BMC Medicine最新文献

{"title":"Genetic prioritization of HSDL2 in suicide and intentional self-harm: multi-omics evidence linking lipid metabolism and neuronal vulnerability.","authors":"Ziyan Zhang, Yutong Wu, Fanxu Meng, Hanbing Ji, Hai Zhong, Shucheng Si, Yun Wei, Yilei Ge, Sijia Wu, Qingxin Luo, Le Wang, Tiemei Liu, Jiawei Xiu, Yiman Guo, Yue Li, Lei Hou, Hao Chen, Xiaoru Sun, Yuanyuan Yu, Qingzhen Hou, Shanshan Gao, Fuzhong Xue, Hongkai Li","doi":"10.1186/s12916-026-05066-6","DOIUrl":"https://doi.org/10.1186/s12916-026-05066-6","url":null,"abstract":"<p><strong>Background: </strong>Suicide or other intentional self-harm (SSH) represents a critical global public health burden, yet biologically informed targets remain poorly defined due to its complex and incompletely understood etiology. This study aimed to prioritize genetically supported candidate targets for SSH and characterize their biological and translational relevance.</p><p><strong>Methods: </strong>We developed a multi-omics evidence framework integrating transcriptomic and proteomic Mendelian randomization, colocalization, and sensitivity diagnostics. The primary SSH outcome was from FinnGen R12 (11,538 cases; 488,810 controls). eQTLGen and GTEx were used for transcriptomic analyses, and UKB-PPP and ARIC for proteomic validation. Downstream analyses included functional enrichment, tissue expression profiling, exploratory metabolomic pathway analysis, brain cell-type-specific eQTL analyses, phenome-wide liability scanning, structural modeling with docking, virtual screening and molecular dynamics simulations, and baseline SSH classification in UKB-PPP individual-level proteomic data.</p><p><strong>Results: </strong>Transcriptome-wide MR identified 1,164 FDR-significant genes, of which 55 were retained as Tier 1-4 prioritized candidates after proteomic validation, colocalization, and sensitivity assessment. HSDL2 was the sole Tier 1 candidate, supported by consistent eQTL and pQTL evidence, adequate instrument strength, and colocalization at the HSDL2 locus (PP.H4 = 0.797). Genetically predicted HSDL2 expression was associated with higher SSH risk in eQTLGen (OR = 1.133, 95% CI: 1.076-1.192) and showed directionally consistent protein-level evidence in UKB-PPP (OR = 1.050, 95% CI: 1.005-1.098). Enrichment and metabolomic analyses implicated lipid-, bile acid-, and organelle-related pathways. Brain cell-type-specific analyses suggested neuronal involvement, with consistent excitatory-neuron associations across discovery and validation datasets and additional support for inhibitory neurons in SingleBrain, while oligodendrocyte signals required cautious interpretation. Structural analyses supported a putative HSDL2 ligand-binding pocket, providing hypothesis-generating structural context for the metabolic findings. Phenome-wide MR analyses identified additional disease associations, providing phenotypic context for future target evaluation. UKB-PPP baseline classification analyses provided complementary individual-level support for the prioritized protein signal.</p><p><strong>Conclusions: </strong>HSDL2 was prioritized as a genetically supported and biologically plausible candidate target for SSH, implicating a potential lipid-metabolic and neuronal vulnerability axis. These findings provide a foundation for future mechanistic validation and translational investigation.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149243171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ionomics powered single-cell mapping reveals targetable iron dysregulation in endometriosis associated macrophages.","authors":"Ming Yuan, Xue Jiao, Le Xu, Shuang Wang, Lei Yan, Zhaoyang Zhong, Qianhui Ren, Xiaoyu Dong, Hongwei Guan, Na Li, Chunyan Li, Jing Zhao, Kun Liu, Xiaoli Meng, Guoyun Wang","doi":"10.1186/s12916-026-05095-1","DOIUrl":"https://doi.org/10.1186/s12916-026-05095-1","url":null,"abstract":"<p><strong>Background: </strong>Endometriosis affects approximately 10% of women of reproductive age worldwide. Although elemental components of refluxed menstrual blood have been implicated in disease progression, comprehensive ionomic profiling of the endometriotic microenvironment remains limited. Characterizing the localized elemental landscape may generate new hypotheses regarding disease mechanisms.</p><p><strong>Methods: </strong>We employed inductively coupled plasma mass spectrometry (ICP-MS) to profile 63 elements in endometriotic cyst fluid. Single-cell RNA sequencing (scRNA-seq) was performed to explore cellular subpopulations potentially associated with elemental dysregulation. Senescent red blood cells (sRBCs) were used to model retrograde menstruation in endometriosis. The effects of iron chelation with deferoxamine (DFO) and ferroptosis inhibition with ferrostatin-1 (Fer-1) were evaluated.</p><p><strong>Results: </strong>ICP-MS identified iron as the most significantly elevated element in patients with endometriosis, supported by flow cytometry and Prussian blue staining. ScRNA-seq revealed a macrophage subcluster enriched in endometriotic lesions, co-expressing M2-associated markers and ferroptosis-related genes. Mechanistically, sRBC phagocytosis activated HIF-1α and HO-1 expression in macrophages, accompanied by intracellular iron accumulation, sublethal ferroptotic stress characterized by elevated lipid peroxidation and reactive oxygen species, M2-like polarization, and impaired phagocytic capacity. These iron-laden macrophages suppressed CD8⁺ T and NK cell effector functions, at least in part through the CXCL12-CXCR4 signaling axis. In the mouse model, treatment with DFO and Fer-1 partly reversed macrophage polarization, restored phagocytic function, alleviated lymphocyte suppression, and reduced ectopic lesion growth.</p><p><strong>Conclusions: </strong>This exploratory study suggests that sRBC-derived iron overload may be associated with a shift of macrophages toward an immunosuppressive phenotype, potentially linked to the HIF-1α/HO-1/GPX4 pathway. These changes may contribute to local immune dysfunction in endometriosis. These findings highlight macrophage iron metabolism as a potential therapeutic target that warrants validation in larger and independent cohorts.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149243188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial cell-specific TGM2 deficiency promotes progression of temporal lobe epilepsy by disrupting S1P metabolism and intercellular communication.","authors":"Sijing Ren, Yanli Wang, Haiqing Zhang, Chengyu Pan, Xuehua Shen, Wanxiang Chen, Liuyan Zhou, Xinyu Wang, Qing-Xia Kong","doi":"10.1186/s12916-026-05077-3","DOIUrl":"https://doi.org/10.1186/s12916-026-05077-3","url":null,"abstract":"<p><strong>Background: </strong>Temporal lobe epilepsy (TLE) is a common and medically refractory neurological disorder with a complex pathogenesis. Blood-brain barrier (BBB) dysfunction is a key pathogenic factor. As a multifunctional protein, TGM2 has been shown to participate in vascular homeostasis, metabolic pathway regulation, and immune-inflammatory responses. This study aimed to systematically investigate the expression pattern, core functions, and molecular regulatory mechanisms of TGM2 in TLE, and to clarify its clinical value.</p><p><strong>Methods: </strong>Temporal cortex tissue and plasma samples from drug-resistant TLE patients and control subjects were collected, alongside kainic acid (KA)-induced epileptic mouse models. Single-cell RNA sequencing was adopted to identify TGM2's cell-specific expression pattern, and qPCR, Western blot and ELISA validated its expression levels. With endothelial cell-specific TGM2 conditional knockout mice, in vivo experiments assessed seizure severity and BBB permeability through behavioral observation, intracranial local field potential (LFP) recording and Evans blue (EB) assay. In vitro siRNA-mediated TGM2 knockdown in brain microvascular endothelial cells verified endothelial functional changes. Metabolomics, RNA-seq, nucleocytoplasmic separation, immunofluorescence and molecular docking were used to clarify regulatory mechanisms, and intercellular communication networks were constructed to analyze ligand-receptor interactions.</p><p><strong>Results: </strong>Results indicated that endothelial TGM2 was significantly downregulated in TLE patients and epileptic mice. Endothelial TGM2 deficiency aggravated recurrent seizures, increased BBB permeability, impaired endothelial function, and reduced the expression of tight junction protein CLDN5. Mechanistically, TGM2 positively regulated sphingosine-1-phosphate (S1P) synthesis. Reduced S1P production abolished the inhibition of RelA nuclear translocation, thereby activating downstream inflammatory genes and triggering endothelial inflammation. Molecular docking confirmed the direct binding between S1P and RelA. Furthermore, TGM2 deficiency remodels endothelial-neuron-microglia communication and disrupts neural circuit homeostasis.</p><p><strong>Conclusions: </strong>This study establishes a link between TGM2 and BBB function, metabolic pathways, and intercellular communication in TLE, providing an experimental basis for developing TLE therapeutic strategies targeting this pathway.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149243165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Minocycline for acute basilar artery occlusion stroke undergoing endovascular treatment: a randomized, evaluator-blinded, open-label, pilot trial.","authors":"Zhirong Fan, Jingjing Zhao, Rui Shi, Li Yao, Huiping Zhang, Rong Yin, Weiwang Li, Liping Yu, Xiangjun Yuan, Yi Jia, Bo Song, Baiya Fan, Xingshun Ma, Xue Li, Deshuai Li, Xiao Zhang, Yang Li, Ling Wang, Duolao Wang, Dong Wei, Wen Jiang","doi":"10.1186/s12916-026-05092-4","DOIUrl":"10.1186/s12916-026-05092-4","url":null,"abstract":"<p><strong>Background: </strong>Minocycline is a promising anti-inflammatory agent for reducing futile recanalization, but whether it improves clinical outcomes in basilar-artery stroke patients treated with endovascular therapy (EVT) remains unclear. In this study, we aimed to assess the efficacy and safety of oral minocycline combined with EVT on outcomes in patients who had basilar-artery stroke.</p><p><strong>Methods: </strong>The Minocycline for acute Ischemic Stroke undergoing endovascular Treatment due to Basilar artery occlusion (MIST-B) trial was a multicenter, randomized, evaluator-blinded, open-label, pilot trial in 12 Chinese hospitals. Adults with basilar-artery stroke no more than 24 h after onset were randomized (1:1) to receive oral minocycline (200 mg loading, then 100 mg every 12 h for 5 days) plus EVT or EVT alone. The primary efficacy outcome was the expanded National Institutes of Health Stroke Scale (e-NIHSS) score at day 5; the primary safety outcome was symptomatic intracranial hemorrhage (sICH) within 24 h. Participants were followed up 90 days after randomization. Modified intention-to-treat analysis examined treatment effect for the primary efficacy outcome using linear mixed models, with the baseline measurement of e-NIHSS score as a covariate.</p><p><strong>Results: </strong>From March 4, 2023, to March 4, 2025, 90 patients were randomized, and 89 were analyzed (mean age 61.7 years, 31.5% women). At day 5, median e-NIHSS was 12.0 (IQR 3.5 to 30.0) in the minocycline group and 10.5 (IQR 2.0 to 35.0) in the control group; corresponding mean values were 15.0 (SD 13.5) and 17.2 (SD 16.9), respectively (adjusted mean difference - 2.83 [95% CI -7.86 to 2.20]; P = 0.27). sICH within 24 h occurred in 2/37 (5.4%) of participants in the minocycline group vs. 6/41 (14.6%) in the control group (adjusted risk ratio, 0.70; 95% CI, 0.11 to 4.67). Other secondary efficacy and safety outcomes, including 90-day modified Rankin Scale, mortality, and adverse events, showed no significant differences between groups.</p><p><strong>Conclusions: </strong>Minocycline was well-tolerated in this population; however, these results did not provide evidence to support prescribing minocycline to improve early neurological outcomes. Larger trials of minocycline with extended treatment duration are warranted.</p><p><strong>Registration: </strong>The trial was registered at ClinicalTrials.gov (NCT05512910) on August 23, 2022.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13688725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149236951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polygenicity shapes distinct brain patterns and clinical profiles of bipolar disorder.","authors":"Yu Feng, Xiaonan Guo, Peng Huang, Ningning Jia, Li Wang, Xiaolong Ji, Zeyu Qin, Meng Li, Jianbo Lai, Xiaofeng Qin, Weihua Yue, Sheng Yang, Shaohua Hu","doi":"10.1186/s12916-026-05096-0","DOIUrl":"https://doi.org/10.1186/s12916-026-05096-0","url":null,"abstract":"<p><strong>Background: </strong>Bipolar disorder (BD) manifests both genetic predispositions and brain imaging abnormalities. Genetic analyses provide a powerful approach to disentangling the associations between BD and brain imaging-derived phenotype (IDP). However, in East Asian (EAS) populations, the genetic basis of these neuroimaging changes and their clinical relevance remains underexplored due to limited integrative evidence.</p><p><strong>Methods: </strong>We investigated the genetic architecture and clinical relevance of BD and brain IDPs in East Asian populations using individual-level data from the Chinese Bipolar Disorder (CN-BD) cohort (N = 3,920), summary statistics of BD from the Psychiatric Genomics Consortium (PGC) (N = 16,915) and of IDPs from the CHIMGEN Consortium (N = 7,058), and genotype and clinical data from the Chinese Longitudinal and Systematic Study of Bipolar Disorder cohort (CLASS-BD). We employed genetic correlation (GNOVA), multi-trait meta-analysis (MTAG, CPASSOC), and ancestry-specific fine-mapping (MESuSiE) to identify shared genetic loci. Functional annotation, protein association (SMR, BLISS), and spatiotemporal expression trajectory analyses were conducted. Bidirectional Mendelian Randomization (MR) assessed causal relationships, and polygenic risk score (PRS)-PheWAS explored phenome-level associations with clinical traits.</p><p><strong>Results: </strong>Our multi-trait meta-analysis identified 11 pleiotropic single nucleotide variants (SNVs) implicated in BD-IDP pairs, showing convergent enrichment in lipid metabolism and neurotransmitter biosynthesis pathways. Fine-mapping revealed an EAS-specific causal signal (rs7941324 near RPS27P20), which demonstrated high posterior inclusion probability in EAS but not European ancestries, and colocalized with BD and specific brain alterations. MR revealed 27 IDP-to-BD and 35 BD-to-IDP causal relationships, distinguishing structural changes of the parietal and temporal gyri as markers preceding BD onset and the right precuneus area as a state marker that followed BD onset. Clinically, BD-IDP polygenic risk scores were significantly associated with depressive symptoms, anxiety, and suicide risk. Mediation analysis further indicated that depressive and anxiety symptoms statistically mediated the relationship between BD-IDP PRS and suicide risk. Moreover, PRS-PheWAS identified 135 significant associations with metabolic phenotypes, highlighting a psycho-metabolic nexus in BD.</p><p><strong>Conclusions: </strong>Our findings reveal associations between polygenicity and distinct BD brain patterns and clinical profiles. We identified ancestry-specific causal variants and bidirectional BD-IDP relationships. PRS associations with depressive symptoms, anxiety, suicide risk, and metabolic phenotypes highlight precision medicine potential for BD.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149243230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnostic accuracy of point-of-care ultrasound in adult non-traumatic emergency medicine: an umbrella review.","authors":"Claudio Schneider, Nico Frei, Antoine Fernandez, Catherine Frei, Katharina Wahedi, Julius Husarek, Tanya Karrer, Carole Elodie Aubert, Beat Lehmann, Martin Müller","doi":"10.1186/s12916-026-05094-2","DOIUrl":"10.1186/s12916-026-05094-2","url":null,"abstract":"<p><strong>Background: </strong>Point-of-care ultrasound (POCUS) has become an increasingly used diagnostic tool in adult emergency departments (ED). Although numerous diagnostic test accuracy systematic reviews (DTA-SR) evaluating various POCUS applications are available, clinicians often face uncertainty due to ungraded accuracy estimates and inconsistent evidence. We conducted an umbrella review to (i) summarize diagnostic accuracy evidence for POCUS across adult non-traumatic emergency medicine-relevant conditions, (ii) provide GRADE-based ratings of pooled sensitivity and specificity, and (iii) synthesize findings when multiple DTA-SR addressed the same condition.</p><p><strong>Methods: </strong>We systematically searched PubMed and Embase from database inception to April 2026 for DTA-SR with meta-analysis evaluating the diagnostic performance of POCUS in adult ED populations for non-traumatic emergency medicine-relevant conditions. DTA-SR were included if they reported pooled sensitivity and specificity against accepted reference standards. The methodological quality was assessed using a DTA-adapted AMSTAR 2 tool. Sensitivity and specificity estimates were graded using the GRADE approach. Results were synthesized using a predefined hierarchical decision framework to account for overlap between primary studies.</p><p><strong>Results: </strong>A total of 197 DTA-SR were included, most focusing on cardiovascular, gastrointestinal, respiratory, or musculoskeletal conditions. About half were conducted in ED; the rest examined emergency medicine-relevant conditions in specialist settings. Methodological quality was mostly low or moderate. Diagnostic utility varied substantially across conditions. Among 91 evaluated conditions, 12 fulfilled predefined criteria for combined rule-in/rule-out supportive applications, 17 for primarily rule-in supportive applications, and 6 for primarily rule-out supportive applications (defined as pooled sensitivity or specificity ≥ 90% with at least moderate certainty of evidence). The remaining conditions were categorized as adjunctive because these thresholds were not met. Overall, certainty of evidence was frequently low or very low.</p><p><strong>Conclusions: </strong>POCUS shows promising diagnostic accuracy across adult non-traumatic emergency medicine-relevant conditions, often with moderate to high sensitivity and very high specificity. However, the overall strength and consistency of the evidence are limited. Therefore, diagnostic performance estimates should be interpreted with caution and within the context of each specific clinical condition, and should not be considered directly comparable or additive across different indications. Further high-quality research is needed to better define its role in emergency care.</p><p><strong>Clinical trial number: </strong>Clinical trial number: CRD42024587695.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13689006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149236999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated proteomics and machine learning reveal AHNAK as a discriminative biomarker of atrial fibrillation in heart failure.","authors":"Wengen Zhu, Zhenbang Gu, Yuwen Huang, Min Ye, Ruicong Xue, Yugang Dong, Yuzhong Wu, Chen Liu","doi":"10.1186/s12916-026-05079-1","DOIUrl":"10.1186/s12916-026-05079-1","url":null,"abstract":"<p><strong>Background: </strong>Atrial fibrillation (AF) is a frequent complication of heart failure (HF), markedly increasing morbidity and mortality. Although atrial fibrosis is increasingly recognized as a central mechanistic substrate linking HF to AF, the molecular determinants driving fibrotic remodeling and enabling early AF discrimination in HF remain poorly defined.</p><p><strong>Methods: </strong>We integrated label-free quantitative plasma proteomics with machine learning-based feature selection to analyze samples from 59 age- and sex-matched patients hospitalized with acute decompensated HF. Differentially expressed proteins were subjected to functional and pathway enrichment analyses, and candidate biomarkers were prioritized using an incremental feature selection framework. AHNAK, the top-ranked candidate, was functionally interrogated in vitro using TGF-β1-stimulated primary mouse atrial fibroblasts with siRNA-mediated knockdown and in vivo using a pressure overload-induced HF model in AHNAK heterozygous mice. A two-sample Mendelian randomization analysis was performed to evaluate the association between genetically proxied AHNAK expression and AF risk.</p><p><strong>Results: </strong>Plasma proteomic profiling identified 126 proteins that were significantly dysregulated in HF patients with AF compared with those in sinus rhythm, among which AHNAK was the most upregulated. Machine learning-based feature selection consistently ranked AHNAK as the most discriminative protein, with robust performance for AF discrimination in HF patients (AUC = 0.897, 95% confidence interval: 0.82-0.97). Functionally, AHNAK heterozygous deficiency promoted a profibrotic phenotype, characterized by increased expression of α-smooth muscle actin, fibronectin, and collagen Iα in atrial fibroblasts and exacerbated atrial fibrosis and cardiac dysfunction in pressure-overloaded mice. Mendelian randomization analysis demonstrated a significant protective effect of higher AHNAK expression against AF, with no evidence of horizontal pleiotropy.</p><p><strong>Conclusions: </strong>This study identifies AHNAK as a discriminative plasma biomarker for AF in HF patients and implicates AHNAK deficiency as a contributor to atrial fibrotic remodeling and AF pathogenesis. External validation in larger and prospective HF cohorts will be required to confirm the clinical utility of AHNAK for AF risk stratification and early detection.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13685328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative validation and local adaptation of gastric cancer risk assessment models in a large multicenter endoscopic screening cohort in China.","authors":"Xue Li, Ying Chen, Juan Zhu, Wei-Yan Yu, Huan-Qing Tao, Gang Chen, Hui-Zhang Li, Ling-Bin Du","doi":"10.1186/s12916-026-05082-6","DOIUrl":"10.1186/s12916-026-05082-6","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer (GC) is a major public health challenge in China, highlighting the need for effective risk stratification to improve early detection. This study aimed to validate existing GC risk assessment models and develop a locally adapted screening approach for GC and precancerous lesions.</p><p><strong>Methods: </strong>From 2022 to 2024, a total of 144,329 participants were recruited through a large multicenter endoscopic screening cohort in Zhejiang Province, China, with baseline data collected via interviews and endoscopic examinations. Participants screened in 2022 were used for model development, whereas those screened during 2023-2024 were used for validation and comparative analyses. Least absolute shrinkage and selection operator regression and logistic regression were used to construct a new model and a weighted point-based risk score. Six previously published models were externally validated for comparison across the validation set. Model performance and clinical utility were assessed and compared using area under the curve (AUC), detection rates, and decision curve analysis for both GC and the composite outcome of GC/high-grade intraepithelial neoplasia (HGIN).</p><p><strong>Results: </strong>A total of 1,419 GC cases were identified in the screening cohort. The newly developed model demonstrated favorable discriminative performance, with an AUC of 0.759 (95% CI: 0.744-0.775) for GC and 0.754 (95% CI: 0.740-0.768) for the composite outcome of GC/HGIN in the validation set. External evaluation of six previously published models showed AUCs ranging from 0.594 (95% CI: 0.558-0.629) to 0.742 (95% CI: 0.725-0.758) for GC, and from 0.602 (95% CI: 0.570-0.635) to 0.744 (95% CI: 0.730-0.759) for GC/HGIN. Risk stratification analyses demonstrated progressively increasing odds of both GC and GC/HGIN across higher-risk quartiles in most evaluated models. In the newly developed model, the highest-risk quartile accounted for 62.25% of GC cases and 58.56% of HGIN cases, indicating substantial enrichment of clinically significant lesions. Decision curve analysis indicated a favorable net benefit of the newly developed model across the evaluated range of threshold probabilities.</p><p><strong>Conclusions: </strong>The newly developed model demonstrated favorable discrimination, stable geographic performance, and effective risk stratification in a large multicenter screening cohort. These findings support its potential utility for risk-adapted GC screening in Chinese populations.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13685247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted lipidomics unveils complex lipids in cervicovaginal environment as diagnostic and prognostic biomarkers for endometrial cancer.","authors":"Anita Garwolinska, Paweł Łaniewski, Melissa M Herbst-Kralovetz","doi":"10.1186/s12916-026-05070-w","DOIUrl":"10.1186/s12916-026-05070-w","url":null,"abstract":"<p><strong>Background: </strong>Global incidence of endometrial cancer (EC) is on the rise. EC-associated risk factors like obesity, metabolic syndrome, and genetic predisposition increase a person's risk for developing EC in their lifetime and negatively affect prognostic outcomes. Present methods for EC diagnosis rely on invasive endometrial biopsies or dilation and curettage. Our previous global untargeted metabolomics analysis of minimally invasive cervicovaginal lavage (CVL) samples revealed an enrichment in simple lipid signatures associated with EC presence and pathophysiology. This study investigated complex lipids beyond those reported previously, with intent to identify novel lipid biomarkers for accurate, minimally invasive EC detection and prognosis.</p><p><strong>Methods: </strong>We analysed 223 CVL samples collected by a physician from women diagnosed with EC (n = 66), benign pathological conditions (n = 108) and asymptomatic, healthy women (n = 49). The concentrations (nmol/mL) of 914 individual lipid species, 14 lipid classes and 28 fatty acid (FA) side chains were detected across CVL samples using the Complex Lipid Targeted Panel (Metabolon Inc.). Tumour size, grade, myometrial invasion, and mismatch repair (MMR) status in women with EC were determined from histopathologic reports. MetaboAnalyst and Prism were used for statistical and biomarker analysis which included Receiver Operating Characteristic (ROC) curves, measuring the Area Under the Curve (AUC) and Youden Index (J).</p><p><strong>Results: </strong>Women with EC exhibited significant enrichment of neutral lipid species, especially those containing long chained polyunsaturated fatty acid side chains. Cholesteryl ester (CE) species, specifically CE(22:4), were consistently identified as top predictive features when applied individually and when incorporated into multivariable diagnostic models. A 10-feature model developed in the exploratory dataset, discriminated EC from a combined group of benign and healthy controls with ≥75% sensitivity and specificity when validated using previously internal held-out samples. Top predictive CE species for EC also held prognostic value as they related to MMR status and histologic type.</p><p><strong>Conclusions: </strong>These findings revealed EC-associated alterations in lipid metabolism within the cervicovaginal environment, highlighting the potential use of complex lipid species detected in CVLs as minimally invasive diagnostic biomarkers for EC and markers associated with EC prognostic features.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13682092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defining optimal treatment strategies for nasopharyngeal carcinoma based on the ninth edition TNM staging system: insights from a multicenter cohort study in an endemic region.","authors":"Gaoyuan Wang, Lanqing Huo, Xiaodong Zhu, Feng Lei, Liangfang Shen, Kunyu Yang, Yaqian Han, Guanjie Qin, Minyu Wen, Jibin Li, Jun Ma, Xiaojing Du","doi":"10.1186/s12916-026-05085-3","DOIUrl":"10.1186/s12916-026-05085-3","url":null,"abstract":"<p><strong>Background: </strong>The ninth edition AJCC/UICC staging system (TNM-9) for nasopharyngeal carcinoma (NPC) was released in 2025, prompting a need to redefine evidence-based treatment regimens. This study aimed to identify optimal therapies under the new criteria.</p><p><strong>Methods: </strong>In this multicenter cohort, we enrolled patients from endemic Chinese regions (2016‑2017) with non‑metastatic (M0) or de novo metastatic (M1) NPC. Propensity score matching (1:1 or 1:M) and inverse probability of treatment weighting minimized selection bias. Survival was compared via Kaplan‑Meier and Cox models.</p><p><strong>Results: </strong>The cohort comprised 6049 non-metastatic patients restaged by TNM-9 criteria, categorized into the following risk groups: low-risk (stage IA), intermediate-risk (stage IB and T3N0), high-intermediate-risk (T3N1), and high-risk (T1-3N2 and stage III). Additionally, 127 de novo metastatic patients were enrolled. Survival between concurrent chemoradiotherapy (CCRT) and intensity-modulated radiotherapy (IMRT) alone in the stage IA group was not significantly different (hazard ratio [HR]: 0.50; 95% CI: 0.05-5.50; P = 0.562). However, within the intermediate-risk group, CCRT demonstrated significantly improved 5-year OS (97.9% vs. 91.0%; P = 0.001). Among high-risk patients, induction chemotherapy (IC) followed by CCRT with or without adjuvant chemotherapy resulted in superior 5-year OS (83.9% vs. 78.6%; P = 0.003). Although reclassification under TNM-9 affected only a limited number of patients (n = 301), this subgroup exhibited a substantial survival benefit from the addition of IC (5-year OS: 83.2% vs. 66.4%; P = 0.001). A comprehensive treatment strategy combining systemic therapy, locoregional radiotherapy (LRRT), and maintenance therapy (MT) was associated with significantly prolonged survival (HR: 0.36; 95% CI: 0.23-0.55; and HR: 0.45, 95% CI: 0.25-0.79). Furthermore, local consolidation therapy of metastases (LCT) in M1a was associated with a non-significant trend longer median OS (89.0 vs. 62.4 months; P = 0.122).</p><p><strong>Conclusions: </strong>Under the TNM-9, management recommendations were as follows: radical IMRT alone for stage IA; CCRT for stage IB and T3N0; and high-intensity therapy for high-risk disease, including reclassified subsets. For metastatic disease, the addition of LRRT and MT to systemic therapy was associated with improved survival in both M1a and M1b patients, whereas a trend toward potential benefit from LCT was observed only in M1a subgroup.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13682135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}