renal disease. A 7-year-old sister presented with proteinuria and bilateral medullary sponge kidney, with proteinuria resolving after one year of follow-up. A 3-year-old brother died after kidney transplantation due to severe pneumonia. The literature review included 45 patients with hereditary kidney disease caused by PLCE1 gene mutations. The main clinical phenotype was nephrotic syndrome (87%, 39/45), and renal pathology predominantly showed focal segmental glomerulosclerosis (57%, 16/28). No mutation hotspots were identified. CONCLUSIONS Compound heterozygous mutations in the PLCE1 gene can lead to rapid progression of the disease to end-stage renal disease, with favorable outcomes following kidney transplantation. Family screening is crucial for early diagnosis, and medullary sponge kidney may be a novel phenotype associated with these gene mutations.
Humans ; Male ; Proteinuria/genetics* ; Kidney Failure, Chronic/etiology* ; Child ; Mutation ; Female ; Child, Preschool ; Retrospective Studies ; Phosphoinositide Phospholipase C

OBJECTIVE: To investigate the clinical characteristics and prognostic of venetoclax (VEN) combined targeted therapy in acute leukemia (AL) patients with PICALM∷MLLT10 fusion gene positivity. METHODS: A retrospective analysis was conducted on 16 PICALM∷MLLT10-positive AL patients treated at the First Affiliated Hospital of Soochow University from January 2021 to August 2024. These patients were diagnosed by targeted RNA sequencing (RNA-seq) or reverse transcription multiplex PCR, including newly diagnosed and relapsed/refractory (R/R) cases. The immunophenotypes, genetic features, gene mutations, and the efficacy of VEN combination targeted therapy of patients were evaluated. RESULTS: Among the 16 cases, 3 were confirmed by reverse transcription multiplex PCR, and 13 were detected through targeted RNA-seq among 528 AL patients, with a detection rate of 2.46%. The averge age of patients was (28.0±8.58) years. Patients exhibited diverse immunophenotypes, including 7 cases of acute myeloid leukemia, 5 of acute T-lymphoblastic leukemia, 1 of acute B-lymphoblastic leukemia, 1 of acute undifferentiated leukemia, and 2 of mixed-phenotype acute leukemia. Among them, 11 had extramedullary disease (EMD), 14 expressed CD7, and 12 expressed CD33. Major co-occurring mutations included PHF6 (6 cases), NOTCH1 (5 cases), and 7 cases with complex karyotypes. Of the 12 patients who received standard induction therapy, 7 did not achieve remission (PR+NR). All 4 patients treated with VEN combination therapy achieved complete remission (CR). Among the 7 induction failure cases, 4 achieved CR upon re-induction with VEN, while the remaining 3 re-induced with standard therapy, did not achieve CR. Thirteen patients received allogeneic hematopoietic stem cell transplantation, including 6 who received maintenance therapy with hypomethylating agents (HMA) alone or in combination with VEN, and seven were followed up. Survival analysis showed that the overall survival was better in the maintenance therapy group (P =0.044). CONCLUSION PICALM∷MLLT10-positive AL involves multiple lineages and demonstrates poor response to conventional chemotherapy. VEN combination therapy shows promising efficacy in both newly diagnosed and R/R patients. Post-transplant maintenance therapy with HMA alone or combined with VEN may extend survival; however, further clinical validation is required.
Humans ; Sulfonamides/therapeutic use* ; Retrospective Studies ; Prognosis ; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use* ; Adult ; Male ; Female ; Leukemia, Myeloid, Acute/genetics* ; Mutation ; Oncogene Proteins, Fusion/genetics* ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy*

OBJECTIVE: To explore the effect of Lactobacillus reuteri on testicular injury in mice exposed to neonicotinoid insecticides (NNI). METHODS: Fifteen C57BL/6 male mice were randomly divided into control group (CTRL group), exposure group (NNI group) and Lactobacillus intervention group (NNI-L group). The mice in CTRL group were given 0.02ml/g of 0.5% carboxymethyl cellulose sodium solution by gavage for 14 days. The mice in NNI group were given 0.02 ml/g of NNI mixture by gavage for 14 days. The mice in NNI-L group were given 0.02 ml/g of NNI mixture by gavage and 5×108cfu/ml of Lactobacillus reuteri powder solution for 14 days. Then, the histomorphology and function of testicle were evaluated by hematoxylin-eosin staining, immunofluorescence staining and RNA sequencing. RESULTS: Compared with CTRL group, the thickness of testicular seminiferous epithelium in the NNI group was significantly thinner. And the decline in the number of spermatogenic cells and sperm was observed. And the expression of spermatogonial stem cell marker UCHL1 was down-regulated which was significantly improved in NNI-L group compared with the NNI group. The abnormal expressions of hormone and sperm methylation related genes in testis of NNI group were detected by RNA sequencing, with significant down-regulation being found in NPFF and IGF2. While the expression of HSD3B8 was significantly up-regulated. The abnormal expression of these genes could be significantly improved after oral administration of Lactobacillus reuteri. CONCLUSION Testicular spermatogenesis and endocrine function can be damaged by NNI exposure. And oral administration of Lactobacillus reuteri protects testis from the adverse effects of NNI toxicity.
Animals ; Male ; Limosilactobacillus reuteri ; Testis/pathology* ; Mice ; Mice, Inbred C57BL ; Insecticides/toxicity* ; Neonicotinoids/toxicity* ; Probiotics ; Spermatogenesis/drug effects*