European Journal of Medical Research最新文献

Background: As alternatives to brominated flame retardants, Organophosphorus Flame Retardants (OPFRs) have raised concerns regarding their potential nephrotoxicity. However, population-based evidence remains inconsistent. This study aimed to examine the associations between urinary metabolites of OPFRs and Chronic Kidney Disease (CKD), along with renal function markers (estimated Glomerular Filtration Rate [eGFR] and the urinary Albumin‒Creatinine Ratio [ACR]), in the general U.S. population while exploring potential underlying mechanisms.

Methods: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 2011-2016, which included 2156 adults. Five OPFR metabolites, including Diphenyl Phosphate (DPHP), Bis(1,3-dichloro-2-propyl) Phosphate (BDCPP), Bis(1-chloro-2-propyl) Phosphate (BCPP), Bis(2-chloroethyl) Phosphate (BCEP), and Dibutyl Phosphate (DBUP), were measured in the urine. Multivariate logistic regression, subgroup analyses, Restricted Cubic Spline (RCS), and Weighted Quantile Sum (WQS) regression were performed, with CKD defined as an eGFR < 60 mL/min/1.73 m² or an ACR ≥ 30 mg/g.

Results: BCPP was inversely associated with CKD risk (Q4 vs. Q1: OR = 0.42, 95% CI 0.23-0.77, P = 0.007), particularly in hypertensive, elderly, and high-income populations. DPHP and BDCPP were significantly positively correlated with the eGFR (P for trend < 0.05), although the association weakened after adjustment. DBUP exhibited an inverted U-shaped relationship with the eGFR (P-nonlinear = 0.048). WQS analysis indicated that OPFR mixtures were associated with higher eGFRs (β = 1.20, 95% CI 0.38-2.02, P = 0.004), which was driven primarily by DBUP and DPHP.

Conclusions: Our analysis reveals complex, non-monotonic associations between OPFR metabolites and renal function in U.S. adults, presenting a challenge to the prevailing assumption of linear nephrotoxicity. The observed associations warrant cautious interpretation due to potential reverse causality, underscoring the complexity of low-dose exposure assessment and the need for refined risk assessment frameworks.

Background and aims: Pancreatic cancer (PC) exhibits significant immune evasion. The roles of N6-methyladenosine (m6A) RNA modification and long non-coding RNAs (lncRNAs) in PC immunity are emerging. We aimed to elucidate the function and mechanism of METTL3-mediated m6A modification of lncRNA AFAP1-AS1 in PC progression and immune escape, focusing on its interaction with early growth response 2 (EGR2).

Methods: Expression of METTL3, AFAP1-AS1, and EGR2, along with AFAP1-AS1 m6A levels, were measured in human PC tissues/cell lines via quantitative reverse transcription PCR, Western blot, and methylated RNA immunoprecipitation. Functional assays (proliferation, invasion, CD8⁺ T cell co-culture) were performed using knockdown/overexpression strategies in PANC-1 cells. Mechanistic insights were gained through RNA immunoprecipitation, stability assays, chromatin immunoprecipitation (ChIP), and fluorescence in situ hybridization. An in vivo murine subcutaneous tumor model validated key findings, with comprehensive immune microenvironment profiling including regulatory T cells (Tregs) and tumor-associated macrophages (TAMs).

Results: METTL3, AFAP1-AS1, and EGR2 were significantly upregulated in PC, where AFAP1-AS1 exhibited increased m6A modification and correlated with poor prognosis. METTL3 directly mediated AFAP1-AS1 m6A modification, enhancing its stability through the m6A readers YTHDF2 and IGF2BP1. Functionally, AFAP1-AS1 promoted PC cell malignancy and immune evasion, characterized by resistance to T cell killing, suppressed T cell function, and increased programmed death-ligand 1 (PD-L1). Mechanistically, AFAP1-AS1 stabilized EGR2 mRNA through direct binding, elevating EGR2 protein expression. ChIP assays confirmed that EGR2 directly binds to the promoters of PD-L1 and Snail. EGR2 knockdown phenocopied AFAP1-AS1 knockdown effects, and EGR2 overexpression rescued the AFAP1-AS1 knockdown phenotype. In vivo, METTL3 depletion inhibited tumor growth and enhanced anti-tumor immunity, characterized by decreased Tregs and M2 macrophages infiltration, effects partially reversed by EGR2 restoration.

Conclusion: METTL3 enhances AFAP1-AS1 stability via m6A modification recognized by YTHDF2 and IGF2BP1, which subsequently increases EGR2 expression by improving its mRNA stability. EGR2 directly activates transcription of immune checkpoint and epithelial-mesenchymal transition (EMT)-related genes. This METTL3/AFAP1-AS1/EGR2 signaling axis drives PC malignancy and immune resistance, offering potential therapeutic targets for PC treatment.

Background: Nail positioning is highly adjustable during the proximal femoral nail anti-rotation (PFNA) procedure for treating intertrochanteric fractures. Our published study demonstrates that changes in nail position can significantly affect local stress distribution, and ventral side nail insertion may increase the risk of varus deformity in the femoral head, particularly in unstable fracture types. However, adjusting the guidewire position tends to prolong operation time and increase blood loss. The necessity of this adjustment in stable fracture cases remains to be clarified.

Methods: This retrospective study reviewed the clinical data of patients with stable intertrochanteric fractures (AO 31-A1 and A2.1) who were treated with PFNA operation and had a minimum follow-up of 6 months. Nail position was assessed using immediate postoperative lateral radiographs. A correlation between nail positioning and femoral head varus has been established. Furthermore, to corroborate the clinical findings, the biomechanical effects of nail position variation were evaluated using a stable fracture model. Specifically, femoral head displacement, as well as stress values within the femoral head and at the bone-screw interfaces, were analyzed.

Results: This study integrated retrospective clinical data analysis with computational mechanical simulations, which yielded a similar trend. The clinical review included a total of 53 patients, comprising 27 with ventral and 26 with dorsal nail positions. No statistically significant difference was observed in the femoral head varus angle between the ventral and dorsal placement groups (t = - 0.683, p = 0.497). Furthermore, computational simulations indicated that variations in nail position did not significantly alter the stress distribution or displacement of either the femoral head or the anti-rotation blade under compressive or physiological loading conditions.

Conclusions: The position of the PFNA nail has only a minimal impact on fixation stability and stress distribution around the femoral head in stable intertrochanteric fractures. Therefore, intraoperative guidewire adjustments are unnecessary when treating such stable fractures with PFNA.

Background: Hypocalcemia is a frequent complication in patients undergoing maintenance hemodialysis and is closely linked to disturbances in mineral metabolism, increased cardiovascular risk, and bone disorders. Early identification of high-risk individuals is essential for effective prevention and management. This study aimed to evaluate risk factors associated with hypocalcemia and to develop a nomogram prediction model for individualized risk assessment.

Methods: This retrospective study included 386 adult patients receiving maintenance hemodialysis between January 2020 and December 2024. Hypocalcemia was defined as total serum calcium < 2.1 mmol/L. Patients were categorized into a hypocalcemia group (n = 135) and a normocalcemia group (n = 251). Demographic, dialysis-related, biochemical, and clinical variables were collected. Univariate and multivariate logistic regression analyses were performed to identify independent predictors. A nomogram prediction model was constructed and its discrimination, calibration, and clinical utility were assessed using the receiver operating characteristic (ROC) curve, calibration plots, and decision curve analysis (DCA). Internal validation was performed using bootstrap resampling with 1000 iterations to assess model stability.

Results: Multivariate logistic regression revealed that thyroid disease, elevated serum creatinine, and hyperphosphatemia were independent risk factors for hypocalcemia, while higher parathyroid hormone (PTH) levels and compound α-ketoacid use were protective factors. The nomogram incorporating these variables demonstrated good discrimination (AUC = 0.846, 95% CI 0.802-0.891), with a sensitivity of 81.5% and specificity of 77.3%. The calibration curve showed strong agreement between predicted and observed outcomes, and DCA indicated favorable net clinical benefit. Internal validation showed robust performance with a bootstrap-corrected area under the ROC curve (AUC) of 0.832.

Conclusions: The developed nomogram provides a reliable and clinically applicable tool for individualized prediction of hypocalcemia in hemodialysis patients, facilitating improved risk stratification and management.

Objective: Chronic kidney disease (CKD) is associated with an increased risk of contrast-associated acute kidney injury (CA-AKI), but the pathways underlying this relationship, including the contribution of intermediate factors, are not well characterized. We investigated the association between CKD and CA-AKI in patients undergoing coronary angiography or percutaneous coronary intervention and evaluated the potential mediating roles of serum albumin and high-sensitivity C-reactive protein (hsCRP) in this association.

Methods: During the study period, a total of 13,024 patients underwent coronary angiography of these, 3740 met the predefined inclusion criteria and formed the final study cohort. Multivariable logistic regression and formal mediation analyses were subsequently employed to evaluate the associations of interest.

Results: Among the 3740 patients, 414 (11.1%) developed CA-AKI. Lower pre-procedural serum albumin and higher log-transformed hsCRP (LnhsCRP) were independently associated with increased CA-AKI risk (OR [95% CI] 0.730 [0.583-0.913], P = 0.006, and 1.385 [1.215-1.579], P < 0.001, respectively). The initial association between CKD and CA-AKI (OR 1.906 [1.552-2.342]) was attenuated after adjustment for albumin and hsCRP (OR 1.253 [0.975-1.609]). Subsequent mediation analysis indicated that serum albumin and hsCRP statistically accounted for approximately 31.3% and 56.6% of the attenuation in the association between CKD and CA-AKI, with an additional co-mediation effect of 12.1%.

Conclusions: Systemic inflammation and hypoalbuminemia, beyond reduced kidney function, may help explain CA-AKI risk in CKD and could inform risk stratification strategies using inflammatory and nutritional biomarkers.

Background: Low-grade gliomas (LGG) are aggressive brain tumors with high rates of recurrence and poor prognosis. PSMC4, a proteasome subunit, plays a role in various cancers, but its function in LGG remains poorly understood. This study explores PSMC4's impact on LGG progression.

Methods: PSMC4 expression in LGG patients was analyzed using data from TCGA, CGGA, and GEO. Kaplan-Meier and Cox regression models assessed survival outcomes. Gene Set Enrichment Analysis (GSEA) identified key pathways affected by PSMC4. Immune infiltration was evaluated using the TIMER database. In vitro, SHG44 cells were transfected with shRNA targeting PSMC4, and assays for cell proliferation, migration, clonogenicity, and invasion were performed. In vivo xenograft assays were also conducted.

Results: High PSMC4 expression was linked to higher tumor grade and poor prognosis in LGG patients. Kaplan-Meier analysis revealed shorter overall survival for patients with high PSMC4 expression. ROC curve analysis confirmed the diagnostic value of PSMC4 for predicting poor prognosis. GSEA identified pathways like Notch, Toll-like receptor, and VEGF signaling that may be regulated by PSMC4. In vitro, PSMC4 knockdown significantly reduced SHG44 and T98 cell proliferation, migration, and invasion, while clonogenic assays showed decreased colony formation. In vivo, PSMC4 knockdown led to smaller tumor volumes in xenograft models, confirming its role in tumor progression.

Conclusion: PSMC4 overexpression promotes LGG progression and may be an independent marker of poor prognosis. Targeting PSMC4 can reduce tumor growth and metastasis, providing a promising strategy for LGG treatment. Further research on its regulatory mechanisms and clinical implications is warranted.

Background: Current understanding of B cell heterogeneity in diffuse large B cell lymphoma (DLBCL) and its functional impact on disease progression remains incomplete. This study applies single-cell RNA sequencing to identify and characterize a distinct proliferation-related B cell subpopulation in DLBCL, aiming to address this knowledge gap.

Methods: We utilized dataset GSE182434 from the Gene Expression Omnibus (GEO) database for the analysis, with the aim of identifying genes that are specifically highly expressed in different cell clusters. The copy number variation analysis was performed using B cells of normal samples as the control. Thereafter, the cell-cell communication analysis was implemented to reveal the potential ligand-receptor pairs, and the functional enrichment analysis was performed to uncover the enriched pathways. Further, the potential transcription factors-target genes networks were plotted via SCENIC analysis, and a series of validation assays were implemented using DLBCL cells.

Results: The single-cell landscape of DLBCL revealed a reduced proportion of B cells, CD8⁺ T cells, and naïve T cells. Malignant B cells exhibited chr1q amplification and chr6 deletion, with genes in these regions linked to immune suppression and impaired antigen presentation, respectively. Further subclustering identified a proliferative B cell subcluster (subcluster 2) enriched in nucleotide metabolism and cell cycle pathways. This subcluster was characterized by elevated XBP1 activity, regulating ER stress response, and downregulation of SPIB, RELB, and IRF factors involved in lymphocyte activation and interferon signaling. Functionally, XBP1 silencing suppressed DLBCL cells proliferation and invasion. Cell communication analysis revealed crosstalk between this B cell subpopulation and CD8+ T/NK cells via MIF-(CD74+CXCR4) and LTA-TNFRSF pathways.

Conclusion: This analysis has identified and characterized the proliferation-related B cells in DLBCL, which may provide some ideas for the treatment strategies in immune-oncology and cellular therapies.

Background: Human immunodeficiency virus type 1 (HIV-1) causes immune deficiency, particularly CD4+T-cell depletion. This cross-sectional study explored circulating cell-free DNA (ccfDNA) as a biomarker for immune function and disease progression in HIV-1-infected individuals.

Methods: We measured ccfDNA levels, CD4+T-cell counts, immune activation/apoptosis markers, and viral load in 79 patients receiving antiretroviral therapy (37 immune responders, 42 non-responders) and 35 controls. Correlation and receiver operating characteristic (ROC) curve analysis were performed to assess relationships between ccfDNA and immunological/virological parameters.

Results: ccfDNA negatively correlated with CD4+T-cell counts (r = - 0.78, P < 0.01) and positively correlated with viral load (r = 0.58, P < 0.01) and T-cell immune activation/apoptosis markers (r = 0.78 ~ 0.89, P < 0.01). Multivariate regression showed CD4+T-cell counts independently associated with lower ccfDNA, while CD4+AnnexinV+, CD8+PD1+, and CD8+AnnexinV+T cells correlated with higher ccfDNA. ROC analysis (area under curve = 0.799) indicated ccfDNA's potential as a complementary biomarker for monitoring HIV-1 patients.

Conclusions: Preliminary evidence from this study indicates that ccfDNA levels are closely linked to immune dysfunction and may have potential as a complementary biomarker for monitoring immune status in HIV-1-infected patients.

Acute kidney injury (AKI), a common and severe complication of acute pancreatitis (AP), is amenable to early intervention. Phosphorus-to-albumin ratio (PAR) is a novel composite biomarker unexplored in AP largely. Data of ICU patients with AP were extracted from MIMIC-IV database and eICU-CRD, respectively. PAR's link to prognosis and AKI in AP were analyzed via Kaplan-Meier curves, Cox regression, restricted cubic splines (RCS), and logistic regression. Subgroup analysis tested interactions. Key variables were identified using least absolute shrinkage and selection operator regression. AKI prediction models were built and evaluated via seven machine learning (ML) algorithms. Shapley additive explanations (SHAP) interpreted variable contributions. Survival analysis, Cox models, and RCS collectively demonstrated PAR, as a potential risk factor, is associated with 28-day and 1-year all-cause mortality in patients with AP. Logistic regression identified PAR as a risk factor for AKI development in AP. AKI-related clinical features including PAR were indentified. Seven ML models were constructed, among which the Light Gradient Boosting Machine (LightGBM) model achieved an area under receiver operating characteristic curve (AUROC) of 0.880 (95% CI 0.825-0.935) and area under precision-recall curve (AUPRC) of 0.944 in the test set, and an AUROC of 0.837 (95% CI 0.785-0.889) and AUPRC of 0.784 in the external validation set. SHAP analysis of the LightGBM model confirmed that higher PAR levels corresponded to a higher predicted probability of AKI. PAR is associated with prognosis and AKI of patients with AP. Integrating PAR with other key clinical features, our LightGBM model provides physicians with a streamlined and efficient tool for early AKI identification in high-risk AP patients.

Objective: This study aimed to prospectively assess whether dual-source CT‑guided identification of uric acid stones can effectively direct patients to successful medical dissolution therapy.

Methods: A retrospective diagnostic study of 760 patients with urinary stones was conducted. Preoperative dual-source CT parameters were compared with postoperative infrared spectroscopy to establish diagnostic cut-off values. In the prospective intervention study, 60 patients with uric acid stones-identified by a dual-energy ratio ≤ 1.15 on dual-source CT-were randomized to an experimental group (stone dissolution therapy with sodium potassium hydrogen citrate plus lifestyle guidance) or a control group (lifestyle guidance only). Treatment outcomes were evaluated at 3 months.

Results: In the retrospective cohort, dual-source CT demonstrated excellent diagnostic accuracy for uric acid stones, with an area under the curve of 0.998 for the dual-energy ratio. Optimal cut-offs were as follows: dual-energy ratio ≤ 1.165, attenuation at 100 kV < 641.5 HU, and attenuation at 150 kV < 570.5 HU. In the prospective trial, the experimental group achieved significantly higher complete dissolution rates (80% vs. 20%), lower non-response rates (3.3% vs. 33.3%), and lower surgical rates (3.3% vs. 30%). Urine pH improved in the experimental group without significant change in serum uric acid.

Conclusion: Dual-source CT accurately identifies uric acid stones using a dual-energy ratio threshold of ≤1.15, enabling targeted medical therapy. This imaging-guided strategy significantly improves stone dissolution outcomes and reduces the need for surgical intervention.