Military Medical Research最新文献

Sepsis is a dysregulated host response to infection that frequently results in fatal multiple organ dysfunction. Despite advances in clinical identification and management, both its incidence and mortality have remained persistently high. Emerging evidence indicates that cell-free DNA (cfDNA), as a novel biomarker and molecular therapeutic target, holds promise for improving the clinical management of sepsis. cfDNA refers to DNA fragments present in body fluids, including naked DNA, membrane-coated DNA, nucleosomes, and neutrophil extracellular traps (NETs). cfDNA is released from host cells or pathogens into body fluids through pathways, such as NETosis, mitochondrial damage, cell necrosis, apoptosis, pyroptosis, and erythroblast enucleation. The released cfDNA triggers a strong inflammatory response by activating Toll-like receptor (TLR) 9, the absent in melanoma 2 (AIM2) inflammasome, and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. At the same time, cfDNA activates the coagulation cascade and inhibits anticoagulant and fibrinolytic systems through multiple mechanisms, resulting in microcirculatory disorders. These pathological effects are closely associated with sepsis-related organ dysfunction and poor prognosis. Elucidation of the release and pathological mechanisms of cfDNA provides a foundation for the development of targeted treatment strategies. Currently, molecular therapeutic approaches targeting cfDNA, including peptidylarginine deiminase (PAD) 4 inhibitors, pore-forming inhibitors, antioxidants, cfDNA scavengers, and deoxyribonucleases (DNases), have shown certain efficacy in treating sepsis and systemic inflammation. In terms of sepsis monitoring, compared with traditional markers, cfDNA exhibits extremely high timeliness and dynamic monitoring capability. cfDNA can simultaneously indicate the complex interplay among infection, host response, and organ damage, making it suitable for early diagnosis, prognosis assessment, treatment monitoring, organ function evaluation, and pathogen detection. Given its broad application prospects in the diagnosis and treatment of sepsis, this paper systematically elaborates on the mechanisms of cfDNA release and pathological effects in sepsis, reviews progress in cfDNA-targeted monitoring and therapeutic strategies, discusses technical challenges, and outlines potential future directions.

Background: Peritoneal fibrosis represents a major clinical challenge for end-stage renal disease (ESRD) patients when they are undergoing peritoneal dialysis (PD). Single-cell RNA sequencing identified that peritoneal mesothelial cells undergo a senescence fate transition in long-term PD patients. Whereas the existence of mesothelial cell senescence and the underlying mechanisms should be thoroughly explored.

Methods: To further investigate mesothelial cell senescence, we utilized a clinical cohort comprising dialysate effluents from PD patients and peritoneal biopsy specimens, peritoneal dialysis fluid (PDF)-induced mouse models, and cultured primary mesothelial cells. Single-cell RNA sequencing, transcriptome sequencing, immunofluorescence, Western blotting, and other analyses were administered. To validate the critical role of β-catenin in mesothelial cell senescence, β-catenin knockout mice were employed. Additionally, the senolytic drugs dasatinib plus quercetin were administered to PDF mice to assess the key role of mesothelial cell senescence in peritoneal fibrosis.

Results: Single-cell RNA sequencing demonstrated that mesothelial cells derived from long-term PD patients are major trend to senescence fate. Moreover, β-catenin signaling was significantly upregulated, as well as transforming growth factor-β (TGF-β) pathways. We observed that senescent mesothelial cells were highly increased in both dialysate effluent and peritoneal biopsies of long-term PD patients. In dialysate effluent, matrix metalloproteinase-7 (MMP-7), an indicator of downstream targets of β-catenin, was positively correlated with TGF-β1. Both biomarkers were also positively associated with PD duration. Mechanistically, we found that β-catenin promotes dynamin-related protein 1 (Drp1) expression, a key mediator of mitochondrial fission, thereby inducing mesothelial cell senescence. Then, TGF-β1 was secreted to activate the Smad signaling pathway in fibroblasts, leading to myofibroblast activation and subsequent peritoneal fibrosis. Notably, administration of senolytic drugs, dasatinib plus quercetin, significantly alleviated peritoneal fibrosis regardless of treatment timing.

Conclusion: Targeting β-catenin signaling and mesothelial cell senescence may represent potential therapeutic interventions for preventing peritoneal fibrosis.

Background: Targeted alpha therapy (TAT) has emerged as a promising strategy for cancer treatment by selectively delivering high linear energy transfer (LET) alpha-emitters to tumor cells while minimizing off-target toxicity. However, the clinical translation of alpha-emitters, particularly radium-223 (²²³Ra), remains challenging due to inefficient targeted delivery and uncontrolled release of recoil daughter products, leading to systemic toxicity.

Methods: Herein, a dual-locked pretargeted strategy was developed integrating platinum^IV (Pt^IV)-loaded hydrogel nanoparticles (HNPs) (HAQ@HNPs) and ²²³Ra-loaded HNPs (²²³Ra@HNPs) into an inverse electron demand Diels-Alder (IEDDA)-activated drug delivery system. In vitro cytotoxicity, ROS, and apoptosis, together with in vivo biodistribution, imaging, and therapeutic studies, were performed to evaluate the therapeutic efficacy and immune activation.

Results: This caged dual-locked approach enables precise pretargeted accumulation at the tumor site, followed by rapid dissociation and controlled release of ²²³Ra and Pt^IV upon IEDDA-triggered activation, thereby ensuring high tumor specificity while minimizing systemic exposure. The synergistic combination of TAT and chemotherapy effectively disrupts redox homeostasis, induces immunogenic cell death (ICD), and elicits a robust antitumor immune response. Furthermore, when combined with programmed death-ligand 1 (PD-L1) blockade, this strategy significantly enhances systemic antitumor immunity, leading to robust inhibition of tumor growth and metastasis.

Conclusions: These findings underscore the potential of dual-locked pretargeted strategies to advance TAT by improving therapeutic efficacy and addressing the critical challenge of radionuclide leakage, paving the way for next-generation precision-targeted radiopharmaceuticals.

Background: Risk-adapted colorectal cancer (CRC) screening has the potential to balance effectiveness with resource demands, yet evidence comparing it with established methods remains limited. This study aims to compare outcomes of risk-adapted CRC screening with colonoscopy and fecal immunochemical test (FIT) strategies.

Methods: We adopted a hybrid methodology combining real-world data from a population-based CRC screening randomized controlled trial (TARGET-C) with projections from a validated Markov-based microsimulation model (MIMIC-CRC). The TARGET-C trial enrolled 19,582 participants aged 50-74 years from 6 centers in China, randomized in a 1:2:2 ratio into 3 groups. After applying the exclusion criteria, the final analysis included 3883 participants in the one-time colonoscopy group, 7793 in the annual FIT group, and 7697 in the risk-adapted screening group. In the latter group, screening allocation was determined by a composite risk score incorporating age, sex, family history of CRC, smoking status, and body mass index, with high-risk participants referred for colonoscopy and low-risk participants for FIT. The primary outcome was detection rates of advanced neoplasm (CRC and advanced adenoma) over 4 rounds. Secondary outcomes included screening participation, colonoscopy demand, and costs from a societal perspective. Long-term effectiveness and cost-effectiveness were modeled over 15 years using MIMIC-CRC.

Results: Across 4 rounds, overall participation rates (attending at least one screening round) were 42.3% (colonoscopy), 99.8% (FIT), and 92.5% (risk-adapted). Detection rates of advanced neoplasms were 2.8%, 2.3%, and 2.6%, respectively, with no significant differences (P > 0.05). Colonoscopies needed to detect 1 advanced neoplasm were 15.4, 7.9, and 9.3, respectively. From a societal perspective, the cost for detecting 1 advanced neoplasm was 15,341, 21,754, and 24,300 Chinese Yuan, respectively. Over 15 years, risk-adapted screening reduced incidence by 16.7% and mortality by 21.5% compared with no screening, slightly less effective than colonoscopy (24.6% and 24.8%, respectively). Under observed real-world adherence, colonoscopy was the most cost-effective; under perfect full adherence, risk-adapted screening was the most cost-effective.

Conclusions: In this population-based CRC screening trial, risk-adapted screening, colonoscopy, and FIT demonstrated comparable effectiveness, but differed in participation rates, resource utilization, and cost-effectiveness. Risk-adapted screening could serve as a complementary approach to established strategies, particularly when health resources are limited.

Trial registration: Chinese Clinical Trial Registry (ChiCTR1800015506).

Ferroptosis, a form of iron-dependent regulated cell death (RCD), is emerging as a critical mechanism in the pathogenesis and progression of sepsis. This review highlights the intricate molecular pathways and hallmark features of ferroptosis, including lipid peroxidation, dysregulation of iron metabolism, and glutathione depletion, which exacerbate sepsis progression and sepsis-associated multi-organ damage. The systemic interactions of ferroptosis with inflammation, innate, and adaptive immunity, and organ injury are elucidated, emphasizing the role ferroptosis plays both in immunity including sepsis-associated immune cell damage/dysfunction, immune dysregulation, and immunosuppression, and in sepsis-associated multi-organ injury such as acute lung injury (ALI), acute kidney injury (AKI), acute hepatic injury (AHI), acute intestinal injury, septic cardiomyopathy, and septic encephalopathy. Therapeutic strategies targeting ferroptosis hold promise for improving sepsis outcomes. Approaches include pharmacological interventions of ferroptosis-associated pathways, nanoparticle-based delivery systems, and combinatorial therapies aimed at preventing immune dysfunction and protecting against multi-organ failure. Nonetheless, challenges remain in translating preclinical findings into clinical application, necessitating further research into ferroptosis-specific regulatory networks. This review underscores the potential of therapeutics targeting ferroptosis as a transformative approach to addressing sepsis, paving the way for innovative and precision-based clinical interventions.

Background: Tenascin-C (TNC) is an extracellular matrix (ECM) protein involved in tissue damage and fibrosis. Chimeric antigen receptor (CAR) cell therapy is a novel therapeutic approach that has attracted increasing attention in recent years. Here, we engineered CAR-macrophages targeting TNC (TNC-CAR-Ms) and explored the underlying mechanism through which TNC-CAR-Ms treat liver fibrosis.

Methods: The role of TNC in liver fibrosis was studied in established Tnc knockout (KO) and littermate control mice. A TNC-targeted single-chain variable fragment (scFv) was designed to generate TNC-CAR-Ms and evaluate their biological function. The phagocytosis and killing effects of TNC-CAR-Ms were tested in vitro, while the antifibrotic efficacy and safety of TNC-CAR-Ms were evaluated in vivo. The underlying mechanism through which TNC-CAR-Ms treat liver fibrosis was investigated by Western blotting, flow cytometry, and RNA sequencing.

Results: TNC expression was significantly upregulated in the liver and activated hepatic stellate cells (HSCs) in carbon tetrachloride (CCl₄)-treated mice. Animal studies showed that Tnc KO protects mice from CCl₄-induced liver damage and fibrosis. Upon demonstrating their ability to engulf and kill activated HSCs, we intravenously administered TNC-CAR-Ms to fibrotic mice and found that TNC-CAR-Ms significantly reduced liver fibrosis. Mechanistically, TNC-CAR-Ms specifically migrated to liver tissues, potently reduced TNC expression, and decreased the activity of the Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) and integrin/focal adhesion kinase (FAK) signaling pathway. In addition, TNC-CAR-Ms significantly modified the hepatic immune microenvironment, characterized mainly by an increase in the numbers of M2-polarized macrophages and CD8⁺ T cells in the liver. Finally, in CCl₄-treated mice, the depletion of CD8⁺ T cells with an anti-CD8α antibody significantly impaired the antifibrotic effect of TNC-CAR-Ms.

Conclusions: Our proof-of-concept study demonstrates the therapeutic potential of TNC-CAR-Ms in alleviating liver fibrosis and may inform the development of future therapeutic strategies for the treatment of a range of liver diseases with a fibrotic phenotype.

Systemic complications are common after acute brain injury (ABI) and may trigger coagulation cascades, systemic inflammation, as well as dysfunction of the cardiovascular, respiratory, and gastrointestinal systems, etc. The pathogenesis of these systemic manifestations is multifactorial but not yet fully elucidated. This paper introduces the novel term neurogenic organ dysfunction syndrome (NODS) to characterize systemic instability arising from internal and external perturbations of the neuronal center following ABI. Elucidating the central neurogenic mechanisms of NODS is critical for early detection and prevention of complications, thereby reducing mortality and improving patient outcomes following ABI. In this paper, we explore the potential central neurogenic mechanisms of NODS from the perspective of complex brain network theory, focusing on the structural network of the central autonomic system (CAS) that maintains systemic stability, and the functional network governed by the central stress system (CSS). The CAS can be divided into the cortical autonomic network, which involves higher cortical regions, and the subcortical autonomic network, which is relatively conserved, with its main connections located in deep brain structures. The CSS is a large-scale complex network characterized by hierarchy, hubs, and modularity, which together enable the competitive optimization of functional segregation and integration. Under physiological conditions, modules (mediating functional segregation) and hubs (functional integration) within the CSS dynamically trade-off with each other to maintain the overall homeostasis. However, this balance is disrupted following pathological insults or injury, resulting in weakened functional integrity of the CSS following ABI, impaired module activity, and disturbed hub integration. This paper also demonstrates the distinct pathological manifestations arising from disturbances at different levels of the homeostatic system. Finally, this study proposes potential clinical interventions, including analgesia and sedation, neuromodulation, and receptor regulation, for early interventions and potential treatment of NODS, aiming to improve patient outcomes.