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Background:Gastric cancer remains a leading cause of cancer-related mortality worldwide, frequently diagnosed at advanced stages due to the limitations of current diagnostic approaches. While cell-free DNA (cfDNA)-based epigenetic profiling has emerged as a promising avenue for early cancer detection, comprehensive investigations into the epigenetic landscape of cfDNA in gastric cancer remain scarce. To address this gap, we aimed to develop and validate a multimodal epigenetic blood test for the non-invasive detection of gastric cancer.Methods:We developed GastroAlert, a multimodal epigenetic blood test that integrates cfDNA methylation, nucleosome footprinting, and fragmentation features into a single diagnostic approach for gastric cancer detection. A custom-designed capture probe panel was utilized to target gastric cancer-associated differentially methylated CpG sites and functionally relevant genes. Targeted enzymatic methylation sequencing was then performed on a discovery dataset consisting of 136 participants, including 53 gastric cancer patients, 55 individuals with benign gastric conditions, and 28 healthy controls. Subsequently, the diagnostic performance of GastroAlert was rigorously validated in an independent external dataset of 149 participants, comprising 79 gastric cancer cases and 70 non-cancer controls.Results:In cross-validation of the discovery dataset, GastroAlert achieved an area under the receiver operating characteristic curve (AUC) of 0.950 [95% confidence interval (CI) 0.874-0.995], with observed AUCs for conventional protein biomarkers ranging from 0.507 to 0.687. Notably, the locked GastroAlert model exhibited robust and reproducible performance in the independent validation dataset, yielding an AUC of 0.965 (95% CI 0.940-0.989) for distinguishing gastric cancer patients from non-cancer controls. For the clinically critical subset of early-stage gastric cancer cases, the model still maintained high diagnostic efficacy with an AUC of 0.921 (95% CI 0.862-0.980) in the discovery dataset and 0.948 (95% CI 0.910-0.985) in the validation dataset. Among all 79 gastric cancer cases in the validation dataset, the model attained an overall sensitivity of 0.898 (95% CI 0.813-0.948) at a specificity of 0.900 in the validation dataset.Conclusions:The findings demonstrate that multimodal epigenetic analysis of cfDNA provides a robust, non-invasive strategy for early gastric cancer detection, with potential clinical utility to improve patient outcomes.

Although hypoxia plays a central role in the pathobiology of cardiovascular and cerebrovascular diseases, controlled hypoxic stimuli, such as intermittent hypoxia conditioning (IHC), can trigger beneficial adaptations that counteract those diseases. IHC has been studied as a readily administered, non-pharmacological intervention for almost a century, it has not yet been widely adopted in clinical practice. Growing evidence demonstrates the beneficial preventive and therapeutic effects of IHC on the cardiovascular system, and although less conclusively established, on the brain. Moreover, IHC is highly feasible and raises few safety concerns. A notable limitation, similar to that of remote ischemic conditioning, is the lack of refined IHC protocols for personalized, disease-specific applications in the individual patient. Significant progress has been achieved in addressing this limitation. For example, increasingly sophisticated modern hypoxia equipment permits customization of IHC parameters according to each individual’s responses to and tolerance of hypoxia. Still to be evaluated are the persistence of IHC’s effects and the capacity of IHC booster protocols to renew its benefits. Comparative analyses of the mechanisms and efficacy of IHC and remote ischemic conditioning could aid in defining their respective applications and possible synergistic effects. This perspective article summarizes the historical development of IHC, presents a selection of preclinical and clinical studies exemplifying recent research progress, and discusses strategies to address the lingering concerns limiting clinical IHC applications.

Background:Cisplatin is a widely used chemotherapeutic agent, but its clinical application is limited by serious ototoxic side effects, including hearing loss, tinnitus, and vertigo. Inflammation is now recognized as a significant contributor to cisplatin-induced hearing loss, but the upstream regulators remain largely undefined. This study aimed to identify novel regulators of cisplatin-induced ototoxicity through CRISPR-Cas9 screening and to determine the role of growth arrest and DNA damage-inducible alpha (GADD45A) in cochlear inflammation and hearing loss.Methods:To identify upstream regulators of cisplatin-induced ototoxicity, a CRISPR-Cas9-based loss-of-function screen was first performed in OC1 cells. Following the identification of Gadd45a as a candidate gene, its effects on cisplatin-induced cytotoxicity were evaluated using cell viability assays, flow cytometry, and TUNEL staining. Integrated transcriptomic and proteomic analyses were subsequently conducted to elucidate the downstream molecular mechanisms. Finally, the protective role of Gadd45a inhibition was validated in vivo through siRNA delivery into the posterior semicircular canal and in Gadd45a conditional knockout (cKO) mice.Results:Gadd45a knockout significantly inhibited cisplatin-induced cell death in the OC1 cell line while simultaneously enhancing autophagy signaling. Transcriptomic profiling revealed a marked downregulation of the expression of C-X-C motif chemokine ligand (CXCL) family cytokines following Gadd45a loss, which was further supported by proteomic analysis of culture supernatants. Mechanistically, Gadd45a knockout specifically inhibited nuclear factor κB subunit 1(NF-κB1) but not RELA proto-oncogene, NF-κB subunit (RELA). Immunofluorescence staining demonstrated that Gadd45a knockout inhibited the nuclear translocation of the NF-κB1 protein, and subsequent studies revealed that the NF-κB1 protein was degraded through the lysosomal pathway. In vivo, both si-Gadd45a injection into the semicircular canal and the knockout of Gadd45a effectively attenuated cisplatin-induced ototoxicity.Conclusions:This study identifies GADD45A as a key regulator of cisplatin ototoxicity and links the balance between apoptosis and autophagy with NF-κB1-CXCL-mediated inflammation. Targeted inhibition of GADD45A signaling may represent a promising therapeutic strategy to prevent hearing loss in patients receiving cisplatin chemotherapy.

Venous leg ulcers (VLUs) result from a multifactorial interplay of etiological factors, posing significant challenges in clinical management. Effective treatment requires a comprehensive assessment to identify the underlying pathophysiological mechanisms, followed by the implementation of an individualized, multidisciplinary approach that integrates the expertise of vascular surgeons, wound care specialists, and other pertinent healthcare professionals. Although both domestic and international vascular surgery societies, as well as other relevant specialties, have issued consensus statements on the diagnosis and treatment of VLUs or clinical guidelines for managing chronic lower extremity venous diseases, there remains a notable gap in systematic guidance specifically focused on wound repair for VLUs. In particular, standardized protocols for surgical wound repair are either lacking or insufficiently detailed in these documents. With the establishment and advancement of wound repair as a specialized field in China, Chinese experts have accumulated substantial clinical experience in the diagnosis and management of VLU-related wound healing. To standardize the surgical repair of VLUs and improve both therapeutic outcomes and patients’ quality of life, the Wound Repair Professional Committee of Chinese Medical Doctor Association convened a panel of multidisciplinary experts for extensive deliberations. Based on a synthesis of current international and domestic evidence and clinical practice, the committee reached consensus on evidence-based recommendations for key issues in VLU wound management, including debridement techniques, indications, timing, and approaches to wound repair for VLUs. This consensus is intended to serve as a practical reference for clinicians involved in the care of patients with VLUs.

Background:Spinal cord injury (SCI) triggers persistent neuroinflammation, gliosis, neuronal loss, and demyelination, leading to motor deficits and neuropathic pain (NeP). Botulinum neurotoxin type A (BoNT/A) has shown anti-inflammatory and neuroprotective effects in acute SCI, but its potential in the chronic phase remains unclear. This study investigates whether combining BoNT/A with electrical muscle stimulation (EMS) enhances recovery in chronic SCI.Methods:Adult mice with severe thoracic SCI (paraplegic) underwent EMS (30 min/d for 10 non-consecutive days starting 3 d post-injury) or no stimulation. Fifteen days after SCI, animals received a single intrathecal injection of BoNT/A (15 pg/5 μl) or saline. Functional recovery was assessed up to 60 d as well as in moderate and mild SCI mice. NeP onset and maintenance were evaluated. Spinal cord tissue was analysed for astrocytic and microglial morphology, neuronal and oligodendroglial survival, myelin protein expression, and in vitro effects on oligodendrocyte precursor cells (OPCs). The phenotype of hindlimb muscles was evaluated through morphological and gene expression analyses.Results:EMS was able to counteract muscle atrophy and fibrosis, and when combined with BoNT/A, also denervation. Moreover, the combination restored hindlimb motor function in chronic SCI, whereas BoNT/A or EMS alone were ineffective. NeP, a common comorbidity associated with SCI, was mitigated by BoNT/A treatment even when administered in the chronic phase. BoNT/A reduced astrocytic hypertrophy and excitatory synapse association and was associated with a morphology-based redistribution of microglial profiles toward a resting-like classification, decreased apoptosis, and increased neuronal and oligodendroglial survival. Myelin basic protein (MBP) expression was significantly elevated in vivo. In vitro, BoNT/A promoted OPC differentiation into myelinating oligodendrocytes, increased process complexity, and upregulated MBP, galactocerebroside C, proteolipid protein, and myelin oligodendrocyte glycoprotein under both proliferative and differentiating conditions. Cleaved synaptosomal-associated protein 25 colocalization with OPC confirmed direct BoNT/A internalization and activity.Conclusions:BoNT/A exerts neuroprotective effects in chronic SCI by reducing neuroinflammation and supporting neuronal and oligodendroglial preservation. When combined with EMS, it also promotes remyelination and improves muscle homeostasis, suggesting that early stimulation creates a permissive environment for recovery. These findings support the clinical evaluation of BoNT/A as a therapeutic strategy for chronic SCI.

Background:Hypertension affects around one billion adults worldwide, with abnormal glucose metabolism and vascular smooth muscle cell (VSMC) phenotype switch playing crucial roles in its pathogenesis. Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme, but its regulation and roles in VSMC phenotype switch and hypertension are unknown. Using the Gene Importance Calculator (GIC) to predict gene essentiality, we identified ribosomal modification protein rimK-like family member A (RIMKLA) as a highly relevant gene and explored its regulatory contributions to hypertension.Methods:Internal mammary arteries from patients with hypertension and normotension, as well as arteries from angiotensin II (Ang II)-induced hypertensive mice, salt-sensitive hypertensive Dahl/SS rats, and spontaneously hypertensive rats, were analyzed in this study. Adenoviruses and adeno-associated viruses were used for ex vivo and in vivo gene overexpression. VSMC-specific RIMKLA or PKM2 knockout mice were generated using the Cre-Loxp system. Arterial tension was measured by wire myography, and blood pressure was assessed by the tail-cuff method and remote radio-telemetry. Protein-protein interactions were determined by co-immunoprecipitation with mass spectrometry. Non-targeted metabolomics, in vitro phosphorylation, adenosine triphosphate (ATP), reactive oxygen species (ROS), and cytoplasmic calcium assays were performed to identify the signaling axis involved.Results:RIMKLA expression was increased in the medial layer of the internal mammary arteries of patients with hypertension, as well as in hypertensive rat and mouse arteries. RIMKLA overexpression in the mesenteric arteries of Sprague-Dawley rats significantly increased vessel contractility. VSMC-specific RIMKLA overexpression increased arterial contractility and blood pressure in mice. VSMC-specific RIMKLA deletion attenuated Ang II-induced hypertension in mice. Mechanistically, we identified RIMKLA as a scaffold protein that binds to protein-tyrosine phosphatase 1B (PTP1B) and PKM2. RIMKLA phosphorylated PTP1B at tyrosine (Tyr)66, leading to PKM2 dephosphorylation and activation at Tyr105. Once activated, PKM2 enhanced glucose metabolism, increased ROS production, and boosted ATP secretion, driving VSMC phenotype switch. RIMKLA-induced vasoconstriction and hypertension were reversed by VSMC-specific PKM2 deletion. Additionally, a PKM2 inhibitor reduced arterial contractility and blood pressure.Conclusions:RIMKLA functioned as a scaffold protein kinase, recruiting both PTP1B and PKM2, and orchestrating PTP1B phosphorylation and its subsequent recruitment to activate PKM2. These findings position RIMKLA as a key regulator of PKM2 activation, promoting VSMC phenotype switch and contributing to hypertension.

Background:Laparoscopic gastrectomy is technically demanding and errors often arise from limited situational awareness. Artificial intelligence (AI)-based computer vision may enhance intraoperative recognition of instruments and anatomy, but evidence for generalizable, real-time deployment remains limited.Methods:We conducted a multicenter study using laparoscopic gastrectomy videos from 4 tertiary hospitals. Data were split by institution into training, internal test, and external validation sets. A You Only Look Once version 10 (YOLOv10)-based model was developed to recognize 18 categories (11 instruments and 7 organs) and integrated into a lightweight user interface for bedside use. Mean average precision at Intersection over Union (IoU) 0.50 (mAP@50) and average precision (AP)@[0.50–0.95] for boxes and masks, recall, and F1 score were calculated. The feasibility of live operating-room deployment was assessed. Surgeon cognitive workload was assessed using the National Aeronautics and Space Administration Task Load Index (NASA-TLX), and system usability was evaluated with the System Usability Scale (SUS).Results:The training set comprised 4308 frames (41,066 labels); the internal testing set, 1803 frames (17,211 labels); and the external validation set, 721 frames (6685 labels). Training performance reached box precision 0.896, recall 0.891, mAP@50 0.937, and AP@[0.50–0.95] 0.846; mask AP@[0.50–0.95] was 0.809. On the internal testing set, box AP@ [0.50–0.95] was 0.670 and mask AP@[0.50–0.95] 0.642. External validation achieved box precision 0.798, recall 0.773, F1 score 0.785, mAP@50 0.832, and AP@[0.50–0.95] 0.684; mask mAP@50 was 0.836 and AP@[0.50–0.95] 0.658. High-performing classes included stapler, ultrasonic scalpel, and forceps, whereas omentum and pancreas were relatively lower. The system operated in real time during laparoscopic gastrectomy on a laptop-grade GPU, providing on-demand overlays without workflow disruption. The NASA-TLX score was 26.72±6.51, indicating low cognitive burden, and the SUS score was 78.33±5.20, demonstrating good usability.Conclusions:We present development, external validation, and live deployment of a real-time AI navigation system for laparoscopic gastrectomy across multiple centers. The model demonstrated robust detection and segmentation of instruments and organs and was feasible for bedside use. Prospective trials are warranted to evaluate effects on intraoperative safety, efficiency, and training.

Background:High alcohol use, defined as consumption exceeding the theoretical minimum risk exposure level, poses a major public health challenge in China, yet comprehensive long-term estimates combining disease burden and indirect economic burdens are limited. This study quantified national and subnational trends in disease and indirect economic burdens attributable to high alcohol use in China from 1990 to 2023 and forecasted the high alcohol userelated indirect economic burden to 2050.Methods:Disease burden data were obtained from the Global Burden of Disease Study 2023. Economic parameters were sourced from the China Statistical Yearbook 2024, the Penn World Table, and the Seventh National Population Census. The indirect economic burden was estimated using a cost-of-illness model. The estimated annual percentage change (EAPC) was calculated to assess trends (1990–2023) in age-standardized mortality and Disability-adjusted life year (DALY) rates, as well as productivity losses due to premature death, morbidity, and total indirect economic burden. Spatial distributions of all-cause burden and the top six leading diseases (ranked by DALYs) were compared between 1990 and 2023. Sex and age-specific patterns were analyzed using absolute DALY numbers and indirect economic burden values. Finally, the Bayesian age-period-cohort model was used to forecast productivity losses due to premature death and morbidity, along with the total indirect economic burden to 2050.Results:National age-standardized mortality rate attributable to high alcohol use declined from 27.68/100,000 [95% uncertainty interval (UI) 13.17–48.69] in 1990 to 10.58/100,000 (95% UI 4.60–19.26) in 2023 [EAPC=–3.02%, (95% UI –4.15 to –1.85), P<0.01], and the age-standardized DALY rate attributable to high alcohol use declined from 1012.53/100,000 (95% UI 567.90–1565.46) to 492.91/100,000 (95% UI 311.38–751.27) [EAPC=–2.26%, (95% UI –3.05 to–1.52), P<0.01]. Corresponding indirect economic burden as a percentage of Gross Domestic Product (GDP) decreased from 0.15% (95% UI 0.13–0.18) to 0.13% (95% UI 0.11–0.16) [EAPC=–0.47%, (95% UI –0.77 to –0.17), P<0.01]. High disease burden consistently clustered in Southwest and North China, while high economic burden mainly concentrated in East and Southwest, with notable regional mismatches. Burden was higher in males than in females, and the age profile of indirect economic loss shifted toward older working-age adults. Forecasts indicated that the overall indirect economic burden as a percentage of GDP reached a nadir around 2039 [EAPC=0.12%, (95% UI 0.10–0.14)], before rising to 0.14% (95% UI 0.12–0.21) in 2050.Conclusions:From 1990 to 2023, age-standardized mortality and DALY rates attributable to high alcohol use declined substantially in China, and the indirect economic burden as a share of GDP decreased modestly, despite marked growth in absolute productivity loss. Subnational heterogeneity persisted among different regions. Forecasts of the indirect economic burden indicate a nadir around 2039, followed by a subsequent increase with uncertainty.

Background:Osteoarthritis (OA) is currently the most common age-related degenerative joint disease, but there remains a lack of disease-modifying therapy for OA treatment. This study aimed to elucidate the critical roles and underlying mechanism of the fat mass and obesity associated gene (FTO) in OA pathogenesis induced by high fat diet (HFD) and HFD coupled with destabilized medial meniscus (DMM) surgery, and to ascertain the synergistic action of the two in OA pathogenesis.Methods:Mouse models were established using solely HFD feeding and combined HFD feeding and DMM surgery. Primary mouse chondrocytes were treated with palmitic acid (PA) and interleukin-1β (IL-1β) to simulate lipotoxicity and inflammation. FTO expression was modulated via genetic, adenoviral, or pharmacological methods. Downstream pyruvate dehydrogenase phosphatases 2 (PDP2) and YTH N⁶-methyladenosine RNA binding protein 2 (YTHDF2) were similarly manipulated by siRNA or overexpression plasmids; adenovirus-mediated knockdown/overexpression of Pdp2 was applied in vivo. Mechanistic studies included RNA sequencing (RNA-Seq) and methylated RNA immunoprecipitation sequencing (MeRIP-Seq).Results:The results revealed reduced FTO expression in the cartilage of both obese OA patients and mouse models. Genetically, adenovirus-induced or pharmacologically-induced FTO inhibition exacerbated OA progression in HFD-fed and HFD+DMM mice. Mechanistically, Fto knockdown downregulated the PDP2 level in an m⁶A-dependent manner via YTHDF2. Pdp2 knockdown exacerbated OA progression in HFD-fed and HFD+DMM mice, whereas PDP2 overexpression markedly alleviated cartilage degeneration. Moreover, YTHDF2 overexpression reversed the role of Fto knockdown in lipid deposition and cartilage degeneration.Conclusions:Our study identifies that downregulation of FTO exerts a pivotal effect on OA with obesity. FTO drives disease progression by regulating PDP2 activity, and YTHDF2 mediates the m⁶A modification of FTO to PDP2. Targeting the FTO/YTHDF2/PDP2 axis offers promising therapeutic potential for OA treatment.

Background:A cancer diagnosis is usually associated with a substantial loss of life years. However, few studies have quantified life expectancy (LE) and years of life lost (YLL) among cancer patients, particularly in China. This study aims to estimate LE and YLL by cancer type, sex, age at diagnosis, and attained age (i.e., the age a cancer survivor has reached at a given time) for cancer patients in China.Methods:This is a comparative assessment based on population-based cancer registration and death surveillance in China. Data on all-cause deaths, cancer cases, and relative survival in 2021 were obtained from publicly available reports released by the National Cancer Center and the Chinese Center for Disease Control and Prevention. Life tables for the general population were constructed using age-specific all-cause mortality rates, whereas relative survival rates and parameterized long-term excess hazard functions were used to construct life tables for cancer patients. We used the standard period life table method to estimate LE of both the general population and cancer patients, assuming that mortality probabilities remained constant over time. The YLL was the LE difference between cancer patients and the sex- and age-matched general population.Results:For cancer patients diagnosed at the median age of 64 years, the LE is 8.8 years [95% confidence interval (CI)8.7–9.0], corresponding to a YLL of 9.2 years (95% CI 9.0–9.3). Male patients have an LE and YLL of 6.7 years (95% CI 6.6–6.8) and 9.8 years (95% CI 9.7–9.9), respectively, while females have 11.2 years (95% CI 11.1–11.4) and 8.4 years (95% CI 8.3–8.6). Thyroid cancer had the highest LE [31.9 years (95% CI 31.5–32.0)], while pancreatic cancer had the lowest [2.6 years (95% CI 2.4–2.8)]. Female patients had better LEs than males across 20 cancer types that affect both sexes. Younger patients experienced greater YLL, except in cases of thyroid cancer, oropharyngeal cancer, ovarian cancer, and male bladder cancer. LE gradually increased in patients who survived the first three years; thereafter, the decline depended on attained age, approaching that of the general population.Conclusions:LE of cancer patients in China varied by sex, cancer type, age at diagnosis, and attained age. Cancer patients, healthcare providers, and policymakers may incorporate these estimates into their decision-making.

Fine particulate matter (PM2.5) is a prevalent environmental pollutant that has been well established as a contributor to morbidity on a global scale. An increasing body of scientific evidence suggests that PM2.5 promotes various modes of regulated cell death (RCD), including apoptosis, necroptosis, pyroptosis, PANoptosis, ferroptosis, and autophagy-dependent cell death, as well as potentially cuproptosis, across a broad spectrum of human diseases. These interconnected pathways demonstrate how exposure to pollutants induces oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress (ERS), and inflammatory responses. Alterations in lysosomal permeability serve as a critical link, connecting environmental pollutants to health conditions. Importantly, dysregulation of RCD mechanisms is associated with exposure to PM2.5 and numerous health disorders, such as cardiovascular diseases (CVDs), neurological conditions, respiratory illnesses, renal and hepatic dysfunctions, reproductive health issues, and ocular diseases. Collectively, RCD functions as a central molecular framework through which PM2.5 exposure accelerates the progression of pathological conditions. This review synthesizes recent mechanistic insights, identifies promising therapeutic candidates, and highlights critical knowledge gaps. It offers a strategic framework to guide future research endeavors aimed at mitigating the impact of PM2.5-induced RCD in human diseases. Additionally, we will identify and explore the research gaps that need to be addressed to effectively translate preclinical PM2.5 studies into clinical trials. We will also provide a comprehensive overview that both highlights these gaps and offers pathways to bridge them.

Medical large language models (Med-LLMs) have shown considerable promise across a broad range of clinical tasks, including decision support, medical documentation, patient communication, multimodal analysis, and telemedicine. Their rapid development has generated growing interest in how large language models (LLMs) may support healthcare practice, while also raising important questions about reliability, clinical validity, and safe deployment. This review provides a structured overview of recent progress in Med-LLMs by examining their major application areas, key challenges, and emerging future directions. Current evidence shows that the clinical usefulness of Med-LLMs cannot be judged by model performance alone. Their value in practice depends on whether they are supported by reliable evidence, remain consistent with current medical knowledge, and can be integrated into clinical workflows. Important challenges remain in evaluation, safety, knowledge updating, and real-world deployment. These issues reflect a gap between performance in controlled settings and clinical practice. Future progress will require stronger clinical validation, better alignment with medical practice, and more careful deployment across different settings. The clinical impact of Med-LLMs will depend on whether they can be used as reliable tools in clinical care.

Background:Simulated microgravity, modeled by head-down tilt (HDT), induces cephalad fluid shifts that perturb intracranial hemodynamics and may affect cognitive function. However, the temporal adaptation of cerebral arterial blood flow (CaBF), both during simulated microgravity and throughout the recovery phase, remains incompletely understood.Methods:In this study, 38 healthy male participants underwent a 7-day -6° HDT protocol followed by a 5-day recovery phase. Four-dimensional flow magnetic resonance imaging (4D flow MRI) was performed at 8 time points [baseline, HDT 12 h, HDT 1 d, HDT 3 d, HDT 7 d, recovery (R) 1 d, R 3 d, and R 5 d] to quantify CaBF and total cerebral blood inflow (TCBI) in the basilar artery (BA), left and right internal carotid arteries (ICAL and ICAR), and left and right middle cerebral arteries (MCAL and MCAR). Systemic vitals and fasting cortisol/renin were collected, and a computerized reaching task assessed reaction time (RT), movement time (MT), and peak velocity (PV). Time effects were tested with repeated-measures analysis of variance (RM ANOVA) or the Friedman test. Predictors of ≥10% TCBI decrease during HDT and ≥10% TCBI increase during the recovery phase were assessed using logistic regression, and flow–behavior associations were examined using Spearman correlation.Results:No significant vessel lumen area changes were found after post-hoc analysis, despite an overall difference observed in the MCAR (χ²=17.40, P=0.015). However, average blood flow significantly changed in the ICAL (χ²=34.16, P<0.001), MCAL (χ²=73.11, P<0.001), and MCAR (χ²=49.02, P<0.001), while BA was stable (RM ANOVA F=0.787, P=0.599) and ICAR showed no significant pairwise effects despite an overall difference (χ²=16.35, P=0.022). TCBI progressively declined during HDT and rebounded rapidly at the onset of recovery (P<0.001). Logistic regression identified systolic blood pressure (SBP) as an independent predictor of a ≥10% TCBI reduction during HDT [P=0.044, odds ratio (OR)=3.004, 95% confidence interval (CI) 1.028-8.777], and baseline cortisol levels predicted significant TCBI decreases from baseline to HDT 7 d (P=0.047, OR=1.306, 95% CI 1.004-1.699). Cognitive-motor testing further revealed phase-dependent changes, with RT and MT generally shortening, most consistently in the no-beep condition, while PV remained stable with beep but increased without beep. Apart from an exploratory negative correlation between TCBI rebound and cued PV (r=-0.360, P=0.031), TCBI changes were largely decoupled from behavioral outcomes.Conclusions:This study demonstrates vessel-specific, lateralized adaptation of cerebral arterial inflow during 7 d of -6° HDT and 5 d of recovery, with anterior circulation more responsive to posture-induced fluid shifts and TCBI gradually decreasing then rapidly rebounding after re-ambulation. Interindividual TCBI susceptibility reflects blood pressure and endocrine status, while cognitive-motor changes remain weakly coupled, underscoring the importance of incorporating early-recovery assessments into HDT studies to better characterize cerebrovascular readaptation after re-ambulation.

Background:Severe bacterial sepsis caused by Klebsiella pneumoniae (KP) is characterized by dysregulated inflammation, multiorgan injury, and high mortality, yet the key molecular drivers of this process remain incompletely understood. This study aimed to elucidate how the Z-DNA binding protein 1 (ZBP1) regulates inflammatory injury during KP-induced sepsis and to identify potential therapeutic targets with translational relevance.Methods:To investigate the role of macrophage ZBP1 in sepsis, we combined transcriptomic datasets from human sepsis cohorts and murine sepsis and KP-infection models with single-cell RNA sequencing of infected tissues. We further established both global and myeloid-specific Zbp1 knockout (Zbp1^fl/flLyz2-Cre^+/-) mice, as well as myeloid-specific Lgmn (encoded Legumain) knockout (Lgmn^fl/flLyz2-Cre^+/-, Lgmn^CKO) mice, to delineate the macrophage-dependent mechanisms of immune regulation. In addition, macrophage-targeted adeno-associated virus 9 (AAV9) vectors driven by the F4/80 promoter were used to overexpress Lgmn in vivo. Flow cytometry, immunofluorescence, and survival analyses were performed to evaluate systemic inflammation, organ injury, and sepsis severity. The effect of recombinant LGMN supplementation on macrophage activation and barrier restoration was also assessed.Results:ZBP1 activation was driven by both type I interferon (IFN-I) signaling and mitochondrial damage. Mechanistically, ZBP1 directly interacted with signal transducer and activator of transcription 3 (STAT3), suppressed its phosphorylation and nuclear translocation, and consequently inhibited transcription of Lgmn, a gene associated with anti-inflammatory macrophage polarization and tissue repair. Genetic and myeloid-specific deletion of Zbp1 resulted in reduced proinflammatory cytokine production and improved survival in both KP- and cecal ligation and puncture (CLP)-induced sepsis models. In contrast, Lgmn^CKO aggravated systemic inflammation, organ injury, and barrier dysfunction, whereas macrophage-targeted AAV9-mediated Lgmn overexpression or recombinant LGMN supplementation alleviated macrophage inflammation, restored epithelial function, and improved survival.Conclusion:These findings reveal a previously unrecognized ZBP1-STAT3-LGMN signaling axis that contributes to immune and inflammatory dysregulation in KP-induced sepsis and suggest that targeting ZBP1 or restoring LGMN activity may represent a promising therapeutic strategy for severe bacterial infections.

Brain tumors, including primary intracranial tumors and brain metastases (BrMs), represent a major threat to human health and are associated with extremely poor prognoses. The brain tumor microenvironment (BTME) is a complex ecosystem composed of various elements, including tumor cells, immune cells, neurons, the vascular system, the extracellular matrix, and cytokines. These elements not only coexist spatially but are also functionally connected, interacting through intricate networks that collectively influence tumor initiation, progression, and therapeutic efficacy. In recent years, the application of novel technologies such as single-cell and spatial transcriptomics has uncovered complex cellular heterogeneity and spatial organization within the BTME. This review comprehensively summarizes the key components and functions of the BTME in tumor development and therapy, the mechanisms underlying intercellular interactions, with an emphasis on their clinical potential and challenges.

Bone is a multifunctional organ essential for structural support, protection, hematopoiesis, and endocrine regulation. Emerging research increasingly highlights the pivotal role of the nervous system in bone metabolism, repair, and musculoskeletal disease progression, particularly the autonomic nervous system (ANS), which precisely regulates bone tissue cells via sympathetic and parasympathetic pathways. The ANS regulates the activity of mesenchymal stem cells (MSCs), osteoblasts, osteoclasts, chondrocytes, and nucleus pulposus cells (NPCs) via neurotransmitters such as norepinephrine (NE), acetylcholine (ACh), neuropeptide Y (NPY), and vasoactive intestinal peptide (VIP), thereby modulating core pathological processes in bone-related disorders including osteoporosis (OP), osteoarthritis (OA), intervertebral disc degeneration (IVDD), and traumatic fractures. Targeted neuromodulation is emerging as a promising therapeutic strategy for musculoskeletal disorders. This review aims to summarize the regulatory roles of the ANS in bone cell metabolism and bone-related pathologies and to evaluate current ANS-bone axis-based interventions to promote skeletal health and alleviate the burden of musculoskeletal diseases.

Background:Epilepsy is a major public health challenge affecting individuals of all ages, especially in low- and middle-income countries (LMICs). Reliable prevalence projections are critical for healthcare planning and resource allocation. This study aimed to forecast the prevalence of epilepsy and its trends in LMICs by age, sex, year, and income level by 2050.Methods:Using data from the Global Burden of Disease Study (GBD) 2023, we projected the prevalence and number of idiopathic and secondary epilepsy cases in LMICs from 2024 to 2050. We developed a hybrid deep neural network (DNN) Transformer framework that integrates Poisson regression and Autoregressive Integrated Moving Average (ARIMA) models for prevalence projection. Decomposition analysis was applied to quantify the contributions of population growth, aging, and prevalence change to the increase in epilepsy cases. Dementia-attributable epilepsy was independently projected to address secondary causes not included in GBD 2023.Results:By 2050, the age-standardized prevalence rate (ASPR) of epilepsy in LMICs was projected to reach 907.22 per 100,000 [95% uncertainty interval (UI) 731.01-1083.56], a 33.32% increase from 2023, with cases rising to 72.04 million (95% UI 57.86-86.23), a 58.68% increase. The ASPRs of idiopathic and secondary epilepsy were estimated at 323.11 and 584.10 per 100,000 in 2050, respectively, with the increase in secondary epilepsy being more than 7-fold that of idiopathic epilepsy since 2023. The ASPR of secondary epilepsy due to neonatal disorders was projected to rise by 65.76%. Model validation demonstrated good predictive performance (root mean squared error <0.001). From 2023 to 2050, the increases in idiopathic and secondary epilepsy cases were forecast to be highest in low-income countries (LICs; 76.12% and 241.50%, respectively), with growth declining as income levels increased. Population growth (21.40%) primarily drove the increase in idiopathic epilepsy cases, whereas changes in prevalence (59.89%) predominantly drove the rise in secondary epilepsy cases. Dementia-attributable secondary epilepsy was projected to reach 3.40 million cases by 2050.Conclusions:We forecast a continuous increase in the prevalence and number of epilepsy cases in LMICs through 2050, with secondary epilepsy increasing more rapidly than idiopathic epilepsy. LICs may exhibit the greatest increases over the next three decades, necessitating targeted interventions and further investigation.

Glucocorticoids (GCs), steroid hormones synthesized and secreted by the adrenal cortex, have been the subject of intensive scientific investigation for over eight decades due to their critical roles in physiological and pathological processes. The systemic secretion, bioavailability, and tissue-specific concentrations of GCs are strictly orchestrated by the hypothalamic-pituitary-adrenal axis, serum corticosteroid-binding globulin levels, and the enzymatic activation of 11β-hydroxysteroid dehydrogenase type 1 and 2 (11β-HSD1 and 11β-HSD2). As pivotal metabolic messengers, GCs signal through binding to glucocorticoid receptors (GR) to maintain metabolic homeostasis by modulating the transcriptional landscape of genes central to glucose and lipid metabolism. Any imbalance in GC levels, whether excess or deficiency, leads to the development of diverse metabolic disorders. Elucidating the underlying mechanisms of this metabolic regulation remains a primary objective of contemporary research. This review summarizes landmark discoveries and focuses on the metabolic impact and dysfunction of glucocorticoids, aiming to establish a robust foundation for the development of optimized therapeutic interventions for patients with metabolic diseases.

BackgroundEmerging evidence indicates that diverse bacteria colonize tumors and facilitate oncogenesis through multifaceted mechanisms, predominantly through immunosuppression of the tumor microenvironment (TME). Fusobacterium nucleatum (F.n) exemplifies this phenomenon in colorectal cancer (CRC), where it mediates immune evasion via tumor cell autophagy and upregulation of programmed death-ligand 1 (PD-L1). Effective strategies for combining precise elimination of intratumoral F.n with chemotherapy remain lacking.MethodsA targeted multimodal nano-based chemoimmunotherapy was engineered by co-loading hyaluronic acid (HA)-coated silver nanoparticles (Ag NPs) and paclitaxel (PTX) into tumor-targeting cationic liposomes (Cls). The combination was mechanistically evaluated for F.n eradication capacity, antitumor effects, and remodeling of the tumor immune microenvironment. Antitumor efficacy and safety were also evaluated in vivo using a tumor-bearing mouse model.ResultsIntratumoral F.n subverted antitumor immunity through a dual mechanism, coupling major histocompatibility complex class I (MHC-I) degradation with PD-L1 upregulation. HA@Ag NPs/PTX Cls exerted synergistic antitumor effects through multimodal mechanisms. HA@Ag NPs/PTX Cls eliminated intratumoral bacteria, restoring microbial homeostasis, enhancing MHC-I antigen presentation, increasing production of tumor necrosis factor (TNF) and interferon (IFN), and downregulating PD-L1 to promote tumor immunorecognition. Combined with PTX-induced apoptosis, the nanotherapy inhibited both primary and metastatic tumors. Notably, bacterial clearance-triggered immune activation established long-term immunological memory, providing durable protection against tumor recurrence. These results highlighted the dual benefit of liposomes in addressing microbial dysbiosis and immune evasion in CRC.ConclusionThis innovative liposomal strategy disrupts the immunosuppressive TME and synergizes with a small-molecule chemotherapeutic agent to induce tumor cell apoptosis, representing a novel approach to potentiate cancer immunotherapy.

BackgroundAs the world’s leading producer and consumer of tobacco, China bears a significant health burden attributable to tobacco. This study aims to provide a precise, updated analysis of the demographic, temporal, and spatial dimensions of the tobacco-attributable disease burden across China.MethodsUsing the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 comparative risk assessment framework and its hierarchical taxonomy, we analyzed tobacco use as a Level 2 (behavioral) risk. We estimated the national and provincial burdens of tobacco use in China from 1990 to 2023, quantifying deaths, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life years (DALYs) stratified by sex, age, cause, and the three Level 3 tobacco sub-categories: smoking, secondhand smoke (SHS), and chewing tobacco. Temporal trends were assessed via average annual percentage change (AAPC).ResultsIn 2023, tobacco use caused 2.38 million [95% uncertainty interval (UI) 2.02−2.83] deaths and 57.27 million (95% UI 48.28−60.82) DALYs, predominantly premature mortality [YLLs 49.45 million (95% UI 42.23−59.25)]. Direct smoking was the primary driver (2.01 million deaths), followed by SHS and chewing tobacco. A profound sex disparity existed in smoking burden, with the male (ASMR; 167.78/100,000) being 9.5-time higher than that of females, although females bore a greater SHS-attributable burden. From 1990 to 2023, absolute deaths and DALYs increased, but their age-standardized rates (ASRs) significantly declined (AAPC for mortality: −2.34%). The burden is concentrated in older adults, with the disease spectrum shifting from respiratory infections in youth to chronic diseases such as heart disease and lung cancer later in life. Geographically, northern provinces had the highest burden, whereas coastal areas had the lowest burden.ConclusionsDespite declining ASRs, China’s tobacco attributable burden is concentrated among males, older adults, and northern provinces. In the context of rapid aging and the long-term harmful effects of tobacco smoking, more stringent and targeted policies should be implemented to address the challenges associated with tobacco use in China.

Radiopharmaceutical therapy (RPT) is a pivotal modality in cancer treatment, with its efficacy substantially modulated by the tumor microenvironment (TME). The TME regulates RPT penetration and influences therapeutic outcomes. Concurrently, RPT actively reconfigures the TME by enhancing immune activation and partially reversing immunosuppression. Specifically, RPT induces tumor cell senescence and immunogenic cell death, and catalyzes immune activation. RPT diminishes immunosuppressive elements, including regulatory T cells and tumor-associated macrophages, and augments populations of CD8⁺ T cells and natural killer cells, thereby fostering a more immunostimulatory TME. Additionally, RPT modulates critical cytokines and upregulates immune checkpoint molecules, bolstering anti-tumor immunity. Nevertheless, pathological features like hypoxia and extracellular matrix stiffness within the TME can hinder RPT biodistribution and therapeutic efficacy. Strategically targeting the TME through approaches, such as fibroblast depletion, hypoxia mitigation, metabolic reprogramming, nerve-immune-cancer interactions, or nanocarrier drug delivery, can amplify RPT effectiveness. Combination immunotherapies that integrate RPT with immune checkpoint inhibitors, chimeric antigen receptor (CAR)-T cells, or cancer vaccines have demonstrated enhanced anti-tumor responses and survival advantages in malignancies such as prostate cancer and neuroendocrine tumors. Given the complexity and heterogeneity of the TME, emerging strategies, including radiation-responsive nanocarriers, CAR-T cells engineered to secrete radiosensitizers, senolytic therapies, and artificial intelligence-driven multimodal data integration, are promising in addressing the challenges and refining precision cancer therapy. In summary, the TME serves as a critical bridge between RPT and immunotherapy; elucidating the interplay among these three elements is essential for advancing combination strategies.

From cold-weather training to deployments in high altitude and arctic conditions, frostbite injury and its sequelae remain a serious concern in military operations. Frostbite harms tissue in two distinct ways. The first involves ice crystal formation within tissue, resulting in mechanical damage and ischemia. The second occurs secondary to the inflammatory and prothrombotic state caused by reperfusion from rewarming frozen tissue. Frostbite injuries can be classified in a number of ways, but no perfect system exists. Initial work-up and diagnosis are primarily clinical. However, in equipped treatment facilities, advanced imaging modalities such as technetium-99m (^99mTc) bone scintigraphy, magnetic resonance angiography, single-photon emission computed tomography/computed tomography (SPECT/CT), and more can play a role in diagnosis and treatment. In resource-constrained environments, such as the deployed setting, management should involve an algorithmic approach. After concurrent hypothermia and/or trauma have been evaluated for and treated, active rewarming should take place so long as there is no risk of refreezing. During re-warming, surgical consultation and evacuation considerations should be considered. Once evacuated to a definitive treatment facility, thrombolytic as well as other therapies may be indicated. Unless there is evidence of severe damage or infection, surgical management is typically delayed until injury margins are fully demarcated. Longer-term prognosis is dependent on severity, with deeper injuries often resulting in longer hospital stays, more amputations, and chronic disability. Looking forward, future frostbite research should aim to bridge field and hospital care with the goal of minimizing tissue loss and accelerating functional recovery.

Background:Spiral ganglion neurons (SGNs) relay auditory sensory information from the cochlea to the brain. Their loss results in permanent hearing impairment in humans due to their limited regenerative capacity. Progress in hearing restoration has been constrained by the inaccessibility of human inner ear tissue and challenges in generating functionally mature human SGN-like neurons from stem cells in vitro.Methods:To generate human SGN-like neurons from human induced pluripotent stem cells (hiPSCs), we recapitulated key signaling pathways involved in human inner ear development. On day (D) 11 of differentiation, nerve growth factor receptor-positive cells (precursors of pre-placodal ectoderm and neural crest) were isolated using magnetic sorting. From D18 to D25, cultures were treated with sonic hedgehogs to induce otic neural progenitors. Neuronal maturation was subsequently promoted by a cocktail of brain-derived neurotrophic factor, neurotrophin-3, and insulin-like growth factor-1, which supports SGN development. Cellular identity and functionality were assessed using single-cell RNA sequencing, immunocytochemistry, whole-cell patch-clamp electrophysiology, co-culture assays, and calcium ion (Ca²⁺) imaging.Results:hiPSC-derived SGN-like neurons exhibited morphological, molecular, electrophysiological, and functional characteristics of SGNs in vivo. Neurons acquired bipolar morphology and were wrapped by glial cells. Transcriptomic analysis revealed that SGN-like neurons were distinct from other neuronal lineages and showed similarity to type I and type Ⅱ SGNs based on expression of synaptic and intrinsic excitability-related genes. Electrophysiological recordings revealed progressive hyperpolarization of resting membrane potential and emergence of overshooting action potentials, consistent with neuronal maturation. In co-culture systems, human SGN-like neurons formed functional synaptic connections with mouse cochlear hair cells and cochlear nucleus neurons, evidenced by Ca²⁺ transients and induction of the immediate early gene c-Fos.Conclusions:This study reports a robust and reproducible protocol for generating human SGN-like neurons from hiPSCs, providing a versatile platform for studying human auditory development, disease modeling, drug screening, and cell-based therapies for hearing restoration.

Oral squamous cell carcinoma (OSCC) is a major global health challenge, with most cases being diagnosed at advanced stages. Traditional diagnostic methods are often invasive and costly, and can delay diagnosis. Saliva has emerged as a promising non-invasive source of biomarkers for OSCC detection. This highlights the need for accessible, non-invasive, and sensitive biomarkers for OSCC detection. This review critically evaluates the current status and future potential of salivary biomarkers in OSCC, with an emphasis on their diagnostic efficacy, sensitivity, specificity, clinical validation, and advantages over traditional serum- and plasma-based markers. Saliva is a promising liquid for biopsy due to its non-invasive collection and molecular richness. We summarize evidence on diverse salivary biomarkers, including microRNAs (miRNAs), proteins, metabolites, circulating tumor cells (CTCs), and circulating tumor DNA (ctDNA), highlighting their dysregulation in OSCC and diagnostic utility. Particular emphasis is placed on CTCs, ctDNA, and miRNAs, which demonstrate stability in saliva and potential for early detection. We further discuss advances in next-generation sequencing, mass spectrometry, and artificial intelligence/machine learning that enable the development of biomarker panels with improved diagnostic accuracy over single markers. Despite challenges such as sample heterogeneity and the lack of standardized protocols, salivary biomarkers hold strong potential to transform OSCC care by enabling earlier detection, guiding personalized therapies, and supporting non-invasive disease monitoring. However, achieving methodological standardization, validating biomarkers across diverse cohorts, and integrating them into clinical workflows are imperative before their routine application in practice.

Background:Bacteria-mediated cancer therapy leverages bacteria to modulate the tumor immune microenvironment and deliver therapeutics. However, its clinical application is limited by toxicity, off-target effects, and uncontrolled drug release. Improving tumor targeting and precise payload delivery through rational bacterial engineering is essential for increasing efficacy and safety.Methods:An attenuated Salmonella ΔhtrA::luxI-VNP20009 strain expressing OmpA-SpyTag (AISI-ST) was constructed for the modular surface conjugation of SpyCatcherΔ (SC)-fused quadruple arginine-glycine-aspartic acid (RGD) peptides (named AISI-ST/SC-RGD×4) and for building biointerfaces for enhanced tumor adhesion via RGD-mediated integrin αvβ3 interactions. The tumor-bearing mice received intravenous injections of AISI-ST/SC-RGD×4, and their biodistribution was analyzed using bioluminescence imaging and colony-forming unit (CFU) counts. Quorum-sensing (QS)-regulated high-temperature requirement A (HtrA) and anti-programmed cell death protein 1 (anti-PD1) nanobody expression based on the LuxI promoter in strains was validated by Western blotting. Immune responses were assessed using flow cytometry.Results:The incubation of the fused proteins with the AISI-ST strain for 1 h was sufficient to form a stable biological interface. The quadruple RGD-modified bacteria (AISI-ST/SC-RGD×4) exhibited greater enrichment in various solid tumors and lung metastases with reduced off-target accumulation. QS induced the expression of the HtrA protein within tumors, resulting in enhanced extracellular polysaccharide-mediated immunogenicity to activate immune cells. Further expression of anti-PD1 nanobodies synergistically enhanced antitumor immunity, increasing the percentage of M1 macrophages (MACS) and CD8⁺ T cell proliferation while suppressing M2 MACS and regulatory T cells (Tregs). This approach achieves potent tumor suppression via targeted immune remodeling.Conclusions:This study presents octopus-inspired engineered bacteria with a “plug-and-display” system and tumor-specific drug delivery that achieves enhanced tumor targeting and potent antitumor effects. This study describes a promising strategy for the precise and safe clinical translation of bacteria-mediated cancer immunotherapy.

Histone deacetylase 6 (HDAC6) is a unique, predominantly cytoplasmic enzyme that regulates a broad spectrum of cellular and physiological processes, including cell proliferation, migration, intracellular transport, and differentiation. Its distinct structural configuration, comprising two catalytic deacetylase domains and a zinc finger ubiquitin-binding domain (ZnF-BUZ), enables HDAC6 to deacetylate a variety of non-histone substrates, such as α-tubulin, heat shock protein 90 (Hsp90), cortactin, and peroxiredoxin (Prdx). Furthermore, HDAC6 plays a key role in cellular stress responses and cell survival by facilitating the clearance of misfolded proteins, inducing autophagy, and modulating the unfolded protein response. Despite its cytoprotective roles, HDAC6 has emerged as a therapeutic target due to its involvement in multiple pathological pathways and age-related disorders. Tubastatin A (Tub A), a novel and highly selective HDAC6 inhibitor, demonstrates strong therapeutic potential against neurodegenerative, cardiovascular, autoimmune, metabolic, cancer, and other diseases. Tub A enhances the acetylation of both histone and non-histone proteins, thereby modulating gene expression and diverse cellular processes. It shows pharmacological effects, including anti-inflammatory, neuroprotective, anti-diabetic, anti-obesity, anti-oxidant, and other activities. Moreover, preclinical evidence suggests that Tub A effectively regulates multiple pathological pathways by inhibiting HDAC6, which contributes to ameliorating age-related disorders. Therefore, Tub A represents a promising epigenetic modulator with broad therapeutic relevance. Hence, further comprehensive and large-scale investigations are warranted to elucidate its clinical potential and its roles in disease management, as no clinical data related to Tub A activity are available. This review highlights the therapeutic potential of the selective HDAC6 inhibitor Tub A across various pathological conditions, discusses current preclinical findings, and outlines key challenges and future directions for clinical translation.

Background:Early-onset (<50 years) and never-smoker lung cancers are increasing global concerns. The emerging trends challenge current screening guidelines, which focus on adults aged >50 years with heavy smoking histories. We applied the US Preventive Services Task Force (USPSTF) 2021 screening criteria as the primary definition of high-risk individuals eligible for lung cancer screening and assessed the potential optimization of these criteria using real-world lung cancer data in China.Methods:In this nationwide, multicenter, hospital-based observational study, we enrolled asymptomatic patients with surgically resected primary lung cancer across 26 tertiary hospitals from January 1, 2014 to December 31, 2021. Screening eligibility was classified using USPSTF 2021 criteria (aged 50–80 years, ≥20 pack-year smoking history, and ≤15 quit-years for former smokers). Temporal trends in eligibility, screening utilization, and mortality risks were assessed through joinpoint regression and Cox proportional hazards models.Results:A total of 106,266 asymptomatic patients with lung cancer were enrolled. Among the 102,555 patients with complete age and smoking information, only 8.8% (8985/102,555) met the USPSTF 2021 eligibility criteria. The eligibility proportion declined sharply from 21.6% (350/1617) in 2014 to 6.1% (1737/28,582) in 2021, with the annual percentage change being –17.4% [95% confidence interval (CI) –19.1 to –15.9]. Patients with screening utilization, irrespective of eligibility status, demonstrated a higher proportion of stage Ia diagnoses compared with those who were not screened. Screening- ineligible group exhibited 40% lower mortality risk overall [adjusted hazard ratio (HR)=0.60, 95% CI 0.55–0.66], with consistent survival advantages across stage I (adjusted HR=0.63, 95% CI 0.54–0.74) and stage Ⅲ (adjusted HR=0.76, 95% CI 0.64–0.90) subgroups.Conclusions:Rigid age- and smoking-based criteria overlook substantial at-risk populations in China. Implementing individualized risk stratification is essential to advance equitable lung cancer screening.

Background:Metabolic syndrome (MetS) is characterized by chronic low-grade inflammation and immune dysregulation, which may increase susceptibility to sepsis. However, epidemiologic evidence remains limited. This study aimed to evaluate the association of MetS with the risk of sepsis and sepsis-related mortality.Methods:This study included 359,633 participants from the UK Biobank and 152,317 participants from the Kailuan Study. MetS was defined as the presence of ≥3 metabolic abnormalities. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of MetS with risk of sepsis and 28-day mortality following sepsis. Stratified analyses were conducted to assess potential effect modification. In the UK Biobank, we further evaluated the dose-response relationship between the number of MetS components and sepsis outcomes, explored potential mediation by inflammatory and immune biomarkers, and investigated the joint effect of MetS and lifestyle; in the Kailuan Study, we further investigated the impact of MetS evolution on sepsis risk. Sensitivity analyses were performed to evaluate the robustness of the results.Results:During a median follow-up of 13.7 years, 11,040 sepsis cases were identified in the UK Biobank, whereas 5672 cases were documented in the Kailuan Study during a median follow-up of 16.4 years. After multivariable adjustment, MetS was associated with higher risks of sepsis (HR=1.55, 95% CI 1.49–1.61) and 28-day mortality following sepsis (HR=1.51, 95% CI 1.37–1.65) in the UK Biobank; corresponding HRs were 1.32 (95% CI 1.25–1.40) and 1.49 (95% CI 1.32–1.69) in the Kailuan Study, respectively (all P<0.001). These associations were generally consistent across stratified analyses. Moreover, the risk of sepsis outcomes increased with the number of MetS components and was partly mediated by inflammation. Compared with individuals free of MetS, individuals with MetS and an unfavorable lifestyle had substantially higher risks of sepsis (HR=1.91, 95% CI 1.81–2.00) and 28-day mortality following sepsis (HR=1.84, 95% CI 1.64–2.07), whereas those with MetS but a favorable lifestyle showed only a modestly increased risk of sepsis and no excess risk of 28-day mortality (HR=1.18, 95% CI 1.09–1.28 and HR=1.05, 95% CI 0.88–1.27, respectively). In analyses of MetS evolution, using individuals with persistently normal metabolic status as the reference, those with a persistent MetS demonstrated the highest risks of sepsis (HR=1.46, 95% CI 1.32–1.61) and 28-day mortality following sepsis (HR=1.88, 95% CI 1.50–2.35), followed by individuals with progressive MetS (HR=1.17, 95% CI 1.05–1.31 and HR=1.36, 95% CI 1.04–1.77, respectively), whereas those who recovered from MetS did not show a significantly increased risk (HR=1.09, 95% CI 0.96–1.25 and HR=1.19, 95% CI 0.87–1.61, respectively). Sensitivity analyses confirmed the robustness of the findings.Conclusions:This study demonstrated that MetS was associated with an increased risk of sepsis and sepsis-related mortality. These associations were partially mediated through inflammatory responses. The findings highlight the importance of maintaining metabolic health as well as promoting healthy lifestyles as strategies to reduce its burden.

Background:Cancer in women represents a significant disease burden, posing challenges for prevention, treatment, and caregiving. This study aimed to analyze the epidemiological trends of the women’s cancer burden and the main influencing factors in the group of twenty (G20) from 1990 to 2023.Methods:Incidence, prevalence, mortality, and disability-adjusted life years (DALYs) for breast, cervical, uterine, and ovarian cancers, as well as fertility rates for G20 and its 98 locations, were sourced from the Global Burden of Disease Study 2023. Age-standardized rates (ASRs), quality of care index (QCI), and 5-year relative survival of integrated women’s cancers were calculated. Average annual percent changes (AAPCs) were used to determine the temporal trends by age and region. Decomposition analysis identified drivers of changes in case numbers, linear regression assessed the associations with DALY rate changes, and dominance analysis identified dominant predictors.Results:In 2023, the incidence, prevalence, mortality, and DALYs from women’s cancers in G20 were 3.29 [95% uncertainty interval (UI) 2.60–4.14], 26.71 (95% UI 21.99–32.40), 1.16 (95% UI 0.91–1.45), and 36.58 million (95% UI 28.40–46.32), respectively, with ASRs of 87.63/100,000 (95% UI 65.12–115.85), 706.16/100,000 (95% UI 555.75–890.02), 30.03/100,000 (95% UI 22.10–39.58), and 994.79/100,000 (95% UI 728.43–1328.81). The QCI was 75.13 [95% confidence interval (CI) 73.67–76.59], and the 5-year relative survival rate was 65.74% (95% CI 65.53–65.95). From 1990 to 2023, there was a significant increase in incidence, prevalence, mortality, and DALYs in G20, primarily driven by population growth. Age-standardized incidence rate, QCI, and 5-year relative survival increased, while age-standardized mortality and DALY rates decreased. Changes in prevalence rates of breast cancer and cervical cancer for women aged 15–49 years were positively associated with changes in DALY rates of women’s cancers, whereas changes in the total fertility rate were negatively associated. Dominance analysis confirmed these three factors consistently as dominant predictors between 1990 and 2023. Reducing the prevalence of breast and cervical cancers and increasing fertility among women aged 15–49 years could lower the overall DALY burden attributable to women’s cancer.Conclusions:The incidence, prevalence, mortality, and DALYs of women’s cancers in G20 have increased substantially from 1990 to 2023. Tailored prevention strategies should consider age and cancer type, emphasizing reproductive health for women of reproductive age.

Neurodegenerative diseases (NDs) are characterized by progressive neuronal loss and proteostatic failure, driven by impaired clearance of misfolded proteins via the ubiquitin-proteasome system (UPS) and autophagy. In UPS, E3 ubiquitin ligases are crucial for regulating protein ubiquitination and degradation. Mutations in E3 ligases, along with dysfunctions of specific ligases such as Parkin, the C-terminus of HSC70-interacting protein (CHIP), and tripartite motif-containing proteins, have been identified as key factors in the buildup of amyloid-β, α-synuclein, tau, transactive response DNA-binding protein 43, and mutant huntingtin. These accumulations are associated with NDs like Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Therapeutic strategies targeting E3 ligases, particularly proteolysis-targeting chimeras (PROTACs), are being developed for ND treatment and are currently in clinical trials. These approaches aim to enhance E3 ligase activity and promote selective protein degradation. Here, we examine how individual E3 ligases influence cell-fate decisions in NDs, showing that their substrate selection determines whether neurons survive or die. Building on this knowledge, we present an innovative therapeutic pipeline that includes ligase activators, PROTAC degraders, and miRNA switches, which are molecules designed to transition from research to clinical application.

Background:Abnormal glucose metabolism often contributes to myofibroblast activation and the pathogenesis of skin fibrotic diseases. All-trans retinoic acid (ATRA), the active component of tretinoin cream, can regulate glucose metabolism and activate myofibroblasts. Importantly, investigating the potential of ATRA to inhibit myofibroblast activation by modulating glucose metabolism could reveal the translational significance of ATRA in attenuating hypertrophic scar (HS) formation.Methods:We first conducted a multicenter, double-blind, randomized controlled trial (RCT) to compare the effects of tretinoin cream with those of the first-line medication, silicone gel. In the mechanistic study, the characteristics of glucose metabolic reprogramming and the activation of hypertrophic scar fibroblasts (HSFs) after ATRA treatment were identified through multi-omics profiling, complemented by glucose metabolism assays and functional validations. Besides, genetic overexpression targeting the potential downstream molecules of ATRA, including hypermethylated in cancer 1 (HIC1), phosphoenolpyruvate carboxykinase (PCK)1, and PCK2, was conducted in vitro in HSFs and in vivo in skin fibroblasts of Col1a2-CreER mice.Results:Our RCT demonstrated that tretinoin cream is non-inferior to silicone gel in preventing HS formation, with the absdute risk difference of incidence rates [–8.65% 90% two-sided (confidence interval) CI –23.03 to 5.74] and in decreasing scar thickness [(2856.20±211.83) μm vs. (1664.57±273.50) μm], attributing to the reduction in HSF proliferation and the proportion of myofibroblasts. Moreover, tretinoin cream effectively mitigated HS formation in both mice and rabbits without impeding normal wound healing. Mechanistically, HSFs underwent glucose reprogramming, characterized by increased aerobic glycolysis, which facilitated the transition of HSFs to myofibroblasts and their proliferation. However, ATRA upregulated HIC1, PCK1, and PCK2 expression through retinoic acid receptor alpha (RARα) activation, thereby inhibiting the fibrotic phenotypes of HSFs by suppressing aerobic glycolysis and facilitating gluconeogenesis. The fibroblast-specific overexpression of HIC1, PCK1, or PCK2 in Col1a2-CreER mice significantly reduced myofibroblast activation and hypertrophic scarring.Conclusions:Our study not only substantiated that topical tretinoin cream could serve as an effective strategy to prevent HSs in clinical settings, but also established ATRA as a regulator of glucose metabolism. Importantly, ATRA/RARα-mediated glucose reprogramming was identified as a potential therapeutic target for attenuating HS formation.

Sepsis is a life-threatening condition characterized by an exaggerated and uncontrolled immune response, leading to widespread inflammation throughout the body. This immune response can compromise the integrity of the endothelial barrier, resulting in increased vascular permeability. The degree of vascular permeability in septic shock patients correlates with disease severity and significantly influences the outcomes of resuscitation and prognosis. This review systematically examines the structural regulation of the endothelial barrier and the dynamic mechanisms of its injury in subgroups of sepsis. In response to these mechanisms, emerging therapeutic strategies focus on glycocalyx protection, signal pathway modulation, cytoskeleton stability, and immune regulation, aiming to restore endothelial barrier function through multi-target synergism. In the future, combining analysis of endothelial barrier function and the dynamic regulation mechanism provides a new perspective for the precise treatment of sepsis.

Hypoxia is a central pathophysiological driver of inflammatory airway diseases, shaping disease progression largely through hypoxia-inducible factor 1α (HIF-1α) signaling. Across these disorders, hypoxia exacerbates airway inflammation through shared mechanisms. As a key signaling hub, HIF-1α disrupts epithelial barrier integrity and initiates inflammatory cascades; reprograms immune responses, promoting the activation and trafficking of eosinophils, T cells, and macrophages while reshaping cytokine profiles, to drive tissue injury; and accelerates airway remodeling, thereby worsening airflow limitation and perpetuating inflammatory cycles. Realizing effective targeted therapies will require rigorous validation of HIF-1α as a therapeutic node and the development of disease-tailored interventions aligned with distinct pathological features. In parallel, strengthened translational and clinical research on hypoxia is essential to build a robust evidence base for practice. This review synthesizes hypoxia-driven mechanisms shared across airway diseases, articulates a unifying framework for HIF-1α signaling across pathological contexts, and highlights the therapeutic implications of fundamental discoveries. By addressing the paucity of cross-disease analyses of hypoxia pathways, it provides both a conceptual foundation and a practical roadmap for developing precise and efficient targeted therapies for inflammatory respiratory diseases.

With the advancement of manned spaceflight technology, significant progress has been made in the fields of aerospace medicine and space biology to address the needs of astronauts in terms of health, safety, and mission performance. The physiological and pathological changes during microgravity exposure, including perception, response, and adaptation mechanisms, are gradually being unraveled. This study aimed to systematically summarize the common features of various molecules and structures within the cell membrane, cytoplasm, and nucleus responsible for sensing microgravity. It further examined the heterogeneous responses across different tissues, organs, and cells, as well as systemic-level interactions and synergies, and proposed a novel multilevel gravity-sensing theory. Additionally, the study highlighted cutting-edge in-orbit health monitoring technologies, including rapid fluid analysis using sensitive biomarkers and non-invasive evaluation using two-photon fluorescence microscopy. Furthermore, it explored the promising applications of emerging therapeutic approaches for microgravity adaptation, including small nucleic acid drugs targeting gene regulation, exosome-based drug delivery systems, and natural small-molecule drugs aimed at combating microgravity effects.

Throughout pregnancy, the immune microenvironment undergoes dynamic changes in patients with concomitant autoimmune diseases (AIDs). These alterations not only affect disease activity and clinical manifestations, but also play a pivotal role in sustaining maternal-fetal immune tolerance and pregnancy outcomes. Extensive preclinical studies have elucidated the mechanisms of immune regulation in normal pregnancy, whereas the dynamic immune changes in pregnancies complicated by AIDs remain poorly understood. Recent studies have revealed significant variations in immune responses to pregnancy among individuals with AIDs, which may contribute to distinct patterns of AIDs flares during this period. Despite substantial progress in immunology and reproductive medicine, comprehensive reviews addressing the dynamic changes in the immune microenvironment during pregnancy in the context of AIDs are lacking. In this review, we summarize existing knowledge and incorporate recent multidisciplinary findings, focusing on the dynamic changes in systemic immune adaptation and maternal-fetal immune interactions in the context of AIDs during pregnancy. We emphasize the clinical significance of these immune dynamics for optimizing management and therapeutic strategies. Additionally, we propose new perspectives and provide recommendations to guide future research and the development of personalized treatment approaches.

Background:Different glycemic indicators and diagnostic criteria for prediabetes and diabetes identify overlapping but distinct populations. However, the extent to which these definitions lead to differences in estimated prevalence and associated health outcomes remains unclear. This study aimed to compare the prevalence of prediabetes and newly diagnosed diabetes across different glycemic indicators and diagnostic criteria, and to examine their associations with mortality and life expectancy.Methods:We analyzed data from 141,945 adults from a nationally representative cohort study (the 2013 cycle of China Chronic Disease and Risk Factors Surveillance) in China, with follow-up through December 2021. Using fasting plasma glucose (FPG), 2-hour postload glucose (2hPG), and hemoglobin A1c (HbA1c) levels, prediabetes was defined according to the American Diabetes Association (ADA), World Health Organization (WHO), or International Expert Committee (IEC) criteria, and newly diagnosed diabetes was defined according to the ADA criteria. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) of all-cause and cause-specific mortality associated with different definitions, with adjustment for demographic characteristics, socioeconomic status, lifestyle factors, dietary factors, and baseline comorbidities. Life expectancy was estimated using sex- and age-specific abridged life tables by integrating population mortality rates with exposure-specific HRs and prevalence.Results:Prediabetes prevalence varied widely across glycemic indicators, with the highest estimate of 26.2% (95% CI 24.0–28.4) based on ADA FPG criteria and the lowest estimate of 3.0% (95% CI 2.8–3.2) based on IEC HbA1c criteria, while the prevalence of newly diagnosed diabetes was 4.4% (95% CI 4.1–4.8) based on ADA FPG, 2.6% (95% CI 2.4–2.8) based on ADA HbA1c, and 3.6% (95% CI 3.3–3.8) based on ADA 2hPG. Over a median follow-up of 9.0 years, a total of 6924 deaths were documented. Compared with people with normoglycemia, prediabetes defined by FPG (either ADA or WHO criteria) was not significantly associated with increased risks of all-cause or cardiovascular disease (CVD) mortality (all P-values >0.05). In contrast, prediabetes defined by 2hPG or HbA1c (either ADA or IEC criteria), was associated with higher risks of all-cause mortality (HRs ranged from 1.13 to 1.23; all P-values <0.001) and CVD mortality (HRs ranged from 1.12 to 1.25; all P-values <0.001). Prediabetes defined by 2hPG or HbA1c, but not FPG, was associated with 1.1–2.3 years reduction in life expectancy, with the largest loss observed for IEC HbA1c. In addition, diabetes defined by FPG, 2hPG or HbA1c was each significantly associated with a higher risk of all-cause and CVD mortality (HRs ranged from 1.25 to 1.51; all P-values <0.001), and a reduction in life expectancy (2.0–3.7 years). Furthermore, the 2hPG-based definition of prediabetes and diabetes was associated with mortality risk, independent of FPG and HbA1c levels.Conclusions:These findings suggest that reliance on FPG alone may fail to identify certain individuals at elevated mortality risk. In contrast, 2hPG and HbA1c provide additional prognostic information beyond FPG.

Chronic wounds pose a substantial global health burden, due to the high incidence and recurrence rates, and associated morbidity. Excessive and sustained production of reactive oxygen species (ROS) is a hallmark of the chronic wound microenvironment, ultimately stalling the repair process. The pathological accumulation of ROS in chronic wounds has motivated the development of ROS-responsive drug delivery systems (DDS), which show considerable potential in improving wound healing outcomes. In this review, we provide a comprehensive overview of the advances in ROS-responsive DDS for chronic wound healing, summarizing the design principles, material chemistry, and underlying ROS-triggered functional mechanisms. Key translational challenges are discussed, including material biocompatibility, stability in protease- and ROS-rich wound exudates, manufacturing scalability, and regulatory considerations. Finally, we outline future perspectives, emphasizing the integration of multi-responsive functionalities, real-time ROS monitoring, and advanced biomaterial engineering to accelerate clinical translation. By aligning therapeutic release with the dynamic redox status of chronic wounds, ROS-responsive DDS holds considerable potential to redefine precision therapy for wound management.