BACKGROUND:ITGB5 encodes integrin subunit beta 5 of that has been implicated in the eosinophilic asthma phenotype. However, the secretory profile of ITGB5 in induced sputum and its clinical significance in asthma remains poorly understood. OBJECTIVE:This study aimed to measure ITGB5 levels in induced sputum supernatant from asthma patients and investigate its potential clinical implications. METHODS:We enrolled 78 participants (18 healthy controls and 60 asthma patients) and quantified ITGB5 protein levels in induced sputum supernatant using ELISA. Correlations between ITGB5 and inflammatory markers, as well as airway obstruction parameters, were analyzed. Subsequently, we performed comparative analyses to evaluate variations in inflammatory cytokines between high- and low-ITGB5 expression subgroups. RESULTS:Induced sputum ITGB5 levels were significantly elevated in asthma patients and markedly increased following inhaled corticosteroid (ICS) treatment. ITGB5 levels showed positive correlations with Th2-associated cytokines (IL-4, IL-5, IL-13, IL-25, IL-33, and TSLP) and Th2 signature genes (SERPINB2, CLCA1, and POSTN). Notably, IL-5, FeNO, and POSTN were significantly higher in the high-ITGB5(n = 30) than the low- ITGB5 (n = 30) expression group. Furthermore, sputum ITGB5 levels were inversely associated with pulmonary function (FEV1% pred, FVC% pred, MEF% pred, MEF25% pred and MEF50% pred). CONCLUSIONS:Increased sputum ITGB5 in asthma was positively associated with inflammatory mediators and negatively correlated with pulmonary function, suggesting that ITGB5 upregulation may be involved in airway inflammation and obstruction in asthma pathogenesis.

ABSTRACT Tumor stroma is a critical component of the tumor microenvironment (TME) that plays a pivotal role in cancer progression and therapeutic response. Beyond providing structural support, stromal components actively regulate tumor growth, metastasis, immune evasion, and drug resistance. Tumor stroma consists of both noncellular elements, particularly the extracellular matrix (ECM), and diverse stromal cells such as cancer‐associated fibroblasts and mesenchymal stem cells. These components collectively form a dense and dynamic barrier that restricts drug penetration, increases interstitial pressure, and promotes an immunosuppressive microenvironment. Despite growing recognition of the importance of stromal biology, a systematic understanding of stromal‐targeted therapeutic strategies and their translational potential remains incomplete. In this review, we comprehensively summarize the biological functions of major stromal components in tumor development and therapy resistance. We further discuss current therapeutic strategies targeting the tumor stroma, including stromal cell depletion, vascular normalization, ECM‐modulating approaches, and emerging nanomaterial‐based delivery systems designed to enhance drug penetration and therapeutic efficacy. In addition, recent progress in preclinical studies and clinical trials of stromal‐targeted therapies is highlighted. By integrating advances in tumor biology, nanomedicine, and translational oncology, this review provides a comprehensive perspective on stroma‐targeted cancer therapy and outlines future directions for precision medicine.

Purpose:This study aims to characterize the nasal lavage fluid (NLF) microbiota in asthma and explore its relationship with lung radiomic features. Patients and Methods:We collected NLF from 39 participants (12 controls and 27 asthma) for 16S rRNA gene sequencing. Lung radiomics of asthma were analyzed manually and with NeuLungCARE software. The relationships between microbiota and radiomic features were investigated by correlation and regression analyses. Asthma microbiota was further characterized via Jensen-Shannon Divergence (JSD) clustering. Results:After adjusting for sex and age, the asthma group had a significantly elevated NLF bacterial load compared with the control group, while the microbial dysbiosis index (MDI) remained comparable between the two groups. The asthma group exhibited significantly elevated NLF bacterial load compared with the controls (P<0.05). The NLF bacterial load was positively correlated with sputum eosinophil percentage and mucus plugs score (both P<0.05) in asthma. Linear regression revealed that Shannon index was negatively correlated with the wall area percentage of the first-generation bronchi and the percentage of low attenuation area (LAA%) (both P<0.05). The Chao index showed significantly negative correlations with forced expiratory volume in 1s (P<0.05). Two distinct microbiota clusters were further identified by JSD clustering in asthma. Cluster 1 demonstrated significantly higher α diversity indices than Cluster 2, along with significant MDI deviation from the control group (all P<0.05). Patients in Cluster 1 had a significantly higher prevalence of CT-indicated bronchiectasis, lower LAA%-910, and a higher proportion of exacerbation-prone patients than Cluster 2 (all P<0.05). Conclusion:The NLF microbiota correlated significantly with the lung radiomic, functional, and inflammatory markers. It is highly necessary to conduct further prospective research on the impact of NLF microbiota on the lower airway characteristics of asthma patients.

The cGAS-STING signaling pathway serves as a critical link between DNA sensing and innate immunity, and has tremendous potential to improve anti-tumor immunity by generating type I interferons. However, STING agonists have shown decreasing biotherapeutic efficacy in clinical trials. Tumor metabolism, characterized by aberrant nutrient utilization and energy production, is a fundamental hallmark of tumorigenesis. And modulating metabolic pathways in tumor cells has been discovered as a therapeutic strategy for tumors. As research concerning STING progressed, emerging evidence highlights its role in metabolic reprogramming, independent its immune function, indicating metabolic targets as a strategy for STING activation in cancers. In this review, we delve into the interplay between STING and multiple metabolic pathways. We also synthesize current knowledge on the antitumor functions of STING, and the metabolic targets within the tumor microenvironment (TME) that could be exploited for STING activation. This review highlights the necessity for future research to dissect the complex metabolic interactions with STING in various cancer types, emphasizing the potential for personalized therapeutic strategies based on metabolic profiling.

Introduction: The persistence of microbial infection can lead to endodontic failure. Enterococcus faecalis (E. faecalis) is acknowledged to be a closely associated bacterium. This study investigated the antimicrobial effects of mesoporous silica nanoparticles (nMS) carrying nano-silver and chlorhexidine (nMS-nAg-Chx) on E. faecalis. Methods: Analyses were conducted to assess the antimicrobial efficacy of nMS-nAg-Chx toward planktonic E. faecalis, including the zone of inhibition, minimal inhibitory concentration, and growth curves. The measurement of lactic acid, scanning electron microscopy, live-dead bacteria staining, and quantitative real-time PCR were done to further investigate its anti-biofilm effect. Colony forming unit and scanning electron microscopy were used to assess its efficacy in infected root canals. Results: The growth of planktonic E. faecalis was suppressed with a minimal inhibitory concentration value of 25 m g/mL (P<.05). nMS-nAg-Chx concentration-dependently inhibited biofilm formation of E. faecalis with the reduction of lactic acid (P < .05), sparse biofilm structure, reduced percentage of viable bacteria (P < .05), and suppressed expression of ebpR, gelE, ace, and efa genes (P < .05). The 7-day sealing of nMS-nAg-Chx resulted in a notable reduction in bacterial counts compared to the saline control group in the E. faecalis infected root canals (P < .05). Conclusions: nMS-nAg-Chx effectively inhibits E. faecalis and removes its biofilm from infected human root canals. It may be used for endodontic treatments in the control of E. faecalis bacteria as an intracanal medication. (J Endod 2025;51:54-63.)

Secondary caries is a leading cause of restoration failure. Inhibiting caries through antimicrobial efficacy is essential for extending the restoration’s service life. Antimicrobial agents have been incorporated into restorative materials for decades. Based on their mechanism of antimicrobial action, these materials are classified as either releasing or non-releasing types. However, the simple release strategy is often insufficient for long-term caries prevention, as it lacks the precision, durability, and adaptability now required. This necessitates the development of next-generation systems that can provide a controlled, sustained, and targeted antimicrobial activity. To this end, this review focuses on advanced, controlled-release antimicrobial strategies, exploring the design of novel nanomaterials, their functional efficacy, and the mechanisms of their representative antimicrobial agents.

Estrogen receptor α (ERα) is involved with the hyperresponsiveness and airway remodeling in asthma, but developing therapies targeting ERα remains challenging due to its multifaceted roles in different cell types and the poor efficacy of systemic ERα intervention in asthma. Previously, we uncovered the association of increased ERα expression in airway epithelial cells with poor pulmonary function and epithelial-mesenchymal transition (EMT) in asthma patients. This study further investigated the association of ERα expression with the ferroptosis and EMT levels in a cohort of eosinophilic asthma (EA) patients as well as in an eosinophil-epithelial coculture cell model. By loading small interfering RNA (siRNA) into a mesoporous silica nanoparticle (MSN) and then coating the extracted bronchial epithelial cytomembrane (CM), a bronchial epithelial CM home-targeting nanoplatform (siRNA@MSN@CM) was constructed to selectively decrease the ERα expression in bronchial epithelial cells. The targeting effect of bronchial epithelial cells was confirmed in vitro and in vivo, demonstrating the successful targeted knockdown of ERα expression. Silencing ERα in epithelial cells effectively prevented ferroptosis and EMT induced by coculturing with ferroptotic eosinophils. Targeted intervention of epithelium ERα with intratracheal delivery of siRNA(ERα)@MSN@CM nanoparticle significantly reduced the levels of ferroptosis in bronchial epithelial cells, airway inflammation, and airway remodeling in asthmatic mouse models. This study introduces an innovative nanomaterial for targeted drug delivery to epithelial cells and underscores the potential of targeted knockdown ERα in bronchial epithelial cells as a therapeutic strategy for asthma treatment.

ObjectiveTo delineate the distribution of perineural invasion (PNI), evaluate its impact on patient survival, and identify optimal criteria for initiating adjuvant radiation therapy (RT) in cases of PNI associated with salivary gland cancer (SGC).MethodsThis retrospective study categorized enrolled patients into three groups based on PNI status (none, minor, or major), defined by the extent of nerve involvement. The influence of PNI on overall survival and locoregional control was assessed using a Cox proportional hazards model.ResultsA total of 555 patients were incorporated into the study. Logistic regression analysis indicated that tumor stage, neck stage, histological grade, and pathological type were independently linked to the occurrence of PNI. In the Cox model assessing overall survival, patients exhibiting minor nerve PNI demonstrated a hazard ratio (HR) of 1.78 [95% CI: 1.14-2.47] in comparison to those without PNI, a difference that was statistically significant (p<0.001). Conversely, the variation in HR between patients with major nerve PNI and those with minor nerve PNI was not statistically significant (p=0.673). In the Cox model for locoregional control, patients with minor and major nerve PNI exhibited HRs of 1.64 [95% CI: 1.17-2.78] and 1.65 [95% CI: 1.03-2.90], respectively, when compared to those without PNI. Subgroup analyses revealed that the incorporation of chemotherapy into radiotherapy did not significantly modify the risk of mortality or locoregional recurrence in comparison to patients treated with radiotherapy alone, irrespective of PNI classification.ConclusionBoth minor and major nerve PNI exerting comparable influences on prognosis, the adjunctive use of chemotherapy in combination with RT did not yield improvements in overall survival or locoregional control, irrespective of PNI status.

Objectives: This research first investigated the effect of mesoporous silica nanoparticles (nMS) carrying chlorhexidine and silver (nMS-nAg-Chx) on periodontitis-related biofilms. This study aimed to investigate (1) the antibacterial activity on Porphyromonas gingivalis (P. gingivalis) biofilm; (2) the suppressing effect on virulence of P. gingivalis biofilm; (3) the regulating effect on periodontitis-related multispecies biofilm. Methods: Silver nanoparticles (nAg) and chlorhexidine (Chx) were co-loaded into nMS to form nMS-nAg-Chx. Inhibitory zone test and minimum inhibitory concentration (MIC) against P. gingivalis were tested. Growth curves, crystal violet (CV) staining, live/dead staining and scanning electron microscopy (SEM) observation were performed. Biofilm virulence was assessed. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and Quantitative Real Time-PCR (qPCR) were performed to validate the activity and composition changes of multispecies biofilm (P. gingivalis, Streptococcus gordonii and Streptococcus sanguinis). Results: nMS-nAg-Chx inhibited P. gingivalis biofilm dose-dependently (p<0.05), with MIC of 18.75 g/mL. There were fewer live bacteria, less biomass and less virulence in nMS-nAg-Chx groups (p<0.05). nMS-nAg-Chx inhibited and modified periodontitis-related biofilms. The proportion of pathogenic bacteria decreased from 16.08 to 1.07% and that of helpful bacteria increased from 82.65 to 94.31% in 25 mu g/mL nMS-nAg-Chx group for 72 h. Conclusion: snMS-nAg-Chx inhibited P. gingivalis growth, decreased biofilm virulence and modulated periodontitis-related multispecies biofilms toward healthy tendency. pH-sensitive nMS-nAg-Chx inhibit the pathogens and regulate oral microecology, showing great potential in periodontitis adjunctive therapy. [GRAPHICS]

Pulmonary arterial hypertension (PAH) is a progressive and rapidly fatal disease with an intricate etiology. Identifying biomarkers for early PAH lesions based on the exploration of subtle biological processes is significant for timely diagnosis and treatment. In the present study, nine distinct cell populations identified based on gene expression profiles revealed high heterogeneity in cell composition ratio, biological function, distribution preference, and communication patterns in PAH. Notably, compared to other cells, endothelial cells (ECs) showed prominent variation in multiple perspectives. Further analysis demonstrated the endothelial-to-mesenchymal transition (EndMT) in ECs and identified a subgroup exhibiting a contrasting phenotype. Based on these findings, a machine-learning integrated program consisting of nine learners was developed to create a PAH Endothelial-to-mesenchymal transition Signature (PETS). This study identified cell populations underlying EndMT and furnished a potential tool that might be valuable for PAH diagnosis and new precise therapies.

PURPOSE:Although estrogen receptors (ERs) signal pathways are involved in the pathogenesis and development of asthma, their expressions and effects remain controversial. This study aimed to investigate the expressions of ERα and ERβ as well as their mechanisms in airway remodeling and mucus production in asthma.METHODS:The expressions of ERα and ERβ in the airway epithelial cells of bronchial biopsies and induced sputum cells were examined by immunohistochemistry. The associations of ERs expressions with airway inflammation and remodeling were evaluated in asthmatic patients. In vitro, the regulations of ERs expressions in human bronchial epithelial cell lines were examined using western blot analysis. The epidermal growth factor (EGF)-mediated ligand-independent activation of ERα and its effect on epithelial-mesenchymal transitions (EMTs) were investigated in asthmatic epithelial cells by western blot, immunofluorescent staining, and quantitative real-time polymerase chain reaction.RESULTS:ERα and ERβ were expressed on both bronchial epithelial cells and induced sputum cells, and the expressions showed no sex difference. Compared to controls, male asthmatic patients had higher levels of ERα on the bronchial epithelium, and there were cell-specific expressions of ERα and ERβ in induced sputum. The expression of ERα in the airway epithelium was inversely correlated to forced expiratory volume in 1 second (FEV1) % and FEV1/forced vital capacity. Severe asthmatic patients had significantly greater levels of ERα in the airway epithelium than mild-moderate patients. ERα level was positively correlated with the thickness of the subepithelial basement membrane and airway epithelium. In vitro, co-stimulation of interleukin (IL)-4 and EGF increased the expression of ERα and promoted its nuclear translocation. EGF activated the phosphorylation of ERα via extracellular signal-regulated kinase and c-Jun N-terminal kinase pathways. ERα knockdown alleviated EGF-mediated EMTs and mucus production in airway epithelial cells of asthma.CONCLUSIONS:ERα contributes to asthmatic airway remodeling and mucus production through the EGF-mediated ligand-independent pathway.

Background and Aims: HCC is a highly heterogeneous disease that is caused largely by genomic copy number variations. Herein, the mechanistic and therapeutically targeted role of vacuolar protein sorting 72 homologue (VPS72), a novel copy number variation cis-driven gained gene identified by genome-wide copy number variation and transcriptome analyses in HCC, is not well understood. Approach and Results: First, overexpression of VPS72 enhanced the initiation and progression of HCC in vitro and in vivo. Mechanistically, VPS72 interacted with the oncoproteins MYC and actin-like 6A (ACTL6A) and promoted the formation of the ACTL6A/MYC complex. Furthermore, ACTL6A regulated VPS72 protein stability by weakening the interaction between tripartite motif containing 21 (TRIM21) and VPS72. Thus, the interaction between VPS72 and ACTL6A enhanced the affinity of MYC for its target gene promoters and promoted their transcription, thereby contributing to HCC progression, which was inhibited by adeno-associated virus serotype 8 (AAV8)-mediated short hairpin RNA (shRNA) against VPS72. Conclusions: This study reveals the molecular mechanism of ACTL6A/VPS72/MYC in HCC, providing a theoretical basis and therapeutic target for this malignancy.

Objective: This study aims to describe the imaging features of naïve asthma patients, defined as not receiving corticosteroids or other asthma medications for at least 1 month, and their association with therapeutic response, and to discover novel unbiased imaging phenotypes. Methods: A total of 109 naïve asthma patients and 50 healthy controls were enrolled in this study. Clinical data and imaging indices of high-resolution computed tomography were collected. The correlation between imaging indices and clinical features was analyzed. Cluster analyses were adopted to determine three novel imaging phenotypes. Results: Compared with healthy controls, naïve asthma patients presented higher scores of airway remodeling, bronchiectasis, and mucus plugs. Mean airway wall area (WA)% was inversely correlated with mid-expiratory flow velocity% predicted. The extent score of bronchiectasis was positively correlated with smoking history and significantly increased in the high mucus group. Mucus plugs were related to improving lung function and type 2 (T2) inflammation, as assessed by sputum and blood eosinophils and fraction of exhaled nitric oxide. Cluster 1 patients had a high proportion of emphysema, the best lung function, and the lowest T2 inflammation; cluster 2 patients had severe airway remodeling, relatively good lung function, and moderate T2 inflammation; cluster 3 patients had severe airway remodeling, mucus plugs, and bronchiectasis, and showed the worst lung function and highest T2 inflammation. Conclusion: Naïve asthma patients had the imaging traits of airway remodeling, bronchiectasis, and mucus plugs. The unbiased imaging phenotypes had good consistency with clinical characteristics, therapeutic response, and T2 inflammation expression in naïve asthma patients.

Background Asthma patients potentially have impaired adaptive immunity to virus infection. The levels of SARS-CoV-2-specific adaptive immunity between COVID-19 survivors with and without asthma are presently unclear. Methods COVID-19 survivors (patients with asthma n=11, with allergies n=8, and COVID-19 only n=17) and non-COVID-19 individuals (asthmatic patients n=10 and healthy controls n=9) were included. The COVID-19 patients were followed up at about 8 months and 16 months after discharge. The clinical characteristics, lymphocyte subsets, memory T cells, and humoral immunity including SARS-CoV-2 specific antibodies, SARS-CoV-2 pseudotyped virus neutralization assay, and memory B cells were analyzed in these subjects. Results The strength of virus-specific T cell response in COVID-19 survivors was positively correlated with the percentage of blood eosinophils and Treg cells (r=0.4007, p=0.0188; and r=0.4435, p=0.0086 respectively) at 8-month follow-up. There were no statistical differences in the levels of SARS-CoV-2-specific T cell response between the COVID-19 survivors with, and without, asthma. Compared to those without asthma, the COVID-19 with asthma survivors had higher levels of SARS-CoV-2-specific neutralizing antibodies (NAbs) at the 8-month follow-up (p<0.05). Moreover, the level of NAbs in COVID-19 survivors was positively correlated with the percentage of Treg and cTfh2 cells (r=0.5037, p=0.002; and r=0.4846, p=0.0141), and negatively correlated with the percentage of Th1 and Th17 cells (r=-0.5701, p=0.0003; and r=-0.3656, p=0.0308), the ratio of Th1/Th2, Th17/Treg, and cTfh1/cTfh2 cell (r=-0.5356, r=-0.5947, r=-0.4485; all p<0.05). The decay rate of NAbs in the COVID-19 survivors with asthma was not significantly different from that of those without asthma at 16-month follow-up. Conclusion The level of SARS-CoV-2-specific NAbs in COVID-19 survivors with asthma was higher than that of those without asthma at 8-month follow-up. The SARS-CoV-2-specific T cell immunity was associated with blood eosinophils and Treg percentages. The SARS-CoV-2-specific humoral immunity was closely associated with cTfh2/cTfh1 imbalance and Treg/Th17 ratio. According to the findings, asthmatic patients in COVID-19 convalescent period may benefit from an enhanced specific humoral immunity, which associates with skewed Th2/Th1 and Treg/Th17 immune.

Gastrointestinal adenocarcinoma (GIAD) has caused a serious disease burden globally. Targeted therapy for the transforming growth factor beta (TGF-β) signaling pathway is becoming a reality. However, the molecular characterization of TGF-β associated signatures in GIAD requires further exploration. Multi-omics data were collected from TCGA and GEO database. A pivotal unsupervised clustering for TGF-β level was performed by distinguish status of TGF-β associated genes. We analyzed differential mRNAs, miRNAs, proteins gene mutations and copy number variations in both clusters for comparison. Enrichment of pathways and gene sets were identified in each type of GIAD. Then we performed differential mRNA related drug response by collecting data from GDSC. At last, a summarized deep neural network for TGF-β status and GIADs was constracted. The TGF-βhigh group had a worse prognosis in overall GIAD patients, and had a worse prognosis trend in gastric cancer and colon cancer specifically. Signatures (including mRNA and proteins) of the TGF-βhigh group is highly correlated with EMT. According to miRNA analysis, miR-215-3p, miR-378a-5p, and miR-194-3p may block the effect of TGF-β. Further genomic analysis showed that TGF-βlow group had more genomic changes in gastric cancer, such as TP53 mutation, EGFR amplification, and SMAD4 deletion. And drug response dataset revealed tumor-sensitive or tumor-resistant drugs corresponding to TGF-β associated mRNAs. Finally, the DNN model showed an excellent predictive effect in predicting TGF-β status in different GIAD datasets. We provide molecular signatures associated with different levels of TGF-β to deepen the understanding of the role of TGF-β in GIAD and provide potential drug possibilities for therapeutic targets in different levels of TGF-β in GIAD.

To describe the long-term health outcomes of patients with COVID-19 and investigate the potential risk factors. Clinical data during hospitalization and at a mean (SD) day of 249 (15) days after discharge from 40 survivors with confirmed COVID-19 (including 25 severe cases) were collected and analyzed retrospectively. At follow-up, severe cases had higher incidences of persistent symptoms, DLCO impairment, and higher abnormal CT score as compared with mild cases. CT score at follow-up was positively correlated with age, LDH level, cumulative days of oxygen treatment, total dosage of glucocorticoids used, and CT peak score during hospitalization. DLCO% at follow-up was negatively correlated with cumulative days of oxygen treatment during hospitalization. DLCO/VA% at follow-up was positively correlated with BMI, and TNF-α level. Among the three groups categorized as survivors with normal DLCO, abnormal DLCO but normal DLCO/VA, and abnormal DLCO and DLCO/VA, survivors with abnormal DLCO and DLCO/VA had the lowest serum IL-2R, IL-8, and TNF-α level, while the survivors with abnormal DLCO but normal DLCO/VA had the highest levels of inflammatory cytokines during hospitalization. Altogether, COVID-19 had a greater long-term impact on the lung physiology of severe cases. The long-term radiological abnormality maybe relate to old age and the severity of COVID-19. Either absent or excess of inflammation during COVID-19 course would lead to the impairment of pulmonary diffusion function.

Hypoxia contributes to the progression and metastasis of lung adenocarcinoma (LUAD). However, the specific underlying molecular mechanisms have not been fully elucidated. Here we report that Notch4 is upregulated in lung tissue from lung cancer patients. Functionally, Hypoxia activates the expressions of Delta-like 4 and Notch4, resulting in the excessive proliferation and migration of LUAD cells as well as apoptotic resistance. Notch4 silencing reduced ERK, JNK, and P38 activation. Meanwhile, Notch4 overexpression enhanced ERK, JNK, and P38 activation in LUAD cells. Furthermore, Notch4 exerted pro-proliferation, anti-apoptosis and pro-migration effects on LUAD cells that were partly reversed by the inhibitors of ERK, JNK, and p38. The binding interaction between Notch4 and ERK/JNK/P38 were confirmed by the co-immunoprecipitation assay. In vivo study revealed that Notch4 played a key role in the growth and metastasis of LUAD using two xenograft models. This study demonstrates that hypoxia activates Notch4-ERK/JNK/P38 MAPK signaling pathways to promote LUAD cell progression and metastasis.

BACKGROUND:Immune cell infiltration in the tumor microenvironment (TME) affects tumor initiation, patients' prognosis and immunotherapy strategies. However, their roles and interactions with genomics and molecular processes in hepatocellular carcinoma (HCC) still have not been systematically evaluated. METHODS:We performed unsupervised clustering of total 1000 HCC samples including discovery and validation group from available public datasets. Immune heterogeneity of each subtype was explored by multi-dimension analysis. And a support vector machine (SVM) model based on multi-omics signatures was trained and tested. Finally, we performed immunohistochemistry to verify the immune role of signatures. RESULTS:We defined three immune subtypes in HCC, with diverse clinical, molecular, and genomic characteristics. Cluster1 had worse prognosis, better anti-tumor characteristics and highest immune scores, but also accompanied by immunosuppression and T cell dysfunction. Meanwhile, a better anti-PD1/CTLA4 immunotherapeutic response was predicted in cluster1. Cluster2 was enriched in TAM-M2 and stromal cells, indicating immunosuppression. Cluster3, with better prognosis, had lowest CD8 T cell but highest immune resting cells. Further, based on genomic signatures, we developed an SVM classifier to identify the patient's immunological status, which was divided into Type A and Type B, in which Type A had poorer prognosis, higher T cell dysfunction despite higher T cell infiltration, and had better immunotherapeutic response. At the same time, MMP9 may be a potential predictor of the immune characteristics and immunotherapeutic response in HCC. CONCLUSIONS:Our work demonstrated 3 immune clusters with different features. More importantly, multi-omics signatures, such as MMP9 was identified based on three clusters to help us recognize patients with different prognosis and responses to immunotherapy in HCC. This study could further reveal the immune status of HCC and provide potential predictors for immune checkpoint treatment response.

Background: Since December 2019, coronavirus disease 2019 (COVID-19), as an infectious disease with cytokine storm, has become an emerging global challenge. To assess the duration of SARS-COV-2 viral shedding and associated risk factors in COVID-19 patients. Methods: COVID-19 patients with interleukin (IL)-1b, soluble interleukin-2 receptor (sIL-2R), IL-6, IL-8, IL-10 and tumor necrosis factor (TNF)-α cytokines data consecutively admitted to Tongji Hospital from January 27, 2020 through February 5, 2020 were enrolled and been followed up until March 24, 2020. We utilized Kaplan-Meier method and Cox proportional hazards regression analysis to assess the duration of viral shedding and risk factors affecting virus clearance. Results: 246 inpatients with laboratory confirmed COVID-19 were enrolled. The median duration of viral shedding was 24 days, ranging from 6 to 63 days. Age, severity of COVID-19, albumin, lactate dehydrogenase (LDH), D-dimer, ferritin and sIL-2R were associated with duration of viral shedding. Administration of lopinavir-ritonavir, arbidol, oseltamivir and intravenous immunoglobulin did not shorten viral shedding time. Multivariate cox regression analysis revealed that sIL-2R, LDH and severity of COVID-19 were independent factors associated with duration of viral shedding. At stratified analysis, the viral shedding time was positively correlated with age, sIL-2R and LDH in non-corticosteroid subgroup, while negatively correlated with lymphocyte count in corticosteroid group. Conclusions: The present study demonstrated that elevated sIL-2R, increased LDH and severe status were related to prolongation of viral shedding in COVID-19 inpatients. Further research is urgent to investigate the mechanism of immune reaction involved in the virus clearance process and aim to the optimal antiviral therapy.