Background:Poor pathological response to neoadjuvant immunotherapy combined with chemotherapy (nICT) limits long-term survival in resectable lung cancer. How to improve response rates and the regulatory mechanism of tumor inflammatory signaling in nICT efficacy remain unclear. Methods:In this study, patients were stratified into molecular subgroups using unsupervised consensus clustering based on inflammatory response genes (IRGs) expression profiles. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics were applied to characterize tumor inflammatory states, immune microenvironment heterogeneity, and spatial organization between major pathological response (MPR) and non-MPR (NMPR) patients. Differentially expressed gene (DEG) analysis was performed to identify potential therapeutic targets, followed by preliminary functional validation to explore their biological roles. Results:Consensus clustering identified four molecular subgroups with distinct survival outcomes and clinical characteristics. scRNA-seq profiling uncovered that intratumoral inflammatory activation was markedly elevated in NMPR patients relative to MPR patients, with neutrophil subsets exhibiting the most robust inflammatory response among all immune cell populations. Further subset analysis identified two pro-inflammatory neutrophil populations (N3_CXCL8 and N4_VCAN), which were enriched in hypoxic tumor regions and contributed to immune evasion and angiogenesis. OLR1 was identified as a key regulatory hub associated with inflammatory activation, immunosuppression, and pro-angiogenic signaling. In addition, OLR1+ monocytes and macrophages exhibited consistent pro-tumor inflammatory phenotypes. Conclusion:This study identifies an OLR1-associated inflammatory regulatory axis that contributes to impaired response to nICT in lung cancer. Targeting OLR1 may represent a promising strategy to enhance immunotherapy efficacy and improve clinical outcomes in patients with resectable lung cancer. However, the study is limited by a relatively small validation cohort and a strong reliance on bioinformatics analyses, underscoring the need for further translational research and clinical validation to facilitate potential therapeutic application.
Background:Sepsis is a life-threatening syndrome resulting from a dysregulated host response to infection, which substantially increases the risk of progressive organ dysfunction and mortality. This study employs a comprehensive bibliometric analysis to systematically map the global scientific output and evolving research trends pertaining to sepsis and nutritional interventions. Methods:A systematic literature search was conducted in the Web of Science Core Collection (WoSCC) to identify peer-reviewed publications addressing the nexus between nutrition and sepsis. Bibliometric analysis and visualization were subsequently performed through R (version4.4.0) with the R-bibliometrix package (version4.2.3), VOSviewer software (version 1.6.20) and CiteSpace (version 6.4.1). Results:From 2005 to 2025, a total of 2615 English articles on nutrition and sepsis were identified. The Journal of Parenteral and Enteral Nutrition was the most productive journal in this field (138 articles). The United States contributed the largest share of publications (609 articles) and accumulated the highest total citation count (24624 citations). Among individual authors, Greet Van den Berghe was the most prolific contributor. Keyword analysis further identified sepsis, parenteral nutrition and enteral nutrition as the top three most frequently occurring research themes. Conclusion:This study provided a comprehensive overview of the global research landscape on sepsis and nutrition. The research results showed that parenteral and enteral nutrition, as the two core methods of clinical nutritional support, are currently the research focus. These findings might help guide researchers in determining the future directions of sepsis and nutrition research.
Background:The neutrophil percentage-to-albumin ratio (NPAR) is a novel inflammatory marker. However, its prognostic role in acute heart failure (AHF) remains unclear. Methods:This post hoc analysis included 4622 patients with AHF from a nationwide prospective cohort in China. The outcomes were all-cause mortality (ACM), cardiovascular mortality (CVM), major adverse cardiovascular events (MACE), and hospitalization for HF (HHF). Multivariable Cox regression was used to assess the associations between NPAR and outcomes. The predictive performance of the models was evaluated using Harrell's concordance index (C-index), 4-year time-dependent continuous net reclassification improvement (cNRI) and integrated discrimination improvement (IDI). Results:During a median follow-up of 4.61 years, higher NPAR and high-sensitivity C-reactive protein (hs-CRP) showed positive graded associations with mortality. Compared with the lowest NPAR quartile, the hazard ratios (95% CIs) for the second, third, and fourth quartiles were 1.29 (1.12-1.47), 1.38 (1.20-1.58), and 1.74 (1.52-1.99) for ACM, and 1.30 (1.10-1.53), 1.39 (1.18-1.63), and 1.72 (1.46-2.03) for CVM, respectively (all P < 0.001). Similar graded associations were observed for 1-year MACE and HHF. Adding NPAR to the primary multivariable model improved the predictive ability for ACM (C-index from 0.693 to 0.701; cNRI 9.90%; IDI 1.20%) and CVM (C-index from 0.705 to 0.712; cNRI 9.30%; IDI 1.00%) (all P < 0.001). NPAR outperformed hs-CRP for mortality prediction, whereas their combination did not further improve model performance. Conclusion:NPAR was positively associated with risks of ACM, CVM, MACE, and HHF and provided incremental prognostic value for mortality beyond hs-CRP. NPAR may be useful for prognostic risk assessment in AHF and warrants further investigation as a potential alternative to hs-CRP.
Acute kidney injury (AKI) is a heterogeneous syndrome characterized by substantial variation in etiology, clinical course, and recovery. Persistent tubular stress, mitochondrial dysfunction, and dysregulated inflammatory and immune responses can prolong tissue injury and lead to incomplete kidney recovery and maladaptive repair. When released into the cytosol, mitochondrial DNA (mtDNA) can activate cyclic GMP-AMP synthase (cGAS), which generates 2',3'-cGAMP and activates stimulator of interferon genes (STING). Downstream TBK1-IRF3 and NF-κB signaling programs amplify inflammation, regulated cell death, and failed repair. This structured narrative review follows the sequence of mitochondrial injury, mtDNA release, cGAS-STING activation, inflammation and regulated cell death, and maladaptive repair. We examine how these mechanisms vary across AKI etiologies, cell types, and disease stages and critically appraise preclinical evidence for traditional Chinese medicine (TCM) formulas and preparations, bioactive fractions and extracts, isolated natural products, and natural product-based delivery systems. Genetic and pharmacological studies support the involvement of this axis in selected AKI models. However, the mitochondrial origin of cGAS-sensed cytosolic DNA, the requirement for cGAS-STING signaling in observed protective effects, and the relevance of these mechanisms to human AKI remain incompletely established. Most TCM and natural product studies use cisplatin models and initiate treatment before or at the time of injury; they generally report parallel improvements in kidney injury endpoints and reductions in pathway-associated markers. Thus, selected interventions show preclinical renoprotective activity in specific models, but neither clinical efficacy nor in vivo pathway dependence has been demonstrated. Future translational studies should prioritize post-injury administration, causal pathway validation, kidney-compartment exposure, safety assessment, and functional testing in human-relevant systems.
Lytic cell death has long been regarded as an irreversible process culminating in plasma membrane rupture. However, accumulating evidence indicates that the activation of lytic pathways does not invariably result in cell lysis. Instead, cells can undergo sublethal membrane damage, a state in which membrane injury is limited, allowing cells to remain viable while triggering persistent inflammation, barrier dysfunction and other functional alterations. This potentially reversible state may provide a therapeutic window in which limiting membrane rupture or enhancing membrane repair could preserve viable but compromised cells. This review focuses on the three major forms of lytic cell death: pyroptosis, necroptosis, and ferroptosis. We summarize the canonical molecular mechanisms, processes of membrane injury, regulatory pathways, and consequences of sublethal membrane damage. Furthermore, we discuss the shared features and biological impacts of sublethal membrane damage. Given the heterogeneous responses in sepsis, sublethal membrane damage may provide a relevant framework for understanding sepsis pathophysiology. A deeper understanding of this intermediate state may offer novel strategies for sepsis that aim not only to prevent complete cell lysis but also to modulate the function of viable but compromised cells.
Shuo Qiang,1 Yunke Liu,1 Yonghui Dong,1 Cheng Cheng,1 Yifan Huang,1 Jia Zheng,1 Chao Tang,1 Siyu Zhao21Department of Orthopedics, Zhengzhou University People’s Hospital, Zhengzhou, Henan, People’s Republic of China; 2Department of Intensive Care Unit, The First Affiliated Hospital of Jinan University, Jinan, Guangdong, People’s Republic of ChinaCorrespondence: Siyu Zhao, Email zsyguke@163.com Chao Tang, Email 56091352@qq.comBackground: FibroNPC is a degeneration associated subtype in intervertebral disc degeneration (IVDD), yet its markers and immune crosstalk remain poorly characterized. ITGBL1 and RPN1 recur as IVDD associated genes in bulk studies, but where they are expressed within the heterogeneous disc has not been resolved.Methods: Three GEO datasets comprising 81 bulk profiles were integrated and screened by LASSO, SVM-RFE, and Random Forest, with external validation in an independent 15 sample cohort. Two human IVDD scRNA-seq cohorts were analyzed by subclustering, signature scoring, and within scRNA-seq per-subpopulation contribution analysis. CellChat, AUCell pathway scoring, and drug prediction were used as exploratory analyses; IL-1β stimulated HNPCs served as the in vitro model.Results: Machine learning analysis prioritized ITGBL1 and RPN1 as consensus core genes (combined AUC = 0.925), with their differential expression further supported in an independent external cohort. Single cell mapping preferentially localized both genes to a FibroNPC subpopulation and associated this cell state with coupled integrin/focal adhesion and ER protein processing/N-glycosylation programs. Notably, although FibroNPCs comprised less than one-fifth of NP/AF cells, they contributed approximately 48% of total ITGBL1 expression and disproportionate shares of several canonical fibrotic transcripts. CellChat further inferred increased macrophage SPP1–integrin communication involving structural cell populations in IVDD. In IL-1β stimulated HNPCs, both ITGBL1 and RPN1 were increased at the mRNA and protein levels.Conclusion: ITGBL1 and RPN1 represent FibroNPC associated molecular markers linked to coupled integrin signaling and N-glycosylation programs in IVDD. The disproportionate contribution of FibroNPCs to ITGBL1 and fibrotic gene expression highlights the importance of cell state resolved localization beyond conventional bulk hub-gene identification. Further functional validation is required before therapeutic implications can be established.Keywords: IVDD, single-cell RNA sequencing, ITGBL1, RPN1, FibroNPC, pseudotime
Afaf Ennahal, Olaf Wendler, Vanessa Vivien Pesold, Sarina Katrin MuellerDepartment of Otolaryngology, Head and Neck Surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, GermanyCorrespondence: Sarina Katrin Mueller, Department of Otolaryngology, Head and Neck Surgery, Friedrich-Alexander-Universität Erlangen-Nürnberg, Waldstrasse 1, Erlangen, 91054, Germany, Tel +49 913108533156, Fax +49 91318533833, Email sarina.mueller@uk-erlangen.dePurpose: High-level expression of pappalysin-A/insulin-like growth factor binding protein/insulin-like growth factor-1 (PAPP-A/IGFBP-4/5/IGF-1 axis) in Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) was previously demonstrated by our group. PAPP-A plays a key role in inflammatory diseases and cancer. The aim of this study was to localize PAPP-A in Chronic Rhinosinusitis (CRS), within tissue, inflammatory and different primary cells.Patients and Methods: PAPP-A was localized by immunohistochemistry (IHC) in tissues of CRSwNP (n=41), CRSsNP patients (n=12) as well as in controls (n=12). The data of eosinophil abundance in CRSwNP tissues was obtained from routine pathology. ELISA was used to quantify PAPP-A and ECP non-invasively in CRSwNP mucus (n=67). On a cellular level, PAPP-A was localized by immunofluorescence (IF) in immune and primary cells from CRSwNP (n=18).Results: IHC revealed three distribution patterns of PAPP-A in CRSwNP correlated to the eosinophil abundance. Moreover, IF of different immune cells confirmed the high PAPP-A synthesis by eosinophils, in addition to unspecified subpopulation of T-cells and moderately in mast cells. Besides, a vesicular distribution of PAPP-A in the cytoplasm and the membrane of epithelial and fibroblast cells was shown. Finally, ECP and PAPP-A proved a significant correlation in CRSwNP mucus.Conclusion: Our work is the first to illustrate the three distribution patterns of PAPP-A in CRSwNP. This underlines the potential inflammatory role of PAPP-A, particularly in CRSwNP. Targeting the PAPP-A/IGFBP/IGF-1-axis may be a new therapeutic approach for CRSwNP with high eosinophil abundance.Keywords: chronic rhinosinusitis, chronic rhinosinusitis with nasal polyps, inflammation, mucus, PAPP-A
Meiling Huang,1 Meng Yang,2 Tianhong Shen,3 Aoyang Long,2 Mingyang Gao,2 Yuzhe Wang,2 Wenhao Shan,2 Zijian Ye,2 Qiang Wu,2 Gangcai Zhu,2 Xueyang Li,4 Manlin Hu,2 Yuyang Xiao21Department of Otorhinolaryngology, Head and Neck Surgery, Xiangtan Central Hospital (The Affiliated Hospital of Hunan University), Xiangtan, Hunan, People’s Republic of China; 2Department of Otolaryngology, Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 3Department of Cardiology, Xiangtan Central Hospital, Xiangtan, Hunan, People’s Republic of China; 4Department of Orthopedics, The Second Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of ChinaCorrespondence: Yuyang Xiao, Department of Otolaryngology, Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of China, Email 8303211701@csu.edu.cn Manlin Hu, Department of Otolaryngology, Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People’s Republic of China, Email 8303230811@csu.edu.cnAbstract: The nervous and immune systems engage in intricate bidirectional interactions that constitute a central hub in the pathogenesis of cutaneous and intestinal inflammation. As primary barrier organs, the skin and gut share analogous structural and immunological features and are functionally linked through an integrated neuroimmune network and shared inflammatory signaling, forming the "skin-gut axis”. Nevertheless, comprehensive and systematic reviews that simultaneously address neurogenic inflammation in both the cutaneous and intestinal compartments remain scarce, and translational research targeting their reciprocal crosstalk is hampered by insufficient clinical evidence and inadequate target precision. In this narrative review, we focus on the neuroimmune mechanisms underlying neurogenic skin disorders, including atopic dermatitis, psoriasis, and rosacea. Given the strong association between intestinal inflammation and infection, we further summarize neuroimmune interactions in gut infectious inflammation, with particular emphasis on the unique innervation patterns of the intestine. Additionally, we discuss therapeutic strategies that target convergent and clinically relevant neuroimmune circuits shared by skin and gut inflammation. This review aims to provide a theoretical framework for deciphering the neuroimmune pathogenesis and stereotyped interconnections between skin and gut inflammation, and to inspire novel anti-inflammatory approaches that specifically modulate neuroimmune pathways.Keywords: neuroimmune, neurogenic inflammation, skin-gut axis, neuroimmunotherapy
Hui Du,1,2 Qianhua Huang,1,2 Xiaoming Su,1,2 Ping Song,1,2 Shuxian Liang,1,3 Xiaoqiang Li1,41Xiaolan Clinical Institute of Shantou University Medical College, Zhongshan, Guangdong, People’s Republic of China; 2Department of Blood Transfusion, Xiaolan People’s Hospital of Zhongshan(The Fifth People’s Hospital of ZhongShan), Guangdong, People’s Republic of China; 3Department of Laboratory Medicine, Xiaolan People’s Hospital of Zhongshan(The Fifth People’s Hospital of ZhongShan), Guangdong, People’s Republic of China; 4Department of Neurology, Xiaolan People’s Hospital of Zhongshan(The Fifth People’s Hospital of ZhongShan), Guangdong, People’s Republic of ChinaCorrespondence: Xiaoqiang Li, Xiaolan Clinical Institute of Shantou University Medical College; Department of Neurology, Xiaolan People’s Hospital of Zhongshan(The Fifth People’s Hospital of ZhongShan), No. 65, Jucheng Road Xiaolan District, Zhongshan, Guangdong, 528415, People’s Republic of China, Email liboleq@163.comBackground: Stroke-associated pneumonia (SAP) is a common and serious complication in patients with acute ischemic stroke (AIS), leading to prolonged hospitalization and poor prognosis. The neutrophil percentage-to-albumin ratio (NPAR), a novel inflammatory biomarker, has been linked to stroke-associated infections; however, no prior study has characterized the dose-response relationship between NPAR and SAP or explored potential sex-based effect modification.Methods: This retrospective cohort study included 1008 patients with AIS. NPAR was calculated as neutrophil percentage divided by serum albumin level (g/L) at admission. SAP was defined as pneumonia occurring within 7 days of stroke onset. Multivariable logistic regression models were constructed to evaluate the association between NPAR and SAP, with NPAR analyzed both as a continuous variable (per 0.1-unit increase) and as tertiles. Restricted cubic spline (RCS) analysis was performed to assess the dose-response relationship. Subgroup analyses with interaction tests were conducted to explore potential effect modification, including by sex.Results: Among 1008 AIS patients (mean age 62.18 years; 68.25% male), 90 (8.93%) developed SAP. After full adjustment, each 0.1-unit increase in NPAR was independently associated with SAP (OR = 1.22; 95% CI: 1.13– 1.32; P < 0.001), with a linear dose-response relationship (P for nonlinearity = 0.80). Patients in the highest NPAR tertile had approximately 5-fold higher odds of SAP compared with the lowest tertile (OR = 5.18; P < 0.001). A significant sex-based interaction was identified (P = 0.01): the association was prominent in males (OR = 1.38; P < 0.001) but non-significant in females (OR = 1.11; P = 0.09). Sex-stratified ROC analysis further confirmed this difference, with a significantly higher AUC in males (0.77) than in females (0.58; DeLong P < 0.05).Conclusion: Higher NPAR is independently and linearly associated with an increased risk of SAP in AIS patients, with a significant dose-response relationship. This association is significantly stronger in males than in females. NPAR may serve as a readily accessible and cost-effective candidate biomarker for early risk stratification of SAP, particularly in male AIS patients, pending external validation in prospective, multi-center studies.Keywords: neutrophil percentage-to-albumin ratio, stroke-associated pneumonia, acute ischemic stroke, sex difference, inflammatory biomarker
Xiayan Qian,1,* Huan Ma,1,* Yanping Zhu,1,* Shuhe Li,2 Saiya Ma,1 Ruoxu Dou,1 Zhaoxia Tang,1 Xiangdong Guan,1 Ka Yin Lui,1 Changjie Cai11Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China; 2Department of Clinical Science, University of Exeter Medical School, Exeter, Devon, UK*These authors contributed equally to this workCorrespondence: Changjie Cai; Ka Yin Lui, Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Zhongshan 2nd Road, Yuexiu District, Guangzhou, Guangdong, 510080, People’s Republic of China, Email caichjie@mail.sysu.edu.cn; lvjiax@mail2.sysu.edu.cnBackground: Identifying the phenotypes of patients with surgical sepsis is crucial for improving their management. This study aims to identify the clinical subtypes of critically ill surgical sepsis patients and develop parsimonious classifier model for rapid subtype identification.Methods: A retrospective cohort study was conducted on 4,027 adult surgical sepsis patients admitted to the Surgical Intensive Care Unit at the First Affiliated Hospital of Sun Yat-sen University from 2018 to 2023, with external validation using the MIMIC-IV (the Medical Information Mart for Intensive Care) database. We extracted the worst values of clinical variables within 24 hours before and after diagnosis and performed K-means clustering. The elbow method and the silhouette coefficient was used to determine the optimal number of clusters. Survival analysis was used to evaluate the prognostic differences among different subtypes. A multivariate logistic regression model was constructed to identify the subtypes, and the model was evaluated by the area under the receiver operating characteristic curve (AUROC), decision curve analysis (DCA), calibration curve and SHAP (Shapley Additive Explanations).Results: Three subtypes were finally determined. Subtype-1 (13%) exhibited severe organ dysfunction and the highest 1-year mortality (73.3%), subtype-2 (59%) had mild organ dysfunction and the lowest 1-year mortality (26.4%), while subtype-3 (28%) was characterized by older age and prevalent comorbidities. External validation confirmed similar subtype distributions and clinical profiles in the MIMIC-IV cohort. A four-variable logistic regression model (including prothrombin time (PT), dosage of norepinephrine, lactate and pH) was developed to predict the high-risk subtype-1. The model demonstrated satisfactory discriminative ability in the derivation cohort (AUC: 0.970) and robust performance in external validation (AUC: 0.889). SHAP analysis highlighted PT, lactate, and dosage of norepinephrine as core predictors of subtype-1.Conclusion: This study identified three clinical subtypes of critically ill patients with surgical sepsis based on early clinical variables. A multivariate logistic regression model was developed to identify the high-risk subtype-1, with core impact factors including PT, dosage of norepinephrine and lactate.Keywords: surgical sepsis, subtypes, K-means clustering, parsimonious classifier model
Objective:This study investigated whether the postoperative advanced lung cancer inflammation index (ALI) has prognostic significance in patients with prostate cancer who underwent radical prostatectomy. It also explored the potential role of ALI as a biomarker for assessing postoperative recurrence risk. Patients and Methods:This retrospective, single-center study included 425 patients with localized or selected locally advanced prostate cancer who underwent radical prostatectomy at the First Affiliated Hospital of Chengdu Medical College. Postoperative ALI was calculated using clinical and laboratory data obtained at the first follow-up visit, approximately three months after surgery. Patients were categorized into low- and high-ALI groups according to the optimal ALI cut-off value. Associations between postoperative ALI and overall survival and biochemical recurrence-free survival were evaluated using Kaplan-Meier analysis, Cox proportional hazards regression, and propensity score matching. The median follow-up duration was 56 months, 38 patients dead, and 156 patients had biochemical recurrences at the end of follow-up. Results:A low postoperative ALI was significantly associated with a lower body mass index (p = 0.001), higher Gleason scores (p = 0.0036), elevated preoperative prostate-specific antigen levels (p < 0.0001), more advanced pathological T stage (p < 0.0001), and a greater frequency of lymph-node metastasis (p = 0.002). Kaplan-Meier survival curves demonstrated that patients in the low-ALI group experienced worse survival outcomes, including reduced overall survival (HR = 3.32; 95% CI, 2.41-5.87; p = 0.012) and shorter biochemical recurrence-free survival (HR = 2.57; 95% CI, 1.58-3.65; p = 0.002), compared with those in the high-ALI group. In multivariable Cox regression models, ALI remained an independent predictor of both overall survival (p < 0.0001) and biochemical recurrence-free survival (p < 0.0001) after adjustment of confounding factors. Conclusion:Among patients with prostate cancer undergoing radical prostatectomy, a low postoperative ALI was associated with shorter overall survival and biochemical recurrence-free survival compared with a high postoperative ALI. These findings suggest that postoperative ALI may provide prognostic information in patients undergoing radical prostatectomy; however, its clinical utility requires confirmation through prospective, multicenter studies and external validation.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovitis and progressive structural joint damage. Its pathology involves immune-cell infiltration, pannus formation, cartilage degradation, and bone destruction. Although autoantibodies, inflammatory cytokines, and aberrant immune activation are central to RA pathogenesis, they do not fully explain the persistence of synovitis, defective inflammation resolution, or structural joint damage in some patients. Emerging evidence indicates that fatty acid metabolic reprogramming may actively shape RA-related cellular dysfunction by linking lipid substrate availability, membrane remodeling, mitochondrial metabolism, oxidative stress, and lipid mediator generation. This review organizes current evidence within a cell-specific immune-synovial-bone destruction framework. In immune cells, alterations in fatty acid uptake and transport, de novo lipogenesis, fatty acid oxidation, and lipid mediator generation influence monocyte/macrophage-driven inflammatory amplification, T-cell effector responses and regulatory imbalance, and potential B-cell contributions to autoimmunity. In RA fibroblast-like synoviocytes, reprogrammed fatty acid metabolism supports proliferation, migration, invasion, inflammatory mediator production, and matrix degradation, thereby promoting synovial aggression. In osteoclast-lineage cells, fatty acid oxidation and related metabolic adaptations facilitate precursor fusion and bone resorption. In addition, an imbalance between arachidonic acid-derived pro-inflammatory mediators and eicosapentaenoic acid- and docosahexaenoic acid-derived specialized pro-resolving mediators may contribute to persistent inflammation and defective resolution. By integrating inflammatory amplification, defective resolution, synovial aggression, and bone destruction, this review highlights fatty acid metabolism as a context- and cell-dependent regulator of RA progression. Potential therapeutic approaches include limiting excessive fatty acid uptake and de novo lipogenesis, selectively modulating fatty acid oxidation, restoring pro-resolving lipid mediator balance, targeting relevant lipid-sensing receptors, and modulating microbiota-derived fatty acid metabolites. These strategies may complement existing anti-inflammatory and immunomodulatory therapies, although successful translation will require cell-selective targeting, disease-stage stratification, biomarker-guided patient selection, and careful safety evaluation.
Background:Early identification of pediatric sepsis patients at high risk of in-hospital mortality is crucial. However, the clinical utility of existing machine learning (ML) models is limited by temporal data leakage and a lack of robust external validation. Objective:To develop, interpret, and externally validate an interpretable ML model for predicting in-hospital mortality in pediatric sepsis, utilizing only predictors available within the first 24 hours of ICU admission. Methods:Based on a retrospective development cohort from the Children's Hospital of Chongqing Medical University, eight ML algorithms were evaluated. Predictor variables were strictly limited to the first 24 ICU hours to prevent temporal bias. The best-performing model was interpreted via SHAP, calibrated with spline-based regression, and externally validated on the Pediatric Intensive Care (PIC) database (pediatric cohort) and the MIMIC-IV database (adult cohort, to test biological generalizability). A web-based calculator was developed. Results:XGBoost achieved the best performance (AUC: 0.821, 95% CI: 0.751-0.892). In external validation, the model demonstrated strong generalizability, yielding AUCs of 0.735 (95% CI: 0.700-0.770) in the pediatric PIC cohort and 0.778 (95% CI: 0.763-0.793) in the adult MIMIC-IV cohort. The calibrated model showed excellent agreement (pediatric Brier score: 0.060, calibration slope: 1.000, intercept: 0.000). Decision curve analysis confirmed clinical net benefit between 3% and 27% thresholds. SHAP analysis identified pH, fibrinogen, lactate, platelet count, urea, and chloride as the key predictors. Conclusion:We developed a validated, interpretable XGBoost model for early risk stratification of pediatric sepsis. By restricting predictors to the initial 24 hours, the model avoids temporal bias while maintaining stable performance across pediatric and adult cohorts. This web-based tool is ready to support clinical bedside decision-making.
Background:Ventricular septal rupture (VSR) is a life-threatening complication of acute myocardial infarction (AMI). The C-reactive protein-triglyceride glucose index (CTI) integrates insulin resistance (IR) and inflammation. The present study was designed to investigate the correlation between CTI and 1-year all-cause mortality in VSR patients after AMI. Methods:284 VSR patients were consecutively enrolled at Fuwai Central China Cardiovascular Hospital between January 2018 and April 2025. According to the median CTI value (6.408), the 284 VSR patients were divided into two groups. The relationship between CTI and clinical outcomes was evaluated using multivariate logistic regression analysis, followed by mediation analysis to explore indirect statistical associations. Results:1-year all-cause mortality in VSR patients was 71.8% (204/284). The mortality of the high CTI group was significantly higher than that of the low CTI group (87.3% vs 56.3%, P < 0.001). Multivariate logistic regression analysis revealed that CTI was associated with mortality (OR = 2.89, 95% CI: 1.85-4.51, P < 0.001), with mortality showing an upward trend as CTI levels increased (P < 0.001). Mediation analyses identified indirect statistical associations involving neutrophil count and NT-proBNP, with mediation proportions of 65.8% and 35.3%, respectively (both P < 0.05). Conclusion:CTI is associated with mortality but not independently, with indirect statistical associations involving inflammation and increased cardiac load.
Purpose:Identifying biomarkers associated with intracranial aneurysm (IA) rupture status is critical for clinical management. This study investigated the association between serum albumin-to-globulin ratio (AGR) and IA rupture status. Methods:We conducted a case-control study including 545 patients with unruptured intracranial aneurysms (uIAs) and 404 patients with ruptured intracranial aneurysms (rIAs). Propensity score matching (PSM) was further performed based on five key variables: age, sex, hypertension status, aneurysm location, and size, yielding 235 pairs. Associations between serum AGR and IA rupture status were evaluated using both unconditional and conditional multivariate logistic regression models. We assessed the incremental model performance of AGR beyond conventional clinical variables for aneurysm rupture status using net reclassification improvement, integrated discrimination improvement, likelihood ratio test, and calibration test. Results:After adjustment for confounding factors, patients in the highest AGR quartile had 52% lower odds of presenting with a ruptured intracranial aneurysm than those in the lowest quartile (OR: 0.48, 95% CI: 0.28-0.80; P for trend = 0.01). In the propensity score-matched pairs, the highest AGR tertile was independently associated with lower odds of presenting with a ruptured intracranial aneurysm than the lowest tertile (OR: 0.42, 95% CI: 0.21-0.81; P for trend = 0.01). Furthermore, the addition of AGR improved model fit, calibration, and reclassification in both the unmatched and matched analyses. Conclusion:Serum AGR was associated with rupture status in patients with intracranial aneurysms. Prospective studies are warranted to further clarify the temporal relationship of this association and to explore potential underlying mechanisms.
Yuhang Huang,1– 3,* Xiancheng Hei,4,5,* Xiang Fu,4,* Linxi Ma,1– 3 Yiling Chen,2,3 Yi Zhang,4 Yunchao Wang,6 Ruirui Duan,2,3 Xinhua Wang,4 Ting Yang1– 31China-Japan Friendship Hospital (Institute of Clinical Medical Sciences), Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 3National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 4School of Public Health, Gansu University of Traditional Chinese Medicine, Lanzhou, Gansu, People’s Republic of China; 5Department of Respiratory and Critical Care Medicine, The First People’s Hospital of Baiyin, Baiyin, Gansu, People’s Republic of China; 6School of Basic Medical Sciences, Gansu University of Traditional Chinese Medicine, Lanzhou, Gansu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ting Yang; Xinhua Wang, Email zryyyangting@163.com; wxh@gszy.edu.cnObjective: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. However, the effects of chronic hypobaric hypoxia on COPD in high-altitude areas remain controversial. This study aimed to evaluate the impact of chronic hypobaric hypoxia on COPD in high-altitude areas.Methods: C57BL/6J mice were randomized into the sham control (MOCK; intranasal PBS), cigarette smoke extract/lipopolysaccharide (CSE/LPS, CL; intranasal CSE five times/week and LPS twice/week), chronic hypobaric hypoxia (Hy; hypobaric hypoxia at simulated 4000 meters with intranasal PBS), and chronic hypobaric hypoxia plus CL (HyCL; CSE/LPS plus chronic hypobaric hypoxia) groups for 12 weeks. After 12 weeks, pulmonary function, bronchoalveolar lavage fluid cell counts, and pulmonary histopathology were assessed. To elucidate the effects of chronic hypobaric hypoxia on COPD, we performed RNA sequencing on lung tissues to profile molecular alterations and validated key targets using qPCR and Western blotting.Results: The results indicate that chronic hypobaric hypoxia promotes COPD progression, characterized by exacerbated pulmonary function decline, emphysema, as well as small airway remodeling. Transcriptome analysis reveals that "chemical carcinogenesis–reactive oxygen species” and "extracellular matrix–receptor interactions” are common transcriptomic characteristics of COPD both with and without chronic hypobaric hypoxia exposure, whereas inflammatory and immune responses are major transcriptomic signatures driven by chronic hypobaric hypoxia. Furthermore, our results identify Cstdc4 as a key differentially expressed gene (DEG) implicated in COPD progression under chronic hypobaric hypoxia.Conclusion: These results indicate that chronic hypobaric hypoxia in high-altitude areas promotes COPD progression and correlates with a transcriptomic signature marked predominantly by the activation of inflammatory and immune responses.Keywords: chronic obstructive pulmonary disease, chronic hypobaric hypoxia, inflammatory response, immune response, Cstdc4
Xinyi Xiao,1 Gege Cao,1 Shuai Hou,1,2 Haiyan Yin11School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People’s Republic of China; 2Department of Rehabilitation, Xianning Central Hospital, Xianning, 437000, People’s Republic of ChinaCorrespondence: Haiyan Yin, School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, No. 1166 Liutai Avenue, Wenjiang District, Chengdu, Sichuan, 611137, People’s Republic of China, Email yinhaiyan@cdutcm.edu.cnAbstract: Rare diseases (RDs) are individually uncommon but collectively affect a large global population, and the vast majority still lack effective disease-modifying therapies. With advances in genomics and data-sharing platforms, research has increasingly shifted from a single-disease perspective to the search for convergent molecular pathways that might be shared across clinically distinct entities. In this context, the purinergic P2X7 receptor (P2X7R) has emerged as a putative "shared molecular platform” due to its central role in inflammation amplification, cell death and immune regulation. P2X7R is an ATP-gated ion channel with unique structural and functional features: under high extracellular ATP, it not only forms a non-selective cation channel but can also dilate into a "large pore” permeable to macromolecules, thereby triggering Ca2+overload, NLRP3 inflammasome assembly, reactive oxygen species (ROS) production and apoptotic/necrotic-like cell death. This review briefly outlines the epidemiology of RDs and the structural–functional characteristics of P2X7R, then systematically summarizes current evidence linking P2X7R to multiple rare diseases, including Charcot–Marie–Tooth disease, Guillain–Barré syndrome, amyotrophic lateral sclerosis, Huntington’s disease, multiple sclerosis, and selected inflammatory and metabolic RDs (CAPS, familial Mediterranean fever, Systemic sclerosis, Dravet syndrome and Gaucher disease). By comparing P2X7R expression and functional alterations, downstream signaling pathways and pharmacological data from animal models across these conditions, we propose that a P2X7R-dependent network centered on a "Ca2+–NLRP3–inflammation/cell death axis” may constitute a common pathogenic backbone for diverse RDs. At the same time, disease-specific spatiotemporal expression patterns of P2X7R in central vs peripheral nervous systems and in immune vs target organ cells confer marked context dependence and "double-edged sword” properties. Finally, we discuss opportunities and challenges for P2X7R-targeted strategies, including the impact of disease stage and sex differences on therapeutic efficacy, and key bottlenecks in translating preclinical findings into clinical benefit. A deeper understanding of both shared and disease-specific roles of P2X7R may provide a conceptual framework and therapeutic entry point for precision stratification and multi-target interventions in rare diseases.Keywords: P2X7 receptor, purinergic signaling, rare diseases, inflammasome, neuroinflammation, precision medicine
Background:Anti-tumour necrosis factor (anti-TNF) agents, particularly infliximab and adalimumab, represent first-line biologic therapy for moderate-to-severe paediatric inflammatory bowel disease (IBD). However, approximately one-third of patients experience treatment failure over time, predominantly due to secondary loss of response (LOR), while primary non-response (PNR) occurs in approximately 8% of cases. Strategies for switching and structured treatment optimization are required to address these issues. Aim:To provide an organized, evidence-based clinical guide on biologic switching strategies in paediatric IBD, including intra-class and inter-class approaches, and to propose an author-derived, evidence-informed clinical framework for practical decision-making. Methods:A narrative review was conducted using PubMed/MEDLINE, Embase, and the Cochrane Library to identify relevant studies on biologic switching strategies in paediatric IBD. Data from randomised controlled trials, cohort studies, registry analyses, systematic reviews, and international guidelines published between 2007 and 2026 were included. A total of 119 references, comprising approximately 60% paediatric studies and 40% supportive adult studies, were synthesised qualitatively, focusing on efficacy, safety, therapeutic drug monitoring (TDM), and treatment sequencing. Results:Intra-class switching between anti-TNF agents achieves remission in approximately 43% of patients overall, with higher success rates in intolerance (61%) and secondary LOR (45%) than in PNR (30%). TDM is central to guiding switching decisions: pharmacokinetic failure-characterised by low drug levels with or without anti-drug antibodies-may benefit from dose optimization or within-class switching, whereas pharmacodynamic failure generally requires transition to a different therapeutic class. Among second-line therapies, vedolizumab and ustekinumab show disease-specific differences; available evidence suggests that vedolizumab may be more effective in ulcerative colitis (UC), while current data indicate that ustekinumab may be more effective in Crohn's disease (CD), particularly after anti-TNF exposure. JAK inhibitors, notably upadacitinib, and S1P receptor modulators show promising results, although paediatric data remain limited. An author-derived, evidence-informed stepwise clinical framework integrating objective disease assessment, TDM-guided failure classification, and phenotype-driven therapy selection is proposed. Conclusion:Biologic switching in paediatric IBD requires a mechanism-based, individualised approach integrating TDM, disease phenotype, and prior treatment exposure. Early optimisation and appropriate sequencing are critical to improve long-term outcomes. The proposed clinical framework is intended to support, rather than replace, individualized clinical judgment.
Kai Lu,1,2,* Yi-Ming Zhao,1,2,* Kui-Yuan Chai,1,2 Yi Lyu,1,2 Xu-Feng Zhang1,21Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2National-Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xu-Feng Zhang, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Road, Xi’an, People’s Republic of China, Tel +86-29-85323626, Email xfzhang125@xjtu.edu.cnBackground: Liver transplantation is the standard treatment for end-stage liver disease, but donor organ shortage has increased the use of marginal donor livers (eg, steatotic grafts). These livers are highly sensitive to liver ischemia/reperfusion injury (LIRI), worsening transplant outcomes, with unclear molecular mechanisms limiting targeted therapies.Methods: We adopted an integrative bioinformatics approach combining transcriptomic analysis of public datasets (GSE151648, GSE135251, GSE15480, GSE23649 and GSE193764), machine learning (LASSO, SVM-RFE), and scRNA-Seq analysis (GSE171539, CRA004061) to identify hub genes and pathways. Key findings were validated in vitro (AML12 hepatocytes under hypoxia/reoxygenation) and in vivo (murine model of steatotic liver under I/R).Results: Weighted gene co-expression network analysis (WGCNA) identified LIRI-, NAFLD-, and NASH-associated modules enriched in immune/inflammatory pathways. Machine learning pinpointed distinct hub genes for NAFLD-related LIRI (JUN, CCL2) and NASH-related LIRI (PHLDA1, PNRC1, GADD45B, NFKBIA, JUND; all AUC > 0.7). CCL2 emerged as the top predictor via SHAP analysis. scRNA-seq revealed cell-type-specific expression patterns and distinct immune infiltration signatures between NAFLD and NASH cohorts, with remodeled cell-cell communication via CCL/CXCL pathways. In vitro/in vivo models confirmed the upregulation of key genes under LIRI, and CCR2 inhibition significantly attenuated liver injury, pathological damage, and pro-inflammatory cytokine (IL-1β, TNF-α, IL-6) expression.Conclusion: Our study identifies distinct molecular signatures and hub genes for LIRI in NAFLD versus NASH allografts, revealing differential immune landscapes between these two conditions. The findings further support the CCL2-CCR2 axis as a therapeutically targetable pathway driving LIRI in steatotic livers and provide potential biomarkers to improve marginal liver transplantation outcomes.Keywords: hub gene, molecular biomarkers, ischemia-reperfusion injury, liver transplantation, non-alcoholic fatty liver disease
