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Glioblastoma remains one of the most aggressive and treatment-resistant brain tumors, with current standard-of-care therapies offering limited survival benefits. Immunotherapy has emerged as a promising avenue to enhance anti-tumor immunity, with chimeric antigen receptor T (CAR-T) cell therapy gaining significant attention. While CAR-T therapies have demonstrated remarkable success in hematologic malignancies, their application in glioblastoma faces several challenges, including tumor heterogeneity, an immunosuppressive tumor microenvironment, limited blood-brain barrier penetration, T-cell exhaustion, and potential neurotoxicity. This review explores recent advancements in CAR-T therapy for glioblastoma, focusing on key tumor-associated antigens and innovative strategies to overcome treatment barriers. These include multi-antigen targeting, checkpoint inhibition, locoregional CAR-T delivery, synNotch, personalized CAR-T systems, and combination approaches with oncolytic viruses. We also discuss future directions for optimizing efficacy and safety. As the field advances, integrating synthetic biology and personalized antigen selection may further refine CAR-T therapy, offering renewed hope for glioblastoma patients.
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Beyond the established oral-gut axis links in inflammatory bowel disease (IBD), this review provides an in-depth mechanistic analysis of how specific oral pathobionts disrupt the five intestinal barriers, microbial, chemical, physical, immune, and vascular, driving disease pathogenesis through distinct yet synergistic mechanisms. We synthesize evidence that key pathogens (e.g., Fusobacterium nucleatum (Fn), Porphyromonas gingivalis (Pg)) orchestrate multistep pathogenesis: ectopic translocation followed by targeted barrier disruption, Fn degrading tight junctions, Pg eroding mucus via gingipains, and Klebsiella spp. hijacking T helper 1 cells (Th1) immunity. This pathogen-centric taxonomy reveals pathophysiological sequences: mucosal invasion by Fn precedes microbiota dysbiosis, while Pg virulence factors directly compromise vascular integrity, decoupling translocation routes from barrier-specific outcomes. Notably, we characterize how barrier-specific damage generates therapeutic targets: mucus restoration counters Pg enzymatic degradation, toll-like receptor 4 (TLR4) blockade inhibits Klebsiella-driven inflammation, and Fusobacterium adhesin A (FadA) inhibition prevents Fn endothelial invasion, transitioning from associative findings to mechanism-based interventions. By integrating spatially resolved mechanisms across barrier layers, this work establishes a conceptual framework: oral pathogens act as “barrier disruptors” whose targeted neutralization may improve the IBD disease trajectory. This mechanistic framework positions oral barrier disruption as a druggable axis in IBD, offering actionable biomarkers and microbiota-directed therapeutic strategies.
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With the accelerated pace of modern life and evolving work patterns, an increasing number of individuals experience circadian rhythm reversal and irregular work-rest schedules. This altered lifestyle profoundly impacts the human metabolic system, particularly by elevating the risk of type 2 diabetes. Alterations in circadian rhythms may heighten this risk of type 2 diabetes through mechanisms such as interference with insulin secretion and glucose metabolism. This study reviewed the circadian rhythm system, behaviors associated with circadian dysregulation and diabetes, circadian rhythm synchronization, and metabolic health to provide scientific evidence for managing type 2 diabetes induced by circadian rhythm disruption.
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Background: This study aimed to investigate the possible therapeutic benefits of Huperzine A on autistic behaviours and histological alterations in the cerebellum of a rat model of autism.
Methods: This study utilized 30 male neonatal rat pups (10 per group) to investigate the effects of valproic acid on the rat cerebellum. Pregnant Wistar female rats received valproic acid (VPA) on the 12.5th gestation day, and their pups were administered VPA on postnatal day 14, while the control group received saline on the corresponding days. It was determined that the experimental group received Huperzine A (0.80 μmol/kg) administered via intraperitoneal injection from postnatal day 14 to postnatal day 40. The elevated plus-maze, rotarod, and Morris water maze assessments were employed to investigate autism-like behaviours. Furthermore, on postnatal day 41, the brains of all puppies were excised and prepared for histological examination, and hippocampus homogenates were obtained for the quantification of acetylcholinesterase (AChE) in cerebellar tissue homogenates.
Results: Huperzine A (HupA) treatment reduced anxiety in VPA-induced autism spectrum disorder (ASD) rats. The elevated plus-maze revealed that, at postnatal day (PND) 40, significant decreases in open-arm entries and time were observed (p < 0.0001). Non-significant effects at PND 21 (p = 0.99, p = 0.98). Moreover, HupA improved memory in ASD rats. Morris water maze test revealed that escape latency significantly decreased (p < 0.0001) at PND 39. Memory retrieval improved with HupA (p < 0.0001). Non-significant escape delay increased at PND 38 (p = 0.24). HupA also improved motor coordination in ASD rats. Rotarod test showed a significant endurance time decrease in ASD rats (p < 0.0001). HupA mitigated effects at PND 25 and PND 26 (p < 0.0001) but not at PND 24 (p = 0.10). HupA increased AChE levels in ASD rats. Group II had significantly lower AChE (p < 0.0001) than controls. Group III showed a non-significant increase versus controls (p = 0.0698). Huperzine A treatment considerably improved the cerebellar histological and immunohistochemical structural alterations.
Conclusions: These findings stress the critical impact of Huperzine A on neurobehavioral alterations, acetylcholinesterase, and cerebellar histological alterations in ASDs.
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Background: Bone healing is a complex biological process influenced by various cellular and molecular factors. Piezo-type mechanosensitive ion channel component 1 (Piezo1) is closely associated with function of bone cells. This study aims to investigate the effects of Piezo1 on bone healing, specifically examining its ability to enhance the growth and osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs), as well as assessing its effect on the Phosphoinositide 3-kinase/Protein kinase B (PI3K/AKT) signaling pathway.
Methods: This study utilized a rat fracture model to evaluate the effects of rat Piezo1 recombinant proteins on bone healing. Micro-computed tomography (Micro-CT) scans were performed during weeks 6 and 8 after fracture to assess the formation of callus during the healing process, including trabecular thickness (Tb.Th), trabecular number (Tb.N), and bone mineral density (BMD). The serum levels of alkaline phosphatase (ALP) and transforming growth factor beta 1 (TGF-β1) were evaluated using an enzyme-linked immunosorbent assay. Histological evaluation included hematoxylin–eosin staining to examine tissue composition and quantitative analysis of bone morphogenetic protein (BMP)-2 expression through immunohistochemistry. Furthermore, BM-MSCs were treated with different doses of Piezo1, and cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay. ALP staining and alizarin red staining were conducted to evaluate osteogenic differentiation. Additionally, the expression levels of osteogenic markers and the activation of the PI3K/AKT signaling pathway were examined using Western blot analysis.
Results: Piezo1 significantly enhanced trabecular bone formation in a rat fracture model, with micro-CT analysis showing amplified callus formation and improved Tb.Th, Tb.N, and BMD at weeks 6 and 8 (p < 0.05). The serum levels of ALP and TGF-β1 were elevated in the Piezo1 group (p < 0.05). Histological evaluation revealed more mature bone in the Piezo1 group than in the fracture group, especially by week 8, along with increased BMP-2 expression (p < 0.05). In vitro, CCK-8 assays indicated that Piezo1 promoted BM-MSC growth in a dose- and exposure duration-dependent manner (p < 0.05). After 7 days of osteogenic differentiation, ALP and alizarin red staining showed enhanced osteogenic activity and calcium deposition in Piezo1-treated cells (p < 0.05). Western blot analysis confirmed increased expression of osteogenic markers in treated BM-MSCs, and Piezo1 activated the PI3K/AKT signaling pathway by increasing the phosphorylation levels of PI3K and AKT (p < 0.05).
Conclusions: Piezo1 significantly enhances the growth and osteogenic differentiation of BM-MSCs, accelerating bone healing by activating the PI3K/AKT signaling pathway and increasing osteogenic marker expression. These findings support the potential use of Piezo1 as a bone healing enhancer.
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Background: Hepatocellular carcinoma (HCC) is a major contributor to cancer-related mortality worldwide, with its progression significantly influenced by immune evasion mechanisms. This research aimed to identify key genes associated with immune evasion and assess their clinical significance in HCC.
Methods: Gene expression data from 342 HCC patients were obtained from The Cancer Genome Atlas (TCGA) repository. The Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) algorithm was employed to calculate immune and stromal scores. Differential gene expression analysis was conducted between high and low immune score groups, as well as between high and low stromal score groups. The resulting differentially expressed genes (DEGs) underwent functional enrichment analysis. A prognostic risk score model for HCC was constructed utilizing Least Absolute Shrinkage and Selection Operator (LASSO)-Cox, univariate, and multivariate Cox regression analyses. The prognostic performance of the model was evaluated through Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curve analysis. Tumor and adjacent normal tissues from HCC patients were collected, and immune cell infiltration was quantified utilizing the Tumor Immune Estimation Resource (TIMER) database. Immunohistochemistry was performed to validate the expression of immune evasion-related proteins in clinical specimens.
Results: A total of 999 DEGs were identified from the immune and stromal score-based groups. These genes were predominantly enriched in immune-related pathways, including cytokine-cytokine receptor interactions, chemokine signaling, Wnt signaling, and the Hippo signaling pathway. Using univariate and multivariate Cox regression analysis, a prognostic model comprising six genes (Myocardin (MYOCD), Matrix Metallopeptidase 7 (MMP7), Matrix Metallopeptidase 16 (MMP16), PR/SET Domain 9 (PRDM9), Caudal Type Homeobox 2 (CDX2), and T Cell Receptor Beta Variable 10-3 (TRBV10-3)) was developed and demonstrated a significant association with overall survival (OS) in HCC patients (p < 0.05). The model yielded a concordance index (C-index) of 0.764, indicating robust prognostic performance. MYOCD was associated with a protective effect, showing an inverse correlation with the risk score (p < 0.001). Conversely, MMP7, PRDM9, CDX2, and MMP16 were risk-associated, with their expression levels positively correlating with the risk score (p < 0.001), whereas TRBV10-3 showed no significant difference between high- and low-risk groups (p > 0.05). Immunohistochemical validation confirmed the downregulation of MYOCD and upregulation of MMP7, MMP16, PRDM9, and CDX2 in HCC tissues (p < 0.001). Analysis of immune cell infiltration revealed a significant negative correlation between MYOCD expression and both stromal and ESTIMATE scores (p < 0.001), while MMP7 and MMP16 exhibited significant positive correlations with stromal, immune, and ESTIMATE scores (p < 0.001). PRDM9 and CDX2 also showed significant positive correlations with stromal scores (p < 0.05).
Conclusion: This study presents the first comprehensive identification of immune evasion-related genes (IERGs) within the tumor microenvironment (TME) of HCC and introduces a novel prognostic model based on immune evasion with strong clinical applicability. These findings offer valuable insights into the immunobiology of HCC and highlight potential therapeutic targets for precision immunotherapy.
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Background: Ferroptosis is an iron-dependent form of regulated cell death, which offers therapeutic potential in non-small cell lung cancer (NSCLC). This study aimed to evaluate whether Micheliolide (MCL) induces ferroptosis in NSCLC cells via the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway.
Methods: H1299 cells were treated with different concentrations of MCL. Cellular assays, including the Cell Counting Kit-8 (CCK-8), colony formation, scratch test, and Transwell, were used to evaluate the viability, proliferation, migration, and invasion of the cells. Ferroptosis-related indicators (reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), Fe2+) and protein expression (Nrf2, glutathione peroxidase 4 (GPX4), Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4), Transferrin Receptor 1 (TFR1) were assessed via flow cytometry, biochemical assays, and Western blot. Additionally, Nrf2-specific activator (tert-butylhydroquinone (tBHQ)) and ferroptosis inhibitors (Fer-1) were used to verify the involvement of this pathway.
Results: MCL inhibited proliferation, migration, and invasion of H1299 cells in a dose-dependent manner and induced ferroptosis as evidenced by elevated ROS, MDA, and Fe2+ levels, and reduced GSH concentration. Western blot analysis revealed significantly increased ACSL4 and TFR1 and decreased Nrf2 and GPX4 expression. These MCL-induced effects were reversed by tBHQ or Fer-1, confirming the involvement of Nrf2.
Conclusions: MCL induces ferroptosis in NSCLC cells by suppressing the Nrf2 pathway. Targeting Nrf2 may enhance the anticancer efficacy of Micheliolide, offering new therapeutic insights for NSCLC.
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Background: The incorporation of chlorhexidine (CHX) into dental composite resins (DCR) offers antibacterial benefits but may affect their mechanical and esthetic properties. This in vitro study aimed to evaluate the impact of different CHX concentrations (0.12%–3%) on polymerization, hardness, bond strength, shade, and antibacterial activity.
Methods: A flowable composite resin was enriched with CHX at various concentrations. The degree of conversion (DC%) was measured using Fourier-transform infrared spectroscopy. Hardness was assessed with a Shore-D durometer, and shear bond strength (SBS) was tested on human dentin surfaces. Shade variations were evaluated using spectrophotometry. Antibacterial efficacy was determined by measuring inhibition halos against Streptococcus mutans (S. mutans), Lactobacillus fermentum and Lactobacillus paracasei. Scanning electron microscopy (SEM) analyzed CHX distribution in the resin matrix.
Results: CHX up to 1.5% did not significantly alter DC%, but the concentration of 3% impaired polymerization (p = 0.049 vs. control). Both hardness and SBS decreased significantly compared to the control group from concentrations as low as 0.2% for hardness and 0.12% for SBS (p < 0.001 in both cases). Notably, SBS values fell below 5 MPa at a concentration of 1% CHX. Shade modifications exceeded the perceptibility threshold, with CHX-containing composites appearing lighter. SEM images revealed inhomogeneous CHX distribution and microgaps in the resin matrix. Antibacterial tests demonstrated a dose-dependent inhibition of bacterial growth, with significant effects at 0.5%–1% CHX.
Conclusion: While CHX incorporation enhances antibacterial properties, concentrations above 0.5% compromise mechanical properties and esthetics, limiting clinical applicability. Future research should explore strategies to optimize CHX release and maintain mechanical integrity, such as hybrid antibacterial agents or controlled-release systems, to balance antibacterial efficacy with structural stability.
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Background: Arteriosclerosis (AS) is a globally prevalent disease for which there is currently no effective treatment. Therefore, identifying potential drug targets is of crucial importance. The Cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS)–STING pathway is an intracellular immune sensing mechanism that detects DNA damage and viral infections, and it could contribute to the progression of AS through its influence on immune regulation. By using bioinformatics methods, we identified critical genes involved in the progression of AS that are associated with the cGAS–STING pathway, providing potential molecular targets for further investigation.
Methods: Datasets related to AS were extracted from the Gene Expression Omnibus (GEO) database, including GSE100927, GSE28829, and GSE43292. Furthermore, we conducted a search in the GeneCards database to identify genes associated with the cGAS–STING signaling pathway. Key gene identification was carried out through comparative expression analysis using Limma and weighted gene co-expression network analysis (WGCNA). Machine learning (ML) algorithms were then applied to screen and evaluate the diagnostic value of potential biomarkers. After obtaining both cGAS–STING-related and AS-related differentially expressed genes (cASDEGs), we utilized gene set enrichment analysis (GSEA) approach to analyze the potential function of cASDEGs and CIBERSORT algorithm to assess immune cell infiltration in AS. Finally, experiments including reverse transcription quantitative polymerase chain reaction (RT-qPCR), Western blotting and immunofluorescence were conducted to validate the expression patterns of cASDEGs.
Results: By intersecting the Limma and WGCNA results, we identified a total of 741 differentially expressed genes (DEGs) related to AS from the GSE100927 dataset. An intersection of these DEGs with the cGAS–STING-related genes identified 16 cASDEGs. Four pivotal cASDEGs (C-src tyrosine kinase (CSK), fatty acid binding protein 5 (FABP5), B-cell lymphoma 2-associated athanogene (BAG2), and alpha-galactosidase A (GLA)) were identified through the ML-based screening, all of which showing significant diagnostic relevance. Further immune profiling uncovered dysregulated immunity in AS and a link between these genes and immune cell interactions. Experimental validation confirmed that the four central cASDEGs exhibited expression patterns aligning with the bioinformatics predictions.
Conclusion: Our study identified four genes (CSK, FABP5, BAG2, and GLA) that may promote the development of AS through the cGAS–STING pathway, providing new insights into the pathogenesis and potential treatment of AS.
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Background: Breast cancer remains one of the most commonly diagnosed malignancies, yet its underlying mechanisms are incompletely understood. This study aimed to investigate the causal relationships between circulating proteins and breast cancer using Mendelian Randomization (MR) and to identify potential therapeutic targets.
Methods: Genomic data for breast cancer from the FinnGen study and protein quantitative trait loci (pQTL) data from Decode were analyzed. MR was applied to evaluate the effects of specific proteins on breast cancer risk, followed by validation through colocalization analyses and summary-data-based Mendelian Randomization (SMR). Two-step MR was used to assess the mediating role of immune cells in the causal pathway between the target proteins and breast cancer. Moreover, expression patterns and prognostic significance of the identified proteins in breast cancer were examined.
Results: Several proteins [glutathione S-transferase mu (GSTM) 1, N-acylsphingosine amidohydrolase 2 (ASAH2), TNF superfamily member 12 (TNFSF12), hematopoietic prostaglandin D synthase (HPGDS), nidogen 2 (NID2), SEMA4D, snurportin 1 (SNUPN), GSTM3, MYC-associated factor X (MAX), pregnancy zone protein (PZP), GSTM4, and uroporphyrinogen decarboxylase (UROD)] were significantly associated with breast cancer. Colocalization and SMR analyses supported the potential role of GSTM in breast cancer, especially GSTM1 (pSMR = 0.02 and pHEIDI = 0.08). Mediation MR implicated CD11c-expressing monocytes (Z = –2.197, p = 0.028) in the GSTM-breast cancer pathway. Notably, lower GSTM1/4 expression levels correlated with poorer clinical outcomes in breast cancer patients.
Conclusion: This study used cis-pQTL MR and colocalization to identify GSTM1/4 as a potential druggable gene and promising therapeutic target for breast cancer, which might be affected by immunity. These findings contributed to understanding the role of metabolic and immune mechanisms in breast cancer.
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Background: Sepsis is a critical condition characterized by organ failure due to the body's inappropriate reaction to an infection. The disrupted gut microbiome is constantly changing and contributes to the development of sepsis. This research seeks to explore the makeup and role of gut microbiota in individuals experiencing sepsis or septic shock and the sepsis rat model induced by cecal ligation and puncture (CLP).
Methods: Fecal samples from persons in the healthy control group, sepsis, and septic shock patients were collected. The intestinal flora was examined using 16S rRNA-sequencing analysis. Besides, SD rats were subjected to CLP surgery to create a sepsis model. Post-surgery, mice were euthanized at 6, 12, 24, and 48 h to evaluate inflammatory mediators, intestinal microbiota, morphology, and intestinal barrier markers.
Results: In patients and rats with sepsis, the intestinal barrier was notably disrupted, intestinal permeability was significantly increased, and the inflammatory level was conspicuously elevated (p < 0.05). In sepsis patients and CLP-induced rats, the variety and balance of gut microbiota were reduced. Compared with the control group, sepsis patients had lower abundances of Agathobacter, Coprococcus, Erysipelotrichaceae_UCG-003, Faecalibacterium, Fusicatenibacter, Haemophilus, Roseburia and Subdoligranulum, but increased abundances of Corynebacterium and Enterococcus compared to the control group. CLP rats exhibited more severe cortical inflammation and enhanced intestinal permeability. The higher Bacillus, Sutterella, Odoribacter, Pseudomonas, Brochothrix, Clostridium, Enterococcus, and Ruminococcus abundances at the genus level were shown in CLP surgery after 6, 12, 24, and 48 h. KEGG analysis revealed a significant enrichment in carbohydrate metabolism, cofactors and vitamins metabolism, terpenoid and polyketide metabolism, as well as amino acid metabolism.
Conclusion: Taken together, beneficial bacteria like Agathobacter, Coprococcus, Erysipelotrichaceae_UCG-003, and Faecalibacterium decline, while harmful species such as Corynebacterium and Enterococcus increase, which might contribute to triggering intense inflammation and compromising intestinal barrier function in the progression of sepsis. These shifts highlight potential microbial targets for sepsis treatment.
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Background: Coronavirus disease 2019 (COVID-19) has been increasingly associated with neurological complications, mainly through mechanisms involving neuroinflammation and cytokine dysregulation. Attention-deficit/hyperactivity disorder (ADHD), a neurodevelopmental disorder with known immunological and neurotrophic components, has emerged as a potential risk factor for adverse COVID-19 outcomes. This study investigates the genetic interplay between COVID-19 and ADHD using in silico methods, aiming to identify shared molecular pathways and uncover convergent mechanisms that may inform pathophysiology, risk stratification, and potential therapeutic interventions.
Methods: Genes associated with COVID-19 and ADHD were retrieved from the DisGeNET database. Shared genes were identified using FunRich software, and protein-protein interactions were analyzed using the Search Tool for Retrieval of Interacting Genes database. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed to further elucidate the shared molecular mechanisms.
Results: Overall, 216 overlapping genes, including key genes, such as neuropilin-1, brain-derived neurotrophic factor, insulin-like growth factor 1, and interleukin-6, were identified. These genes were involved in three key functional categories: (1) vascular and endothelial function, (2) neurodevelopment and synaptic activity, and (3) immune modulation and inflammatory response generation. These findings indicate the potential shared molecular mechanisms between COVID-19 and ADHD.
Conclusions: The identified overlapping genes highlight potential therapeutic targets for both conditions. The study underscores the significance of their shared molecular pathways and proposes the use of animal models to validate these genetic associations. Further investigation into these pathways may inform strategies for disease prevention and management of COVID-19 and ADHD.
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Background: Muscle-invasive bladder cancer (MIBC) is an aggressive malignancy associated with high mortality. While neoadjuvant chemotherapy (NAC) remains the standard of care, its overall benefit is limited. The addition of immune checkpoint blockade (ICB) to NAC holds potential for improving patient outcomes. This study aimed to compare the pathological response and safety profile of NAC alone versus NAC combined with the programmed cell death protein 1 (PD-1) inhibitor tislelizumab (NAC+ICB) in a real-world cohort of MIBC patients.
Methods: A total of 153 MIBC patients treated between October 2021 and December 2024 were retrospectively reviewed. Among them, 88 received gemcitabine/cisplatin-based NAC, while 65 received the same regimen combined with the PD-1 inhibitor tislelizumab (NAC+ICB). The primary endpoints were pathological complete response (pCR, ypT0N0) and the incidence of grade ≥3 treatment-related adverse events (TRAEs). Multivariate logistic regression was applied to identify factors associated with pCR.
Results: The NAC+ICB group showed a significantly higher pCR rate compared to the NAC group (33.85% vs. 18.18%, p = 0.027). Pathological downstaging rate (≤ypT1N0) was also significantly higher in the combination group (58.46% vs. 38.64%, p = 0.015). The incidence of grade ≥3 TRAEs did not significantly differ between groups (41.54% vs. 38.64%, p = 0.717). Multivariate analysis revealed that lower platelet counts (OR = 0.960, p = 0.003), higher hemoglobin levels (OR = 1.229, p = 0.002), and lower total cholesterol levels (OR = 0.010, p = 0.004) were independently associated with a higher pCR rate in the NAC+ICB group.
Conclusion: Compared with chemotherapy alone, NAC combined with ICB significantly improves pathological response in MIBC patients without increasing severe adverse events, suggesting favorable efficacy and safety. This combination represents a novel strategy for perioperative optimization, though prospective studies are needed to validate its long-term survival benefits.
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Background: Cervical cancer is the leading cause of cancer-related mortality among females worldwide. Although previous studies have implicated tripartite motif-containing protein 37 (TRIM37) in the progression of various malignancies, its precise role and the underlying molecular mechanisms in cervical cancer remain inadequately explored.
Methods: TRIM37 expression, both at protein and mRNA levels, was assessed in immortalized keratinocytes and cervical cancer cell lines using RT-qPCR and Western blotting, respectively. The cervical cancer cells were transfected with TRIM37-specific siRNA employing Lipofectamine. Cellular proliferation, migration, and invasion were evaluated using Transwell assays, flow cytometry, colony formation assays, and cell counting kit (CCK)-8. Western blotting analysis was used to assess the phosphorylation status of proteins involved in the Phosphatase and Tensin Homolog Deleted on Chromosome Ten (PTEN)/Phosphatidylinositol-3-Kinase (PI3K)/Protein Kinase B (Akt)/Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Interaction between TRIM37 and PTEN was examined via co-immunoprecipitation assays. Furthermore, an in vivo nude mice xenograft model was successfully established to assess the impact of TRIM37 on tumor growth.
Results: TRIM37 was substantially upregulated in cervical cancer cell lines compared to immortalized keratinocytes (p < 0.05). TRIM37 knockdown significantly suppressed proliferation, migration, and invasion in cervical cancer cells, thereby promoting apoptosis (p < 0.05). In vivo analysis revealed that TRIM37 knockdown significantly inhibited the growth of tumor (p < 0.05). Moreover, TRIM37 silencing effectively suppressed the activity of the PTEN/PI3K/Akt/NF-κB pathway in cervical cancer cells (p < 0.05).
Conclusions: TRIM37 knockdown inhibits cell proliferation, migration, and invasion, as well as suppresses in vivo tumor growth, potentially through downregulation of the PTEN/PI3K/Akt/NF-κB signaling pathway.
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Background: Acute myocardial infarction (AMI) remains a leading cause of mortality and morbidity worldwide. Early identification of reliable biomarkers is crucial for improving diagnostic accuracy and prognostic assessment in AMI patients. Circular RNAs (circRNAs) have emerged as novel regulators in cardiovascular diseases and may serve as promising biomarkers. Our study aimed to evaluate the expression level of Circular RNA 0049271 (Circ_0049271) and its potential role in diagnosing and predicting acute ST-segment elevation myocardial infarction (STEMI).
Methods: In this prospective cohort study, 188 STEMI patients and 86 healthy controls were enrolled between July 2020 and April 2024. Clinical information, including medical history, biochemical parameters, and cardiac function scores, was collected from all participants. Circ_0049271 expression was quantified using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Spearman's correlation analysis was conducted to assess the association between Circ_0049271 and cardiac troponin I (cTnI) levels. The diagnostic performance of Circ_0049271 for STEMI was evaluated using the receiver operating characteristic (ROC) curve. Additionally, logistic regression was applied to identify associations between various risk factors and STEMI. The Kaplan-Meier method estimated postoperative survival rates, and the Cox proportional hazards regression model analyzed the association between risk factors and the occurrence of major adverse cardiovascular events (MACE) after surgery.
Results: Circ_0049271 expression was significantly elevated in STEMI patients compared to healthy controls and was positively correlated with the myocardial injury marker cTnI (r = 0.65, p < 0.001). ROC curve analysis demonstrated high diagnostic accuracy for Circ_0049271 [area under the ROC curve (AUC) = 0.9099, 95% confidence interval (CI): 0.8618–0.9579]. Logistic regression identified body mass index, diastolic blood pressure, history of hypertension, low-density lipoprotein, high-sensitivity C-reactive protein, and Circ_0049271 as risk factors for STEMI. Furthermore, Kaplan-Meier analysis and the Cox proportional hazards regression model revealed that high Circ_0049271 expression was associated with an increased risk of MACE after percutaneous coronary intervention (PCI), indicating it as an independent risk factor for the occurrence of MACE.
Conclusion: Elevated Circ_0049271 levels in STEMI patients suggest its potential as a biomarker for the diagnosis and prognosis of STEMI. These findings provide valuable insights into the molecular mechanisms of AMI and suggest that Circ_0049271 could aid in developing more effective diagnostic and prognostic assessment tools.
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Background: Pleural metastasis (PM), a driver of malignant pleural effusion (MPE) in lung cancer, remains an unmet clinical need due to the absence of PM/MPE-specific targeted therapies. Therefore, this study aims to explore the clinical and molecular characteristics associated with PM in advanced non-small cell lung cancer (NSCLC).
Methods: This retrospective study analyzed 195 advanced NSCLC patients. Study participants were classified into the PM and non-PM groups based on the occurrence of PM within three years of the initial diagnosis of advanced-stage disease. Clinical and baseline data, including age, gender, smoking history, tumor location, histological classification, tumor-node-metastasis staging (TNM) staging, metastasis profile, and lesion count, were obtained from the hospital's electronic medical records. Genomic DNA was extracted from tumor or liquid biopsy samples, and next-generation sequencing (NGS) was performed using a 139-gene lung cancer panel.
Results: The PM group tended to be older, smoked less, and presented with higher T stages, experiencing less bone metastasis (p < 0.05). Mutation frequencies of anaplastic lymphoma kinase (ALK), Erb-B2 receptor tyrosine kinase 4 (ERBB4), Kirsten rat sarcoma viral oncogene homolog (KRAS), and RB transcriptional corepressor 1 (RB1) were significantly lower in the PM group (p < 0.05) than those in the non-PM group. However, epidermal growth factor receptor (EGFR) driver mutations were significantly higher in the PM group than in the non-PM group (p < 0.05). The incidence of PM was highest (73.5%) in patients carrying only EGFR driver mutations, without ALK, ERBB4, KRAS, or RB1 mutations.
Conclusion: This study identified potential clinical and molecular factors involved in the development of PM in advanced NSCLC, providing valuable insights for future mechanistic research.
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Background: Dysfunctional uterine bleeding (DUB) affects up to 30% of women of reproductive age and may result in anemia, diminished quality of life, and increased healthcare utilization. While stress-axis dysregulation has been implicated in various menstrual disorders, the role of autonomic and hypothalamic-pituitary-adrenal (HPA) axis dysfunction in DUB remains insufficiently understood. This study aims to investigate whether women with the International Federation of Gynecology and Obstetrics (FIGO)-classified DUB exhibit alterations in autonomic nervous system (ANS) function and endocrine profiles compared to healthy controls during the early follicular phase. By assessing heart rate variability (HRV) indices and circulating reproductive and metabolic hormones, the study seeks to clarify the potential role of autonomic imbalance and the HPA axis—related hormonal markers in the pathophysiology of DUB.
Methods: In this prospective case–control study, 34 women with FIGO-classified DUB and 36 age- and body mass index–matched healthy controls underwent biochemical and hormonal assays and five-minute HRV recordings during the early follicular phase (days 3–7 of menses). Serum cortisol was not measured. Time-domain (standard deviation of NN intervals (SDNN), root mean square of successive differences (RMSSD), percentage of successive NN intervals differing by more than 50 ms (pNN50)) and frequency-domain (very-low-frequency power (VLF), low-frequency (LF), high-frequency (HF), LF/HF) HRV metrics were analyzed alongside follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, testosterone, thyroid-stimulating hormone (TSH), dehydroepiandrosterone sulfate (DHEA-SO₄), glucose, and hemoglobin. Statistical comparisons employed Student's t-tests or Mann–Whitney U tests, with Pearson/Spearman correlations exploring interrelationships among variables.
Results: Anthropometric, biochemical, hormonal, and HRV parameters did not differ significantly between DUB and control groups (all p > 0.05). Correlation analyses across the combined cohort revealed expected age-related declines in vagal indices (e.g., RMSSD) and hormone levels (testosterone, DHEA-SO₄), inverse associations between body mass index (BMI) and SDNN/total power, and robust intercorrelations among HRV measures. Notably, FSH positively correlated with VLF power (r = 0.243, p < 0.05), while heart rate inversely tracked RMSSD (r = –0.567, p < 0.01).
Conclusions: In a rigorously controlled, follicular-phase cohort, women with DUB exhibit preserved cardiac autonomic regulation and comparable endocrine profiles to healthy peers. These negative findings suggest that, under resting conditions, ANS imbalance may not drive DUB pathophysiology. Future research should integrate direct HPA-axis biomarkers (e.g., cortisol), longitudinal HRV across the menstrual cycle, and stratification by DUB subtype to uncover subtler stress–reproductive interactions.
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Background: Despite significant advances in therapeutic approaches, the overall prognosis of acute myocardial infarction (AMI) patients remains poor. Poria cocos, a traditional edible medicinal fungus, contains Pachymic acid A (PAA), a triterpenoid compound recognized for its potent anti-inflammatory properties across various inflammatory conditions. Therefore, we investigated the effects of PAA in a murine AMI model and explored its underlying mechanisms.
Methods: AMI was induced in mice by tying the left anterior descending (LAD) coronary artery, and the model mice were treated with different concentrations of PAA. Histological staining was employed to assess cardiac tissue injury. Oxidative stress markers and inflammatory cytokines in myocardial tissues were quantified using Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR). and biochemical assays. Apoptotic cardiomyocytes were identified via the Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) assay. Immunoblotting was conducted to quantify autophagy-associated proteins (Microtubule-associated protein 1A/1B light chain 3 (LC3) II/LC3I, Beclin1, p62) and the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway.
Results: PAA treatment significantly reduced myocardial injury and fibrosis in AMI mice. It suppressed the expression levels of pro-inflammatory cytokines Tumor Necrosis Factor (TNF)-α, Interleukin (IL)-6, and IL-1β, decreased malondialdehyde (MDA), and icreased glutathione peroxidase (GSH-Px) activity (p < 0.05). Furthermore, PAA attenuated cardiomyocyte apoptosis and enhanced autophagy, as evidenced by elevated LC3II/LC3I and Beclin1 expression and reduced p62 levels. The AMPK pathway was found to be activated due to increased p-AMPK/AMPK ratios and reduced p-mTOR/mTOR expression (p < 0.05).
Conclusion: PAA may reduce AMI-induced cardiac injury by activating AMPK signaling and promoting autophagy, thereby reducing inflammation, oxidative stress, and apoptosis in myocardial tissue.
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Background: Endometrial cancer (EC) is a common gynecologic malignancy marked by ever-increasing incidence. This study primarily aimed to evaluate the association between preoperative neutrophil-to-lymphocyte ratio (NLR) and lymphovascular space invasion (LVSI), with the secondary objective to assess NLR's prognostic significance for recurrence-free survival (RFS) in endometrial cancer.
Methods: This single-center retrospective cohort study included 335 endometrial cancer patients at Dongyang Hospital of Wenzhou Medical University from January 2012 to January 2024. Two distinct analyses were conducted: (1) Cross-sectional association analysis using ordinal logistic regression and restricted cubic spline (RCS) modeling to evaluate the relationship between preoperative NLR and LVSI status; (2) Survival analysis using Cox proportional hazards (CPH) modeling to assess NLR's prognostic significance for RFS and examine prognostic interactions between NLR and LVSI status.
Results: Multivariate logistic regression revealed no significant association between NLR and LVSI after comprehensive adjustment (odds ratio [OR] = 1.09, 95% confidence interval [CI]: 0.77–1.53, p = 0.636). Though exploratory spline modeling showed stable risk estimates across the NLR spectrum, formal statistical testing revealed no significant non-linear relationship (p = 0.465). Survival analysis showed borderline significance in patients with superficial invasion (hazard ratio [HR] = 1.56, 95% CI: 1.00–2.43) for RFS, with consistent prognostic patterns across clinicopathological subgroups (all interaction p > 0.05).
Conclusion: This study revealed no significant association with NLR and LVSI, indicating no independent predictive value of NLR in LVSI risk stratification. However, patients with superficial myometrial invasion may present borderline risk for recurrence LVSI. Multi-center validation studies are needed to verify the prognostic value of NLR for LVSI risk stratification in clinical settings.
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Background: Extracellular vesicles derived from stem cells (SC-EVs) show promise in regenerative medicine and inflammation resolution because of their low immunogenicity and translational potential. However, low SC-EV yields hinder their clinical scalability and therapeutic utility. Therefore, we aimed to enhance SC-EV production.
Methods: We explored strategies to enhance SC-EV production using Bafilomycin A1 (Baf-A1). The data are expressed as mean ± standard deviation (SD) values, and differences with p < 0.05 were considered significant.
Results: Baf-A1 increased the production of EVs from mesenchymal stem cells derived from induced pluripotent stem cells (iPSC-MSC-EVs) (p < 0.01). Mechanistically, Baf-A1 promotes iPSC-MSC-EV secretion while inhibiting their reuptake by the parent cells (p < 0.0001). Baf-A1 treatment preserved the gene and protein expression profiles of iPSC-MSC-EVs, maintaining their intrinsic biological properties and ensuring their reliability and safety for application. Furthermore, Baf-A1-treated induced pluripotent stem cell-derived mesenchymal stem cell extracellular vesicles (iPSC-MSC-EVs) demonstrated comparable therapeutic efficacy to untreated iPSC-MSC-EVs in acute liver injury (ALI) and inflammatory bowel disease (IBD) models, confirming their retained ability to promote tissue regeneration and anti-inflammation in these models.
Conclusions: These findings highlight Baf-A1 as a safe and potent modulator of iPSC-MSC-EV production, offering a strategy to overcome yield limitations and advance the clinical translation of iPSC-MSC-EVs in regenerative medicine and inflammatory disease therapy.
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Background: Investigating the pathogenesis of non-small cell lung cancer (NSCLC) is crucial to identify early diagnostic markers and novel therapeutic targets. Myod family inhibitor (MDFI) has been associated with the occurrence and progression of tumors; however, its potential role in NSCLC remains uninvestigated. Therefore, this study explores the role of MDFI in NSCLC and its association with autophagy in disease progression.
Methods: In vitro cellular models and in vivo mouse models were used to assess the impact of MDFI in NSCLC progression. MDFI knockdown (sh-MDFI) and overexpression (oe-MDFI) cellular models were successfully established. Expression levels of MDFI were assessed using real-time quantitative polymerase chain reaction (RT-qPCR), while protein levels were analyzed using Western blot analysis. Cell proliferation, migration, and invasion abilities were determined using clonal formation, 5-ethynyl-2′-deoxyuridine (EdU), wound healing, and Transwell invasion assays, respectively. For rescue experiments, cells were subjected to 3-methyladenine (3-MA) treatment for 24 hours. The in vivo xenograft mouse model was established through subcutaneous injection of A549 cells. The expression levels of nuclear proliferation-associated antigen (Ki-67) were evaluated using immunohistochemistry (IHC).
Results: We observed significantly elevated MDFI expression in NSCLC cells (p < 0.05). MDFI overexpression promoted cell proliferation, migration, and invasion capabilities (p < 0.05); however, MDFI knockdown suppressed these cellular behaviors (p < 0.05). MDFI overexpression enhanced the microtubule-associated protein 1 light chain 3 II/I (LC3II/I) ratio and autophagy-related gene 12 (ATG12) expression, and decreased sequestosome-1 (p62) levels (p < 0.05), while MDFI knockdown showed an opposite trend (p < 0.05). Furthermore, 3-MA treatment counteracted MDFI overexpression-induced malignant behavior and autophagy of NSCLC cells (p < 0.05). The tumor experiment revealed that knocking down MDFI suppressed tumor growth and autophagy in nude mice (p < 0.05).
Conclusion: MDFI modulates NSCLC cell proliferation, migration, and invasion by regulating autophagy, underscoring MDFI as a potential biomarker and a novel therapeutic target.
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Background: Adverse cardiac remodeling following acute myocardial infarction (AMI) is one of the leading causes of mortality due to heart failure. This study aims to investigate the efficacy of GATA binding protein 4 (GATA4)-overexpressing dental pulp stem cells (GATA4-DPSCs) in mitigating post-AMI pathological remodeling by exploring their proliferative advantage, paracrine capacity, and cardiac repair potential.
Methods: H9c2 cardiomyocytes co-cultured with GATA4-DPSCs were subjected to hypoxia/reoxygenation (H/R) injury. Cell viability was assessed using Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase release assays. Oxidative stress was detected by malondialdehyde levels and flow cytometry-based reactive oxygen species. Apoptosis was evaluated by Annexin V-fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI) staining and Western blotting, whereas cardiomyogenic differentiation markers were analyzed via Western blotting and reverse-transcription quantitative polymerase chain reaction (RT-qPCR). Transcriptomic analysis was also performed. Rat AMI models were established. Cardiac function, myocardial injury, angiogenesis, and myocardial fibrosis markers were evaluated to assess the cardiac repair effect of transplanted GATA4-overexpressing DPSCs post-AMI. Downstream effector proteins of relevant signaling pathways were validated by Western blotting.
Results: In vitro, GATA4-DPSCs enhanced antioxidant protection from damage and reduced apoptosis in H9c2 cardiomyocytes post-H/R, while promoting their own cardiomyogenic differentiation. Multi-omics sequencing highlighted the involvement of mitogen-activated protein kinase (MAPK) pathway regulation. In vivo, GATA4-DPSCs transplantation improved cardiac function, reduced myocardial damage, enhanced angiogenesis, and ameliorated myocardial fibrosis in AMI rats. This effect correlated with downregulation of MAPK pathway effector proteins.
Conclusions: Transplantation of GATA4-overexpressing DPSCs attenuates post-AMI myocardial remodeling by modulating the MAPK signaling, ultimately mitigating fibrosis and restoring cardiac functional recovery.
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Background: Cryptococcus spp. is an opportunistic fungal pathogen rarely infecting immunocompetent individuals. Cryptococcal osteomyelitis is an uncommon disease characterized by the invasion of bone tissue by Cryptococcus. It typically arises in disseminated infection, while isolated cryptococcal osteomyelitis is scarcely diagnosed. This study seeks to review all published Cryptococcus spp. osteomyelitis cases in humans, focusing on epidemiology, microbiology, clinical complications, treatment, and clinical outcomes.
Methods: A systematic review was conducted through a literature search of PubMed and Scopus databases. The protocol was registered in Prospero (ID: CRD42024627780).
Results: In total, 106 studies provided data on 118 patients with Cryptococcus spp. osteomyelitis. The mean age of patients was 41.83 years and 56.41% were male. Immunosuppression constituted the most common predisposing risk factor (17.8%), followed by history of tuberculosis (15.25%) or diabetes mellitus (12.71%). The most frequently infected bone structures included the thorax (24.58%), vertebrae, and upper extremities (15.25% respectively), while in 16.1%, multiple bones were involved. Cryptococcus neoformans was the identified pathogen in most cases (97.22%). Fluconazole (72.41%), amphotericin B (62.93%), and flucytosine (34.48%) were the most commonly used antifungals. In 47.41%, a combination of antifungals was administered. Overall mortality was relatively low (7.63%), while only 4.24% of deaths were attributed to the infection.
Conclusions: Given the potential of Cryptococcus spp. to cause severe bone infection, clinicians should include this disease in the differential when encountering yeast microorganisms in microbiological specimens, especially in patients with significant comorbidities or immunodeficiency. This is essential for ensuring accurate diagnosis and appropriate treatment.
