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Abstract Dysregulation of splicing factor expression plays a crucial role in the progression of hepatocellular carcinoma (HCC). Our research found that the expression level of splicing factor ZMAT2 was increased in HCC, promoting the proliferation of HCC cells. RNAseq data indicated that the absence of ZMAT2 induced skipping exon of mRNA, while RIPseq data further revealed the mRNA binding motifs of ZMAT2. A comprehensive analysis of RNAseq and RIPseq data indicateed that ZMAT2 played a crucial role in the maturation process of TRIM28 mRNA. Knocking down of ZMAT2 led to the deletion of 25 bases in exon 11 of TRIM28, ultimately resulting in nonsense-mediated decay (NMD). Our data revealed that ZMAT2 could regulate TRIM28 to reduce the accumulation of ROS in HCC cells, thereby promoting their proliferation. Our research also discovered that ZMAT2 was capable of undergoing phase separation, resulting in the formation of liquid droplet condensates within HCC cells. Additionally, it was found that ZMAT2 was able to form protein-nucleic acid condensates with TRIM28 mRNA. In summary, this study is the first to reveal that ZMAT2 and TRIM28 mRNA form protein-nucleic acid condensates, thereby regulating the splicing of TRIM28 mRNA. The increased expression of ZMAT2 in HCC leads to upregulated TRIM28 expression and reduced ROS accumulation, ultimately accelerating the proliferation of HCC cells.

Abstract Engineered Salmonella has emerged as a promising microbial immunotherapy against tumors; however, its clinical effectiveness has encountered limitations. In our investigation, we unveil a non-dose-dependent type of behavior regarding Salmonella’s therapeutic impact and reveal the regulatory role of neutrophils in diminishing the efficacy of this. While Salmonella colonization within tumors recruits a substantial neutrophil population, these neutrophils predominantly polarize into the pro-tumor N2 phenotype, elevating PD-L1 expression and fostering an immunosuppressive milieu within the tumor microenvironment. In order to bypass this challenge, we introduce MnO2 nanoparticles engineered to activate the STING pathway. Harnessing the STING pathway to stimulate IFN-β secretion prompts a shift in neutrophil polarization from the N2 to the N1 phenotype. This strategic repolarization remodels the tumor immune microenvironment, making the infiltration and activation of CD8+ T cells possible. Through these orchestrated mechanisms, the combined employment of Salmonella and MnO2 attains the synergistic enhancement of anti-tumor efficacy, achieving the complete inhibition of tumor growth within 20 days and an impressive 80% survival rate within 40 days, with no discernible signs of significant adverse effects. Our study not only unveils the crucial in vivo constraints obstructing microbial immune therapy but also sets out an innovative strategy to augment its efficacy. These findings pave the way for advancements in cell-based immunotherapy centered on leveraging the potential of neutrophils. Graphical Abstract

Abstract Background Hepatocellular carcinoma (HCC) represents one of the most significant causes of mortality due to cancer-related deaths. It has been previously reported that the TGF-β signaling pathway may be associated with tumor progression. However, the relationship between TGF-β signaling pathway and HCC remains to be further elucidated. The objective of our research was to investigate the impact of TGF-β signaling pathway on HCC progression as well as the potential regulatory mechanism involved. Methods We conducted a series of bioinformatics analyses to screen and filter the most relevant hub genes associated with HCC. E. coli was utilized to express recombinant protein, and the Ni–NTA column was employed for purification of the target protein. Liquid liquid phase separation (LLPS) of protein in vitro, and fluorescent recovery after photobleaching (FRAP) were utilized to verify whether the target proteins had the ability to drive force LLPS. Western blot and quantitative real-time polymerase chain reaction (qPCR) were utilized to assess gene expression levels. Transcription factor binding sites of DNA were identified by chromatin immunoprecipitation (CHIP) qPCR. Flow cytometry was employed to examine cell apoptosis. Knockdown of target genes was achieved through shRNA. Cell Counting Kit-8 (CCK-8), colony formation assays, and nude mice tumor transplantation were utilized to test cell proliferation ability in vitro and in vivo. Results We found that Smad2/3/4 complex could regulate tyrosine aminotransferase (TAT) expression, and this regulation could relate to LLPS. CHIP qPCR results showed that the key targeted DNA binding site of Smad2/3/4 complex in TAT promoter region is −1032 to −1182. In addition. CCK-8, colony formation, and nude mice tumor transplantation assays showed that Smad2/3/4 complex could repress cell proliferation through TAT. Flow cytometry assay results showed that Smad2/3/4 complex could increase the apoptosis of hepatoma cells. Western blot results showed that Smad2/3/4 complex would active caspase-9 through TAT, which uncovered the mechanism of Smad2/3/4 complex inducing hepatoma cell apoptosis. Conclusion This study proved that Smad2/3/4 complex could undergo LLPS to active TAT transcription, then active caspase-9 to induce hepatoma cell apoptosis in inhibiting HCC progress. The research further elucidate the relationship between TGF-β signaling pathway and HCC, which contributes to discover the mechanism of HCC development.

Abstract Background Clear cell renal cell carcinoma (ccRCC) is one of the most prevalent renal cancers, and the molecular mechanisms underlying its progression are still not fully understood. The expression of CCDC25, a notably underexpressed gene in many tumors, has been understudied in ccRCC. This research aims to explore the role of CCDC25 in ccRCC's clinical outcomes and uncover the molecular pathways influenced by it. Methods A multi-tiered approach was adopted involving bioinformatic analysis, tissue sample evaluation, in vitro and in vivo experiments. CCDC25 expression levels in tumor vs. normal tissues were quantified using Western blot and immunofluorescence studies. Cell proliferation and migration were analyzed using CCK8, EDU, Transwell assays, and wound healing assays. RNA sequencing was performed to elucidate the molecular pathways affected, followed by detailed protein–protein interaction studies and mouse xenograft models. Results CCDC25 was predominantly underexpressed in ccRCC tumors and associated with advanced clinical stages and poor prognosis. Overexpression of CCDC25 in renal cancer cell lines resulted in reduced proliferation and migration. RNA sequencing revealed significant alterations in the Hippo pathway. Overexpression of CCDC25 inhibited the expression of downstream Hippo pathway proteins ITGA3 and CCND1 and promoted YAP phosphorylation. Mechanistic studies showed that CCDC25 interacts with YAP and influences YAP phosphorylation through LATS1. In vivo, CCDC25 overexpression inhibited tumor growth and promoted apoptosis. Conclusion CCDC25 acts as a potential tumor suppressor in ccRCC by inhibiting cell proliferation and migration, potentially through regulating the Hippo signaling pathway. These findings highlight the potential of CCDC25 as a therapeutic target in ccRCC treatment. Graphical Abstract

BackgroundBody composition is recognized to be associated with clinical outcomes in patients with locally advanced rectal cancer (LARC). This study aimed to determine the prognostic role of regional adipose tissue distribution in patients with resectable LARC treated with or without neoadjuvant chemoradiotherapy (nCRT).MethodsThis retrospective study included 281 consecutive patients who underwent radical surgery for LARC with or without preoperative nCRT between 2013 and 2019. Patients underwent contrast-enhanced CT scans before nCRT and before surgery. Visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (aSAT), and gluteal subcutaneous adipose tissue (gSAT) were quantified on the CT images. The association of adipose tissue distribution with progression-free survival (PFS) was analyzed using Cox proportional hazards analysis.ResultsA total of 102 nCRT-treated and 179 primarily resected patients were included. During a median follow-up period of 24 months, 74 (26.3%) patients experienced local recurrence or metastasis. Multivariable analysis showed that VAT was associated with PFS in all patients (hazard ratio [HR] 1.28, 95% confidence interval [CI] 1.04–1.57; P = 0.021). This association was only maintained in primarily resected patients (HR 1.31, 95% CI 1.02–1.69; P = 0.037). For patients receiving preoperative nCRT, VAT was not significantly associated with PFS, while the dynamic change in gSAT (ΔgSAT) between nCRT and surgery was associated with PFS (HR 0.43, 95%CI 0.27–0.69, P = 0.001).ConclusionVisceral obesity is an adverse prognostic factor in patients with resectable LARC treated by primary resection, while increased gluteal subcutaneous adiposity during preoperative nCRT may indicate favorable clinical outcomes.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in December 2019 with staggering economic fallout and human suffering. The unique structure of SARS-CoV-2 and its underlying pathogenic mechanism were responsible for the global pandemic. In addition to the direct damage caused by the virus, SARS-CoV-2 triggers an abnormal immune response leading to a cytokine storm, culminating in acute respiratory distress syndrome and other fatal diseases that pose a significant challenge to clinicians. Therefore, potential treatments should focus not only on eliminating the virus but also on alleviating or controlling acute immune/inflammatory responses. Current management strategies for COVID-19 include preventative measures and supportive care, while the role of the host immune/inflammatory response in disease progression has largely been overlooked. Understanding the interaction between SARS-CoV-2 and its receptors, as well as the underlying pathogenesis, has proven to be helpful for disease prevention, early recognition of disease progression, vaccine development, and interventions aimed at reducing immunopathology have been shown to reduce adverse clinical outcomes and improve prognosis. Moreover, several key mutations in the SARS-CoV-2 genome sequence result in an enhanced binding affinity to the host cell receptor, or produce immune escape, leading to either increased virus transmissibility or virulence of variants that carry these mutations. This review characterizes the structural features of SARS-CoV-2, its variants, and their interaction with the immune system, emphasizing the role of dysfunctional immune responses and cytokine storm in disease progression. Additionally, potential therapeutic options are reviewed, providing critical insights into disease management, exploring effective approaches to deal with the public health crises caused by SARS-CoV-2.

Abstract Background Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial lung disease. Clinical models to accurately evaluate the prognosis of IPF are currently lacking. This study aimed to construct an easy-to-use and robust prediction model for transplant-free survival (TFS) of IPF based on clinical and radiological information. Methods A multicenter prognostic study was conducted involving 166 IPF patients who were followed up for 3 years. The end point of follow-up was death or lung transplantation. Clinical information, lung function tests, and chest computed tomography (CT) scans were collected. Body composition quantification on CT was performed using 3D Slicer software. Risk factors in blood routine examination-radiology-pulmonary function (BRP) were identified by Cox regression and utilized to construct the “BRP Prognosis Model”. The performance of the BRP model and the gender-age-physiology variables (GAP) model was compared using time-ROC curves, calibration curves, and decision curve analysis (DCA). Furthermore, histopathology fibrosis scores in clinical specimens were compared between the different risk stratifications identified by the BRP model. The correlations among body composition, lung function, serum inflammatory factors, and profibrotic factors were analyzed. Results Neutrophil percentage > 68.3%, pericardial adipose tissue (PAT) > 94.91 cm3, pectoralis muscle radiodensity (PMD) ≤ 36.24 HU, diffusing capacity of the lung for carbon monoxide/alveolar ventilation (DLCO/VA) ≤ 56.03%, and maximum vital capacity (VCmax) 3 years; intermediate risk: TFS = 2–3 years; high risk: TFS ≈ 1 year). Patients with a high-risk stratification according to the BRP model had a higher fibrosis score on histopathology. Additionally, serum proinflammatory markers were positively correlated with visceral fat volume and infiltration. Conclusions In this study, the BRP prognostic model of IPF was successfully constructed and validated. Compared with the commonly used GAP model, the BRP model had better performance and generalization with easily obtainable indicators. The BRP model is suitable for clinical promotion.

Abstract Background Liver cancer is a prevalent and deadly form of cancer with high incidence and mortality rates. The PCMT1 protein has been linked to cell anti-apoptosis and tumor metastasis, but its significance in liver hepatocellular carcinoma (LIHC) remains largely unexplored. Methods We conducted a pan-cancer analysis to examine the expression differences of PCMT1. Kaplan–Meier curves were employed to assess the prognostic impact of PCMT1 on LIHC patients, and we investigated the association between PCMT1 and clinical features, which we validated using a GEO therapeutic dataset. Gene enrichment analysis helped identify signaling pathways associated with PCMT1 expression. Moreover, we evaluated the relationship between PCMT1 and immune cell infiltration, as well as the differences in gene mutations between high-expression and low-expression groups. In vitro and in vivo experiments were performed to assess the effect of PCMT1 on tumor cell lines and mouse tumor models, and potential pathways were explored through gene sequencing. Result PCMT1 is highly expressed in most tumors and exhibits a significant association with prognosis in LIHC patients. Pathway enrichment analysis revealed that PCMT1 is involved in cell cycle regulation, immunity, and other processes. Further immune analysis demonstrated that high expression of PCMT1 could reduce tumor-killing immune cell infiltration. In vitro experiments indicated that PCMT1 knockdown could inhibit cancer cell proliferation and migration while promoting apoptosis. In vivo experiments showed that PCMT1 knockdown significantly reduced tumor growth rate, enhanced CD8+T cell infiltration, and increased caspase-3 expression in the tumor area. Gene sequencing suggested that PCMT1 may function through the PI3K–AKT pathway. Conclusion Our findings suggest that PCMT1 acts as a promoter of liver cancer progression and may serve as a novel prognostic indicator and therapeutic target for patients with LIHC.

Abstract Introduction PTEN often mutates in tumors, and its manipulation is suggested to be used in the development of preclinical tools in cancer research. This study aims to explore the biological impact of gene expression related to PTEN mutations and to develop a prognostic classification model based on the heterogeneity of PTEN expression, and to explore its sensitivity as an indicator of prognosis and molecular and biologic features in hepatocellular carcinoma (HCC). Material and methods RNA-seq data and mutation data of the LIHC cohort sample downloaded from The Cancer Genome Atlas (TCGA). The HCC samples were grouped according to the mean expression of PTEN, and the tumor microenvironment (TME) was evaluated by ESTIMATE and ssGSEA. The prognostic classification model related to PTEN were constructed by COX and LASSO regression analysis of differentially expressed genes (DEGs) between PTEN-high and -low expressed group. Results The expression of PTEN was affected by copy number variation (CNV) and negatively correlated with immune score, IFNγ score and immune cell infiltration. 1281 DEGs were detected between PTEN-high and PTEN-low expressed group, 8 of the DEGs were finally filtered for developing a prognosis classification model. This model showed better prognostic value than other clinicopathological parameters, and the prediction accuracy of prognosis and ICB treatment for immunotherapy cohorts was better than that of TIDE model. Conclusions This study demonstrated the effect of CNV on PTEN expression and the negative immune correlation of PTEN, and constructed a classification model related to the expression of PTEN, which was of guiding significance for evaluating prognostic results of HCC patients and ICB treatment response of cancer immunotherapy cohorts.

Abstract Background Great progress has been made in applying immunotherapy to the clinical treatment of tumors. However, many patients with triple-negative breast cancer (TNBC) cannot benefit from immunotherapy due to the immune desert type of TNBC, which is unresponsive to immunotherapy. DMKG, a cell-permeable derivative of α-KG, has shown potential to address this issue. Method We investigated the effects of combining DMKG with radioimmunotherapy on TNBC. We assessed the ability of DMKG to promote tumor cell apoptosis and immunogenic death induced by radiotherapy (RT), as well as its impact on autophagy reduction, antigen and inflammatory factor release, DC cell activation, and infiltration of immune cells in the tumor area. Result Our findings indicated that DMKG significantly promoted tumor cell apoptosis and immunogenic death induced by RT. DMKG also significantly reduced autophagy in tumor cells, resulting in increased release of antigens and inflammatory factors, thereby activating DC cells. Furthermore, DMKG promoted infiltration of CD8 + T cells in the tumor area and reduced the composition of T-regulatory cells after RT, reshaping the tumor immune microenvironment. Both DMKG and RT increased the expression of PD-L1 at immune checkpoints. When combined with anti-PD-L1 drugs (α-PD-L1), they significantly inhibited tumor growth without causing obvious side effects during treatment. Conclusion Our study underscores the potential of pairing DMKG with radioimmunotherapy as an effective strategy for treating TNBC by promoting apoptosis, immunogenic death, and remodeling the tumor immune microenvironment. This combination therapy could offer a promising therapeutic avenue for TNBC patients unresponsive to conventional immunotherapy. Graphical Abstract

The Zhu III Depression, situated in the northern Pearl River Mouth Basin, features a complex fault system composed of NE–SW-, nearly E–W-, and NW–SE-oriented faults. However, there is limited research on NW-trending faults, especially regarding their formation mechanisms. Through structural analysis of 3D seismic profiles, we have revealed the geometric and kinematic characteristics of NW-trending faults and categorized them into three types based on their formation mechanisms: extensional fault, dextral transtensional fault, and sinistral strike–slip fault. The extensional faults predominantly developed as boundary faults during the rifting I period, caused by tectonic inversion of the NW–NWW-trending basement faults since early Eocene. The transtensional fault resulted from the dextral strike–slip motion of the NE-trending basin-controlling faults since late Eocene, under the regional dextral extension stress setting. The sinistral strike–slip faults have been dominant during the post-rifting period since early Oligocene. This is due to the sinistral shearing action related to the southeastward lateral extrusion of the Indochina Block and slab pull southward by subduction of the proto-SCS. The NW-trending faults controlled the development of local tectonics and structures, the depocenter migration during the rifting period, and the trapping, migration, and preservation of oil and gas.

Abstract Bacteria‐based microbial immunotherapy shows various unique properties for tumor therapy owing to their active tropism to tumor and multiple anti‐tumor mechanisms. However, its clinical benefit is far from satisfactory, which is limited by rapid systemic clearance and neutrophils‐mediated immune restriction to compromise the efficacy, as well as non‐specific distribution to cause toxicity. To address all these limitations, herein we reported a polyserotonin (PST) coated Salmonella (Sal) with surface adsorption of DNAzyme (Dz)‐functionalized MnO2 nanoparticles (DzMN) for tumor therapy. PST could facilely coat on Sal surface via oxidation and self‐polymerization of its serotonin monomer, which enabled surface stealth to avoid rapid systemic clearance while maintaining the tumor homing effect. Upon targeting to tumor, the PST was degraded and exfoliated in response to acidic tumor microenvironment, thus liberating Sal to recover its anti‐tumor activities. Meanwhile, the DzMN was also delivered into tumor via hitchhiking Sal, which could release Dz and Mn2+ after tumor cells internalization. The Dz was then activated by its cofactor of Mn2+ to cleave target PD‐L1 mRNA, thus serving as a self‐activated system for gene silencing. Combining Sal and Dz for immune activation and PD‐L1 knockdown, respectively, anti‐tumor immunotherapy was achieved with enhanced efficacy. Notably, PST coating could significantly decrease infection potential and non‐specific colonization of Sal at normal organs, achieving high in vivo biosafety. This work addresses the key limitations of Sal for in vivo application via biomaterials modification, and provides a promising platform for better microbial immunotherapy.

Chemotherapy is an important adjuvant treatment of glioma, while the efficacy is far from satisfactory, due not only to the biological barriers of blood‒brain barrier (BBB) and blood‒tumor barrier (BTB) but also to the intrinsic resistance of glioma cells via multiple survival mechanisms such as up-regulation of P-glycoprotein (P-gp). To address these limitations, we report a bacteria-based drug delivery strategy for BBB/BTB transportation, glioma targeting, and chemo-sensitization. Bacteria selectively colonized into hypoxic tumor region and modulated tumor microenvironment, including macrophages repolarization and neutrophils infiltration. Specifically, tumor migration of neutrophils was employed as hitchhiking delivery of doxorubicin (DOX)-loaded bacterial outer membrane vesicles (OMVs/DOX). By virtue of the surface pathogen-associated molecular patterns derived from native bacteria, OMVs/DOX could be selectively recognized by neutrophils, thus facilitating glioma targeted delivery of drug with significantly enhanced tumor accumulation by 18-fold as compared to the classical passive targeting effect. Moreover, the P-gp expression on tumor cells was silenced by bacteria type III secretion effector to sensitize the efficacy of DOX, resulting in complete tumor eradication with 100% survival of all treated mice. In addition, the colonized bacteria were finally cleared by anti-bacterial activity of DOX to minimize the potential infection risk, and cardiotoxicity of DOX was also avoided, achieving excellent compatibility. This work provides an efficient trans-BBB/BTB drug delivery strategy via cell hitchhiking for enhanced glioma therapy.

IntroductionGenerally, Traditional Chinese Medicine (TCM) courses are now given to modern medicine students without proper course scheduling, resulting in poor teaching results.MethodsTo analyze the main factors affecting TCM learning, we surveyed the medical students and TCM teachers from Xiangya School of Medicine of Central South University via online questionnaires. The questionnaire comprised two parts, the students' part included the basic information, the subjective cognition in TCM, the attitude toward TCM course arrangements, and the attitude toward curriculum content and the design of TCM. The teachers' part included the basic information, the attitudes and opinions on TCM course arrangements, and suggestions and views on TCM teaching reform. The related data were collected from 187 medical students divided into two groups, namely, clinical medical students and non-clinical medical students.ResultsWe found a more positive attitude toward TCM [including “Scientific nature of TCM” (P = 0.03) and “Necessity for modern medicine students to learn TCM” (P = 0.037)] in clinical medical students compared with non-clinical medical students, clinical and non-clinical medical students tended to find TCM courses difficult, and the students prefer clinical training to be better than theoretical teaching, while the teachers believe that lecture-based education should have a more significant proportion.DiscussionHence, to optimize the current TCM teaching, we conducted education reform, including differentiated teaching, hybrid teaching, and selective teaching.

Visualization techniques are effective tools in diagnosis and therapy for biomedical applications. Due to the unavoidable shortcomings of single optical or magnetic resonance imaging, the introduction of dual functional imaging system is of great significance. Herein a new Gd1-xNdx(CO3)OH@SiO2 core–shell nanostructure were developed to fulfill the corresponding demands. Uniform nanospheres were acquired with surface modification and coated with thickness tunable silica shells. The samples presented strong luminescence penetrating biological tissue, due to the wide spectral region covering NIR I & II window of Nd3+ under 808 nm laser excitation. On the other hand, distinct contrast enhancement could be viewed for in vitro and in vivo MRI trials, which generates from high paramagnetic relaxation of Gd3+ and well dispersibility caused by silica shells. Along with the non-toxicity proved by the low concentration of leaching Gd3+ and nice biocompatibility of silica coated nanospheres, it is a superior candidate for NIR and MRI dual functional imaging platform in biological applications.

Aim PD-1/PD-L1 inhibitors in combination with CTLA-4 inhibitors are being tested in a number of ongoing clinical trials. As a result, it is critical to fully comprehend the toxicity characteristics of adverse events in combination therapy. This study aims to extensively compare the incidences and ORs of treatment-related adverse events between two combination strategies.Methods The eligible articles were searched from PubMed, EMBASE and Cochrane databases for studies published between 1 January 2010 and 1 May 2021, investigating PD-1/PD-L1 inhibitors plus CTLA-4 inhibitor-based combined clinical therapies. The mean incidences and pooled ORs of all-grade and grade 3 or higher adverse events were calculated by random-effects model using Stata 12.1. Heterogeneity between studies was assessed with I2 statistics and Chi square-based Q statistic. The overall risk of bias was assessed by Review Manager 5.3.Results A total of 26 eligible studies of 3607 patients were selected; 2852 patients developed at least one all-grade adverse event. PD-L1 inhibitors plus CTLA-4 inhibitors regimen (incidence 0.67, 95% CI: 0.57–0.77) had marked advantage over PD-1 inhibitors plus CTLA-4 inhibitors regimen (incidence 0.89, 95% CI: 0.86–0.93).Conclusion PD-L1 inhibitors plus CTLA-4 inhibitors shows better safety in treatment-related adverse events than PD-1 inhibitors plus CTLA-4 inhibitors.

In recent years, with the development of artificial intelligence, especially deep learning technology, researches on automatic detection of cerebrovascular diseases on medical images have made tremendous progress and these models are gradually entering into clinical practice. However, because of the complexity and flexibility of the deep learning algorithms, these researches have great variability on model building, validation process, performance description and results interpretation. The lack of a reliable, consistent, standardized design protocol has, to a certain extent, affected the progress of clinical translation and technology development of computer aided detection systems. After reviewing a large number of literatures and extensive discussion with domestic experts, this position paper put forward recommendations of standardized design on the key steps of deep learning-based automatic image detection models for cerebrovascular diseases. With further research and application expansion, this position paper would continue to be updated and gradually extended to evaluate the generalizability and clinical application efficacy of such tools.

ILC3s have been identified as crucial immune regulators that play a role in maintaining host homeostasis and modulating the antitumor response. Emerging evidence supports the idea that LTi cells play an important role in initiating lymphoid tissue development, while other ILC3s can promote host defense and orchestrate adaptive immunity, mainly through the secretion of specific cytokines and crosstalk with other immune cells or tissues. Additionally, dysregulation of ILC3-mediated overexpression of cytokines, changes in subset abundance, and conversion toward other ILC subsets are closely linked with the occurrence of tumors and inflammatory diseases. Regulation of ILC3 cytokines, ILC conversion and LTi-induced TLSs may be a novel strategy for treating tumors and intestinal or extraintestinal inflammatory diseases. Herein, we discuss the development of ILCs, the biology of ILC3s, ILC plasticity, the correlation of ILC3s and adaptive immunity, crosstalk with the intestinal microenvironment, controversial roles of ILC3s in intestinal diseases and potential applications for treatment.

Clinically, xenotransplantation often leads to T-cell-mediated graft rejection. Immunosuppressive agents including polyclonal regulatory T cells (poly-Tregs) promote global immunosuppression, resulting in serious infections and malignancies in patients. Xenoantigen-expanded Tregs (xeno-Tregs) have become a promising immune therapy strategy to protect xenografts with fewer side effects. In this study, we aimed to identify an efficient and stable subset of xeno-Tregs. We enriched CD27 + xeno-Tregs using cell sorting and evaluated their suppressive functions and stability in vitro via mixed lymphocyte reaction (MLR), real-time polymerase chain reaction, inflammatory induction assay, and Western blotting. A STAT5 inhibitor was used to investigate the relationship between the function and stability of CD27 + xeno-Tregs and the JAK3–STAT5 signaling pathway. A humanized xenotransplanted mouse model was used to evaluate the function of CD27 + xeno-Tregs in vivo . Our results show that CD27 + xeno-Tregs express higher levels of Foxp3, cytotoxic T-lymphocyte antigen-4 (CTLA4), and Helios and lower levels of interleukin-17 (IL-17) than their CD27 − counterparts. In addition, CD27 + xeno-Tregs showed enhanced suppressive function in xeno-MLR at ratios of 1:4 and 1:16 of Tregs:responder cells. Under inflammatory conditions, a lower percentage of CD27 + xeno-Tregs secretes IL-17 and interferon-γ (IFN-γ). CD27 + xeno-Tregs demonstrated an upregulated JAK3–STAT5 pathway compared with that of CD27 − xeno-Tregs and showed decreased Foxp3, Helios, and CTLA4 expression after addition of STAT5 inhibitor. Mice that received porcine skin grafts showed a normal tissue phenotype and less leukocyte infiltration after reconstitution with CD27 + xeno-Tregs. Taken together, these data indicate that CD27 + xeno-Tregs may suppress immune responses in a xenoantigen-specific manner, which might be related to the activation of the JAK3–STAT5 signaling pathway.

Cancer is a major medical problem worldwide. Due to its high heterogeneity, the use of the same drugs or surgical methods in patients with the same tumor may have different curative effects, leading to the need for more accurate treatment methods for tumors and personalized treatments for patients. The precise treatment of tumors is essential, which renders obtaining an in-depth understanding of the changes that tumors undergo urgent, including changes in their genes, proteins and cancer cell phenotypes, in order to develop targeted treatment strategies for patients. Artificial intelligence (AI) based on big data can extract the hidden patterns, important information, and corresponding knowledge behind the enormous amount of data. For example, the ML and deep learning of subsets of AI can be used to mine the deep-level information in genomics, transcriptomics, proteomics, radiomics, digital pathological images, and other data, which can make clinicians synthetically and comprehensively understand tumors. In addition, AI can find new biomarkers from data to assist tumor screening, detection, diagnosis, treatment and prognosis prediction, so as to providing the best treatment for individual patients and improving their clinical outcomes.

Inconsistent training programs for public health emergency (PHE) have been criticized as a contributing factor in PHE's managerial weak points. In response, to analyze the relevant discrepancies among the medical students in the class of 2021 from Xiangya School of Medicine of Central South University, the present study conducted an online questionnaire survey using convenience sampling. The questionnaire comprised four sections, including the basic information, the subjective cognition in PHE, the rescue knowledge and capabilities of PHE, and the mastery of PHE regulations and psychological intervention abilities. To compare the abovementioned aspects, related data were collected from 235 medical students divided into two groups, namely, clinical medical students (Group A) and preventive medical students (Group B). We found a more positive attitude in PHE (P = 0.014) and a better grasp of the PHE classification (P = 0.027) and the reporting system in group B compared with group A. In addition, even if group B showed the same response capability in communicable diseases as group A, the former had less access to clinical practice, resulting in poorer performance in the noncommunicable diseases during a fire, flood, and traffic accidents (P = 0.002, P = 0.018, P = 0.002). The different emphasis of each training program contributed to the uneven distribution of abilities and cognition. Meanwhile, the lack of an integrated PHE curriculum led to unsystematic expertise. Hence, to optimize the PHE management system, equal attention should be paid to medical students with diverse majors along with a complete integrated PHE curriculum.

Background: Anterior cervical fusion (ACF) has become a standard treatment approach to effectively alleviate symptoms in patients with cervical spondylotic myelopathy and radiculopathy. However, alteration of cervical sagittal alignment may accelerate degeneration at segments adjacent to the fusion and thereby compromise the surgical outcome. It remains unknown whether changes in T1 tilt, an important parameter of cervical sagittal alignment, may cause redistribution of biomechanical loading on adjacent segments after ACF surgery.Objective: The objective was to examine the effects of T1 tilt angles on biomechanical responses (i.e.range of motion (ROM) and intradiscal VonMises stress) of the cervical spine before and after ACF.Methods: C2–T1 FE models for pre- and postoperative C4–C6 fusion were constructed on the basis of our previous work. Varying T1 tilts of −10°, −5°, 0°, 5°, and 10° were modeled with an imposed flexion–extension rotation at the T1 inferior endplate for the C2–T1 models. The flexion–extension ROM and intradiscal VonMises stress of functional spinal units were compared between the pre- and postoperative C2–T1 FE models of different T1 tilts.Results: The spinal segments adjacent to ACF demonstrated higher ROM ratios after the operation regardless of T1 tilt. The segmental ROM ratio distribution was influenced as T1 tilt varied and loading conditions, which were more obvious during displacement-control loading of extension. Regardless of T1 tilt, intradiscal VonMises stress was greatly increased at the adjacent segments after the operation. As T1 tilt increased, intradiscal stress at C3–C4 decreased under 30° flexion and increased under 15° extension. The contrary trend was observed at the C6–C7 segment, where the intradiscal stress increased with the increasing T1 tilt under 30° flexion and decreased under 15° extension.Conclusion: T1 tilt change may change biomechanical loadings of cervical spine segments, especially of the adjacent segments after ACF. Extension may be more susceptible to T1 tilt change.

PurposeThis study aimed to evaluate the effect and influence of the undergraduate tutor system on the undergraduate stage of Chinese 8-year medical program students in scientific research.MethodsWe collected related data from 194 medical students in the Xiangya Medical School of Central South University. The questionnaire was composed of three parts, namely, eight questions for basic information about individual and undergraduate tutor system, five questions for the subjective feeling impact of the undergraduate tutor system, and 22 questions for accessing the scientific research ability and academic results. The students were mainly divided into three groups to compare different kinds of undergraduate tutor systems, namely, single tutor for multiple students' system (group A), multiple tutors for multiple students' system (group B), and no tutor system for comparison (group C).ResultsThe type of tutorial system, the frequency of guidance, and the way of guidance were independent influence factors of the view of 8-year medical students on scientific research. Group B behaved better than group C in literature processing (P = 0.012), experimental operation (P < 0.001), statistical analysis (P < 0.001), and manuscript producing (P = 0.019). Group A and B joined in more National college students' innovation and entrepreneurship training programs (P = 0.003, P < 0.001). The most popular types of articles published by students were bioinformatics, meta-analysis, and reviews.ConclusionUndergraduate tutor system has made tremendous achievements in cultivating students' scientific research capacity; however, implement improvement should be considered to better educate students.

Early identification of COVID-19 patients at risk of progression may facilitate more individually aligned treatment plans. Here the authors develop an online nomogram incorporating CT severity score and clinical characteristics for early predicting the disease progression risk among COVID-19 pneumonia patients.

Tumor-associated macrophages (TAMs), the most abundant inflammatory cell group in the tumor microenvironment, play an essential role in tumor immune regulation. The infiltration degree of TAMs in the tumor microenvironment is closely related to tumor growth and metastasis, and TAMs have become a promising target in tumor immunotherapy. Molecular imaging is a new interdisciplinary subject that combines medical imaging technology with molecular biology, nuclear medicine, radiation medicine, and computer science. The latest progress in molecular imaging allows the biological processes of cells to be visualized in vivo , which makes it possible to better understand the density and distribution of macrophages in the tumor microenvironment. This review mainly discusses the application of targeting TAM in tumor immunotherapy and the imaging characteristics and progress of targeting TAM molecular probes using various imaging techniques.

As a DNA receptor, cyclic GMP-AMP synthase (cGAS) plays a crucial role in the immune system by recognizing abnormal DNA in the cytoplasm and activating the stimulator of interferon genes (STING) signaling pathway. This signaling cascade reaction leads to an immune response produced by type I interferon and other immune mediators. Recent advances in research have enhanced our current understanding of the potential role of the cGAS/STING pathway in anticancer therapy; however, in some cases, chronic STING activation may promote tumorigenesis. The present review article discusses the biological mechanisms of the cGAS/STING pathway, its dichotomous role in tumors, and the latest advances with respect to STING agonists and antagonists.

Top management team (TMT) knowledge hiding, which is not only related to the normal operation of the team but also closely related to enterprise innovation performance, has been paid little attention to in the previous studies. Based on the theories of upper echelons, knowledge management, and innovation, this study proposed a moderated mediation model to research how TMT knowledge hiding affected enterprise innovation performance. In this model, TMT knowledge hiding was the independent variable, TMT creativity was the mediating variable, enterprise innovation performance was the dependent variable, and team competitive climate was the moderating variable. MPLUS7.0 was used for the CFAs to evaluate the discriminate validities of the key variables, and SPSS 22.0 was used to calculate the descriptive statistics, analyze the correlations between variables, make the multiple regression analysis, and process the data obtained from 612 executives in 53 TMTs. The results showed that TMT knowledge hiding had a significant negative impact on enterprise innovation performance; TMT creativity had a partial mediating effect between TMT knowledge hiding and enterprise innovation performance, and team competitive climate had a moderating effect on the relationship between TMT knowledge hiding and TMT creativity. These research results fill up the gap of the theoretical research in TMT knowledge hiding and provide scientific guidance to reasonably reduce or eliminate the phenomenon of TMT knowledge hiding and improve enterprise innovation performance.

Cancer precision medicine (CPM) could tailor the best treatment for individual cancer patients, while imaging techniques play important roles in its application. With the characteristics of noninvasion, nonionized, radiation-free, multidimensional imaging function, and real-time monitoring, magnetic resonance imaging (MRI) is an effective way for early tumor detection, and it has become a tower of strength in CPM imaging techniques. Due to linkage with nephrogenic systemic fibrosis (NSF), gadolinium (Gd)-based contrast agent (CA), which was long used in MRI, has been restricted by the Food and Drug Administration (FDA). In this review, we would like to introduce the manganese (Mn)-based CAs that could significantly increase the safety of MRI CAs by realizing more superior performance and functions simultaneously in the diagnosis and treatment of tumors. Also, recent advances in Mn-based hybrid nanomaterials for CPM are summarized and discussed.

PurposeTumor promote disease progression by reprogramming their metabolism and that of distal organs, so it is of great clinical significance to study the changes in glucose metabolism at different tumor stages and their effect on glucose metabolism in other organs.MethodsA retrospective single-centre study was conducted on 253 NSCLC (non-small cell lung cancer) patients with negative lymph nodes and no distant metastasis. According to the AJCC criteria, the patients were divided into different groups based on tumor size: stage IA, less than 3 cm (group 1, n = 121); stage IB, greater than 3-4 cm (group 2, n = 64); stage IIA, greater than 4-5 cm (group 3, n = 36); and stage IIB, greater than 5-7 cm (group 4, n = 32). All of the patients underwent baseline 18F-FDG PET/CT scans, and the primary lesion SUVmax (maximum standardized uptake value), liver SUVmean (mean standardized uptake value), spleen SUVmean, TLR (Tumor-to-liver SUV ratio) and TSR (Tumor-to-spleen SUV ratio) were included in the study, combined with clinical examination indicators to evaluate DFS (disease free survival).ResultsIn NSCLC patients, with the increase in the maximum diameter of the tumor, the SUVmax of the primary lesion gradually increased, and the SUVmean of the liver gradually decreased. The primary lesion SUVmax, liver SUVmean, TLR and TSR were related to disease recurrence or death. The best predictive parameters were different when the tumor size differed. SUVmax had the highest efficiency when the tumor size was less than 4 cm (AUC:0.707 (95% CI, 0.430-0.984) tumor size < 3 cm), (AUC:0.726 (95% CI, 0.539-0.912) tumor size 3-4 cm), liver SUVmean had the highest efficiency when the tumor size was 4-5 cm (AUC:0.712 (95% CI, 0.535-0.889)), and TLR had the highest efficiency when the tumor size was 5-7 cm [AUC:0.925 (95%CI, 0.820-1.000)].ConclusionsIn patients with early NSCLC, glucose metabolism reprogramming occurs in the primary lesion and liver. With the increase in tumor size, different metabolic parameters should be selected to evaluate the prognosis of patients.

The role of Regulatory T cells (Tregs) in tolerance induction post-transplantation is well-established, but Tregs adoptive transfer alone without combined immunosuppressants have failed so far in achieving clinical outcomes. Here we applied a set of well-designed criteria to test the influence of commonly used immunosuppressants (belatacept, tacrolimus, and mycophenolate) on cord blood-derived Tregs (CB-Tregs). Our study shows that while none of these immunosuppressants modulated the stability and expression of homing molecules by CB-Tregs, belatacept met all other selective criteria, shown by its ability to enhance CB-Tregs-mediated in vitro suppression of the allogeneic response without affecting their viability, proliferation, mitochondrial metabolism and expression of functional markers. In contrast, treatment with tacrolimus or mycophenolate led to reduced expression of functional molecule GITR in CB-Tregs, impaired their viability, proliferation and mitochondrial metabolism. These findings indicate that belatacept could be considered as a candidate in Tregs-based clinical immunomodulation regimens to induce transplant tolerance.

Whether chief executive officer (CEO) turnover can improve top management team (TMT) creativity is an important issue that remains to be solved. Based on the theoretical background of CEO turnover, team creativity, and cross-cultural context, this study proposes a theoretical model to answer the question and introduces leadership identity as a moderator simultaneously. The multiple regression analysis of data obtained from 903 executives in 104 top management teams revealed CEO voluntary resignation/internal succession pattern, CEO voluntary resignation/external succession pattern, and CEO forced resignation/internal succession pattern separately had a significant positive impact on TMT creativity in a cross-cultural context; leadership identity partially moderated the relationship between CEO turnover and TMT creativity. According to these findings, only three patterns of CEO turnover could promote TMT creativity, and leadership identity enhanced the positive effects of CEO voluntary resignation/internal succession pattern, CEO voluntary resignation/external succession pattern, and CEO forced resignation/internal succession pattern on TMT creativity in a cross-cultural context. These made up for the lack of theoretical research on the relationships among CEO turnover, TMT creativity and leadership identity, which could provide the scientific guidance to conduct the CEO turnover practice and improve TMT creativity in a cross-cultural context.

The complex tumor microenvironment (TME) plays a vital role in cancer development and dramatically determines the efficacy of immunotherapy. Tertiary lymphoid structures (TLSs) within the TME are well recognized and consist of T cell-rich areas containing dendritic cells (DCs) and B cell-rich areas containing germinal centers (GCs). Accumulating research has indicated that there is a close association between tumor-associated TLSs and favorable clinical outcomes in most types of cancers, though a minority of studies have reported an association between TLSs and a poor prognosis. Overall, the double-edged sword role of TLSs in the TME and potential mechanisms need to be further investigated, which will provide novel therapeutic perspectives for antitumor immunoregulation. In this review, we focus on discussing the main functions of TLSs in the TME and recent advances in the therapeutic manipulation of TLSs through multiple strategies to enhance local antitumor immunity.

Pancreatic beta cells are highly susceptible to oxidative stress, which plays a crucial role in diabetes outcomes. Progress has been slow to identify molecules that could be utilized to enhance cell survival and function under oxidative stress. Itaconate, a byproduct of the tricarboxylic acid cycle, has both anti-inflammatory and antioxidant properties. The effects of itaconate on beta cells under oxidative stress are relatively unknown. We explored the effects of 4-octyl itaconate—a cell-permeable derivative of itaconate—on MIN6 (a beta cell model) under oxidative stress conditions caused by hypoxia, along with its mechanism of action. Treatment with 4-OI reversed hypoxia-induced cell death, reduced ROS production, and inhibited cell death pathway activation and inflammatory cytokine secretion in MIN6 cells. The 4-OI treatment also suppressed lactate dehydrogenase A (LDHA)activity, which increases under hypoxia. Treatment of cells with the ROS scavenger NAC and LDHA-specific inhibitor FX-11 reproduced the beneficial effects of 4-OI on MIN6 cell viability under oxidative stress conditions, confirming its role in regulating ROS production. Conversely, overexpression of LDHA reduced the beneficial effects exerted by 4-OI on cells. Our findings provide a strong rationale for using 4-OI to prevent the death of MIN6 cells under oxidative stress.

Abstract Type 2 innate lymphoid cells (ILC2s) are a subset of ILCs with critical roles in immunoregulation. However, the possible role of ILC2s as immunotherapy against allograft rejection remains unclear. Here, we show that IL‐33 significantly prolonged islet allograft survival. IL‐33‐treated mice had elevated numbers of ILC2s and regulatory T cells (Tregs). Depletion of Tregs partially abolished the protective effect of IL‐33 on allograft survival, and additional ILC2 depletion in Treg‐depleted DEREG mice completely abolished the protective effects of IL‐33, indicating that ILC2s play critical roles in IL‐33‐mediated islet graft protection. Two subsets of ILC2s were identified in islet allografts of IL‐33‐treated mice: IL‐10 producing ILC2s (ILC210) and non‐IL‐10 producing ILC2s (non‐ILC10). Intravenous transfer of ILC210 cells, but not non‐ILC10, prolonged islet allograft survival in an IL‐10‐dependent manner. Locally transferred ILC210 cells led to long‐term islet graft survival, suggesting that ILC210 cells are required within the allograft for maximal suppressive effect and graft protection. This study has uncovered a major protective role of ILC210 in islet transplantation which could be potentiated as a therapeutic strategy.

Islet transplantation is a promising β-cell replacement therapy for type 1 diabetes, which can reduce glucose lability and hypoglycemic episodes compared with standard insulin therapy. Despite the tremendous progress made in this field, challenges remain in terms of long-term successful transplant outcomes. The insulin independence rate remains low after islet transplantation from one donor pancreas. It has been reported that the islet-related inflammatory response is the main cause of early islet damage and graft loss after transplantation. The production of interleukin-1β (IL-1β) has considered to be one of the primary harmful inflammatory events during pancreatic procurement, islet isolation, and islet transplantation. Evidence suggests that the innate immune response is upregulated through the activity of Toll-like receptors and The NACHT Domain-Leucine-Rich Repeat and PYD-containing Protein 3 inflammasome, which are the starting points for a series of signaling events that drive excessive IL-1β production in islet transplantation. In this review, we show recent contributions to the advancement of knowledge of IL-1β in islet transplantation and discuss several strategies targeting IL-1β for improving islet engraftment.

Transplantation of umbilical cord mesenchymal stem cells (UC-MSCs) is currently considered a novel therapeutic strategy for diabetic nephropathy (DN). However, the mechanisms by which UC-MSCs ameliorate renal fibrosis in DN are not well understood. Herein, we firstly investigated the therapeutic effects of mouse UC-MSC infusion on kidney structural and functional impairment in streptozotocin- (STZ-) induced diabetic mice. We found that the repeated injection with mUC-MSCs alleviates albuminuria, glomerulus injury, and fibrosis in DN mouse models. Next, mesangial cells were exposed to 5.6 mM glucose, 30 mM glucose, or mUC-MSC-conditioned medium, and then we performed western blotting, immunofluorescence, wound healing assay, and cell proliferation assay to measure extracellular matrix (ECM) proteins and matrix metalloproteinases (MMPs), myofibroblast transdifferentiation (MFT), and cell proliferation. We demonstrated that mUC-MSC paracrine decreased the deposition of fibronectin and collagen I by inhibiting TGF-β1-triggered MFT and cell proliferation mediated by PI3K/Akt and MAPK signaling pathways, and elevating the levels of MMP2 and MMP9. Importantly, we provided evidence that the antifibrosis role of mUC-MSC paracrine in DN might be determined by exosomes shed by MSCs. Together, these findings reveal the mechanisms underlying the therapeutic effects of UC-MSCs on renal fibrosis in DN and provide the evidence for DN cell-free therapy based on UC-MSCs in the future.

Background and PurposePrevious neuroimaging studies have demonstrated type 2 diabetes (T2D)-related brain structural and functional changes are partly associated with cognitive decline. However, less is known about the underlying mechanisms. Chronic hyperglycemia and microvascular complications are the two of most important risk factors related to cognitive decline in diabetes. Cerebral small vessel diseases (CSVDs), such as those defined by lacunar infarcts, white matter hyperintensities (WMHs) and microhemorrhages, are also associated with an increased risk of cognitive decline and dementia. In this study, we examined brain magnetic resonance imaging (MRI) changes in patients in the early stages of T2D without CSVDs to focus on glucose metabolism factors and to avoid the interference of vascular risk factors on T2D-related brain damage.MethodsT2D patients with disease durations of less than 5 years and without any signs of CSVDs (n = 34) were compared with healthy control subjects (n = 24). Whole-brain region-based functional connectivity was analyzed with network-based statistics (NBS), and brain surface morphology was examined. In addition, the Montreal Cognitive Assessment (MoCA) was conducted for all subjects.ResultsAt the whole-brain region-based functional connectivity level, thirty-three functional connectivities were changed in T2D patients relative to those in controls, mostly manifested as pathological between-network positive connectivity and located mainly between the sensory-motor network and auditory network. Some of the connectivities were positively correlated with blood glucose level, insulin resistance, and MoCA scores in the T2D group. The network-level analysis showed between-network hyperconnectivity in T2D patients, but no significant changes in within-network connectivity. In addition, there were no significant differences in MoCA scores or brain morphology measures, including cortical thickness, surface area, mean curvature, and gray/white matter volume, between the two groups.ConclusionThe findings indicate that pathological between-network positive connectivity occurs in the early stages of T2D without CSVDs. The abnormal connectivity may indicate that the original balance of mutual antagonistic/cooperative relationships between the networks is broken, which may be a neuroimaging basis for predicting cognitive decline in early T2D patients.

An acute viral infection may lead to death, as seen in the recent novel 2009 influenza A (H1N1) virus pandemic that rapidly spread worldwide. Hemophagocytic lymphohistiocytosis (HLH) is a systemic disorder with high mortality rates and can be triggered by various etiological agents, including viral infections. H1N1-associated HLH is a very rare condition that may cause extremely severe complications leading to multiple organ failure (MOF) and death. We report an unusual case of a rapidly progressive and fatal H1N1 infection that was complicated with HLH and MOF in a previously healthy 8-year-old Asian female who initially presented with fever and abdominal pain. To enable early recognition and proper treatment, physicians should be aware of the possibility of this fatal complication, which may present with unusual initial symptoms.

Receptor for Advanced Glycation End Products (RAGE) is an oncogenic trans-membranous receptor overexpressed in various human cancers. However, the role of RAGE in breast cancer development and proliferation is still unclear. In this study, we demonstrated that RAGE expression levels are correlated to the degree of severity of breast cancer. Furthermore, there is a decrease in the proliferation of all sub-types of breast cancer, MCF-7, SK-Br-3 and MDA-MB-231, as a result of the effect of RAGE siRNA. RAGE siRNA arrested cells in the G1 phase and inhibited DNA synthesis (p < 0.05). Moreover, qRT-PCR and Western Blot results demonstrated that RAGE siRNA decreases the expression of transcriptional factor NF-κB p65 as well as the expression of cell proliferation markers PCNA and cyclinD1. RAGE and RAGE ligands can thus be considered as possible targets for breast cancer management and therapy.

The global increase in incidence of Tuberculosis (TB) is returning to be a major health issue grabbing a universal concern. Although extrapulmonary tuberculosis (EPTB) has a broad spectrum of clinical manifestations, primary involvement of the adrenal glands along with spine without pulmonary affection has been rarely reported. We report a case of successfully treated adult Asian male patient presented with primary adrenal TB, complicated with chronic adrenal insufficiency accompanied with upper lumber spinal TB. We also present the follow up of our patient after three years.

Tissue factor (TF) expression on islets has been shown to trigger instant blood-mediated inflammatory reaction (IBMIR), leading to rapid islet loss in portal vein islet transplantation. This study investigated whether antisense RNA-mediated TF gene knockdown in islets could suppress IBMIR as a strategy to overcome IBMIR. Neonatal porcine islet cell clusters (NICCs) were transfected with or without TF-specific antisense RNA or a nonspecific RNA by a lipid-based method. Expression of both TF gene and protein in NICCs was analyzed after transfection by real-time PCR, Western blot, and FACS, respectively. The impact of antisense RNA transfection on NICC viability and in vitro function was examined by FACS and insulin release test, respectively. The effect of TF knockdown in NICCs on IBMIR was assessed with an in vitro tubing loop assay using human blood. A significant reduction in TF gene and protein expression was achieved in TF antisense RNA but not control RNA transfected NICCs, which did not affect NICCs' viability or their insulin secreting capacity. Incubation of TF antisense RNA transfected with human blood resulted in a considerable reduction in blood clot formation, platelet consumption, and complement and coagulation activation compared to that observed in the loops containing human blood and untreated or control RNA transfected NICCs. Consistent with these findings, infiltrating neutrophils in the blood clots with entrapped TF antisense RNA transfected NICCs was also reduced substantially compared to that seen in the clots containing untreated or control RNA transfected NICCs. This study presents a nontoxic TF antisense RNA-mediated TF knockdown in porcine islets that leads to an effective suppression of IBMIR, suggesting a potentially new strategy to improve islet transplantation outcomes.