ABSTRACT Lymph nodes (LNs) are central hubs of adaptive immunity and key relay sites for metastatic tumour cells. However, conventional two‐dimensional histology samples only a small fraction of each node, potentially missing micrometastases and multifocal involvement while obscuring long‐range spatial relationships among tumour deposits, immune populations, stromal structures, vasculature and nerves. Tissue clearing combined with light‐sheet fluorescence microscopy now enables whole‐mount imaging of intact LNs at near‐cellular resolution. Unlike general reviews of tissue clearing or three‐dimensional pathology, this review specifically considers the LN as a spatially organised neuro–immune–tumour organ. The major clearing‐method families and LN‐specific design considerations are summarised, including reagent penetration, fluorescence and epitope preservation, refractive‐index matching, labelling strategies and imaging optics. Quantitative workflows are then outlined for segmenting metastatic deposits and stromal compartments, skeletonising vascular and neural networks, and deriving volumetric and distance‐based metrics. These approaches enable assessment of metastatic burden, multifocality, compartmental localisation, and spatial relationships between tumours and the capsule, blood vessels, lymphatic sinuses, nerves and immune niches. On this basis, the neuro–tumour–immune niche is proposed as a conceptual framework for investigating how neural inputs, tumour cells, immune populations and stromal architecture are spatially coordinated during LN remodelling and metastatic progression. Finally, current research applications, technical limitations and future potential of cleared‐LN imaging are discussed as a complementary approach to conventional histopathology in experimental studies and, after prospective validation, in human sentinel and metastatic LNs.
ABSTRACT Ever since the “Lindbergh Operation” in 2001, the field of remote robotic surgery has transformed from theoretical study toward practical clinical integration on a global scale. Considering the millimeter‐level precision that is required in the field of urological oncology, remote platforms have already turned into necessary tools that are used for giving first‐class surgical therapy to regions that possess restricted resources. This review provides careful granular research on the development of this domain, and therefore highlights the successful application of robotic systems when they implement remote radical prostatectomy (RP), partial nephrectomy (PN), and radical cystectomy (RC) across extremely long distances. Even so, the technological jump provided by 5G, which can keep delay under the 320‐ms boundary, does not take away the risks that have existed already. The analysis points out with great stress the hard issues: the non‐smoothness of network jitter across the Internet, the regulatory vacancy about cross‐locale carrying out work, and the rising risk of web disturbance. In the end, it is concluded that an age without boundaries for surgery, centered on artificial intelligence assistance and multi‐center cooperative networks, is about to come.
ABSTRACT Objective The molecular mechanisms underlying the development of metabolic‐dysfunction‐associated steatotic liver disease (MASLD) are essential for developing appropriate treatments. The purpose of this study was to establish an MASLD model in mice with rapid and consistent progression. Methods Male C57BL/6J mice were randomized into the normal diet control group, ND + CCl4 group, Western diet (WD) group, and WD + CCl4 group. During 16 weeks of modeling, body weight, blood glucose, liver/kidney echo signal ratio, serum biochemical indicators, hepatic histopathology, inflammatory cytokines, oxidative stress levels, and protein expressions related to lipid synthesis and fibrosis were detected. Results The results showed that compared with the ND + CCl4 group and WD group, the WD + CCl4 group exhibited more significant metabolic disorders, including elevated blood glucose, serum transaminases, and lipid profiles. Meanwhile, hepatic steatosis, inflammatory cell infiltration, hepatocyte ballooning, and collagen deposition were markedly aggravated, accompanied by upregulated inflammatory cytokines (IL‐1β, IL‐6, and TNF‐α), enhanced oxidative stress, and increased protein expression of fatty acid synthase and alpha‐smooth muscle actin. Collectively, the WD + CCl4 group represented more severe and significant features of metabolic dysfunction‐associated steatohepatitis (MASH), such as steatosis, inflammatory cell infiltration, and even fibrosis. Conclusion The study demonstrated that CCl4 accelerates liver fibrosis on the basis of WD feeding, suggesting that WD combined with CCl4 is an ideal method to establish an MASLD model.
ABSTRACT Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disease in which right ventricular (RV) failure is the leading cause of mortality. Although current vasodilator therapies improve pulmonary hemodynamics, they do not consistently reverse the structural, metabolic, and inflammatory maladaptive changes of the RV. Traditional Chinese medicine (TCM) and natural products, characterized by multi‐target and system‐oriented actions, may regulate metabolic pathways involved in RV maladaptation and offer potential complementary therapeutic strategies for PAH. Integrating traditional medical knowledge with modern systems biology and precision medicine approaches may further facilitate the development of personalized therapeutic strategies. However, rigorous evaluation of pharmacokinetics, safety, and herb–drug interactions, along with standardized clinical evaluation is essential to facilitate clinical translation. Together, these advances highlight the potential of natural products and TCM to improve RV function and advance mechanism‐based, personalized cardiometabolic therapy for PAH.
ABSTRACT Endothelial cells (ECs) form the dynamic interface between blood and tissue, serving as key regulators of vascular homeostasis, inflammation, and repair. Among the molecular systems governing endothelial behavior, the C‐X‐C motif chemokine receptor (CXCR) family—originally characterized in immunology for its roles in leukocyte trafficking and immune signaling—has recently emerged as a pivotal regulator of vascular biology. Accumulating evidence indicates that CXCRs orchestrate endothelial development, angiogenesis, and injury responses through context‐dependent signaling mechanisms. This review integrates recent advances in endothelial CXCR research, highlighting their molecular functions and translational relevance. We first describe the developmental and homeostatic subgroup in which CXCR4 and its atypical partner CXCR7/ACKR3 coordinate vascular morphogenesis and regeneration. In parallel, we contrast the proangiogenic ELR + receptors (CXCR1 and CXCR2) with the angiostatic ELR − receptor CXCR3 and discuss the emerging roles of CXCR5 and CXCR6 in linking chronic inflammation and adaptive immunity to vascular dysfunction. Collectively, these findings position the CXCR family as an integrated network that fine‐tunes endothelial phenotype and vascular fate, revealing new opportunities for precision therapeutic intervention.
ABSTRACT Next‐generation sequencing (NGS) has increased the detection of mosaic embryos during preimplantation genetic testing for aneuploidy (PGT‐A). However, evidence regarding the postnatal and childhood health outcomes following mosaic embryo transfer remains limited especially in the Chinese mainland population. This retrospective study analyzed 123 mosaic embryo transfer cycles performed on 112 patients between January 2019 and May 2024. These cycles were matched to 130 euploid embryo transfer cycles based on the preimplantation genetic testing (PGT) indications. Statistical methods including differential analysis and multivariable logistic regression were employed to compare pregnancy outcomes and postnatal health status. Outcomes assessed included pregnancy results, prenatal ultrasound findings, amniocentesis results, neonatal outcomes, maternal complications, pediatric hospitalizations, the length and reasons for hospital stay, and cognitive development at 1 and 3 years of age. Results demonstrated that both clinical pregnancy rates and live birth rates were significantly lower in the mosaic embryo transfer group compared to the euploid group (both p < 0.001), and the miscarriage rate (typically in early pregnancy) rate was higher. Despite these differences, no significant association was observed between mosaic embryo transfer and adverse pregnancy complications, preterm birth, low birth weight, pediatric hospitalization rates, the length or cause of hospitalization, or cognitive development at 1 and 3 years of age. Notably, in ongoing pregnancies resulting from mosaic embryo transfer, persistent mosaicism was observed in 2 cases (4.2%, 2/47). Subgroup analyses revealed no significant differences between segmental mosaic embryos and monosomy/trisomy mosaic embryos in biochemical, clinical, or ongoing pregnancy rates. In contrast, low‐level mosaic embryos demonstrated higher ongoing pregnancy rates ( p = 0.007) and live birth rates ( p = 0.004), alongside lower miscarriage rates ( p = 0.002). These findings indicate that although mosaic embryo transfer may reduce pregnancy and live birth rates, healthy offspring can still be achieved.
ABSTRACT Day surgery for thyroid malignancies is gaining traction globally, yet comprehensive health economic evaluations in China remain limited. This study evaluates the cost‐effectiveness and safety of thyroid day surgery versus elective inpatient operations using a large‐scale multicenter dataset. We conducted a retrospective cohort study of 2979 patients with thyroid malignancies across three tertiary academic centers in 2022. Patients were stratified into day surgery (≤ 24 h) and elective inpatient (> 24 h) groups. A generalized linear mixed model was utilized to analyze hospitalization costs, adjusting for confounders and hospital‐level random effects. The day surgery group exhibited a significantly lower complication rate (0.74% vs. 1.94%, p < 0.001) and zero unplanned readmissions. After adjustment, day surgery was associated with a 40.5% reduction in total hospitalization costs (adjusted ratio = 0.595, p < 0.001). A structural cost analysis revealed the most substantial savings in comprehensive medical service fees (ratio = 0.265) and diagnostic fees (ratio = 0.323), whereas surgical technical fees remained stable. Ambulatory thyroidectomy demonstrates superior cost‐effectiveness and operational efficiency without compromising patient safety. These findings advocate for the broader implementation of day surgery pathways to optimize healthcare resource allocation in oncology.
ABSTRACT Their work provides evidence in murine models that the bile acid pool may function as a tunable filter whose selectivity for different fatty acids depends on bile acid concentration and composition. This framework suggests a selective decoupling of the absorption of excessive saturated fatty acids (SFAs) from that of beneficial polyunsaturated fatty acids (PUFAs) in murine models. Importantly, these findings were derived from mice, and their direct applicability to humans is constrained by well‐documented interspecies differences in bile acid composition, a point revisited later in this commentary. This selective mechanism permits the exclusion of metabolically harmful lipids while preserving the uptake of essential nutrients. In this commentary, we examine these findings, contrast them with conventional lipase inhibition strategies, and assess the translational challenges posed by interspecies differences in bile acid profiles.
ABSTRACT Vascular calcification represents an active multifactorial process that mirrors several key features of skeletal bone mineralization. Clinically, it is characterized by diminished arterial compliance and increased arterial wall stiffness, both of which serve as independent predictors of significant adverse cardiovascular events. The primary cellular mechanism involves the phenotypic transformation of contractile vascular smooth muscle cells (VSMCs) into osteo/chondrogenic‐like cells, which produce an extracellular matrix conducive to hydroxyapatite deposition. This transdifferentiation is regulated by intricate cellular signaling networks, including the BMP‐Smad signaling pathway, both canonical and non‐canonical Wnt/β‐catenin pathways, Stat3 activated by inflammatory cytokines, the Notch signaling pathway, and ROS‐activated MAPK (ERK/p38) and NF‐κB pathways. In contrast, the SIRT family proteins (such as nuclear SIRT1/SIRT6), extracellular pyrophosphate (PPi), and matrix Gla protein (MGP) exert inhibitory effects on vascular calcification. Anatomically, calcification can be localized to the intimal layer, often superimposed on advanced atherosclerotic plaques in large conduit arteries, or to the medial layer, a pattern characteristic of small‐ to medium‐sized muscular arteries, known as Mönckeberg's sclerosis. Despite extensive research efforts, the molecular mechanisms governing mineral deposition in vascular tissues remain inadequately understood, and no pharmacological intervention has yet been demonstrated to be both safe and effective in preventing or reversing established calcification. In this review, we examine current insights into the pathobiology of vascular calcification, critically evaluate available in vitro models (including human aortic smooth muscle cells, endothelial cells, and valvular interstitial cell calcification models) and in vivo models (such as pharmacologically induced and genetically modified or surgical models) and highlight emerging therapeutic targets and agents that are currently under preclinical or early clinical investigation.
ABSTRACT Socioeconomic status (SES) disparities may contribute to variations in the rates of chronic diseases. With advancing age, individuals are increasingly susceptible to multiple concurrent chronic conditions, known as multimorbidity. This study investigated the relationship between SES and the prevalence of specific chronic diseases, along with multimorbidity, in middle‐aged and older adults in China. This cross‐sectional analysis was based on data from the 2015 and 2020 waves of the China Health and Retirement Longitudinal Study (CHARLS). Participants aged 45 years with complete data on chronic diseases were enrolled in this study. Multivariable logistic regression models were constructed to examine the correlation between SES, education level, area of residence, and multimorbidity. A total of 17,234 participants were included, comprising 9162 (53.2%) women and 8072 (46.8%) men. A positive association was observed between higher SES and elevated odds of multimorbidity (OR, 1.07; 95% CI, 1.04–1.09; p < 0.001), as well as certain chronic conditions. A higher level of educational attainment demonstrated a significant positive correlation with a greater prevalence of multimorbidity. Urban residence was significantly associated with elevated odds of multimorbidity (OR, 1.17; 95% CI, 1.09–1.26; p < 0.001). Subgroup analyses showed robust associations between SES and multimorbidity across most strata. Higher SES, educational attainment, and urban residence were positively associated with the prevalence of multimorbidity in adults aged ≥ 45 years in China. These associations may partly reflect disparities in diagnostic opportunities rather than differences in true disease burden. Further longitudinal studies are needed to track the evolving relationship between SES and multimorbidity over time.
ABSTRACT The recent Phase III FIBRONEER trials establish nerandomilast, a novel oral phosphodiesterase 4B (PDE4B) inhibitor, as an effective therapy for idiopathic and progressive pulmonary fibrosis. By elevating cyclic adenosine monophosphate (cAMP), it uniquely dual‐targets the NLRP3 inflammasome and TGF‐β pathway, addressing both inflammation and fibrosis. The trials demonstrated significant slowing of lung function decline, with a manageable safety profile. Critically, its efficacy on background antifibrotic therapy provides robust evidence for viable combination regimens, thereby ushering in a new era of combination therapy for this refractory disease. This marks a paradigm shift, offering renewed hope and paving the way for multi‐targeted treatment strategies, although longer‐term outcomes warrant further study.
ABSTRACT High‐grade serous ovarian cancer (HGSOC) is the most common and lethal histological subtype of ovarian cancer. This study aimed to identify peritoneal metastasis‐associated biomarkers of HGSOC to provide directions for subsequent treatment. Transcriptome data were extracted from the GEO database and literature. Differential expression analysis, a PPI network, and machine learning were conducted to obtain key cells and biomarkers, followed by the construction of ROC curves and expression validation to screen biomarkers. The functional mechanism of the biomarkers was explored via a molecular regulatory network and enrichment analysis. Potential drugs targeting biomarkers were also predicted. Based on the single‐cell and spatial transcriptome data, the expression patterns and communication types of key cells and biomarkers were explored. CYTH1 and ARHGEF1 were identified as biomarkers, while ILCs, DC‐1, and macrophages were identified as key cells associated with metastasis in HGSOC. Spatial transcriptome data confirmed that the biomarkers are highly expressed in T and NK cells. Cell interaction analysis indicated that the expression of SPP1 was higher in peritoneal metastases than in primary lesions. Furthermore, in vitro studies demonstrated that macrophage‐derived SPP1 significantly enhanced the proliferation and migration of ovarian cancer cells. This study identifies CYTH1 and ARHGEF1 as metastatic biomarkers and implicates macrophages in promoting metastasis through SPP1, which provides new insights into the understanding of tumor metastatic mechanisms in HGSOC.
ABSTRACT Accumulating evidence highlights the critical role of epigenetic modifications, particularly N 6 ‐methyladenosine (m 6 A), in liver disease. As the most abundant RNA modification in eukaryotic cells, m 6 A is dynamically regulated by multicomponent m 6 A methyltransferases (e.g., METTL3 and METTL14), demethylases (FTO and ALKBH5), and m 6 A‐binding proteins (YTHDF1/2/3, YTHDC1/2, and IGF2BP1/2/3). Recent studies have revealed the pivotal involvement of m 6 A and its regulators in a wide range of physiological and pathological processes in liver disease, including metabolic dysfunction‐associated steatotic liver disease (MASLD), liver fibrosis, hepatocellular carcinoma (HCC), as well as liver injury and regeneration. In this review, we summarize recent advances in understanding the emerging roles of m 6 A modifications in liver disease and discuss their potential as therapeutic targets, offering new perspectives for treating liver disease.
ABSTRACT Large language models (LLMs) have achieved strong performance on medical exam–style tasks, motivating growing interest in their deployment in real‐world clinical settings. However, clinical decision‐making is inherently safety‐critical, context‐dependent, and conducted under evolving evidence. In such situations, reliable LLM performance depends not on factual recall alone but on robust medical reasoning. In this work, we present a comprehensive review of medical reasoning with LLMs. Grounded in cognitive theories of clinical reasoning, we conceptualize medical reasoning as an iterative process of abduction, deduction, and induction, and we organize existing methods into seven major technical routes spanning training‐based and training‐free approaches. We further conduct a unified cross‐benchmark evaluation of representative medical reasoning models under a consistent experimental setting, enabling a more systematic and comparable assessment of the empirical impact of existing methods. To better assess clinically grounded, decision‐oriented reasoning, we introduce MR‐Bench, a benchmark derived from real‐world hospital data. Evaluations on MR‐Bench expose a pronounced gap between exam‐level performance and accuracy on authentic clinical decision tasks. Overall, this survey provides a unified view of existing medical reasoning methods, benchmarks, and evaluation practices and highlights key gaps between current model performance and the requirements of real‐world clinical reasoning.
ABSTRACT Heart failure (HF) continues to be a leading cause of death and disability globally, with an estimated annual prevalence of over 56 million patients and a projected significant increase in occurrence. Although drug treatments based on existing guidelines can enhance the clinical prognosis for patients with HF, the five‐year survival rate remains below 50%. This underscores the critical need for early detection and effective strategies to prevent and manage the progression of HF. Present screening approaches, encompassing individual biomarkers and imaging techniques, exhibit shortcomings in identifying subclinical or incipient‐stage diseases. This review amalgamates the most recent advancements in HF screening, specifically highlighting novel biomarkers that correspond to various pathways involved in cardiac remodeling, inflammation, neurohormones, and emerging pathophysiological pathways. Several emerging biomarkers, notably sST2 and GDF‐15, demonstrate strong potential for inclusion in future clinical guidelines, enhancing early risk stratification and personalized screening. Artificial intelligence‐driven approaches, integrating electrocardiograms, wearable devices, and analysis of medical images using machine learning and multimodal data, represent a promising strategy for improving early risk identification. Nevertheless, it is imperative for researchers to systematically address enduring challenges. These challenges encompass analytical variability in machine learning data, the absence of multicenter clinical trial data, constraints in hardware deployment, and biases prevalent in resource‐limited settings. Future research endeavors should prioritize the integration of multi‐omics technologies, thereby enhancing the precision of biomarkers. This would enhance biomarker accuracy, facilitate dynamic risk stratification for HF, and guarantee equitable global implementation. Combining evidence‐based methodologies with technological innovation will be fundamental to developing scalable screening tools. Implementing such a stepwise integrated screening framework will allow clinicians to optimize therapeutic timing and improve survival outcomes in HF management.
ABSTRACT Endothelin‐1 (ET‐1), a central mediator within the endothelin peptide family, is predominantly synthesized in vascular endothelial and smooth muscle cells. Its expression is observed across a diverse range of tissues and cellular populations. ET‐1 is a critically important endogenous vasoconstrictor, crucial for the maintenance of fundamental vascular tone and overall cardiovascular homeostasis. Beyond its vascular effects, ET‐1 establishes complex crosstalk with immune cells activating critical intracellular signaling pathways such as NF‐κB, MAPK, and PI3K through receptor‐mediated mechanisms. These interactions contribute to vasoconstriction, angiogenesis, inflammatory responses, tissue injury, and cell proliferation. Accumulating evidence demonstrates that ET‐1 exerts important regulatory functions in immune cell infiltration, cytokine release, and inflammatory cell proliferation. Autoimmune diseases (ADs), a group of chronic disorders driven by aberrant immune attacks against self‐tissues, affect various conditions including rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, and organ fibrosis, as well as certain malignancies. Recent studies indicate that ET‐1 plays a crucial role in the initiation and progression of ADs. For example, in systemic sclerosis and systemic lupus erythematosus, ET‐1 promotes vascular remodeling and endothelial dysfunction by stimulating angiogenic factor secretion via receptor‐dependent pathways. In type 1 diabetes, persistent hyperglycemia and oxidative stress activate the ET‐1 system, thereby inducing endothelial impairment and microvascular complications. In rheumatoid arthritis, ET‐1 activates immune cell infiltration, drives vascular dysfunction and the release of inflammatory cytokines, and promotes structural joint damage including synovial hyperplasia and tissue destruction, thus forming a persistent inflammatory loop. Overall, ET‐1 functions not only as a central regulator of vascular homeostasis but also as a key mediator in the pathogenesis of ADs and cancer. Elucidating the therapeutic potential of ET‐1 as an immunomodulatory target may provide novel strategies for disease diagnosis and treatment. This review summarizes the structural and biological features of the ET protein family, the mechanisms of ET‐1‐immune cell interactions, ET‐1‐related signaling pathways, and recent advances regarding ET‐1 in ADs.
ABSTRACT This commentary integrates findings from three recent Cell reports to establish a unified mechanistic model of multiple sclerosis (MS) driven by the interplay between Epstein‐Barr virus (EBV) and the HLA‐DR15 genotype. EBV promotes CNS autoimmunity through three distinct but intersecting mechanisms. First, viral LMP1 provides anti‐apoptotic signals that sustain autoreactive B cells within the CNS. Second, EBV alters the B cell immunopeptidome, enabling the HLA‐DR15‐restricted presentation of myelin basic protein (MBP)‐derived self‐peptides to initiate autoreactive CD4 + T cell responses. Third, the virus triggers a B cell–independent attack via molecular mimicry, wherein EBNA1‐specific CD4 + T cells cross‐recognize the CNS autoantigen ANO2, providing a B cell–independent attack mechanism. By framing MS as an EBV‐driven autoimmune disease in which EBV and HLA‐DR15 act in concert to dysregulate both B cell and T cell compartments, this model identifies precise therapeutic vulnerabilities. Targeting LMP1 survival signals, disrupting the presentation of EBV‐altered self‐peptides, or depleting cross‐reactive T cell clones could shift MS management from generalized immunosuppression toward etiology‐specific interventions, although evaluating their impact on basal antiviral immunity remains a critical next step.
ABSTRACT Sudden cardiac events are the leading cause of death worldwide. Conventional risk stratification methods, which largely depend on clinical history, imaging, and electrocardiography, are usually inadequate for identifying high‐risk individuals, especially those without visible structural heart disease. Through genetic testing, personalized medicine has been revolutionized by enabling the identification of single‐gene variants, population‐specific polymorphisms, and polygenic risk factors that promote susceptibility to arrhythmia. Inherited channelopathies, such as long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia, as well as cardiomyopathies, are characterized by strong genotype–phenotype correlations, allowing more accurate prediction of arrhythmia risk. Single‐gene panels, whole‐exome sequencing (WES), whole‐genome sequencing (WGS), and polygenic risk scores (PRS) are not mutually exclusive; rather, they can be used together to enhance diagnostic yield and risk stratification. Screening of relatives of affected individuals enables the early identification of asymptomatic carriers. Moreover, the combination of clinical, imaging, and molecular data supports individualized risk assessment. The next steps emphasize the integration of multiomics, variant interpretation using artificial intelligence, and the creation of ancestry‐specific genetic repositories, which will facilitate predictive and preventive approaches to cardiology. This review describes current genetic testing approaches for sudden cardiac events, their use in personalized risk assessment, and the potential of personalized medicine to lower the risk of sudden cardiac death.
