Oral squamous cell carcinoma (OSCC) is a common head and neck malignancy. Approximately 50% to 60% of patients with OSCC are diagnosed at a locally advanced stage (clinical staging III-IVa). Even with comprehensive and sequential treatment primarily based on surgery, the 5-year overall survival rate remains below 50%, and patients often suffer from postoperative functional impairments such as difficulties with speaking and swallowing. Programmed death receptor-1 (PD-1) inhibitors are increasingly used in the neoadjuvant treatment of locally advanced OSCC and have shown encouraging efficacy. However, clinical practice still faces key challenges, including the definition of indications, optimization of combination regimens, and standards for efficacy evaluation. Based on the latest research advances worldwide and the clinical experience of the expert group, this expert consensus systematically evaluates the application of PD-1 inhibitors in the neoadjuvant treatment of locally advanced OSCC, covering combination strategies, treatment cycles and surgical timing, efficacy assessment, use of biomarkers, management of special populations and immune related adverse events, principles for immunotherapy rechallenge, and function preservation strategies. After multiple rounds of panel discussion and through anonymous voting using the Delphi method, the following consensus statements have been formulated: 1) Neoadjuvant therapy with PD-1 inhibitors can be used preoperatively in patients with locally advanced OSCC. The preferred regimen is a PD-1 inhibitor combined with platinum based chemotherapy, administered for 2-3 cycles. 2) During the efficacy evaluation of neoadjuvant therapy, radiographic assessment should follow the dual criteria of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune RECIST (iRECIST). After surgery, systematic pathological evaluation of both the primary lesion and regional lymph nodes is required. For combination chemotherapy regimens, PD-L1 expression and combined positive score need not be used as mandatory inclusion or exclusion criteria. 3) For special populations such as the elderly (≥ 70 years), individuals with stable HIV viral load, and carriers of chronic HBV/HCV, PD-1 inhibitors may be used cautiously under the guidance of a multidisciplinary team (MDT), with close monitoring for adverse events. 4) For patients with a poor response to neoadjuvant therapy, continuation of the original treatment regimen is not recommended; the subsequent treatment plan should be adjusted promptly after MDT assessment. Organ transplant recipients and patients with active autoimmune diseases are not recommended to receive neoadjuvant PD-1 inhibitor therapy due to the high risk of immune related activation. Rechallenge is generally not advised for patients who have experienced high risk immune related adverse events such as immune mediated myocarditis, neurotoxicity, or pneumonitis. 5) For patients with a good pathological response, individualized de escalation surgery and function preservation strategies can be explored. This consensus aims to promote the standardized, safe, and precise application of neoadjuvant PD-1 inhibitor strategies in the management of locally advanced OSCC patients.

Interferon stimulating factor STING, a transmembrane protein residing in the endoplasmic reticulum, is extensively involved in the sensing and transduction of intracellular signals and serves as a crucial component of the innate immune system. STING is capable of directly or indirectly responding to abnormal DNA originating from diverse sources within the cytoplasm, thereby fulfilling its classical antiviral and antitumor functions. Structurally, STING is composed of 4 transmembrane helices, a cytoplasmic ligand binding domain (LBD), and a C terminal tail structure (CTT). The transmembrane domain (TM), which is formed by the transmembrane helical structures, anchors STING to the endoplasmic reticulum, while the LBD is in charge of binding to cyclic dinucleotides (CDNs). The classical second messenger, cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), represents a key upstream molecule for STING activation. Once cGAMP binds to LBD, STING experiences conformational alterations, which subsequently lead to the recruitment of Tank-binding kinase 1 (TBK1) via the CTT domain. This, in turn, mediates interferon secretion and promotes the activation and migration of dendritic cells, T cells, and natural killer cells. Additionally, STING is able to activate nuclear factor-κB (NF-κB), thereby initiating the synthesis and release of inflammatory factors and augmenting the body’s immune response. In recent years, an increasing number of studies have disclosed the non-classical functions of STING. It has been found that STING plays a significant role in organelle regulation. STING is not only implicated in the quality control systems of organelles such as mitochondria and endoplasmic reticulum but also modulates the functions of these organelles. For instance, STING can influence key aspects of organelle quality control, including mitochondrial fission and fusion, mitophagy, and endoplasmic reticulum stress. This regulatory effect is not unidirectional; rather, it is subject to organelle feedback regulation, thereby forming a complex interaction network. STING also exerts a monitoring function on the nucleus and ribosomes, which further enhances the role of the cGAS-STING pathway in infection-related immunity. The interaction mechanism between STING and organelles is highly intricate, which, within a certain range, enhances the cells’ capacity to respond to external stimuli and survival pressure. However, once the balance of this interaction is disrupted, it may result in the occurrence and development of inflammatory diseases, such as aseptic inflammation and autoimmune diseases. Excessive activation or malfunction of STING may trigger an over-exuberant inflammatory response, which subsequently leads to tissue damage and pathological states. This review recapitulates the recent interactions between STING and diverse organelles, encompassing its multifarious functions in antiviral, antitumor, organelle regulation, and immune regulation. These investigations not only deepen the comprehension of molecular mechanisms underlying STING but also offer novel concepts for the exploration of human disease pathogenesis and the development of potential treatment strategies. In the future, with further probing into STING function and its regulatory mechanisms, it is anticipated to pioneer new approaches for the treatment of complex diseases such as inflammatory diseases and tumors.

BACKGROUND: Severe stroke has high rates of mortality and morbidity. This study aimed to investigate the clinical course, causes of worsening, and outcomes of severe ischemic stroke. METHODS: This prospective, multicenter cohort study enrolled adult patients admitted ≤30 days after ischemic stroke from nine hospitals in China between September 2017 and December 2019. Severe stroke was defined as a score of ≥15 on the National Institutes of Health Stroke Scale (NIHSS). Clinical worsening was defined as an increase of 4 in the NIHSS score from baseline. Unfavorable functional outcome was defined as a modified Rankin scale score ≥3 at 3 months and 1 year after stroke onset, respectively. We performed Logistic regression to explore baseline features and reperfusion therapies associated with clinical worsening and functional outcomes. RESULTS: Among 4201 patients enrolled, 854 patients (20.33%) had severe stroke on admission. Of 3347 patients without severe stroke on admission, 142 (4.24%) patients developed severe stroke in hospital. Of 854 patients with severe stroke on admission, 33.95% (290/854) experienced clinical worsening (median time from stroke onset: 43 h, Q1-Q3: 20-88 h), with brain edema (54.83% [159/290]) as the leading cause; 24.59% (210/854) of these patients died by 30 days, and 81.47% (677/831) and 78.44% (633/807) had unfavorable functional outcomes at 3 months and 1 year respectively. Reperfusion reduced the risk of worsening (adjusted odds ratio [OR]: 0.24, 95% confidence interval [CI]: 0.12-0.49, P  <0.01), 30-day death (adjusted OR: 0.22, 95% CI: 0.11-0.41, P  <0.01), and unfavorable functional outcomes at 3 months (adjusted OR: 0.24, 95% CI: 0.08-0.68, P <0.01) and 1 year (adjusted OR: 0.17, 95% CI: 0.06-0.50, P  <0.01). CONCLUSIONS: Approximately one-fifth of patients with ischemic stroke had severe neurological deficits on admission. Clinical worsening mainly occurred in the first 3 to 4 days after stroke onset, with brain edema as the leading cause of worsening. Reperfusion reduced the risk of clinical worsening and improved functional outcomes. REGISTRATION ClinicalTrials.gov , NCT03222024.
Humans ; Male ; Female ; Prospective Studies ; Ischemic Stroke/mortality* ; Aged ; Middle Aged ; Aged, 80 and over ; Stroke ; Brain Ischemia

BACKGROUND: Lung cancer is the leading malignancy in China in terms of both incidence and mortality. With increased health awareness and the widespread use of low-dose computed tomography (CT), early diagnosis rates have been steadily improving. Surgical intervention remains the primary treatment option for early-stage lung cancer, and video-assisted thoracoscopic surgery (VATS) has become a common approach due to its minimal invasiveness and rapid recovery. However, post-discharge recovery remains incomplete, underscoring the importance of postoperative care. Traditional follow-up methods, lack standardization, consume significant medical resources, and increase the burden of the patients. Artificial intelligence (AI)-driven disease management platforms offer a novel solution to optimize postoperative follow-up. This study followed 463 lung cancer surgery patients using an AI-based platform, aiming to identify common postoperative issues, propose solutions, improve quality of life, reduce recurrence-related costs, and promote AI integration in healthcare. METHODS: Using the AI disease management platform, this study integrated educational videos, collaboration between healthcare teams and AI assistants, daily health logs, health assessment forms, and personalized interventions to monitor postoperative recovery. The postoperative rehabilitation status of the patients was assessed by the Leicester Cough Questionnaire (LCQ-MC). Two independent t-test and one-way ANOVA were used to analyze the causes of postoperative cough in lung cancer. RESULTS: Most issues occurred within 7 d post-discharge, significantly declined on 14 d post-discharge. Factors such as gender, smoking history, and surgical approaches were found to influence cough recovery. The incidence of cough on 7 d post-discharge in females was higher than that in males (P<0.01), while the incidence of cough on 14 d post-discharge in elderly patients was lower than that in young patients (P=0.03). The AI-based platform effectively addressed cough, pain, and sleep disturbances through phased interventions. CONCLUSIONS The AI-based platform significantly enhanced postoperative management efficiency and the self-care capabilities of the patients, particularly in phased cough management. Future integration with wearable devices could enable more precise and personalized postoperative care, further advancing the application of AI technology across multidisciplinary healthcare domains.
Humans ; Lung Neoplasms/rehabilitation* ; Male ; Female ; Middle Aged ; Aged ; Patient Discharge ; Artificial Intelligence ; Adult ; Postoperative Care ; Postoperative Period ; Disease Management ; Quality of Life

The disturbance of the human microbiota influences the occurrence and progression of many diseases. Live therapeutic bacteria, with their genetic manipulability, anaerobic tendencies, and immunomodulatory properties, are emerging as promising therapeutic agents. However, their clinical applications face challenges in maintaining activity and achieving precise spatiotemporal release, particularly in the harsh gastrointestinal environment. This review highlights the innovative bacterial functionalized encapsulation strategies developed through advances in physicochemical and biological techniques. We comprehensively review how bacterial encapsulation strategies can be used to provide physical barriers and enhanced adhesion properties to live microorganisms, while introducing superior material properties to live bacteria. In addition, this review outlines how bacterial surface coating can facilitate targeted delivery and precise spatiotemporal release of live bacteria. Furthermore, it elucidates their potential applications for treating different diseases, along with critical perspectives on challenges in clinical translation. This review comprehensively analyzes the connection between functionalized bacterial encapsulation and innovative biomedical applications, providing a theoretical reference for the development of next-generation bacterial therapies.

The identification and optimization of mutations in nanobodies are crucial for enhancing their therapeutic potential in disease prevention and control. However, this process is often complex and time-consuming, which limit its widespread application in practice. In this study, we developed a workflow, named Evolutionary-Nanobody (EvoNB), to predict key mutation sites of nanobodies by combining protein language models (PLMs) and molecular dynamic (MD) simulations. By fine-tuning the ESM2 model on a large-scale nanobody dataset, the ability of EvoNB to capture specific sequence features of nanobodies was significantly enhanced. The fine-tuned EvoNB model demonstrated higher predictive accuracy in the conserved framework and highly variable complementarity-determining regions of nanobodies. Additionally, we selected four widely representative nanobody-antigen complexes to verify the predicted effects of mutations. MD simulations analyzed the energy changes caused by these mutations to predict their impact on binding affinity to the targets. The results showed that multiple mutations screened by EvoNB significantly enhanced the binding affinity between nanobody and its target, further validating the potential of this workflow for designing and optimizing nanobody mutations. Additionally, sequence-based predictions are generally less dependent on structural absence, allowing them to be more easily integrated with tools for structural predictions, such as AlphaFold 3. Through mutation prediction and systematic analysis of key sites, we can quickly predict the most promising variants for experimental validation without relying on traditional evolutionary or selection processes. The EvoNB workflow provides an effective tool for the rapid optimization of nanobodies and facilitates the application of PLMs in the biomedical field.

Objective To investigate the repair mechanism of baicalin on gastric mucosa of chronic atrophic gastritis mice based on the network pharmacology and animal experiments.Methods(1)Applied network pharmacology to predict and analyze the potential key targets of baicalin in the treatment of chronic atrophic gastritis.(2)Animal experiment:40 C57BL/6N mice were randomly divided into normal group,model group,Vitacoenzyme group and baicalin group,10 mice in each group.Except for the normal group,the other three groups of mice were treated with N-methyl-N'-nitro-N-nitrosoguanidine(MNNG)by gavage combined with hunger and satiety disorder method to construct a chronic atrophic gastritis model.At the end of drug administration,the histopathological changes of gastric mucosa were observed by hematoxylin-eosin(HE)staining,the changes of gastrin(GAS)and prostaglandin E2(PGE2)levels in serum were detected by enzyme-linked immunosorbent assay(ELISA),and the mRNA and protein expression levels of Janus tyrosine kinase 1(JAK1),signal transducer and activator of transcription 3(STAT3)in the gastric mucosa were detected by real-time fluorescence quantitative polymerase chain reaction(qRT-PCR)and protein immunoblotting(Western Blot)methods,respectively.Results The results of network pharmacology showed that baicalin could spontaneously bind to the core targets JAK1 and STAT3.The results of animal experiments showed that compared with the normal group,the gastric mucosa of mice in the model group suffered from atrophy,disordered gland arrangement,the presence of a large number of lymphocytes,a significant increase in apoptotic index of the gastric mucosa(P＜0.05),a significant decrease in the levels of GAS and PGE2 in serum(P＜0.05),and a significant increase in the levels of mRNA and protein expressions of JAK1 and STAT3 in the gastric mucosa(P＜0.05);compared with the model group,the pathological changes of gastric mucosa in the Vitacoenzyme group and baicalin group were alleviated,the glands were arranged relatively neatly,the structure was more intact,the apoptosis index of gastric mucosal cells was significantly decreased(P＜0.05),the levels of GAS and PGE2 in serum were significantly increased(P＜0.05),and the mRNA and protein expression levels of JAK1 and STAT3 in gastric mucosa were significantly decreased(P＜0.05).There was no significant difference in the above-mentioned indexes between the baicalin group and the Vitacoenzyme group(P＞0.05).Conclusion Baicalin can effectively repair gastric mucosal lesions in mice with chronic atrophic gastritis,and its mechanism may be related to the down-regulation of mRNA and protein expressions of JAK1 and STAT3.

Objective:To study influence of Connect-Introduce-Communicate-Ask-Respond-Exit(CICARE)communication mode on patients with acute heart failure(AHF).Methods:A total of 156 AHF patients treated in our hospital were randomly and equally divided into routine nursing group and CICARE group(received CICARE communication mode based on routine nursing group).Both groups were intervened for one month.General clinical data,hospitalization indexes,scores of Hamilton rating scale for depression(HAMD),Hamilton rating scale for anxiety(HAMA),general self-efficacy scale(GSES)and quality of life scale(QOL-35)before and after inter-vention and incidence of complications were compared between two groups.Results:Compared with routine nursing group,there were significant reductions in first aid time[(42.06±9.77)s vs.(20.27±3.77)s],visit time[(95.67±23.18)min vs.(50.07±11.21)min],admission time[(3.22±0.36)min vs.(2.60±0.67)min]and hospital stay[(22.33±4.82)d vs.(14.13±2.42)d];and scores of HAMD[(14.02±1.42)scores vs.(6.04± 1.57)scores]and HAMA[(13.24±2.07)scores vs.(7.16±2.17)scores]after intervention,and significant rise in scores of GSES[(14.25±3.14)scores vs.(32.03±6.06)scores]and QOL-35[(70.67±5.75)scores vs.(86.93±5.51)scores]in CICARE group after intervention(P=0.001 all).Incidence rate of complications in CICARE group was significantly lower than that of CICARE group(5.13％vs.20.51％,P=0.004).Conclusion:CICARE communication mode can significantly alleviate adverse emotions and improve self-efficacy in patients with acute heart failure.

Objective To investigate the inhibitory effects and mechanisms of α-hederin,an active ingredient in Fruc-tus Akebiae,on hepatocellular carcinoma(HCC)cells.Methods HCC cells were divided into four groups and treated with α-hederin(0,10,20,and 30 μmol·L-1)for 24 h and 48 h,respectively.MTT assays were used to detect the cell proliferation rate,flow cytometry(FCM)was used to detect the apoptotic rate,transcriptomics was used to screen signaling pathways in α-hederin-treated HCC cells,RNA interference was exploited to verify the underlying signaling pathway,and real-time quantitative PCR(qRT-PCR)and Western blotting(WB)were used to detect expression changes of the mRNA and protein of TP53(p53),PMAIP1(Noxa),and apoptosis-associated proteins,Caspase9 and Caspase3.Results α-Hederin induced apoptosis by activa-ting apoptosis-associated proteins,PARP,Caspase9 and Caspase3.Transcriptomics,qRT-PCR,and WB results also showed that α-hederin increased the mRNA and protein expression of p53 and Noxa.Furthermore,α-hederin inhibited the protein degradation of p53 and Noxa,reversing the apoptosis decrease in p53/Noxa siRNA-knocked-down HCC cells.In vivo results showed that α-hederin inhibited the growth of HCC tumors.Conclusion α-hederin may induce the apoptosis of HCC cells by activating and stabilizing the p53/Noxa signaling pathway.

Type Ⅵ secretion system(T6SS)is a lethal weapon that releases effectors in direct contact to kill eukaryotic predators or prokaryotic competitors.T6SS is of great significance in bacterial environmental adaptability,pathogenicity,and gene horizontal transfer.T6SS has been identified in about 25％of Gram-negative bacteria.Because of its widespread existence,T6SS is considered the key factor of ecological competition.T6SS effectors exerting biological functions have high diversity and do not have conserved sequences,and the regulatory mechanisms involved are complex.Therefore,it is a hot and difficult topic in T6SS research.Vibrio fluvialis(V.fluvialis)as a newly emerging foodborne pathogen,has unique characteristics in the quantity,composition,and physiological function of T6SS,which is related to its wide environmental adaptability and pathoge-nicity.This article mainly reviews the research progress of V.fluvialis T6SS,including its composition,structure,functional activity,and regulatory mechanism.