Ubiquitination is a highly dynamic and reversible post-translational modification that is extensively involved in protein degradation,signal transduction,and functional regulation in eukaryotic cells.Through the coordinated action of the ubiquitin-activating enzyme(E1),ubiquitin-conjugating enzyme(E2),and ubiquitin-protein ligase(E3)cascade,ubiquitin molecules are conjugated to substrate proteins through distinct ubiquitin chain linkages,thereby determining proteasomal degradation,subcellular trafficking,or non-degradative scaffold functions of target proteins.In the immune system,E3 ligases and deubiquitinases(DUBs)precisely regulate T cell antigen recognition,receptor signaling,activation,proliferation,and effector differentiation by controlling substrate selection and ubiquitin chain editing.By modulating the stability of T cell receptors,co-stimulatory and cytokine signaling molecules,as well as key transcription factors and metabolic regulators,E3 ligases and DUBs influence T cell activation thresholds,anergic states,survival,and differentiation programs.Together,they constitute an essential regulatory network responsible for maintaining T cell homeostasis and peripheral immune tolerance.Dysregulation of this network can enhance pro-inflammatory T cell responses and impaired regulatory T cell function,thereby weakening peripheral immune tolerance and contributing to the development and progression of various autoimmune diseases,including systemic lupus erythematosus,rheumatoid arthritis,and type 1 diabetes mellitus.Systematic summarization of the molecular mechanisms and key signaling pathways through which E3 ligases and DUBs regulate T cell fate,together with elucidation of substrate landscapes,ubiquitin chain preferences,and their metabolic crosstalk among different T cell subsets,will deepen our understanding of how ubiquitination maintains T cell homeostasis and contributes to autoimmune disease pathogenesis.Furthermore,such insights may provide a theoretical foundation and translational directions for the development of chain-specific and cell-type-selective therapeutic strategies.
Tumor recurrence is a major cause of treatment failure in central nervous system(CNS)tumors,although its underlying mechanisms have not yet been fully elucidated.Recent studies have suggested that neuropsychological stress may activate the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal-medullary system,thereby inducing the release of glucocorticoids,catecholamines,and inflammatory mediators.These processes may contribute to structural damage to the neurovascular unit,resulting in structural disruption of the blood-brain barrier(BBB)and increased BBB permeability.Increased BBB permeability not only provides a route for tumor-cell invasion but also facilitates infiltration of immunosuppressive cells into the brain parenchyma and the passage of proinflammatory cytokines across the BBB.These changes may remodel the tumor microenvironment(TME)and reactivate dormant tumor cells,thereby forming a potential regulatory axis that drives the recurrence of CNS tumors.This review systematically summarizes the potential regulatory axis of"neuropsychological stress-BBB dysfunction-TME remodeling-CNS tumor recurrence",elucidates the molecular mechanisms underlying neuropsychological stress-mediated BBB injury,and discusses how BBB abnormalities regulate the CNS TME and tumor-cell dormancy.Potential strategies,including BBB-targeted vascular normalization,localized and reversible BBB opening,active trans-BBB drug delivery,and psychological interventions,are also discussed.These insights may provide a theoretical basis and new perspectives for the prevention and management of CNS tumor recurrence.
OBJECTIVES:In radiotherapy for cervical cancer, accurate delineation of the clinical target volume (CTV) is essential for ensuring prescription dose coverage while minimizing radiation exposure to organs at risk (OARs). In clinical practice, however, CTV boundaries are often poorly defined on standard medical images and exhibit substantial morphological variability. Consequently, automated methods based solely on image appearance or a single segmentation framework may fail to consistently capture the fine-grained anatomical structures and spatial coherence of the CTV. Existing methods are therefore prone to boundary displacement, morphological discontinuity, and inadequate generalizability across patients, which may compromise the reproducibility and clinical applicability of radiotherapy planning. This study aims to develop a hierarchical anatomical refinement network (HAR-Net) for automatic CTV delineation in cervical cancer. By explicitly integrating anatomical priors and spatial relationships in addition to image appearance information, HAR-Net was designed to improve segmentation accuracy and consistency. METHODS:Computed tomography images and manual delineations of the CTV and 5 OARs, the bladder, rectum, bilateral femoral heads, and small bowel, were retrospectively collected from 132 patients with cervical cancer who received radiotherapy at Xiangya Hospital, Central South University, between May 2022 and May 2025. All patients had stage IB2-IVA disease according to the 2018 International Federation of Gynecology and Obstetrics (FIGO) staging system. The delineations were completed by experienced radiation oncologists. Patients were randomly divided into a training set (n=92), validation set (n=15), and test set (n=25). HAR-Net used nnU-Net as its backbone and incorporated 2 collaborative modules. First, multi-scale OAR-CTV cross-attention (MOCCA) dynamically integrated the anatomical context of OARs into the CTV segmentation pathway through window-based three-dimensional cross-attention. Second, tri-axial coordinate attention (TCA) encoded global positional information along the depth, height, and width axes and spatially refined the features through adaptive reweighting. Segmentation performance was evaluated using the Dice similarity coefficient (DSC), 95th-percentile Hausdorff distance (HD95), and average symmetric surface distance (ASSD). HAR-Net was compared with several mainstream segmentation methods, including MultiResUNet, AMTA-Net, Swin UNETR, ResUNet-a, and nnU-Net. RESULTS:HAR-Net outperformed multiple state-of-the-art segmentation methods. It achieved a mean DSC of 82.420%, an HD95 of 8.390 mm, and an ASSD of 1.920 mm. Compared to the nnU-Net baseline, HAR-Net improved the DSC by 3.260 percentage points and reduced the HD95 by 4.080 mm. Ablation experiments further demonstrated that both the MOCCA and TCA modules contributed significantly to the improvement in model performance. CONCLUSIONS:By hierarchically integrating multi-scale anatomical context from OARs with tri-axial spatial priors, HAR-Net effectively improves the accuracy and anatomical consistency of automatic CTV delineation for cervical cancer. This framework may reduce the need for repeated manual corrections during clinical delineation, decrease the risk of unnecessary radiation exposure to surrounding OARs, and enhance the overall quality and safety of radiotherapy planning. HAR-Net therefore represents a promising auxiliary tool for automated radiotherapy planning.
Incidence of allergic diseases continues to increase,particularly among children,and has become an important public health concern.As a key link connecting environmental exposure,immune development,and susceptibility to allergic diseases,the gut microbiota has emerged as an important focus of related research.The gut microbiota plays a crucial role in immune system maturation during early life,establishment of immune tolerance,and maintenance of mucosal barrier integrity.Gut dysbiosis may contribute to the occurrence and progression of allergic diseases through multiple mechanisms,including reduced metabolite production,promotion of Th2-type immune skewing,impaired T-cell induction,and disruption of epithelial barrier function.Furthermore,the gut microbiota participates in allergic disease development through the"gut-skin axis""gut-nose axis",and"gut-lung axis".Although different allergic phenotypes exhibit distinct clinical manifestations,they share certain common characteristics,including reduced microbial diversity,depletion of key commensal bacteria,and insufficient immune tolerance.Investigation of gut microbiota and metabolic characteristics in patients with allergic diseases,as well as their roles and clinical implications in disease pathogenesis,may provide a theoretical basis for early prevention,risk identification,and precision microbiome-based interventions for allergic diseases.
Bladder cancer(BCa)is a common malignant tumor of the urinary system.Non-muscle-invasive bladder cancer(NMIBC)accounts for approximately 75%of newly diagnosed BCa cases.Transurethral resection of bladder tumor(TURBT)is currently the principal treatment for NMIBC;however,the postoperative recurrence rate remains high,making adjuvant pharmacological therapy an important component of treatment.In recent years,substantial advances have been made in pharmacological strategies for NMIBC,including immunotherapy,targeted therapy,and novel drug delivery systems.Immune checkpoint inhibitors(ICIs)have demonstrated definite efficacy in high-risk patients who are unresponsive to bacillus Calmette-Guérin.Antibody-drug conjugates(ADCs),such as RC-48,have shown favorable antitumor activity in selected patient populations.With regard to targeted therapy,erdafitinib has achieved breakthrough progress in patients with BCa harboring fibroblast growth factor receptor(FGFR)mutations or fusions.Novel drug delivery systems,such as the mitomycin-containing hydrogel formulation UGN-102,has been approved for marketing by the U.S.Food and Drug Administration(FDA).In addition,gene therapies such as nadofaragene firadenovec have entered clinical practice,while novel treatment modalities,including viral therapies,have progressed to the clinical trial stage.An in-depth understanding of the latest advances in intravesical therapy for NMIBC may provide evidence-based support for clinical decision-making and inform future combination and individualized treatment strategies.
