ABSTRACT Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the intestine. In recent years, it has been unveiled that N6‐methyladenosine (also named m 6 A) modification, the most prevalent internal mRNA modification in mammalian cells, plays a pivotal role in the pathogenesis and development of IBD. m 6 A modification exerts on all four components of the intestinal barrier, including the intestinal mechanical barrier, intestinal chemical barrier, intestinal immunological barrier, and intestinal biological barrier. This paper reviews previous studies that focused on the role of m 6 A modification in IBD, aiming to elucidate the epigenetic mechanisms underlying IBD pathogenesis and progression, and offering novel perspectives for IBD diagnosis, treatment and prognosis prediction.
ABSTRACT Chronic gastritis infected by Helicobacter pylori ( H. pylori ), as a common digestive system disorder, often presents with deceptive clinical stability during its inactive phase, making patients highly prone to relapse or secondary gastric damage. However, the long‐standing lack of objective and sensitive blood‐based molecular markers to accurately differentiate between the active and stable phases has not only complicated clinical diagnosis but also significantly hindered the implementation of precise treatment strategies. This study conducted unsupervised clustering analysis based on clinical indicators from 1409 patients, and 60 patients and 20 healthy samples were randomly selected for serum proteomics and untargeted metabolomics analysis, and integrated clinical data to screen biomarkers and evaluate diagnostic efficacy. A potential diagnostic model (HGB–CAPZB–acetic acid) was developed, and three biological mechanisms of blood function, energy metabolism, cytoskeleton reorganization, and cell migration in active and stable phases of H. pylori‐ infected chronic gastritis were found. Although these findings require further validation in larger and independent cohorts, this study provides preliminary evidence supporting the potential utility of blood‐based multi‐omics biomarkers for distinguishing disease activity in H. pylori ‐associated chronic gastritis and offers insights for future mechanistic and translational investigations. Trial Registration: Not applicable
ABSTRACT Positron emission tomography/computed tomography (PET/CT) and PET/magnetic resonance imaging (PET/MRI) have significantly advanced the field of oncologic imaging. This review presents a comparative evaluation of these hybrid modalities in terms of technical principles, image quality, radiation exposure, and diagnostic performance across a range of cancers, including lung, breast, prostate, and brain tumors. We discuss their respective strengths in anatomical and functional characterization, alongside emerging innovations such as artificial intelligence and ultra‐low dose protocols. Despite their growing clinical utility, challenges such as high cost, limited availability, and protocol standardization remain. Both PET/CT and PET/MRI play critical roles in cancer diagnosis and management, with ongoing developments offering further potential for clinical integration.
ABSTRACT With rapid advances in synthetic biology and genetic engineering, genetically engineered bacteria (GEB) have emerged as a promising platform for biological therapy, addressing key limitations of conventional drug delivery systems and demonstrating significant clinical potential. By leveraging a modular design framework, GEB exhibits high biocompatibility and programmability, enabling precise genetic modifications for targeted delivery, dynamic responsiveness, and sustained therapeutic effects. This review systematically examines the therapeutic development of GEB, focusing on its pivotal roles in tumor therapy, inflammatory bowel disease (IBD), metabolic disorders, and the treatment of complex infections. It outlines key design strategies—including sensing, payload release, and biocontainment modules—as well as evaluation frameworks and mechanisms of action. We also discuss major challenges to clinical translation, such as the limited availability of clinically validated chassis strains, the balance between bacterial fitness and therapeutic load, and persistent biosafety concerns. Future progress will depend on advancements in high‐precision genome editing, intelligent responsive systems, and interdisciplinary collaboration to bridge the gap between preclinical promise and clinical application. This review aims to provide an up‐to‐date reference to facilitate the translation of GEB from laboratory discoveries to viable clinical applications in precision medicine.
ABSTRACT We propose a new framework for the analysis of large clinical phenotypic datasets through the repurposing of single‐cell RNA‐sequencing analysis techniques. By utilizing similarities between cellular development and clinical heterogeneity, we show that techniques such as clustering, pseudo‐time, and trajectory analysis can reveal different disease progression trajectories. Our approach permits the extraction of long‐term progression trajectories from large cross‐sectional datasets while overcoming the hurdle of a lack of longitudinal data plaguing many large clinical phenotypic studies. We present this framework on the retinal degenerative disease macular telangiectasia type 2 (MacTel) and derived previously unknown differential disease progression trajectories from 87 clinically graded phenotypic variables measured in 7888 eyes (3971 patients). One progression trajectory was characterized by vascular alterations, the other by severe neurodegeneration and vision loss. Older and diabetic patients were significantly more likely to progress toward the neurodegenerative route. We demonstrate how pseudo‐time calculations reveal a holistic fine‐scale data‐driven progression score useful for analytical investigations, which complements previously established clinical severity scores. Lastly, integration of genetic data on 71% of patients revealed that genetic background affects phenotype heterogeneity, differential progression trajectory, but not progression rate.
ABSTRACT Current clinical liquid biopsy approaches predominantly rely on blood‐derived biomarkers, which are often limited in sensitivity. A paradigm shift toward lymphatic system‐based biomarker analysis could offer an alternative means of addressing these challenges. This proposition is supported by a key scientific insight: the Revised Starling Principle demonstrates that lymphatic vessels, rather than veins, absorb most interstitial fluid, which contains abundant biomarkers, in the majority of tissues. Collectively, these findings indicate that lymphatic‐derived biomarkers may offer distinct advantages for the molecular assessment of lymph node metastasis risk. However, accessing biomarkers from the lymphatic system remains technically challenging owing to the lack of minimally invasive sampling techniques. In this small‐cohort proof‐of‐concept study, we developed a minimally invasive platform (His@PDA@Needle) for the collection and molecular profiling of DNA biomarkers from lymph nodes. The performance of this platform was preliminarily validated in mouse footpad xenograft models, as well as in lymph node samples derived from patients with head and neck cancer. Compared with conventional lymph node biopsy, this DNA sampling approach is less invasive; however, it is intended as a molecular profiling tool to complement existing histopathological evaluation, rather than a tool for direct clinical diagnosis.
ABSTRACT Cholesterol gallstone disease is a prevalent ailment of the digestive system, accumulating evidence indicates a significant association between gut flora and gallstone formation. In the present research, we found that oat β‐glucan promotes gallstone formation, whereas galactooligosaccharides exerted inhibitory effects. Notably, these opposing effects were neutralized upon co‐administration of both prebiotics. Further research demonstrated that both prebiotics act primarily through modulating the abundance of Desulfovibrionales. The metabolic product of Desulfovibrionales, H 2 S, can directly activate the hepatic farnesoid X receptor (FXR) and thereby suppress bile acid production via FXR‐SHP signaling. Additionally, H 2 S can increase secondary bile acid levels (DCA, LCA) by promoting intestinal 7α‐dehydroxylase function. These secondary bile acids further decrease bile acid production in the liver via the intestinal FXR‐FGF15 cascade. Moreover, the upregulated production of secondary bile acids also enhances bile hydrophobicity. Collectively, these effects induce biliary cholesterol overloading, and ultimately promote gallstone formation. Our findings elucidate the effect of oat β‐glucan and galactooligosaccharides on gallstone formation, and suggest that alterations in Desulfovibrionales abundance and its influence on hepatic FXR‐SHP and intestinal FXR‐FGF15 pathways may underlie the potential mechanisms.
ABSTRACT The pathogenesis of colorectal cancer (CRC) is closely associated with gut microbial metabolites, which exert crucial regulatory effects within the tumor immune microenvironment. These metabolites play a dual role in CRC immunity: certain metabolites promote tumor progression by inducing chronic inflammation, recruiting myeloid‐derived suppressor cells, and suppressing CD8 + T cell function; while others, such as short‐chain fatty acids and tryptophan metabolites, enhance anti‐tumor immunity and improve the efficacy of immune checkpoint inhibitors (ICBs). This paper systematically explores intervention strategies targeting this mechanism, including probiotics, prebiotics, metabolite adjuvants, and their combination with immunotherapy to overcome ICB resistance. Furthermore, the analysis of specific metabolites (e.g., cholic acid derivatives) and microbial signatures (e.g., enrichment of F. nucleatum ) has been identified as a potential avenue for the development of novel non‐invasive biomarkers, which could facilitate early screening and differential diagnosis. Notwithstanding the challenges encountered in the clinical translation of these technologies, the integration of multi‐omics and artificial intelligence with the immunoregulatory mechanisms and diagnostic potential of metabolites holds great promise for advancing precision medicine in the comprehensive management of CRC.
ABSTRACT Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of global heart failure cases yet lacks robust pharmacological options. This analysis maps HFpEF drug trials registered on ClinicalTrials.gov from 2003 to 2025. A systematic search conducted on November 10, 2025, identified HFpEF‐specific drug trials (LVEF ≥ 50%). Data regarding geography, phases, status, time, and drug classes were descriptively analyzed using R (version 4.3.1). Of the 272 trials, 236 qualified, with a notable surge post‐2016 (180 [76.3%]). The majority were U.S.‐led (138 [58.5%]). Phase Ⅱ trials were predominant, comprising 92 trials (39.0%), with 111 trials completed (47.0%) and 36 trials terminated (15.2%). The leading classes of drugs included SGLT2 inhibitors (SGLT2i) and novel/targeted therapies, each represented in 31 trials (13.1%). The period from 2021 to 2025 highlighted a focus on SGLT2i (30 trials, or 27.8%) and an increase in GLP‐1 receptor agonists (GLP‐1RA), following recent approvals (sacubitril/valsartan in 2021; empagliflozin/dapagliflozin in 2022–2023; and finerenone by the FDA in 2025). The expansion of trials post‐2016 favors metabolic and targeted agents. However, attrition rates underscore the need to prioritize phenotype‐specific and combination trials.
ABSTRACT Tuberculosis is the second leading infectious disease globally, severely threatening human health. The emergence of drug‐resistant Mycobacterium tuberculosis makes the development of new therapeutic targets particularly urgent. Serine/threonine protein kinase PknG can help the pathogen escape macrophage clearance by phosphorylating host proteins. This study adopted multi‐omics approaches to investigate the regulatory mechanism of mycobacterial PknG on host cell processes. The results showed that host lysine‐tRNA ligase (KARS) is a potential substrate of PknG; PknG, by catalyzing the phosphorylation of KARS at T592 and T595 sites, affects the phosphorylation levels in the MAPK/NF‐κB signaling pathway, thereby regulating the immune response. Furthermore, PknG overexpression ( Ms PknG‐OE) can lead to differential impacts on the lungs, characterized by elevated mRNA levels of Tnfa , Il1b , and Il6 , and more severe histopathological changes. Flow cytometry showed that M. smeg ‐PknG Mtb significantly reduced splenic CD3 + and CD8 + T cells, exhibiting an immunosuppressive trend; whereas M. smeg ‐PknG Ms increased the proportions of MDSCs and multiple regulatory T‐cell subsets while decreasing the proportion of CD8+ T cells, suggesting enhanced regulatory immunity and altered T‐cell subset composition. This study systematically elucidated the mechanism by which mycobacteria regulate the host immune network through the PknG‐KARS axis, and pointed out that the T592 and T595 sites of KARS could be potential targets for treating infection.
ABSTRACT Antibiotics disrupt commensal microbiota, but how this predisposes to secondary infections remains unclear. Metagenomic and whole‐transcriptome sequencing were employed to analyze alterations in microbial compositions and host defense. Fecal microbiota transplantation (FMT) and pathogen infection experiments were performed to identify the effects of antibiotics on host. Gut microbial dynamics induced by four antibiotic classes, revealed distinct taxonomic and functional shifts. Vancomycin and ampicillin enriched antibiotic resistance genes and impaired pathogen clearance via FMT. Vancomycin triggered overgrowth of opportunistic pathogens and increased genes of virulence factors, exacerbating colonic inflammation. Metronidazole selectively enriched Enterococcus avium , which correlated with MHC class I upregulation and impaired gut barrier function, promoting systemic Salmonella dissemination. LncRNA NR_166682.1 mediated E. avium ‐induced barrier damage and immune dysregulation, as validated in colon organoids. Antibiotics compromise host resistance through microbiota‐dependent mechanisms, with vancomycin and metronidazole exhibiting distinct, detrimental profiles via enrichment of resistant pathobionts or barrier‐disrupting species, respectively.
ABSTRACT Precision oncology is evolving from a predictive paradigm towards adaptive decision‐making with dynamic data. This paper systematically presents a forward‐looking conceptual framework for a Closed‐Loop Intelligent Oncology System (CIOS), which aims to support iterative evaluation of candidate treatment strategies and inform timely adjustments in care by updating a patient‐specific digital twin that approximates key aspects of the patient's pathophysiological state. The core idea of CIOS is that it does not only predict tumor evolution but frames decision‐making as a closed‐loop process that evaluates candidate policies within a computational environment under explicit constraints. A five‐layer reference architecture is described to elucidate the operational mechanism of CIOS: (1) Perception Layer: Multimodal data fusion. (2) Simulation Layer: PINN‐based digital twins. (3) Decision Layer: Safe RL for adaptive therapy. (4) Evolution Layer: Meta learning & federated learning. (5) Trust Layer: XAI & uncertainty reporting. This paper systematically reviews the preliminary research progress and application explorations of the key technologies at each of these layers within the field of oncology. It also provides an in‐depth discussion of the technical challenges, clinical translation barriers, and future research directions, aiming to provide a theoretical reference and potential guidance for further research and eventual realization of this conceptual framework.
ABSTRACT Bacterial contamination poses substantial threats to healthcare and industrial production; yet integrated resources for a comprehensive assessment of bacterial biosafety risks are currently limited. To bridge this gap, we developed BacSafe ( http://bacsafe.dmicrobe.cn/ ), a knowledge database that profiles the biosafety risks of bacterial species based on their environmental and clinical risk traits. Environmental risk traits, such as biofilm formation and tolerance to disinfectants, and clinical risk traits, including the presence of virulence and antimicrobial resistance genes, are curated from authoritative literature and genome predictions. In addition to the theoretical characteristics, BacSafe also encompasses empirical indicators reflecting real‐world risks posed by each bacterial species, including food and pharmaceuticals recall events, and document frequency in PubMed literature. Covering 20,630 species across 3902 genera, BacSafe supports natural language querying via a fine‐tuned artificial intelligence (AI)‐driven assistant that significantly outperforms general‐purpose large language models in accuracy and contextual relevance. Additionally, BacSafe provides decision tree‐based tools for evaluation of objectionable microorganisms in non‐sterile products and cleanroom environments. Taken together, by consolidating dispersed aspects of biosafety knowledge, BacSafe serves as a vital resource for bacterial risk assessment in clinical, industrial, and research settings, establishing a foundation for future AI‐assisted, data‐driven biosafety management.
ABSTRACT Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder tightly linked to gut microbiota dysbiosis. While probiotics present a promising therapeutic avenue, the underlying mechanisms remain largely unclear. Here, we investigated the efficacy and mechanism of Bifidobacterium animalis subsp. lactis BGI‐L99 in a dehydroepiandrosterone (DHEA)‐induced PCOS mouse. We found that oral administration of BGI‐L99 significantly ameliorated PCOS phenotypes, including restoring estrous cycle regularity, ameliorating depression‐like behaviors, reducing cystic follicles, decreasing serum testosterone, and increasing estradiol levels. Mechanistically, BGI‐L99 reshaped the gut microbiota and robustly increased the concentrations of beneficial bile acids, notably chenodeoxycholic acid (CDCA) and tauroursodeoxycholic acid (TUDCA). This metabolic shift was associated with a significant upregulation of the protective cytokine interleukin‐22 (IL‐22) in both serum and tissues. Crucially, direct supplementation with CDCA or TUDCA could mimic the beneficial effects of probiotics, effectively restoring the estrous cycle, reducing polycystic follicles, increasing corpus luteum count, and normalizing serum T and E2 levels. These findings confirm the pivotal role of these bile acids in alleviating PCOS symptoms and elevating IL‐22 levels. Our findings demonstrate that B. animalis BGI‐L99 exerts its alleviative effects on PCOS by modulating the gut microbiota‐bile acid‐IL‐22 axis, identifying this pathway as a promising target for probiotic‐based interventions.
ABSTRACT Breast cancer (BC) recurrence and metastasis present formidable therapeutic challenges, accounting for approximately 90% of BC‐related mortalities. One critical driver of these clinical setbacks is tumor dormancy, a phenomenon frequently encountered in BC management. Recent advancements in tumor dormancy research have elucidated multifaceted mechanisms governing cellular quiescence, microenvironmental interactions, and immune evasion during dormant phases. These insights have accelerated the development of multidisciplinary strategies integrating oncology, material technologies, genetic engineering, and systems biology to target dormant tumor reservoirs. By targeting dormant cancer cells through immune checkpoint modulation, metabolic reprogramming, microenvironmental remodeling, and novel therapeutic strategies are emerging to prevent relapse and metastatic progression. This review synthesizes current mechanistic understandings and multidisciplinary approaches, highlighting their potential to transform BC therapy by addressing the unmet clinical need of targeting dormant tumor populations.
ABSTRACT Intratumor microbiome can rewire the tumor microenvironment (TME) by presenting bacterial neoantigens, while integrated in silico tools for identifying bacterial neoantigens remain lacking. We developed bacterial neoantigen ( bacNeo ), a multi‐omics‐based computational framework that contains three modules to classify bacterial components ( BACC ), type bacteria‐bound HLA alleles ( BACH ), and prioritize bacterial peptides as neoantigens ( BACP ) in human cancers. The input options of bacNeo are diverse: we support metagenomic or metatranscriptomic data, as well as sequencing data in different resolutions, including bulk and single‐cell sequencing; aside from sequencing data, mass spectrometry (proteome) data are also recommended for peptide discovery. The neoantigen potential of these peptides is quantified by score for peptide antigenicity recognition & kinetics (SPARK). Artificial neural networks and gradient boosted decision trees enhance the predictive accuracy of bacNeo , which has been validated in bacterial peptide‐HLA experimental pairs. In conclusion, bacNeo can enable personalized neoantigen discovery to accelerate therapeutic strategies across diverse cancer types.
Chronic kidney disease (CKD) is a major global health issue. Kidney fibrosis is a key mechanism leading to end-stage renal disease. Senescence of renal tubular epithelial cells (RTECs) and the senescence-associated secretory phenotype (SASP) factors they release are crucial in kidney fibrosis progression. While isorhamnetin, the active component of Astragalus membranaceus , has demonstrated promise in combating senescence/aging and fibrosis, its precise mechanism of action remains poorly understood. This study aims to elucidate the mechanisms through which isorhamnetin mitigates RTEC senescence and kidney fibrosis, specifically by modulating the interleukin-6 (IL-6) signaling pathway. The findings indicate that isorhamnetin significantly attenuates kidney fibrosis in aging mice, inhibiting IL-6 secretion from senescent RTECs and reducing its accumulation in kidney tissues. In vitro analyses further revealed that isorhamnetin disrupted IL-6 signaling by competitively binding to the IL-6 receptor, thereby slowing RTEC senescence. Additional investigations demonstrated that isorhamnetin's inhibition of IL-6 secretion from senescent RTECs impacted macrophage M2 polarization and the transformation of fibroblasts into myofibroblasts, thus decelerating the progression of kidney fibrosis. This study highlights the critical role of isorhamnetin in alleviating RTEC senescence and kidney fibrosis through the suppression of the IL-6 signaling pathway, underscoring its potential for clinical application in CKD treatment.
Operative duration reflects surgical complexity and is valuable for perioperative planning. To predict prolonged operative time in posterior spinal deformity correction, we developed a preoperative machine-learning model. Data from 162 patients across 11 hospitals were analyzed. Ten algorithms were trained and compared, and the best-performing model was implemented as a web calculator. Boruta identified seven key predictors: interval from illness to surgery, fibrinogen, white blood cell count, activated partial thromboplastin time, American Society of Anesthesiologists class, albumin, and age. LightGBM showed the most consistent performance, achieving an AUC of approximately 0.70. SHAP analyses improved interpretability, and calibration and decision-curve analyses indicated good calibration and net clinical benefit. We developed an interpretable, internally validated model to estimate operative duration in posterior spinal deformity surgery. The web calculator may support individualized planning and more efficient operating-room resource allocation. Clinical Trial Registration: NCT05867732
The tumor microenvironment (TME) plays a pivotal role in shaping cancer progression, immune evasion, and therapeutic response. However, a systematic understanding of immune and stromal cell heterogeneity across cancer types—and their associations with clinical phenotypes—remains lacking due to limited single-cell data and the associated clinical metadata. Here, we present a comprehensive pan-cancer TME cell atlas to date, quantifying the composition of 102 immune and stromal subtypes across 30 cancer types and encompassing over 11,000 bulk RNA-seq samples from TCGA. To enable this unprecedented resolution, we developed DECEPTICONx, a flexible computational framework that integrates single-cell RNA-seq data by constructing high-resolution expression templates, which are then paired with context-optimized deconvolution strategies, dynamically selecting the best-matched template-deconvolution combinations for each task. By leveraging 535,665 single cells spanning T cells, B cells, fibroblasts, macrophages, and NK cells, we constructed high-resolution expression templates and systematically deconvolved bulk samples. The resulting atlas revealed robust and novel associations between specific cell subtypes and patient prognosis, immunotherapy response, and inter-cellular coordination within the TME. In summary, the DECEPTICONx-based atlas not only advances our understanding of tumor-immune ecology but also offers a foundation for biomarker discovery and therapeutic development in precision oncology.
Preeclampsia (PE) is a major pregnancy complication associated with long-term maternal health risks, but how these risks vary by severity, race, and fetal sex is unclear. To identify maternal complications after PE and to evaluate the modifying effects of severity, race, and fetal sex, we conducted a retrospective cohort study of over 100,000 patients from four medical centers (UM, UK Biobank, Cedars-Sinai, Vanderbilt). The discovery cohort included 26,632 UM patients; validation cohorts included 15,313 UK Biobank, 29,821 Cedars-Sinai, and 31,418 Vanderbilt patients. Thirty potential complications within 10 years postpartum were assessed using confounder-adjusted logistic regression. Complications persisting ≥ 5 years were further analyzed with Kaplan–Meier survival. Five complications were consistently associated with PE: hypertension, renal failure, diabetes (complicated or uncomplicated), and obesity. Among them, hypertension (median OR = 6.05) and renal failure (median OR = 4.92) showed the strongest associations. Severe PE was linked to earlier and higher risk of hypertension and renal failure. African Americans had lower relative hypertension risk but higher renal failure risk than Caucasians. Fetal sex appeared to modify outcomes: male fetuses conferred a higher maternal hypertension risk but a lower renal failure risk compared with female fetuses.
