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BackgroundIt is now widely accepted that radiotherapy (RT) can provoke a systemic immune response, which gives a strong rationale for the combination of RT and immune checkpoint inhibitors (ICIs). However, RT is a double-edged sword that not only enhances systemic antitumor immune response, but also promotes immunosuppression to some extent. Nevertheless, many aspects regarding the efficacy and safety of this combination therapy remain unknown. Therefore, a systematic review and meta-analysis was performed in order to assess the safety and efficacy of RT/chemoradiotherapy (CRT) and ICI combination therapy for non-small cell lung cancer (NSCLC) patients.MethodsPubMed and several other databases were searched (according to specific criteria) to find relevant studies published prior to the 28th of February 2022.Results3,652 articles were identified for screening and 25 trials containing 1,645 NSCLC patients were identified. For stage II-III NSCLC, the one- and two-year overall survival (OS) was 83.25% (95% confidence interval (CI): 79.42%-86.75%) and 66.16% (95% CI: 62.3%-69.92%), respectively. For stage IV NSCLC, the one- and two-year OS was 50% and 25%. In our study, the pooled rate of grade 3-5 adverse events (AEs) and grade 5 AEs was 30.18% (95% CI: 10.04%-50.33%, I2: 96.7%) and 2.03% (95% CI: 0.03%-4.04%, I2: 36.8%), respectively. Fatigue (50.97%), dyspnea (46.06%), dysphagia (10%-82.5%), leucopenia (47.6%), anaemia (5%-47.6%), cough (40.09%), esophagitis (38.51%), fever (32.5%-38.1%), neutropenia (12.5%-38.1%), alopecia (35%), nausea (30.51%) and pneumonitis (28.53%) were the most common adverse events for the combined treatment. The incidence of cardiotoxicity (0%-5.00%) was low, but it was associated with a high mortality rate (0%-2.56%). Furthermore, the incidence of pneumonitis was 28.53% (95% CI: 19.22%-38.88%, I2: 92.00%), grade ≥ 3 pneumonitis was 5.82% (95% CI: 3.75%-8.32%, I2: 57.90%) and grade 5 was 0%-4.76%.ConclusionThis study suggests that the addition of ICIs to RT/CRT for NSCLC patients may be both safe and feasible. We also summarize details of different RT combinations with ICIs to treat NSCLC. These findings may help guide the design of future trials, the testing of concurrent or sequential combinations for ICIs and RT/CRT could be particularly useful to guide the treatment of NSCLC patients.

IntroductionSepsis-associated encephalopathy (SAE) is a diffuse cerebral dysfunction resulting from a systemic inflammatory response to infection; however, its pathophysiology remains unclear. Sepsis-induced neuroinflammation and blood–brain barrier (BBB) disruption are crucial factors in brain function disturbance in SAE. Mast cells (MCs) activation plays an important role in several neuroinflammation models; however, its role in SAE has not been comprehensively investigated.MethodsWe first established a SAE model by cecal ligation puncture (CLP) surgery and checked the activation of MCs. MCs activation was checked using immumohistochemical staining and Toluidine Blue staining. We administrated cromolyn (10mg/ml), a MC stabilizer, to rescue the septic mice. Brain cytokines levels were measured using biochemical assays. BBB disruption was assessed by measuring levels of key tight-junction (TJ) proteins. Cognitive function of mice was analyzed by Y maze and open field test. Transwell cultures of brain microvascular endothelial cells (BMVECs) co-cultured with MCs were used to assess the interaction of BMVECs and MCs.ResultsResults showed that MCs were overactivated in the hippocampus of CLP-induced SAE mice. Cromolyn intracerebroventricular (i.c.v) injection substantially inhibited the MCs activation and neuroinflammation responses, ameliorated BBB impairment, improved the survival rate and alleviated cognitive dysfunction in septic mice. In vitro experiments, we revealed that MCs activation increased the sensitivity of BMVECs against to lipopolysaccharide (LPS) challenge. Furthermore, we found that the histamine/histamine 1 receptor (H1R) mediated the interaction between MCs and BMVECs, and amplifies the LPS-induced inflammatory responses in BMVECs by modulating the TLR2/4-MAPK signaling pathway.ConclusionsMCs activation could mediate BBB impairment and cognitive dysfunction in septic mice in a histamine-dependent pathway.

COVID-19 has recently become the most serious threat to public health, and its prevalence has been increasing at an alarming rate. The incubation period for the virus is ~1–14 days and all age groups may be susceptible to a fatality rate of about 5.9%. COVID-19 is caused by a novel single-stranded, positive (+) sense RNA beta coronavirus. The development of a vaccine for SARS-CoV-2 is an urgent need worldwide. Immunoinformatics approaches are both cost-effective and convenient, as in silico predictions can reduce the number of experiments needed. In this study, with the aid of immunoinformatics tools, we tried to design a multi-epitope vaccine that can be used for the prevention and treatment of COVID-19. The epitopes were computed by using B cells, cytotoxic T lymphocytes (CTL), and helper T lymphocytes (HTL) base on the proteins of SARS-CoV-2. A vaccine was devised by fusing together the B cell, HTL, and CTL epitopes with linkers. To enhance the immunogenicity, the β-defensin (45 mer) amino acid sequence, and pan-HLA DR binding epitopes (13aa) were adjoined to the N-terminal of the vaccine with the help of the EAAAK linker. To enable the intracellular delivery of the modeled vaccine, a TAT sequence (11aa) was appended to C-terminal. Linkers play vital roles in producing an extended conformation (flexibility), protein folding, and separation of functional domains, and therefore, make the protein structure more stable. The secondary and three-dimensional (3D) structure of the final vaccine was then predicted. Furthermore, the complex between the final vaccine and immune receptors (toll-like receptor-3 (TLR-3), major histocompatibility complex (MHC-I), and MHC-II) were evaluated by molecular docking. Lastly, to confirm the expression of the designed vaccine, the mRNA of the vaccine was enhanced with the aid of the Java Codon Adaptation Tool, and the secondary structure was generated from Mfold. Then we performed in silico cloning. The final vaccine requires experimental validation to determine its safety and efficacy in controlling SARS-CoV-2 infections.

IntroductionCiltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell therapy approved for patients with relapsed/refractory multiple myeloma (RRMM). In the phase 3 trial, CARTITUDE-4 (NCT04181827), cilta-cel demonstrated improved efficacy vs. standard of care (SOC; daratumumab plus pomalidomide and dexamethasone [DPd] or pomalidomide plus bortezomib and dexamethasone [PVd]) with a ≥ complete response (≥CR) rate of 73.1% vs. 21.8%.MethodsA cost-per-responder model was developed to assess the value of cilta-cel and SOC (87% DPd and 13% PVd) based on the CARTITUDE-4 trial data from a US mixed payer perspective (76.7% commercial, 23.3% Medicare). The model was developed using progression-free survival (PFS), overall survival (OS), and ≥CR endpoints from CARTITUDE-4 over a period of 25.4 months. Inpatient stays, outpatient visits, drug acquisition, administration, and monitoring costs were included. The base-case model assumed an inpatient setting for each cilta-cel infusion; another scenario included 30% outpatient and 70% inpatient infusions. Costs of managing grade 3-4 adverse events (AEs) and grade 1-4 cytokine release syndrome and neurotoxicity were included. Subsequent therapy costs were incurred after disease progression; terminal care costs were considered upon death events. Outcomes included total cost per treated patient, total cost per complete responder, and cost per month in PFS between cilta-cel and SOC. Costs were adjusted to 2024 US dollars.ResultsTotal cost per treated patient, total cost per complete responder, and total cost per month in PFS were estimated at $704,641, $963,941, and $30,978 for cilta-cel, respectively, and $840,730, $3,856,559, and $42,520 for SOC over the 25.4-month period. Cost drivers included treatment acquisition costs before progression and subsequent treatment costs ($451,318 and $111,637 for cilta-cel; $529,795 and $265,167 for SOC). A scenario analysis in which 30% of patients received an outpatient infusion (assuming the same payer mix) showed a lower cost per complete responder for cilta-cel ($956,523) than those with an infusion in the inpatient setting exclusively.DiscussionThis analysis estimated that cost per treated patient, cost per complete responder, and cost per month in PFS for cilta-cel were remarkably lower than for DPd or PVd, highlighting the substantial clinical and economic benefit of cilta-cel for patients with RRMM.

Nasopharyngeal carcinoma with bone marrow metastasis presents a rare and challenging clinical scenario associated with exceedingly poor prognosis. While standard treatment regimens offer limited efficacy and tolerability in such cases, individualized approaches are increasingly necessary. We present the case of a 64-year-old male diagnosed with recurrent nonkeratinizing undifferentiated nasopharyngeal carcinoma with extensive bone marrow metastasis (rTxN0M1). Treatment was initiated with immunotherapy-based combination therapy, consisting of pembrolizumab and low-dose cisplatin, which resulted in an initial response. Subsequently, there was a transition to standard-dose nab-paclitaxel-cisplatin chemotherapy in combination with pembrolizumab, followed by maintenance therapy with pembrolizumab plus fruquintinib. The patient achieved a sustained response with renormalization of tumor markers, imaging findings, and bone biopsies, resulting in complete remission. This case highlights the successful management of nasopharyngeal carcinoma with extensive bone marrow metastasis through an individualized treatment approach incorporating immunotherapy.

SMARCA4-deficient undifferentiated tumor (SMARCA4-dUT) is a devastating subtype of thoracic tumor with SMARCA4 inactivation and is characterized by rapid progression, poor prognosis, and high risk of postoperative recurrence. However, effective treatments for SMARCA4-dUT are lacking. Herein, we describe a patient with SMARCA4-dUT who exhibited an impressive response to the anti-programmed cell death protein-1 (PD-1) antibody (tislelizumab) in combination with conventional chemotherapy (etoposide and cisplatin). To the best of our knowledge, this is the first case of SMARCA4-dUT treated with chemotherapy, comprising etoposide and cisplatin, combined with anti-PD-1 inhibitors. Immunotherapy combined with etoposide and cisplatin may be a promising strategy to treat SMARCA4-dUT.

IntroductionPathological changes in the articular cartilage (AC) and synovium are major manifestations of osteoarthritis (OA) and are strongly associated with pain and functional limitations. Exosome-derived microRNAs (miRNAs) are crucial regulatory factors in intercellular communication and can influence the progression of OA by participating in the degradation of chondrocytes and the phenotypic transformation in the polarization of synovial macrophages. However, the specific relationships and pathways of action of exosomal miRNAs in the pathological progression of OA in both cartilage and synovium remain unclear.MethodsThis study evaluates the effects of fibroblast-like synoviocyte (FLS)-derived exosomes (FLS-Exos), influenced by miR-146a, on AC degradation and synovial macrophage polarization. We investigated the targeted relationship between miR-146a and TRAF6, both in vivo and in vitro, along with the involvement of the NF-κB signaling pathway.ResultsThe expression of miR-146a in the synovial exosomes of OA rats was significantly higher than in healthy rats. In vitro, the upregulation of miR-146a reduced chondrocyte apoptosis, whereas its downregulation had the opposite effect. In vivo, exosomes derived from miR-146a-overexpressing FLSs (miR-146a-FLS-Exos) reduced AC injury and chondrocyte apoptosis in OA. Furthermore, synovial proliferation was reduced, and the polarization of synovial macrophages shifted from M1 to M2. Mechanistically, the expression of TRAF6 was inhibited by targeting miR-146a, thereby modulating the Toll-like receptor 4/TRAF6/NF-κB pathway in the innate immune response.DiscussionThese findings suggest that miR-146a, mediated through FLS-Exos, may alleviate OA progression by modulating cartilage degradation and macrophage polarization, implicating the NF-κB pathway in the innate immune response. These insights highlight the therapeutic potential of miR-146a as a protective agent in OA, underscoring the importance of exosomal miRNAs in the pathogenesis and potential treatment of the disease.

Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease that typically presents with lymphocyte, dendritic cell, and macrophage infiltration of exocrine gland ducts and the formation of ectopic germinal centers. The interactions of lymphocyte homing receptors and addressins and chemokines and their receptors, such as α4β7/MAdCAM-1, LFA-1/ICAM-1, CXCL13/CXCR5, CCL25/CCR9, CX3CL1/CX3CR1, play important roles in the migration of inflammatory cells to the focal glands and the promotion of ectopic germinal center formation in SS. A variety of molecules have been shown to be involved in lymphocyte homing, including tumor necrosis factor-α, interferon (IFN)-α, IFN-β, and B cell activating factor. This process mainly involves the Janus kinase-signal transducer and activator of transcription signaling pathway, lymphotoxin-β receptor pathway, and nuclear factor-κB signaling pathway. These findings have led to the development of antibodies to cell adhesion molecules, antagonists of chemokines and their receptors, compounds interfering with chemokine receptor signaling, and gene therapies targeting chemokines and their receptors, providing new targets for the treatment of SS in humans. The aim of this study was to explore the relationship between lymphocyte homing and the pathogenesis of SS, and to provide a review of recent studies addressing lymphocyte homing in targeted therapy for SS.

BackgroundThrombocytopenia is a known prognostic factor in sepsis, yet the relationship between platelet-related genes and sepsis outcomes remains elusive. We developed a machine learning (ML) model based on platelet-related genes to predict poor prognosis in sepsis. The model underwent rigorous evaluation on six diverse platforms, ensuring reliable and versatile findings.MethodsA retrospective analysis of platelet data from 365 sepsis patients confirmed the predictive role of platelet count in prognosis. We employed COX analysis, Least Absolute Shrinkage and Selection Operator (LASSO) and Support Vector Machine (SVM) techniques to identify platelet-related genes from the GSE65682 dataset. Subsequently, these genes were trained and validated on six distinct platforms comprising 719 patients, and compared against the Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ-Failure Assessment (SOFA) score.ResultsA PLT count

BackgroundThe World Health Organization declared that COVID-19 is no longer a public health emergency of global concern on May 5, 2023. Post-COVID disorders are, however, becoming more common. Hence, there lies a growing need to develop safe and effective treatment measures to manage post-COVID disorders. Investigating the use of TCM medicinal foods in the long-term therapy of post-COVID illnesses may be beneficial given contemporary research’s emphasis on the development of medicinal foods.Scope and approachThe use of medicinal foods for the long-term treatment of post-COVID disorders is highlighted in this review. Following a discussion of the history of the TCM “Medicine and Food Homology” theory, the pathophysiological effects of post-COVID disorders will be briefly reviewed. An analysis of TCM medicinal foods and their functions in treating post-COVID disorders will then be provided before offering some insight into potential directions for future research and application.Key findings and discussionTCM medicinal foods can manage different aspects of post-COVID disorders. The use of medicinal foods in the long-term management of post-COVID illnesses may be a safe and efficient therapy choice because they are typically milder in nature than chronic drug use. These findings may also be applied in the long-term post-disease treatment of similar respiratory disorders.

BackgroundInterstitial lung disease (ILD) is a relatively prevalent extra-articular manifestation of rheumatoid arthritis (RA) and contributes to significant morbidity and mortality. This study aimed to analyze the association between chitinase-3 like-protein-1(CHI3L1) and the presence of RA-ILD.MethodsA total of 239 RA patients fulfilling the American Rheumatism Association (ACR) 1987 revised criteria were enrolled and subclassified as RA-ILD and RA-nILD based on the results of high-resolution computed tomography scans (HRCT) of the chest. The disease activity of RA was assessed by Disease Activity Score for 28 joints (DAS28) and categorized as high, moderate, low, and remission. Chemiluminescence immunoassays were applied to determine the serum levels of CHI3L1. Univariate analysis was performed and the receiver operating characteristics (ROC) curves were plotted to evaluate the correlation between RA-ILD and CHI3L1.ResultsAmong the eligible RA patients studied, 60 (25.1%) patients were diagnosed with RA-ILD. Compared with RA-nILD, RA patients with ILD had significantly higher median age (median [IQR], 68.00 [62.00-71.75] vs 53.00 [40.00-63.00], p

BackgroundInterferon-gamma (IFN-γ), commonly referred to as type II interferon, is a crucial cytokine that coordinates the tumor immune process and has received considerable attention in tumor immunotherapy research. Previous studies have discussed the role and mechanisms associated with IFN-γ in specific tumors or diseases, but the relevant role of IFN-γ in pan-cancer remains uncertain.MethodsTCGA and GTEx RNA expression data and clinical data were downloaded. Additionally, we analyzed the role of IFN-γ on tumors by using a bioinformatic approach, which included the analysis of the correlation between IFN-γ in different tumors and expression, prognosis, functional status, TMB, MSI, immune cell infiltration, and TIDE. We also developed a PPI network for topological analysis of the network, identifying hub genes as those having a degree greater than IFN-γ levels.ResultIFN-γ was differentially expressed and predicted different survival statuses in a majority of tumor types in TCGA. Additionally, IFN-γ expression was strongly linked to factors like infiltration of T cells, immune checkpoints, immune-activating genes, immunosuppressive genes, chemokines, and chemokine receptors, as well as tumor purity, functional statuses, and prognostic value. Also, prognosis, CNV, and treatment response were all substantially correlated with IFN-γ-related gene expression. Particularly, the IFN-γ-related gene STAT1 exhibited the greatest percentage of SNVs and the largest percentage of SNPs in UCEC. Elevated expression levels of IFN-γ-related genes were found in a wide variety of tumor types, and this was shown to be positively linked to drug sensitivity for 20 different types of drugs.ConclusionIFN-γ is a good indicator of response to tumor immunotherapy and is likely to limit tumor progression, offering a novel approach for immunotherapy’s future development.

PurposeTo explore the impact of inactivated COVID-19 vaccination on ovarian reserve as assessed by serum anti-Müllerian hormone (AMH) concentration.MethodsA total of 3160 women were included in this single-center retrospective cohort study between June 2021 and October 2022. Vaccination information were collected from official immunization records available in personal mobile apps. Serum AMH was qualified by electrochemiluminescence immunoassay and compared with previous measurement data within three years. Women were categorized to the vaccinated group if they received two doses of inactivated COVID-19 vaccines (Sinopharm or Sinovac) between AMH tests (n = 488), and to the control group if not vaccinated (n = 2672). Propensity score matching and multivariate linear regression were performed to control for potential confounders. The main outcome measures were the numeric AMH change and percentage AMH change between the two tests.ResultsThere were 474 women left in each group after matching all baseline characteristics. The mean interval from the first to second AMH measurement was 508.0 ± 250.2 and 507.5 ± 253.6 days for vaccinated and unvaccinated women, respectively (P = 0.680). Both groups had a significant AMH decrease in the second test compared with the first test (P = 0.001). However, the second AMH level remained comparable between groups (3.26 ± 2.80 vs. 3.24 ± 2.61 ng/mL, P = 0.757). Similarly, no significant differences were observed in numerical (-0.14 ± 1.32 vs. -0.20 ± 1.56 ng/mL, P = 0.945) and percentage (2.33 ± 58.65 vs. 0.35 ± 48.42%, P = 0.777) AMH changes. The results were consistent in sub-analyses for women aged

Chronic neuroinflammation has been regarded as an important part of the pathological initiation of Alzheimer’s disease (AD), which is associated with the regulation of microglial activation. Preventing microglial activation to inhibit neuroinflammation may become a potential target for the treatment of neurodegenerative diseases. Guizhi Fuling capsule (GZFL) has a strong repression on inflammatory responses. Here, the presenilin1/2 conditional double knockout (PS cDKO) mice, a well-established mouse model of AD, were divided into: WT mice (WT), WT mice+GZFL (WT+GZFL), PS cDKO mice (cDKO), and PS cDKO mice+GZFL (cDKO+GZFL). Mice in the WT+GZFL and cDKO+GZFL group were fed standard chow containing 2000 ppm GZFL for 90 days. After 60 days of GZFL treatment, mice were given to behavioral tests for 30 days in order to explore the effects of GZFL on cognitive and motor function. Then, mice were sacrificed for examining the effects of GZFL on inflammation. Furthermore, primary microglia were obtained from neonatal Sprague-Dawley rats and pretreated with or without GZFL (50 μg/ml) for 1 h in the absence or presence of lipopolysaccharide (LPS) (100 ng/ml) stimulation to speculate whether the underlying mechanism of GZFL’s anti-inflammatory potential was closely associated with Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Our findings indicated that GZFL has the ability to alleviate memory deficits in PS cDKO mice, which attributes to the improvement of neuroinflammation by inhibiting microglial activation and the levels of pro-inflammatory mediators. In addition, GZFL could inverse the tau hyperphosphorylation and the lessened expression of synaptic proteins in hippocampus of PS cDKO mice. Furthermore, GZFL prevented LPS-induced neuroinflammatory responses in primary microglia by decreasing the levels of pro-inflammatory mediators. It is noteworthy that therapeutic effects of GZFL on memory impairment are depended on the inhibition of neuroinflammatory responses by the blockage of JAK2/STAT3 signaling pathway. Taken together, GZFL may be an effective compound Chinese medicine for the improvement and postponement of neurodegenerative progression in AD.

ObjectiveThe purpose of this study was to precisely evaluate the serum Dickkopf-1 (DKK-1) level in patients with ankylosing spondylitis (AS) relative to that in normal controls and to test the causal relationship between DKK-1 and the risk of AS.MethodsEmbase, PubMed, Web of Science, WANFANG DATA, VIP, and China National Knowledge Infrastructure (CNKI) were comprehensively searched until July 2022 for pertinent studies. The pooled standardized mean difference (SMD) with a 95% confidence interval (CI) was calculated by the fixed or random-effect model. In Mendelian randomization (MR) analysis on the causal relationship between serum DKK-1 level and AS risk, the inverse variance weighting method (IVW), MR-Egger regression, weighted median method, and weighted pattern method were applied. Sensitivity analyses, including the horizontal pleiotropy test, heterogeneity test, and leave-one-out test, were also performed.ResultsThe meta-analysis of 40 studies containing 2,371 AS patients and 1,633 healthy controls showed that there was no significant difference in DKK-1 serum level between AS patients and normal controls (pooled SMD=0.207, 95% CI =−0.418-0.832, P=0.516). The subgroup analysis of the CRP ≤ 10 mg/L group showed that AS patients had higher serum DKK-1 concentration than the healthy controls (SMD=2.267, 95% CI = 0.102-4.432, P=0.040). Similarly, MR analysis also demonstrated no significant association between DKK-1 serum level and AS (IVW OR=0.999, 95% CI = 0.989-1.008, P=0.800). All sensitivity analyses revealed consistent results.ConclusionsThere was no significant change in serum DKK-1 concentration between AS patients and healthy controls. In addition, no causal relationship exists between serum DKK-1 levels and AS risk.

BackgroundIBSP is a member of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family that plays a vital role in bone formation, renewal and repair. Emerging evidence revealed that IBSP participated in the tumorigenesis and progression in some cancers. However, its significance in tumour prognosis and immunotherapy is still unknown.MethodsIn the current study, we studied the role of IBSP in tumorigenesis, tumor diagnosis, genomic heterogeneity, methylation modifications, immune infiltration, and therapy response in pan-cancer. In addition, we constructed a risk score model to assessed the prognostic classification efficiency of IBSP using the co-expression genes of IBSP in osteosarcoma (OS), and analyzed the expression and role of IBSP in OS through a series of assays in vitro.ResultsIBSP was upregulated in various cancers compared to the paired normal tissues, and it was strongly correlated with the prognosis, pathological stage, diagnostic accuracy, genomic heterogeneity, methylation modification, immune infiltration, immune and checkpoint. Moreover, the predictive model we established in combination with the clinical characteristics of OS patients showed high survival predictive power in these individuals. The assays in vitro showed that IBSP promoted the proliferation, migration and invasion of OS cells, which further confirmed IBSP’s role in cancers.ConclusionsOur research revealed the multifunctionality of IBSP in the tumorigenesis, progression and therapy in various cancers, which demonstrated that IBSP may serve as a potential prognostic biomarker and a novel immunotherapy target in pan-cancer.

African swine fever (ASF) is an acute, highly contagious, and deadly infectious disease caused by the African swine fever virus (ASFV) and has a huge impact on the pig industry. A lack of vaccines and effective therapeutic drugs has brought great challenges to the prevention and control of ASF. In this study, insect baculovirus expression system was used to express ASFV B602L protein (B602L) alone and the IgG FC-fused B602L protein (B602L-Fc), and evaluate the immune effect of B602L-Fc in mice model. To be specific, the ASFV B602L protein and B602L-Fc fusion protein were successfully expressed by the insect baculovirus expression system. Then, Functional analysis in vitro revealed that the B602L-Fc fusion protein bound and interacted with the FcRI receptor of antigen-presenting cells and significantly promoted the expression of proteins involved in antigen presentation and various cytokines at mRNA levels in porcine alveolar macrophages. Additionally, immunization using B602L-Fc fusion protein remarkably promoted the Th1-biased cellular immune response and humoral immune response in mice. In conclusion, The B602L-Fc fusion protein could up-regulate the expression of molecules involved in antigen presentation in APCs and enhance the humoral and cellular immune responses in mice. These results suggest that ASFV B602L-Fc recombinant fusion protein may be a promising candidate for subunit vaccine. This study provided useful data for the development of subunit vaccines for ASF.

ObjectivesBoth burdens of tuberculosis (TB) and systemic lupus erythematosus (SLE) in China are ranked as top three in the world. SLE patients are at high risk for TB, but so far, there are no guidelines for TB prevention and management targeting this population in China. This study aims to investigate the incidence of active tuberculosis (ATB) and to explore the risk factors for developing ATB in SLE patients, and to provide evidence for TB prevention and management for SLE patients in China.MethodsA multi-center prospective cohort study was conducted. SLE patients were enrolled from clinics and wards of 13 tertiary hospitals in Eastern, Middle, and Western China from September 2014 to March 2016. Baseline demographic features, TB infection status, clinical information, and laboratory data were collected. ATB development was examined during follow-up visits. Kaplan-Meier method was applied to plot survival curves, and Log-rank test was used to evaluate differences. Cox proportional-hazards model was used to explore the risk factors for ATB development.ResultsWith a median follow-up time of 58 months [interquartile range (IQR): 55-62], 16 out of 1361 SLE patients developed ATB. The 1-year incidence of ATB was 368 [95% confidence interval (CI): 46-691] per 100,000. Over a 5-year period, the cumulative incidence of ATB was 1141 [95% CI: 564-1718] per 100,000, and the incidence density was 245 per 100,000 person-years. Cox regression models were constructed with maximum daily dose of glucocorticoids (GCs) as a continuous variable and a categorical variable, respectively. In model 1, maximum daily dose of GCs (pills per day) [adjusted hazard ratio (aHR)=1.16, 95%CI: 1.04-1.30, p=0.010] and TB infection (aHR=8.52, 95%CI: 3.17-22.92, p

Primary liver cancer (PLC) that originates in the liver is a malignant tumor with the worst prognosis. Hepatocellular carcinoma (HCC) is the most common type of PLC. Most PLC cases are diagnosed at advanced stages mainly due to their insidious onset and rapid progression. Patients with PLC undergo surgical intervention or localized treatment, but their survival is often affected by its high relapse rate. Medical treatment is the primary option for patients with liver cancer, especially with advanced extrahepatic metastases. Molecular targeted therapy exerts an anti-tumor effect by acting on various signaling pathways involved in molecular pathogenesis; however, high drug resistance and low therapeutic responsiveness of PLC to molecular targets challenge the treatment option. In recent years, after surgical intervention, radiotherapy, chemotherapy, and/or molecular targeted therapy, autologous cell immunotherapy has been adopted for PLC. As a typical autologous cell immunotherapy, CAR T-cell therapy uses genetically modified T cells to express tumor-specific chimeric antigen receptors (CARs). Its targeting ability, persistent nature, and tumor-killing function result in a significant impact on the treatment of hematological tumors. However, no breakthrough has happened in the research specific to the curation of lung cancer, liver cancer, breast cancer, and other common solid tumors. In this context, a combination of molecular targeted therapy and CAR T-cell therapy was used to treat a patient with advanced HCC to achieve a partial remission(PR) and facilitate further liver transplantation.

BackgroundGut dysbiosis and gut microbiome-derived metabolites have been implicated in both disease onset and treatment response, but this has been rarely demonstrated in pemphigus vulgaris (PV). Here, we aim to systematically characterize the gut microbiome to assess the specific microbial species and metabolites associated with PV.MethodsWe enrolled 60 PV patients and 19 matched healthy family members, and collected 100 fecal samples (60 treatment-naïve, 21 matched post-treatment, and 19 controls). Metagenomic shotgun sequencing and subsequent quality control/alignment/annotation were performed to assess the composition and microbial species, in order to establish the association between gut microbiome with PV onset and treatment response. In addition, we evaluated short-chain fatty acids (SCFAs) in PV patients through targeted metabolomics analysis.ResultsThe diversity of the gut microbiome in PV patients deviates from the healthy family members but not between responder and non-responder, or before and after glucocorticoid treatment. However, the relative abundance of several microbial species, including the pathogenic bacteria (e.g., Escherichia coli) and some SCFA-producing probiotics (e.g., Eubacterium ventriosum), consistently differed between the two groups in each comparison. Escherichia coli was enriched in PV patients and significantly decreased after treatment in responders. In contrast, Eubacterium ventriosum was enriched in healthy family members and significantly increased particularly in responders after treatment. Consistently, several gut microbiome-derived SCFAs were enriched in healthy family members and significantly increased after treatment (e.g., butyric acid and valeric acid).ConclusionsThis study supports the association between the gut microbiome and PV onset, possibly through disrupting the balance of gut pathogenic bacteria and probiotics and influencing the level of gut microbiome-derived SCFAs. Furthermore, we revealed the potential relationship between specific microbial species and glucocorticoid treatment.

IntroductionAnkylosing spondylitis (AS), a chronic autoimmune disease, has been linked to the gut bacteriome.MethodsTo investigate the characteristics of the gut virome in AS, we profiled the gut viral community of 193 AS patients and 59 healthy subjects based on a metagenome-wide analysis of fecal metagenomes from two publicly available datasets.ResultsAS patients revealed a significant decrease in gut viral richness and a considerable alteration of the overall viral structure. At the family level, AS patients had an increased abundance of Gratiaviridae and Quimbyviridae and a decreased abundance of Drexlerviridae and Schitoviridae. We identified 1,004 differentially abundant viral operational taxonomic units (vOTUs) between patients and controls, including a higher proportion of AS-enriched Myoviridae viruses and control-enriched Siphoviridae viruses. Moreover, the AS-enriched vOTUs were more likely to infect bacteria such as Flavonifractor, Achromobacter, and Eggerthellaceae, whereas the control-enriched vOTUs were more likely to be Blautia, Ruminococcus, Collinsella, Prevotella, and Faecalibacterium bacteriophages. Additionally, some viral functional orthologs differed significantly in frequency between the AS-enriched and control-enriched vOTUs, suggesting the functional role of these AS-associated viruses. Moreover, we trained classification models based on gut viral signatures to discriminate AS patients from healthy controls, with an optimal area under the receiver operator characteristic curve (AUC) up to 0.936, suggesting the clinical potential of the gut virome for diagnosing AS.DiscussionThis work provides novel insight into the AS gut virome, and the findings may guide future mechanistic and therapeutic studies for other autoimmune diseases.

IntroductionThe mechanism of the immediate adverse drug reactions (ADRs) induced by ShenMai injection (SMI) has not been completely elucidated. Within 30 minutes, the ears and lungs of mice injected with SMI for the first time showed edema and exudation reactions. These reactions were different from the IV hypersensitivity. The theory of pharmacological interaction with immune receptor (p-i) offered a new insight into the mechanisms of immediate ADRs induced by SMI.MethodsIn this study, we determined that the ADRs were mediated by thymus-derived T cells through the different reactions of BALB/c mice (thymus-derived T cell normal) and BALB/c nude mice (thymus-derived T cell deficient) after injecting SMI. The flow cytometric analysis, cytokine bead array (CBA) assay and untargeted metabolomics were used to explain the mechanisms of the immediate ADRs. Moreover, the activation of the RhoA/ROCK signaling pathway was detected by western blot analysis.ResultsIn BALB/c mice, the vascular leakage and histopathology results showed the occurrence of the immediate ADRs induced by SMI. The flow cytometric analysis revealed that CD4+ T cell subsets (Th1/Th2, Th17/Treg) were imbalanced. And the levels of cytokines such as IL-2, IL-4, IL12P70 and INF-γ increased significantly. However, in BALB/c nude mice, all the indicators mentioned above have not changed significantly. The metabolic profile of both BALB/c mice and BALB/c nude mice was significantly changed after injecting SMI, and the notable increase in lysolecithin level might have a greater association with the immediate ADRs induced by SMI. The Spearman correlation analysis revealed that LysoPC (18:3(6Z,9Z,12Z)/0:0) showed a significant positive correlation with cytokines. After injecting SMI, the levels of RhoA/ROCK signaling pathway-related protein increased significantly in BALB/c mice. Protein-protein interaction (PPI) showed that the increased lysolecithin levels might be related to the activation of the RhoA/ROCK signaling pathway.DiscussionTogether, the results of our study revealed that the immediate ADRs induced by SMI were mediated by thymus-derived T cells, and elucidated the mechanisms of such ADRs. This study provided new insights into the underlying mechanism of immediate ADRs induced by SMI.

IntroductionThe condition of refractory lupus nephritis (LN) negatively affects the prognosis and life expectancy of the patients, posing a challenge to manage in clinical. This interventional study evaluated the efficacy as well as safety of leflunomide in patients with refractory LN.MethodsTwenty patients with refractory LN were enrolled in this study. A daily dose of 20–40 mg of leflunomide was given to the patients orally. Meanwhile, immunosuppressives were withdrawn, and corticosteroids were gradually tapered. There was an average follow-up period of 3, 6, and 12 months for most patients while some were observed for as long as 24 months. We recorded biochemical parameters and side effects. We calculated the response rate using intention-to-treat analysis.ResultsEighteen patients (90%) completed the study. At 3 months, 80% (16/20) of the patients achieved more than a 25% decrease in 24-hour urine protein quantity. At 6 months, three patients (15%) achieved a partial response, and five patients (25%) achieved a complete response. However, by 12 months and 24 months, the complete response rate dropped to 15% and 20%, respectively. The objective responses were 30% (6/20), 40% (8/20), 40% (8/20), and 30% (6/20) at 3, 6, 12, and 24 months, respectively. Two patients withdrew from the study due to developing cytopenia and leucopenia.ConclusionIn patients diagnosed with refractory LN, our study shows that leflunomide could be a promising treatment option owing to its response rate and safety profile.

BackgroundAutophagy in osteoarthritis (OA) has become an active area of research with substantial value and potential. Nevertheless, few bibliometric studies have systematically analyzed the available research in the field. The main goal of this study was to map the available literature on the role of autophagy in OA and identify global research hotspots and trends.MethodsThe Web of Science Core Collection and Scopus databases were interrogated for studies of autophagy in OA published between 2004 and 2022. Microsoft Excel, VOSviewer and CiteSpace software were used to analyze and visualize the number of publications and associated citations, and reveal global research hotspots and trends in the autophagy in OA field.Results732 outputs published by 329 institutions from 55 countries/regions were included in this study. From 2004 to 2022, the number of publications increased. China produced the most publications (n=456), prior to the USA (n=115), South Korea (n=33), and Japan (n=27). Scripps Research Institute (n=26) was the most productive institution. Martin Lotz (n=30) was the highest output author, while Caramés B (n=302) was the highest output author. Osteoarthritis and Cartilage was the most prolific and most co-cited journal. Currently, the autophagy in OA research hotspots include chondrocyte, transforming growth factor beta 1 (TGF-β1), inflammatory response, stress, and mitophagy. The emerging research trends in this field are AMPK, macrophage, senescence, apoptosis, tougu xiaotong capsule (TXC), green tea extract, rapamycin, and dexamethasone. Novel drugs targeting specific molecule such as TGF-β and AMPK have shown therapeutic potential but are still in the preclinical stage of development.ConclusionsResearch on the role of autophagy in OA is flourishing. Martin Lotz, Beatriz Caramés, and Osteoarthritis and Cartilage have made outstanding contributions to the field. Prior studies of OA autophagy mainly focused on mechanisms underlying OA and autophagy, including AMPK, macrophages, TGF-β1, inflammatory response, stress, and mitophagy. Emerging research trends, however, are centered around the relationship between autophagy, apoptosis, and senescence, as well as drug candidates such as TXC and green tea extract. The development of new targeted drugs that enhance or restore autophagic activity is a promising strategy for the treatment of OA.

Histiocytic sarcoma (HS) is a rare hematological malignancy with limited treatment options, and it is also prone to complications such as hemophagocytic lymphohistiocytosis (HLH) in the later stages of the disease, leading to difficulties in treatment and poor prognosis. It highlights the importance of developing novel therapeutic agents. Herein, we present a case of a 45-year-old male patient who was diagnosed with PD-L1-positive HS with HLH. The patient was admitted to our hospital with recurrent high fever, multiple skin rashes with pruritus throughout the body and enlarged lymph nodes. Subsequently, pathological biopsy of the lymph nodes revealed high expression of CD163, CD68, S100, Lys and CD34 in the tumor cells and no expression of CD1a and CD207, confirming this rare clinical diagnosis. Concerning the low remission rate by conventional treatment in this disease, the patient was administered with sintilimab (an anti-programmed cell death 1 [anti-PD-1] monoclonal antibody) at 200 mg/d combined with a first-line chemotherapy regimen for one cycle. Further exploration of pathological biopsy by using next-generation gene sequencing led to the use of targeted therapy of chidamide. After one cycle of combination therapy (chidamide+sintilimab, abbreviated as CS), the patient achieved a favorable response. The patient showed remarkable improvement in the general symptoms and laboratory examination results (e.g., elevated indicators of inflammation); even the clinical benefits was not persistent, he survived one more month after his cessation of treatment by himself due to economic difficulty. Our case suggests that PD-1 inhibitor coupled with targeted therapy might constitute a potential therapeutic option for primary HS with HLH.

Hepatic fibrosis is often secondary to chronic inflammatory liver injury. During the development of hepatic fibrosis, the damaged hepatocytes and activated hepatic stellate cells (HSCs) caused by the pathogenic injury could secrete a variety of cytokines and chemokines, which will chemotactic innate and adaptive immune cells of liver tissue and peripheral circulation infiltrating into the injury site, mediating the immune response against injury and promoting tissue reparation. However, the continuous release of persistent injurious stimulus-induced inflammatory cytokines will promote HSCs-mediated fibrous tissue hyperproliferation and excessive repair, which will cause hepatic fibrosis development and progression to cirrhosis even liver cancer. And the activated HSCs can secrete various cytokines and chemokines, which directly interact with immune cells and actively participate in liver disease progression. Therefore, analyzing the changes in local immune homeostasis caused by immune response under different pathological states will greatly enrich our understanding of liver diseases’ reversal, chronicity, progression, and even deterioration of liver cancer. In this review, we summarized the critical components of the hepatic immune microenvironment (HIME), different sub-type immune cells, and their released cytokines, according to their effect on the development of progression of hepatic fibrosis. And we also reviewed and analyzed the specific changes and the related mechanisms of the immune microenvironment in different chronic liver diseases.Moreover, we retrospectively analyzed whether the progression of hepatic fibrosis could be alleviated by modulating the HIME.We aimed to elucidate the pathogenesis of hepatic fibrosis and provide the possibility for exploring the therapeutic targets for hepatic fibrosis.

The human immunodeficiency virus (HIV) is still a global pandemic and despite the successful use of anti-retroviral therapy, a well-established cure remains to be identified. Viral modulation of cell death has a significant role in HIV pathogenesis. Here we sought to understand the major mechanisms of HIV-induced death of lymphocytes and the effects on viral transmission. Flow cytometry analysis of lymphocytes from five latent HIV-infected patients, and HIV IIIB-infected MT2 cells demonstrated both necrosis and apoptosis to be the major mechanisms of cell death in CD4+ and CD4-/CD8- lymphocytes. Significantly, pro-apoptotic tumor necrosis factor (TNF) peptide (P13) was found to inhibit HIV-related cell death and reduced viral transmission. Whereas pro-necrotic TNF peptide (P16) had little effect on HIV-related cell death and viral transmission. Understanding mechanisms by which cell death can be manipulated may provide additional drug targets to reduce the loss of CD4+ cells and the formation of a viral reservoir in HIV infection.

DNA methylation, including aberrant hypomethylation and hypermethylation, plays a significant role in atherosclerosis (AS); therefore, targeting the unbalanced methylation in AS is a potential treatment strategy. Gualou-xiebai herb pair (GXHP), a classic herb combination, have been used for the treatment of atherosclerotic-associated diseases in traditional Chinese medicine. However, the effects and underlying mechanism of GXHP on AS remain nebulous. In this study, the CCK-8 method was applied to determine the non-toxic treatment concentrations for GXHP. The formation of foam cells played a critical role in AS, so the foam cells model was established after RAW264.7 cells were treated with ox-LDL. The contents of total cholesterol (TC) and free cholesterol (FC) were determined by Gas chromatography-mass spectrometry (GC-MS). Enzyme-linked immunosorbent assay (ELISA) was used to check the expressions of inflammatory factors including IL-1β, TNF-α, and VCAM-1. Methyl-capture sequencing (MC-seq) and RNA-seq were applied to observe the changes in genome-wide DNA methylation and gene expression, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to analyze differentially methylated genes (DMGs) and differentially expressed genes (DEGs). The targeted signaling pathway was selected and verified using western blotting (WB). The results showed that the lipids and inflammatory factors in foam cells significantly increased. GXHP significantly reduced the expression of TC, FC, and inflammatory factors. MC-seq and RNA-seq showed that GXHP not only corrected the aberrant DNA hypermethylation, but also DNA hypomethylation, thus restored the aberrant DEGs in foam cells induced by ox-LDL. GXHP treatment may target the PI3K-Akt signaling pathway. GXHP reduced the protein levels of phosphorylated(p)-PI3K and p-AKT in foam cells. Our data suggest that treatment with GXHP showed protective effects against AS through the inhibition of DNA methylation mediated PI3K-AKT signaling pathway, suggesting GXHP as a novel methylation-based agent.

Immunotherapy plus chemotherapy has been approved for the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC, stage IV). Recently, the 2023 version of the National Comprehensive Cancer Network Guidelines recommended immunotherapy plus chemotherapy as the neoadjuvant regimen in patients with resectable non-small cell lung cancer (NSCLC). However, it is still unclear whether the combination regimen of immunotherapy plus chemotherapy is also beneficial for SCLC in the neoadjuvant context. Here, we report the case of a patient with stage IIIB SCLC who showed long-term survival and good tolerance to the neoadjuvant chemoimmunotherapy consisting of tislelizumab (an anti–PD-1 monoclonal antibody) plus etoposide-carboplatin. The patient achieved pathological complete response after receiving two cycles of neoadjuvant tislelizumab and chemotherapy followed by surgery. Two courses of post-operative tislelizumab and etoposide-carboplatin treatment were performed. The patient has survived for more than 23 months with no recurrence or metastases after neoadjuvant therapy. Multiplexed immunofluorescence and immunohistochemistry staining showed that the post-treatment specimens had remarkable immune cells infiltration, including CD3+ T cells, CD4+ T cells, and CD8+ T cells, which contrasted with very low levels of these cells in the pre-treatment samples. This study is, to the best of our knowledge, the first attempt to present the neoadjuvant chemoimmunotherapy of tislelizumab in combination with etoposide-carboplatin in SCLC. Our study suggested that neoadjuvant tislelizumab plus chemotherapy may facilitate radical resection and benefit patients with locally advanced (stage IIB-IIIC) SCLC.

PurposeThis retrospective study aimed to investigate 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography/computed tomography (PET/CT) as a predictor of response to hypofractionated radiotherapy (HFRT) combined with programmed cell death-1 (PD-1) blockade for lung cancer.MethodsWe included 41 patients with advanced non-small cell lung cancer (NSCLC) in this study. PET/CT was performed before (SCAN-0) and one month (SCAN-1), three months (SCAN-2), and six months (SCAN-3) after treatment. Using the European Organization for Research and Treatment of Cancer 1999 criteria and PET response criteria in solid tumors, treatment responses were classified as complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), or progressive metabolic disease (PMD). Patients were further categorized as those with metabolic benefits (MB; SMD, PMR, and CMR) and those without MBs (NO-MB; PMD). We analyzed the prognosis and overall survival (OS) of patients with new visceral/bone lesions during treatment. Based on the findings, we generated a nomogram to predict survival. Receiver operating characteristics and calibration curves were used to evaluate the accuracy of the prediction model.ResultsThe mean OS based on SCANs 1, 2, and 3 was significantly higher in patients with MB and those without new visceral/bone lesions. The prediction nomogram for survival had a high area under the curve and a high predictive value based on the receiver operating characteristics and calibration curves.Conclusion18FDG-PET/CT has the potential to predict the outcomes of HFRT combined with PD-1 blockade in NSCLC. Therefore, we recommend using a nomogram to predict patient survival.

BackgroundThe relationship between the systemic immune inflammatory index (SII) and the prognosis of hypertensive patients is unclear. This study aims to explore the association of SII with all-cause and cause-specific mortality in patients with hypertension.MethodsThis study included 8524 adults with hypertension from the National Health and Nutritional Examination Surveys (NHANES) 2011–2018, and followed for survival through December 31, 2019. Cox proportional hazards models were used to investigate the associations between SII and mortality from all causes, cardiovascular disease (CVD), and cancer. Restricted cubic spline, piecewise linear regression, subgroup and sensitivity analyses were also used.ResultsDuring a median follow-up of 4.58 years, 872 all-cause deaths occurred. After adjusting for covariates, higher SII was significantly associated with an elevated risk of CVD mortality. There was a 102% increased risk of CVD mortality per one-unit increment in natural log-transformed SII (lnSII) (P < 0.001). Consistent results were also observed when SII was examined as categorical variable (quartiles). The associations of SII with all-cause and cancer mortality were detected as U-shaped with threshold values of 5.97 and 6.18 for lnSII respectively. Below thresholds, higher SII was significantly associated with lower all-cause mortality (HR=0.79, 95%CI=0.64-0.97) and cancer mortality (HR=0.73, 95%CI=0.53-1.00). Above thresholds, SII was significantly positive associated with all-cause mortality (HR=1.93, 95%CI=1.55-2.40) and cancer mortality (HR=1.93, 95%CI=1.22-3.05). The results were robust in subgroup and sensitivity analyses.ConclusionHigher SII (either as a continuous or categorical variable) were significantly associated with a higher risk of CVD mortality. The U-shaped associations were observed between SII and all-cause and cancer mortality.

Lung cancer is responsible for the leading cause of cancer-related death worldwide, which lacks effective therapies. In recent years, accumulating evidence on the understanding of the antitumor activity of the immune system has demonstrated that immunotherapy is one of the powerful alternatives in lung cancer therapy. T cells are the core of cellular immunotherapy, which are critical for tumorigenesis and the treatment of lung cancer. Based on the different expressions of surface molecules and functional points, T cells can be subdivided into regulatory T cells, T helper cells, cytotoxic T lymphocytes, and other unconventional T cells, including γδ T cells, nature killer T cells and mucosal-associated invariant T cells. Advances in our understanding of T cells’ functional mechanism will lead to a number of clinical trials on the discovery and development of new treatment strategies. Thus, we summarize the biological functions and regulations of T cells on tumorigenesis, progression, metastasis, and prognosis in lung cancer. Furthermore, we discuss the current advancements of technologies and potentials of T-cell-oriented therapeutic targets for lung cancer.

The transition period is the stage of the high incidence of metabolic and infectious diseases in dairy cows. Improving transition dairy cows’ health is crucial for the industry. This study aimed to determine the effects of dietary supplementation medium-chain fatty acids (MCFAs) on immune function, metabolic status, performance of transition dairy cows. Twenty multiparous Holstein cows randomly assigned to two treatments at 35 d before calving. 1) CON (fed the basal 2) MCFA treatment (basal diet was supplemented at an additional 20 g MCFAs mixture every day) until 70 d after calving. The results showed that the serum amyloid A myeloperoxidase concentrations in the blood of cows in MCFA treatment significantly decreased during the early lactation (from 1 d to 28 d after calving) 0.03, 0.04, respectively) compared with the CON, while the tumor necrosis factor concentration was significantly decreased at 56 d after calving (P = 0.02). In addition, the concentration of insulin in the pre-calving (from 21 d before calving to calving) blood of cows in MCFA treatment was significantly decreased (P = 0.04), and concentration of triglyceride also showed a downward trend at 28 d after calving 0.07). Meanwhile, MCFAs supplementation significantly decreased the concentrations of lithocholic acid, hyodeoxycholic acid, and hyocholic acid in the blood at 1 d calving (P = 0.02, < 0.01, < 0.01, respectively), and the level of hyocholic acid taurocholic acid concentrations (P < 0.01, = 0.01, respectively) decreased dramatically at 14 d after calving. However, compared with the CON, the pre-calving dry matter intake and the early lactation milk yield in MCFA treatment were significantly decreased (P = 0.05, 0.02, respectively). In conclusion, MCFAs supplementation transition diet could improve the immune function and metabolic status of dairy cows, and the health of transition cows might be beneficial from the endocrine status.

BackgroundPredicting which preschool children with recurrent wheezing (RW) will develop school-age asthma (SA) is difficult, highlighting the critical need to clarify the pathogenesis of RW and the mechanistic relationship between RW and SA. Despite shared environmental exposures and genetic determinants, RW and SA are usually studied in isolation. Based on network analysis of nasal and tracheal transcriptomes, we aimed to identify convergent transcriptomic mechanisms in RW and SA.MethodsRNA-sequencing data from nasal and tracheal brushing samples were acquired from the Gene Expression Omnibus. Combined with single-cell transcriptome data, cell deconvolution was used to infer the composition of 18 cellular components within the airway. Consensus weighted gene co-expression network analysis was performed to identify consensus modules closely related to both RW and SA. Shared pathways underlying consensus modules between RW and SA were explored by enrichment analysis. Hub genes between RW and SA were identified using machine learning strategies and validated using external datasets and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Finally, the potential value of hub genes in defining RW subsets was determined using nasal and tracheal transcriptome data.ResultsCo-expression network analysis revealed similarities in the transcriptional networks of RW and SA in the upper and lower airways. Cell deconvolution analysis revealed an increase in mast cell fraction but decrease in club cell fraction in both RW and SA airways compared to controls. Consensus network analysis identified two consensus modules highly associated with both RW and SA. Enrichment analysis of the two consensus modules indicated that fatty acid metabolism-related pathways were shared key signals between RW and SA. Furthermore, machine learning strategies identified five hub genes, i.e., CST1, CST2, CST4, POSTN, and NRTK2, with the up-regulated hub genes in RW and SA validated using three independent external datasets and qRT-PCR. The gene signatures of the five hub genes could potentially be used to determine type 2 (T2)-high and T2-low subsets in preschoolers with RW.ConclusionsThese findings improve our understanding of the molecular pathogenesis of RW and provide a rationale for future exploration of the mechanistic relationship between RW and SA.

IntroductionRegardless of the degree of stenosis, vulnerable plaque is an important cause of ischemic stroke and thrombotic complications. The changes of the immune microenvironment within plaques seem to be an important factor affecting the characteristics of the plaque. However, the differences of immune microenvironment between stable and vulnerable plaques were remained unknown.MethodsIn this study, RNA-sequencing was performed on superficial temporal arteries from 5 traumatic patients and plaques from 3 atherosclerotic patients to preliminary identify the key immune response processes in plaques. Mass cytometry (CyTOF) technology was used to explore differences in immune composition between 9 vulnerable plaques and 12 stable plaques. Finally, immunofluorescence technique was used to validate our findings in the previous analysis.ResultsOur results showed that more CD86+CD68+ M1 pro-inflammatory macrophages were found in vulnerable plaques, while CD4+T memory cells were mainly found in stable plaques. In addition, a CD11c+ subset of CD4+T cells with higher IFN-r secretion was found within the vulnerable plaque. In two subsets of B cells, CD19+CD20-B cells in vulnerable plaques secreted more TNF-a and IL-6, while CD19-CD20+B cells expressed more PD-1 molecules.ConclusionIn conclusion, our study suggested that M1-like macrophages are the major cell subset affecting plaque stability, while functional B cells may also contribute to plaque stability.

ObjectiveThis study aims to investigate clinical characteristics, potential risk factors, as well as long-term outcome in EGPA patients with GI involvement.MethodsA total of 94 EGPA patients were included in this cohort study. We retrospectively reviewed the clinical data, treatment, and outcome of 21 EGPA patients with GI involvement and compared them with other 73 EGPA patients without GI involvement. Multivariate logistic regression was used to find potential risk factors associated with GI involvement in EGPA patients.ResultsCompared with EGPA patients without GI involvement, EGPA patients with GI involvement had higher level of hs-CRP (65.1 (24.5-138.9) vs. 21.3 (5.7-39.1) mg/L, p=0.005), higher grades of Birmingham vasculitis activity score (BVAS) (20 (13-29.5) vs. 12 (16-19), p=0.022), higher Five Factor Score (FFS) (1 (1-2) vs. 0 (0-1), p

BackgroundA variety of autoantibodies have been detected in primary biliary cholangitis (PBC), while the presence of autoantibody clusters and their clinical significance have not been fully understood. We aimed at defining autoantibody clusters and to better understand the clinical features and prognosis of PBC patients based on autoantibody clusters under real-world conditions.MethodsWe retrospectively analyzed 788 inpatients with PBC evaluated between October 2008 and July 2019, and included 537 patients. Nineteen autoantibodies which were measured routinely were investigated for cluster analysis. Two-step clustering, Kaplan-Meier survival, and Cox regression analyses were used.ResultsFive clusters were defined. A cluster of antinuclear antibodies (ANA) and anti-gp210 positive patients were identified with a high rate of cirrhosis at baseline and low survival rate; a cluster of ANA, anti-centromere antibodies (ACA) and/or anti-CENP-B female dominant patients with older disease onset, low level of platelet count at baseline, high rate of hepatic decompensation, and low survival rate was also characterized; and another cluster of anti-mitochondrial antibodies (AMA) and/or AMA-M2, anti-Ro52 and a high rate of anti-gp210 positive patients were identified with a high proportion of male patients and low survival rate. A subgroup of patients with anti-SSA and/or anti-SSB coexists with SjS was also identified; patients with only AMA and/or AMA-M2-positive with a benign clinical outcome and relatively high complication of non-alcoholic fatty liver disease (NAFLD) were also identified. Only anti-gp210 was considered as a significant predictor for poor outcomes especially in patients with cirrhosis.ConclusionClustering methods allow the identification of distinct autoantibody profiles of PBC that form clinical subsets and can be useful for personalized approaches to diagnosis, clinical management, and the prediction of clinical outcomes. Anti-gp210 was the strongest predictive factor for poor outcomes especially in PBC patients with cirrhosis under real-world conditions.

BackgroundAblative therapy is a recommended treatment for hepatocellular carcinoma (HCC) not only for its effective eradication of tumors, but also for its induction of host immunity. However, the high 5-year recurrence rate after ablation underlines the poor understanding of the antitumor immunity response. Here, we investigated the effects of thermal ablation on antitumor immunity.MethodsWe analyzed the dynamics of tumor-associated antigen (TAA)-specific immune responses and changes in peripheral blood mononuclear cell phenotype in patients with HCC before and after tumor ablation. We used the IFN-γ ELISPOT assay and immunophenotyping by flow cytometry to evaluate the effects of ablation on host immunity. The correlation between the T cell response and disease outcome was explored to uncover the efficacy of the immune response in inhibiting HCC recurrence.ResultsDifferent TAA-specific T cell responses were identified among patients before and after ablation. One week after ablation, there was an improved immune state, with a switch from the dominance of an AFP-specific T cell response to that of a SMNMS-specific T cell response, which was correlated with better survival. Furthermore, an improvement in immune status was accompanied by a lower level of PD1+ and Tim3+ T cells in CD8+ T cells. Although this functional state was not durable, there was a higher degree of AFP-specific T cell responses at 4-weeks post-ablation. Furthermore, T cells presented a more exhausted phenotype at 4-weeks post-ablation than at the 1-week timepoint.ConclusionsAblation elicits a transient antitumor immune response in patients with HCC by changing the profile of the T cell response and the expression of immune checkpoint molecules, which correlated with longer recurrence-free survival of patients with HCC.

Caspase recruitment domain and membrane-associated guanylate kinase-like protein 3 (CARMA3) is a scaffold protein widely expressed in non-hematopoietic cells. It is encoded by the caspase recruitment domain protein 10 (CARD10) gene. CARMA3 can form a CARMA3-BCL10-MALT1 complex by recruiting B cell lymphoma 10 (BCL10) and mucosa-​associated lymphoid tissue lymphoma translocation protein 1 (MALT1), thereby activating nuclear factor-​κB (NF-κB), a key transcription factor that involves in various biological responses. CARMA3 mediates different receptors-dependent signaling pathways, including G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). Inappropriate expression and activation of GPCRs and/or RTKs/CARMA3 signaling lead to the pathogenesis of human diseases. Emerging studies have reported that CARMA3 mediates the development of various types of cancers. Moreover, CARMA3 and its partners participate in human non-cancer diseases, including atherogenesis, abdominal aortic aneurysm, asthma, pulmonary fibrosis, liver fibrosis, insulin resistance, inflammatory bowel disease, and psoriasis. Here we provide a review on its structure, regulation, and molecular function, and further highlight recent findings in human non-cancerous diseases, which will provide a novel therapeutic target.

Since ancient times, Tremella aurantialba has been proposed to have medicinal and food benefits. Modern phytochemistry and pharmacological studies have demonstrated that polysaccharides, the main components from T. aurantialba appear to be an all-round talent resisting a variety of chronic inflammatory diseases and protecting against different types of tumors, diabetes and cardiovascular diseases. These health and pharmacological benefits have gained much attention from scholars around the world. Further, more and more methods for polysaccharides extraction, purification, structure identification have been proposed. Significantly, the bioactivity of fungus polysaccharides is affected by many factors such as extraction and purification conditions and chemical structure. This paper provides an overview of recent advances in the isolation, structural features and biological effects of polysaccharides derived from T. aurantialba, covers recent advances in the field and outlines future research and applications of these polysaccharides.

ObjectivesSeveral COVID-19 vaccines list “uncontrolled epilepsy” as a contraindication for vaccination. This consequently restricts vaccination against COVID-19 in patients with epilepsy (PWE). However, there is no strong evidence that COVID-19 vaccination can exacerbate conditions in PWE. This study aims to determine the impact of COVID-19 vaccination on PWE.MethodsPWE were prospectively recruited from 25 epilepsy centers. We recorded the seizure frequency at three time periods (one month before the first vaccination and one month after the first and second vaccinations). A generalized linear mixed-effects model (GLMM) was used for analysis, and the adjusted incidence rate ratio (AIRR) with 95% CI was presented and interpreted accordingly.ResultsOverall, 859 PWE were included in the analysis. Thirty-one (3.6%) and 35 (4.1%) patients were found to have increased seizure frequency after the two doses, respectively. Age had an interaction with time. The seizure frequency in adults decreased by 81% after the first dose (AIRR=0.19, 95% CI:0.11–0.34) and 85% after the second dose (AIRR=0.16, 95% CI:0.08–0.30). In juveniles (

CD19-directed chimeric antigen receptor (CAR) T cell therapy has been shown to achieve a considerably durable response in patients with refractory or relapsed B cell non-Hodgkin lymphomas, as seen from the results of Zuma-1, Zuma-5, and other clinical trials. Most of these CARs were generated by lentivirus or reverse adenovirus. It is rare to see CARs using non-viral vectors, such as Piggy Bac (pb), in treating lymphoma patients with active diseases. Generally, patients with a high tumor burden tend to have a higher rate of severe cytokine release syndrome (CRS) or neurological events as reported in the literature. Patients with symptomatic pleural effusions are excluded from the Zuma-1 trial because of the risk of severe CRS. We report here that a patient with relapsed follicular lymphoma with bulky disease and massive chylous ascites failed several lines of chemotherapy. After infusion of the CD19-directed pbCAR-T cells at 6 × 106 cells/kg, the patient had a rapid response and achieved a nearly complete metabolic remission on day 28. There was only grade 1 CRS, and no neurotoxicity occurred. The CAR-T cells reached a peak level on day 14 and spread into the ascites and expanded for 3 months. This might be the first case reported for pbCAR-T cells to treat relapsed follicular lymphoma directly. The long-term efficacy will be observed, and more patients be tested in the future.Clinical Trial Registrationhttps://ClinicalTrials.gov, identifier NCT05472610.

BackgroundTransurethral resection of the bladder tumor with or without adjuvant intravesical instillation (IVI) has been the standard treatment for non-muscle-invasive bladder cancer (NMIBC), whereas a high percentage of patients still experience local tumor recurrence and disease progression after receiving the standard treatment modalities. Unfortunately, current relevant prediction models for determining the recurrent and progression risk of NMIBC patients are far from impeccable.MethodsClinicopathological characteristics and follow-up information were retrospectively collected from two tertiary medical centers between October 2018 and June 2021. The least absolute shrinkage and selection operator (LASSO) and Cox regression analysis were used to screen potential risk factors affecting recurrence-free survival (RFS) of patients. A nomogram model was established, and the patients were risk-stratified based on the model scores. Both internal and external validation were performed by sampling the model with 1,000 bootstrap resamples.ResultsThe study included 299 patient data obtained from the Affiliated Hospital of Xuzhou Medical University and 117 patient data obtained from the First Affiliated Hospital of Guangxi Medical University. Univariate regression analysis suggested that urine red blood cell count and different tumor invasion locations might be potential predictors of RFS. LASSO-Cox regression confirmed that prior recurrence status, times of IVI, and systemic immune-inflammation index (SII) were independent factors for predicting RFS. The area under the curve for predicting 1-, 2-, and 3-year RFS was 0.835, 0.833, and 0.871, respectively. Based on the risk stratification, patients at high risk of recurrence and progression could be accurately identified. A user-friendly risk calculator based on the model is deposited at https://dl0710.shinyapps.io/nmibc_rfs/.ConclusionInternal and external validation analyses showed that our model had excellent predictive discriminatory ability and stability. The risk calculator can be used for individualized assessment of survival risk in NMIBC patients and can assist in guiding clinical decision-making.

Vaccines are a key weapon against the COVID-19 pandemic caused by SARS-CoV-2. However, there are inter-individual differences in immune response to SARS-CoV-2 vaccines and genetic contributions to these differences have barely been investigated. Here, we performed genome-wide association study (GWAS) of antibody levels in 168 inactivated SARS-CoV-2 vaccine recipients. A total of 177 SNPs, corresponding to 41 independent loci, were identified to be associated with IgG, total antibodies or neutral antibodies. Specifically, the rs4543780, the intronic variant of FAM89A gene, was associated with total antibodies level and was annotated as a potential regulatory variant affecting gene expression of FAM89A, a biomarker differentiating bacterial from viral infections in febrile children. These findings might advance our knowledge of the molecular mechanisms driving immunity to SARS-CoV-2 vaccine.

Bispecific antibodies (bsAbs) are artificial antibodies with two distinct antigen-binding sites that can bind to different antigens or different epitopes on the same antigen. Based on a variety of technology platforms currently developed, bsAbs can exhibit different formats and mechanisms of action. The upgrading of antibody technology has promoted the development of bsAbs, which has been effectively used in the treatment of tumors. So far, 7 bsAbs have been approved for marketing in the world, and more than 200 bsAbs are in clinical and preclinical research stages. Here, we summarize the development process of bsAbs, application in tumor treatment and look forward to the challenges in future development.

The incidence and mortality of colorectal cancer (CRC) are increasing year by year. The accurate classification of CRC can realize the purpose of personalized and precise treatment for patients. The tumor microenvironment (TME) plays an important role in the malignant progression and immunotherapy of CRC. An in-depth understanding of the clusters based on the TME is of great significance for the discovery of new therapeutic targets for CRC. We extracted data on CRC, including gene expression profile, DNA methylation array, somatic mutations, clinicopathological information, and copy number variation (CNV), from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) (four datasets—GSE14333, GSE17538, GSE38832, and GSE39582), cBioPortal, and FireBrowse. The MCPcounter was utilized to quantify the abundance of 10 TME cells for CRC samples. Cluster repetitive analysis was based on the Hcluster function of the Pheatmap package in R. The ESTIMATE package was applied to compute immune and stromal scores for CRC patients. PCA analysis was used to remove batch effects among different datasets and transform genome-wide DNA methylation profiling into methylation of tumor-infiltrating lymphocyte (MeTIL). We evaluated the mutation differences of the clusters using MOVICS, DeconstructSigs, and GISTIC packages. As for therapy, TIDE and SubMap analyses were carried out to forecast the immunotherapy response of the clusters, and chemotherapeutic sensibility was estimated based on the pRRophetic package. All results were verified in the TCGA and GEO data. Four immune clusters (ImmClust-CS1, ImmClust-CS2, ImmClust-CS3, and ImmClust-CS4) were identified for CRC. The four ImmClusts exhibited distinct TME compositions, cancer-associated fibroblasts (CAFs), functional orientation, and immune checkpoints. The highest immune, stromal, and MeTIL scores were observed in CS2, in contrast to the lowest scores in CS4. CS1 may respond to immunotherapy, while CS2 may respond to immunotherapy after anti-CAFs. Among the four ImmClusts, the top 15 markers with the highest mutation frequency were acquired, and CS1 had significantly lower CNA on the focal level than other subtypes. In addition, CS1 and CS2 patients had more stable chromosomes than CS3 and CS4. The most sensitive chemotherapeutic agents in these four ImmClusts were also found. IHC results revealed that CD29 stained significantly darker in the cancer samples, indicating that their CD29 was highly expressed in colon cancer. This work revealed the novel clusters based on TME for CRC, which would guide in predicting the prognosis, biological features, and appropriate treatment for patients with CRC.

The calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide with critical roles in the development of peripheral sensitization and pain. One of the CGRP family peptides, islet amyloid polypeptide (IAPP), is an important autoantigen in type 1 diabetes. Due to the high structural and chemical similarity between CGRP and IAPP, we expected that the CGRP peptide could be recognized by IAPP-specific CD4 T cells. However, there was no cross-reactivity between the CGRP peptide and the diabetogenic IAPP-reactive T cells. A set of CGRP-specific CD4 T cells was isolated from non-obese diabetic (NOD) mice. The T-cell receptor (TCR) variable regions of both α and β chains were highly skewed towards TRAV13 and TRBV13, respectively. The clonal expansion of T cells suggested that the presence of activated T cells responded to CGRP stimulation. None of the CGRP-specific CD4 T cells were able to be activated by the IAPP peptide. This established that CGRP-reactive CD4 T cells are a unique type of autoantigen-specific T cells in NOD mice. Using IAg7-CGRP tetramers, we found that CGRP-specific T cells were present in the pancreas of both prediabetic and diabetic NOD mice. The percentages of CGRP-reactive T cells in the pancreas of NOD mice were correlated to the diabetic progression. We showed that the human CGRP peptide presented by IAg7 elicited strong CGRP-specific T-cell responses. These findings suggested that CGRP is a potential autoantigen for CD4 T cells in NOD mice and probably in humans. The CGRP-specific CD4 T cells could be a unique marker for type 1 diabetes. Given the ubiquity of CGRP in nervous systems, it could potentially play an important role in diabetic neuropathy.

BackgroundThe absent in melanoma 2 (AIM2) inflammasome is a multi-protein platform that recognizes aberrant cytoplasmic double-stranded DNA(dsDNA) and induces cytokine maturation, release, and pyroptosis. Some studies found that the AIM2 inflammasome was a double-edged sword in many cancers. However, there have been fewer studies on AIM2 inflammasomes in pan-cancer.MethodsGene expression was analyzed using The Cancer Genome Atlas (TCGA) database and The Genotype-Tissue Expression (GTEx) database. Immunohistochemistry (IHC) was used to validate the expression of the AIM2. We used the survival curve to explore the prognostic significance of the AIM2 inflammasomes in pan-cancer. Mutations and methylation of AIM2 inflammasome-related genes (AIM2i-RGs) were also comprehensively analyzed. Single sample gene set enrichment analysis was used to calculate the AIM2 inflammasomes score and explore the correlation of the AIM2 inflammasomes score with immune-related genes and immune infiltrations. The function of AIM2 inflammasomes in pan-cancer was analyzed at the single-cell level. Single-cell transcriptome sequencing (scRNA-seq) data was used to assess the activation state of the AIM2 inflammasomes in the tumor microenvironment.ResultsWe found that AIM2i-RGs were aberrantly expressed in tumors and were strongly associated with prognosis. In pan-cancer, the expression of AIM2i-RGs was positively associated with copy number variation and negatively associated with methylation. In AIM2i-RGs, missense mutations were the predominant type of single nucleotide polymorphism. Moreover, we found that the drugs dimethyloxallyl glycine (DMOG) and Z-LNle-CHO may be sensitive to the AIM2 inflammasomes. The AIM2 inflammasomes score was significantly and positively correlated with the tumor immunity score and the stroma score. In most tumors, the AIM2 inflammasomes score was significantly and positively correlated with CD8+ T cell abundance in the tumor microenvironment. Additionally, the AIM2 inflammasomes score was significantly correlated with immune checkpoint genes in pan-cancer as well as immune checkpoint therapy-related markers including tumor mutational burden (TMB), microsatellite instability(MSI), and tumor immune dysfunction and exclusion(TIDE). scRNA-seq analysis suggested that AIM2 inflammasomes differ significantly among different cells in the tumor microenvironment. IHC confirmed low expression of AIM2 in colorectal cancer.DiscussionAIM2 inflammasomes may be a new target for future tumor therapy It is likely involved in tumor development, and its high expression may serve as a predictor of tumor immunotherapy efficacy.

Gastric cancer (GC) is a malignancy with a high incidence and mortality, and the emergence of immunotherapy has brought survival benefits to GC patients. Compared with traditional therapy, immunotherapy has the advantages of durable response, long-term survival benefits, and lower toxicity. Therefore, targeted immune cells are the most promising therapeutic strategy in the field of oncology. In this review, we introduce the role and significance of each immune cell in the tumor microenvironment of GC and summarize the current landscape of immunotherapy in GC, which includes immune checkpoint inhibitors, adoptive cell therapy (ACT), dendritic cell (DC) vaccines, reduction of M2 tumor-associated macrophages (M2 TAMs), N2 tumor-associated neutrophils (N2 TANs), myeloid-derived suppressor cells (MDSCs), effector regulatory T cells (eTregs), and regulatory B cells (Bregs) in the tumor microenvironment and reprogram TAMs and TANs into tumor killer cells. The most widely used immunotherapy strategies are the immune checkpoint inhibitor programmed cell death 1/programmed death-ligand 1 (PD-1/PD-L1) antibody, cytotoxic T lymphocyte–associated protein 4 (CTLA-4) antibody, and chimeric antigen receptor T (CAR-T) in ACT, and these therapeutic strategies have significant anti-tumor efficacy in solid tumors and hematological tumors. Targeting other immune cells provides a new direction for the immunotherapy of GC despite the relatively weak clinical data, which have been confirmed to restore or enhance anti-tumor immune function in preclinical studies and some treatment strategies have entered the clinical trial stage, and it is expected that more and more effective immune cell–based therapeutic methods will be developed and applied.