Search

BackgroundPeritoneal dialysis-related peritonitis (PDRP) is one of the most common complications of peritoneal dialysis (PD). Understanding the risk factors and etiological characteristics is indispensable for infection prevention and improving the outcome and life quality.MethodsA total of 70 PD patients were separated into the PDRP group (n=25) and the control group (n=45). Variables, including gender, age, body mass index, primary diseases, and history of basic diseases, in the two groups were analyzed to assess the risk factors of PDRP. Metagenomic next-generation sequencing (mNGS) and microbial culture were compared in detecting pathogenic microorganisms. Gut microbiota analysis was performed in 35 PDRP patients based on mNGS data.ResultsDialysis time and times of dialysate change were the risk factors of PDRP, and times of dialysate change was the independent risk factor of PDRP (p = 0.046). mNGS produced higher sensitivity (65.79%) than microbial culture (36.84%) in identifying pathogenic microorganisms. Staphylococcus aureus and Klebsiella pneumoniae (four cases) were the most frequent pathogens causing PDRP, followed by Staphylococcus capitis (three cases). β diversity of the gut microbiota was significantly different between patients with fewer times of dialysate change (≤4) and more (>5), as well as between patients with gram-positive (G+) bacterial and gram-negative (G−) bacterial infection.ConclusionThe dialysis time and times of dialysate changes not only are risk factors for peritonitis in PD patients but also stimulate significant changes in the gut microbiome structure in PDRP patients. These findings may provide a novel viewpoint for the management of patients with PDRP.

PurposeCurrently, chemoimmunotherapy is effective only in a subset of patients with advanced non-squamous non-small cell lung cancer. Robust biomarkers for predicting the efficacy of chemoimmunotherapy would be useful to identify patients who would benefit from chemoimmunotherapy. The primary objective of our study was to develop an artificial intelligence-based immunoscore and to evaluate the value of patho-immunoscore in predicting clinical outcomes in patients with advanced non-squamous non-small cell lung cancer (NSCLC).MethodsWe have developed an artificial intelligence–powered immunoscore analyzer based on 1,333 whole-slide images from TCGA-LUAD. The predictive efficacy of the model was further validated in the CPTAC-LUAD cohort and the biomarker cohort of the ORIENT-11 study, a randomized, double-blind, phase 3 study. Finally, the clinical significance of the patho-immunoscore was evaluated using the ORIENT-11 study cohort.ResultsOur immunoscore analyzer achieved good accuracy in all the three cohort mentioned above (TCGA-LUAD, mean AUC: 0.783; ORIENT-11 cohort, AUC: 0.741; CPTAC-LUAD cohort, AUC: 0.769). In the 259 patients treated with chemoimmunotherapy, those with high patho-immunoscore (n = 146) showed significantly longer median progression-free survival than those with low patho-immunoscore (n = 113) (13.8 months vs 7.13 months, hazard ratio [HR]: 0.53, 95% confidence interval [CI]: 0.38 – 0.73; p < 0.001). In contrast, no significant difference was observed in patients who were treated with chemotherapy only (5.07 months vs 5.07 months, HR: 1.04, 95% CI: 0.71 – 1.54; p = 0.83). Similar trends were observed in overall survival.ConclusionOur study indicates that AI-powered immunoscore applied on LUAD digital slides can serve as a biomarker for survival outcomes in patients with advanced non-squamous NSCLC who received chemoimmunotherapy. This methodology could be applied to other cancers and facilitate cancer immunotherapy.

Toxoplasma gondii (T. gondii) is a zoonotic disease that poses great harm to humans and animals. So far, no effective T. gondii vaccine has been developed to provide fully protection against such parasites. Recently, numerous researches have focused on the use of poly-lactic-co-glycolic acid (PLGA) and chitosan (CS) for the vaccines against T. gondii infections. In this study, we employed PLGA and CS as the vehicles for T. gondii ribosome protein (TgRPS2) delivery. TgRPS2-PLGA and TgRPS2-CS nanospheres were synthesized by double emulsion solvent evaporation and ionic gelation technique as the nano vaccines. Before immunization in animals, the release efficacy and toxicity of the synthesized nanospheres were evaluated in vitro. Then, ICR mice were immunized intramuscularly, and immune protections of the synthesized nanospheres were assessed. The results showed that TgRPS2-PLGA and TgRPS2-CS nanospheres could induce higher levels of IgG and cytokines, activate dendritic cells, and promote the expression of histocompatibility complexes. The splenic lymphocyte proliferation and the enhancement in the proportion of CD4+ and CD8+ T lymphocytes were also observed in immunized animals. In addition, two types of nanospheres could significantly inhabit the replications of T. gondii in cardiac muscles and spleen tissues. All these obtained results in this study demonstrated that the TgRPS2 protein delivered by PLGA or CS nanospheres provided satisfactory immunoprotective effects in resisting T. gondii, and such formulations illustrated potential as prospective preventive agents for toxoplasmosis.

Osteosarcoma (OS) is an aggressive and highly lethal bone tumor, highlighting the urgent need for further exploration of its underlying mechanisms. In this study, we conducted analyses utilizing bulk transcriptome sequencing data of OS and healthy control samples, as well as single cell sequencing data, obtained from public databases. Initially, we evaluated the differential expression of four tumor microenvironment (TME)-related gene sets between tumor and control groups. Subsequently, unsupervised clustering analysis of tumor tissues identified two significantly distinct clusters. We calculated the differential scores of the four TME-related gene sets for Clusters 1 (C1) and 2 (C2), using Gene Set Variation Analysis (GSVA, followed by single-variable Cox analysis. For the two clusters, we performed survival analysis, examined disparities in clinical-pathological distribution, analyzed immune cell infiltration and immune evasion prediction, assessed differences in immune infiltration abundance, and evaluated drug sensitivity. Differentially expressed genes (DEGs) between the two clusters were subjected to Gene Ontology (GO) and Gene Set Enrichment Analysis (GSEA). We conducted Weighted Gene Co-expression Network Analysis (WGCNA) on the TARGET-OS dataset to identify key genes, followed by GO enrichment analysis. Using LASSO and multiple regression analysis we conducted a prognostic model comprising eleven genes (ALOX5AP, CD37, BIN2, C3AR1, HCLS1, ACSL5, CD209, FCGR2A, CORO1A, CD74, CD163) demonstrating favorable diagnostic efficacy and prognostic potential in both training and validation cohorts. Using the model, we conducted further immune, drug sensitivity and enrichment analysis. We performed dimensionality reduction and annotation of cell subpopulations in single cell sequencing analysis, with expression profiles of relevant genes in each subpopulation analyzed. We further substantiated the role of ACSL5 in OS through a variety of wet lab experiments. Our study provides new insights and theoretical foundations for the prognosis, treatment, and drug development for OS patients.

BackgroundCD38 and CD47 are expressed in many hematologic malignancies, including multiple myeloma (MM), B-cell non-Hodgkin lymphoma (NHL), B-cell acute lymphoblastic leukemia (ALL), and B-cell chronic lymphocytic leukemia (CLL). Here, we evaluated the antitumor activities of CD38/CD47 bispecific antibodies (BsAbs).MethodsFive suitable anti-CD38 antibodies for co-targeting CD47 and CD38 BsAb were developed using a 2 + 2 “mAb-trap” platform. The activity characteristics of the CD38/CD47 BsAbs were evaluated using in vitro and in vivo systems.ResultsUsing hybridoma screening technology, we obtained nine suitable anti-CD38 antibodies. All anti-CD38 antibodies bind to CD38+ tumor cells and kill tumor cells via antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Five anti-CD38 antibodies (4A8, 12C10, 26B4, 35G5, and 65A7) were selected for designing CD38/CD47 BsAbs (IMM5605) using a “mAb-trap” platform. BsAbs had higher affinity and binding activity to the CD38 target than those to the CD47 target, decreasing the potential on-target potential and off-tumor effects. The CD38/CD47 BsAbs did not bind to RBCs and did not induce RBC agglutination; thus, BsAbs had much lower blood toxicity. The CD38/CD47 BsAbs had a greater ability to block the CD47/SIRPα signal in CD38+/CD47+ tumor cells than IMM01 (SIRPα Fc fusion protein). Through Fc domain engineering, CD38/CD47 BsAbs were shown to kill tumors more effectively by inducing ADCC and ADCP. IMM5605–26B4 had the strongest inhibitory effect on cellular CD38 enzymatic activity. IMM5605–12C10 had the strongest ability to directly induce the apoptosis of tumor cells. The anti-CD38 antibody 26B4 combined with the SIRPα-Fc fusion proteins showed strong antitumor effects, which were better than any of the mono-therapeutic agents used alone in the NCI-H929 cell xenograft model. The CD38/CD47 BsAbs exhibited strong antitumor effects; specifically, IMM5605–12C10 efficiently eradicated all established tumors in all mice.ConclusionA panel of BsAbs targeting CD38 and CD47 developed based on the “mAb-tarp” platform showed potent tumor-killing ability in vitro and in vivo. As BsAbs had lower affinity for binding to CD47, higher affinity for binding to CD38, no affinity for binding to RBCs, and did not induce RBC agglutination, we concluded that CD38/CD47 BsAbs are safe and have a satisfactory tolerability profile.

Individuals with Kabuki syndrome present with immunodeficiency; however, how pathogenic variants in the gene encoding the histone-modifying enzyme lysine methyltransferase 2D (KMT2D) lead to immune alterations remain poorly understood. Following up on our prior report of KMT2D-altered integrin expression in B-cells, we performed targeted analyses of KMT2D’s influence on integrin expression in T-cells throughout development (thymocytes through peripheral T-cells) in murine cells with constitutive- and conditional-targeted Kmt2d deletion. Using high-throughput RNA-sequencing and flow cytometry, we reveal decreased expression (both at the transcriptional and translational levels) of a cluster of leukocyte-specific integrins, which perturb aspects of T-cell activation, maturation, adhesion/localization, and effector function. H3K4me3 ChIP-PCR suggests that these evolutionary similar integrins are under direct control of KMT2D. KMT2D loss also alters multiple downstream programming/signaling pathways, including integrin-based localization, which can influence T-cell populations. We further demonstrated that KMT2D deficiency is associated with the accumulation of murine CD8+ single-positive (SP) thymocytes and shifts in both human and murine peripheral T-cell populations, including the reduction of the CD4+ recent thymic emigrant (RTE) population. Together, these data show that the targeted loss of Kmt2d in the T-cell lineage recapitulates several distinct features of Kabuki syndrome-associated immune deficiency and implicates epigenetic mechanisms in the regulation of integrin signaling.

Antiphospholipid antibodies (aPL) are both laboratory evidence and causative factors for a broad spectrum of clinical manifestations of antiphospholipid syndrome (APS), with thrombotic and obstetric events being the most prevalent. Despite the aPL-triggered vasculopathy nature of APS, vasculitic-like manifestations rarely exist in APS and mainly appear associated with other concurrent connective tissue diseases like systemic lupus erythematous. Several studies have characterized pulmonary capillaritis related to pathogenic aPL, suggesting vasculitis as a potential associated non-thrombotic manifestation. Here, we describe a 15-year-old girl who develops hepatic infarction in the presence of highly positive aPL, temporally related to prior non-severe COVID-19 infection. aPL-related hepatic vasculitis, which has not been reported before, contributes to liver ischemic necrosis. Immunosuppression therapy brings about favorable outcomes. Our case together with retrieved literature provides supportive evidence for aPL-related vasculitis, extending the spectrum of vascular changes raised by pathogenic aPL. Differentiation between thrombotic and vasculitic forms of vascular lesions is essential for appropriate therapeutic decision to include additional immunosuppression therapy. We also perform a systematic review to characterize the prevalence and clinical features of new-onset APS and APS relapses after COVID-19 for the first time, indicating the pathogenicity of aPL in a subset of COVID-19 patients.

BackgroundAccumulating evidence suggests that the gut microbiota and its metabolites may be involved in autoimmune hypothyroidism. However, the causal association between gut microbiota, metabolites and autoimmune hypothyroidism remains to be determined.MethodsInstrumental variables were screened from the GWAS datasets of 211 gut microbiota taxonomic groups, gut microbiota-derived metabolites, and autoimmune hypothyroidism. Univariable Mendelian randomization (MR) and multivariable Mendelian randomization (MVMR) were used to analyse the potential causal relationship between autoimmune hypothyroidism, these metabolites, or these microbiota. During the MR analysis, we alternated multiple MR methods with different model assumptions to assess the consistency and robustness of the findings: inverse variance weighted (IVW), weighted median, MR pleiotropy residual sum and outlier (MRPRESSO) and MR−Egger methods. Reverse MR analysis was performed to assess the possibility of reverse causality. Finally, enrichment analyses were used to investigate potential biofunctions.ResultsThe IVW results of univariable MR showed that the phyla Actinobacteria, genus DefluviitaleaceaeUCG011, genus Eggerthella, family Defluviitaleaceae, genus Subdoligranulum, genus RuminococcaceaeUCG011, and genus Intestinimonas were associated with autoimmune hypothyroidism. After FDR adjustment, the absence of a causal relationship between gut microbiota and autoimmune hypothyroidism (PFDR > 0.05) suggested a possible marginal association. The results on gut metabolites showed that N-(3-furoyl)glycine, pipecolate, phenylalanine, allantoin, indololactate and alanine were associated with autoimmune hypothyroidism. After FDR correction, only indololactate was associated with hypothyroidism (OR=1.592; 95% CI, 1.228-2.065; PFDR= 0.036). Family Defluviitaleaceae and genus DefluviitaleaceaeUCG011 were suggestively significant in the MVMR. The results of reverse MR analysis showed no reverse causality between autoimmune hypothyroidism and the identified gut microbiota. Enrichment analysis revealed that several key regulatory pathways were significantly enriched.ConclusionThis study supported that there were beneficial or detrimental causal effects of gut microbiota and its metabolites on autoimmune hypothyroidism risk, which provides more theoretical support for mechanistic research on the “thyroid–gut” axis.

Toxoplasma gondii (T. gondii) is a zoonotic disease that poses great harm to humans and animals. So far, no effective T. gondii vaccine has been developed to provide fully protection against such parasites. Recently, numerous researches have focused on the use of poly-lactic-co-glycolic acid (PLGA) and chitosan (CS) for the vaccines against T. gondii infections. In this study, we employed PLGA and CS as the vehicles for T. gondii ribosome protein (TgRPS2) delivery. TgRPS2- PLGA and TgRPS2-CS nanospheres were synthesized by double emulsion solvent evaporation and ionic gelation technique as the nano vaccines. Before immunization in animals, the release efficacy and toxicity of the synthesized nanospheres were evaluated in vitro. Then, ICR mice were immunized intramuscularly, and immune protections of the synthesized nanospheres were assessed. The results showed that TgRPS2-PLGA and TgRPS2-CS nanospheres could induce higher levels of IgG and cytokines, activate dendritic cells, and promote the expression of histocompatibility complexes. The splenic lymphocyte proliferation and the enhancement in the proportion of CD4+ and CD8+ T lymphocytes were also observed in immunized animals. In addition, two types of nanospheres could significantly inhabit the replications of T. gondii in cardiac muscles and spleen tissues. All these obtained results in this study demonstrated that the TgRPS2 protein delivered by PLGA or CS nanospheres provided satisfactory immunoprotective effects in resisting T. gondii, and such formulations illustrated potential as prospective preventive agents for toxoplasmosis. [ABSTRACT FROM AUTHOR]

ObjectiveThis paper observes the efficacy of chemotherapy combined with CD19 and CD20 monoclonal antibodies in clearing minimal residual disease (MRD) and bridging transplantation for refractory acute B-lymphoblastic leukemia (B-ALL) in children and reviews the literature.MethodsA 4-year-old boy diagnosed with B-ALL in our hospital was treated with the SCCLG-ALL-2016 protocol. MRD and gene quantification decreased after induction but remained persistently positive, with poor efficacy. After this patient received three cycles of consolidation chemotherapy combined with blinatumomab and rituximab, MRD and fusion gene quantification became negative, and he received allogeneic hematopoietic stem cell transplantation (allo-HSCT).ResultsDuring the use of monoclonal antibodies, neurotoxicity, CRS, or other side effects did not occur. Before transplantation, MRD became negative, and the bone marrow had been in complete remission since transplantation (13 months).ConclusionChemotherapy combined with blinatumomab for refractory B-ALL in children can bring a better remission rate for patients and is a means of bridging transplantation. Nevertheless, sequential CD20 monoclonal antibody therapy is the first report , and no adverse effects were observed in our case. It is well tolerated and can be used as one of the treatments for refractory B-ALL.

The NLRP3 inflammasome, which belongs to the pyrin domain containing 3 family of NOD-like receptors, has a significant impact on both the innate and adaptive immune responses. Regulating host immune function and protecting against microbial invasion and cell damage, the NLRP3 inflammasome plays a crucial role. By triggering caspase-1, it facilitates the development of the inflammatory cytokines IL-1β and IL-18, and triggers cell pyroptosis, resulting in cell lysis and demise. Common sterile arthritis includes osteoarthritis (OA), rheumatoid arthritis (RA) and gouty arthritis (GA), all of which manifest as bone destruction and synovial inflammation in a complex inflammatory state, placing a significant medical burden on the families of patients and government agencies. In the past few years, there has been a growing interest in investigating the impact of cell pyroptosis on arthritis development, particularly the widespread occurrence of pyroptosis mediated by the NLRP3 inflammasome. The NLRP3 inflammasome’s biological properties are briefly described in this review, along with the presentation of the fundamental processes of pyroptosis resulting from its activation. Furthermore, we provide a summary of the advancements made in studying the NLRP3 inflammasome in various forms of arthritis and enumerate the intervention approaches that target the NLRP3-mediated pyroptosis, either directly or indirectly. These discoveries lay the groundwork for future investigations on medications for arthritis, offering fresh approaches for the clinical identification and treatment of this condition.

Parkinson’s disease (PD) is a common neurodegenerative disorder of middle-aged and elderly people, clinically characterized by resting tremor, myotonia, reduced movement, and impaired postural balance. Clinically, patients with PD are often administered levodopa (L-DOPA) to improve their symptoms. However, after years of L-DOPA treatment, most patients experience complications of varying severity, including the “on-off phenomenon”, decreased efficacy, and levodopa-induced dyskinesia (LID). The development of LID can seriously affect the quality of life of patients, but its pathogenesis is unclear and effective treatments are lacking. Glutamic acid (Glu)-mediated changes in synaptic plasticity play a major role in LID. The N-methyl-D-aspartic acid receptor (NMDAR), an ionotropic glutamate receptor, is closely associated with synaptic plasticity, and neuroinflammation can modulate NMDAR activation or expression; in addition, neuroinflammation may be involved in the development of LID. However, it is not clear whether NMDA receptors are co-regulated with neuroinflammation during LID formation. Here we review how neuroinflammation mediates the development of LID through the regulation of NMDA receptors, and assess whether common anti-inflammatory drugs and NMDA receptor antagonists may be able to mitigate the development of LID through the regulation of central neuroinflammation, thereby providing a new theoretical basis for finding new therapeutic targets for LID.

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has exerted a profound influence on humans. Increasing evidence shows that immune response is crucial in influencing the risk of infection and disease severity. Observational studies suggest an association between COVID‐19 and immunoglobulin G (IgG) N-glycosylation traits, but the causal relevance of these traits in COVID-19 susceptibility and severity remains controversial.MethodsWe conducted a two-sample Mendelian randomization (MR) analysis to explore the causal association between 77 IgG N-glycosylation traits and COVID-19 susceptibility, hospitalization, and severity using summary-level data from genome-wide association studies (GWAS) and applying multiple methods including inverse-variance weighting (IVW), MR Egger, and weighted median. We also used Cochran’s Q statistic and leave-one-out analysis to detect heterogeneity across each single nucleotide polymorphism (SNP). Additionally, we used the MR-Egger intercept test, MR-PRESSO global test, and PhenoScanner tool to detect and remove SNPs with horizontal pleiotropy and to ensure the reliability of our results.ResultsWe found significant causal associations between genetically predicted IgG N-glycosylation traits and COVID-19 susceptibility, hospitalization, and severity. Specifically, we observed reduced risk of COVID-19 with the genetically predicted increased IgG N-glycan trait IGP45 (OR = 0.95, 95% CI = 0.92–0.98; FDR = 0.019). IGP22 and IGP30 were associated with a higher risk of COVID-19 hospitalization and severity. Two (IGP2 and IGP77) and five (IGP10, IGP14, IGP34, IGP36, and IGP50) IgG N-glycosylation traits were causally associated with a decreased risk of COVID-19 hospitalization and severity, respectively. Sensitivity analyses did not identify any horizontal pleiotropy.ConclusionsOur study provides evidence that genetically elevated IgG N-glycosylation traits may have a causal effect on diverse COVID-19 outcomes. Our findings have potential implications for developing targeted interventions to improve COVID-19 outcomes by modulating IgG N-glycosylation levels.

“Dietary fiber” (DF) refers to a type of carbohydrate that cannot be digested fully. DF is not an essential nutrient, but it plays an important part in enhancing digestive capacity and maintaining intestinal health. Therefore, DF supplementation in the daily diet is highly recommended. Inulin is a soluble DF, and commonly added to foods. Recently, several studies have found that dietary supplementation of inulin can improve metabolic function and regulate intestinal immunity. Inulin is fermented in the colon by the gut microbiota and a series of metabolites is generated. Among these metabolites, short-chain fatty acids provide energy to intestinal epithelial cells and participate in regulating the differentiation of immune cells. Inulin and its intestinal metabolites contribute to host immunity. This review summarizes the effect of inulin and its metabolites on intestinal immunity, and the underlying mechanisms of inulin in preventing diseases such as type 2 diabetes mellitus, inflammatory bowel disease, chronic kidney disease, and certain cancer types.

IntroductionIn spontaneous type 1 diabetes (T1D) non-obese diabetic (NOD) mice, the insulin B chain peptide 9-23 (B:9-23) can bind to the MHC class II molecule (IAg7) in register 3 (R3), creating a bimolecular IAg7/InsulinB:9-23 register 3 conformational epitope (InsB:R3). Previously, we showed that the InsB:R3-specific chimeric antigen receptor (CAR), constructed using an InsB:R3-monoclonal antibody, could guide CAR-expressing CD8 T cells to migrate to the islets and pancreatic lymph nodes. Regulatory T cells (Tregs) specific for an islet antigen can broadly suppress various pathogenic immune cells in the islets and effectively halt the progression of islet destruction. Therefore, we hypothesized that InsB:R3 specific Tregs would suppress autoimmune reactivity in islets and efficiently protect against T1D.MethodsTo test our hypothesis, we produced InsB:R3-Tregs and tested their disease-protective effects in spontaneous T1D NOD.CD28-/- mice.ResultsInsB:R3-CAR expressing Tregs secrete IL-10 dominated cytokines upon engagement with InsB:R3 antigens. A single infusion of InsB:R3 Tregs delayed the onset of T1D in 95% of treated mice, with 35% maintaining euglycemia for two healthy lifespans, readily home to the relevant target whereas control Tregs did not. Our data demonstrate that Tregs specific for MHC class II: Insulin peptide epitope (MHCII/Insulin) protect mice against T1D more efficiently than polyclonal Tregs lacking islet antigen specificity, suggesting that the MHC II/insulin-specific Treg approach is a promising immune therapy for safely preventing T1D.

T cells represent a crucial component of the adaptive immune system and mediate anti-tumoral immunity as well as protection against infections, including respiratory viruses such as SARS-CoV-2. Next-generation sequencing of the T-cell receptors (TCRs) can be used to profile the T-cell repertoire. We developed a customized pipeline for Network Analysis of Immune Repertoire (NAIR) with advanced statistical methods to characterize and investigate changes in the landscape of TCR sequences. We first performed network analysis on the TCR sequence data based on sequence similarity. We then quantified the repertoire network by network properties and correlated it with clinical outcomes of interest. In addition, we identified (1) disease-specific/associated clusters and (2) shared clusters across samples based on our customized search algorithms and assessed their relationship with clinical outcomes such as recovery from COVID-19 infection. Furthermore, to identify disease-specific TCRs, we introduced a new metric that incorporates the clonal generation probability and the clonal abundance by using the Bayes factor to filter out the false positives. TCR-seq data from COVID-19 subjects and healthy donors were used to illustrate that the proposed approach to analyzing the network architecture of the immune repertoire can reveal potential disease-specific TCRs responsible for the immune response to infection.

Acute respiratory distress syndrome (ARDS) is associated with high mortality rates in patients admitted to the intensive care unit (ICU) patients with overwhelming inflammation considered to be an internal cause. The authors’ previous study indicated a potential correlation between phenylalanine levels and lung injury. Phenylalanine induces inflammation by enhancing the innate immune response and the release of pro-inflammatory cytokines. Alveolar macrophages (AMs) can respond to stimuli via synthesis and release of inflammatory mediators through pyroptosis, one form of programmed cell death acting through the nucleotide-binging oligomerization domain-like receptors protein 3 (NLRP3) signaling pathway, resulting in the cleavage of caspase-1 and gasdermin D (GSDMD) and the release of interleukin (IL) -1β and IL-18, aggravating lung inflammation and injury in ARDS. In this study, phenylalanine promoted pyroptosis of AMs, which exacerbated lung inflammation and ARDS lethality in mice. Furthermore, phenylalanine initiated the NLRP3 pathway by activating the calcium-sensing receptor (CaSR). These findings uncovered a critical mechanism of action of phenylalanine in the context of ARDS and may be a new treatment target for ARDS.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease involving mainly the colorectal mucosa and submucosa, the incidence of which has been on the rise in recent years. Nuclear factor erythroid 2-related factor 2 (Nrf2), known for its key function as a transcription factor, is pivotal in inducing antioxidant stress and regulating inflammatory responses. Numerous investigations have demonstrated the involvement of the Nrf2 pathway in maintaining the development and normal function of the intestine, the development of UC, and UC-related intestinal fibrosis and carcinogenesis; meanwhile, therapeutic agents targeting the Nrf2 pathway have been widely investigated. This paper reviews the research progress of the Nrf2 signaling pathway in UC.

BackgroundBillions of doses of coronavirus disease 2019 (COVID-19) vaccines have been administered and several cases of thrombocytopenia with thrombosis syndrome (TTS) have been reported after the administration of adenoviral vector vaccines. However, the effects of an inactivated COVID-19 vaccine, CoronaVac, on coagulation are not well understood.MethodsIn this randomized, controlled, open-label phase IV clinical trial, 270 participants including 135 adults aged 18–59 years and 135 adults aged 60 years or older, were enrolled and randomized to the CoronaVac group or to the control group in a 2:1 ratio and received two doses of CoronaVac or one dose of the 23-valent pneumococcal polysaccharide vaccine and one dose of inactivated hepatitis A vaccine on days 0 and 28, respectively. Adverse events were collected for 28 days after each dose. Blood samples were taken on days 0, 4, 14, 28, 32, 42, and 56 after the first dose to evaluate neutralizing antibody titers and laboratory parameters of coagulation function and blood glucose.ResultsFourteen days after the second dose of CoronaVac, the seroconversion rates of neutralizing antibodies against the prototype strain and beta, gamma, and delta variants of concern (VOC) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) reached peak values of 89.31%, 23.3%, 45.3%, and 53.5%, respectively. The incidence of adverse reactions was 43.6% and 52.2% in the CoronaVac group and in the control group, respectively. All were mild or moderate in severity. For the laboratory parameters, there was no difference in the means of any parameter between the two groups at any time point, except for the D-dimer on day 14. However, the D-dimer in the CoronaVac group decreased on day 14 compared to the value at baseline, while a higher D-dimer value, instead of a decreased D-dimer value, was a risk factor for TTS.ConclusionCoronaVac showed a good safety profile and could induce a humoral response against the prototype and VOCs of SARS-CoV-2 in adults 18 years or older, with no abnormal effects on laboratory parameters of blood glucose and coagulation function.

ObjectiveFew data are available on the optimal treatment options after disease progression from first-line treatment of immune checkpoint inhibitors (ICIs) plus chemotherapy. This study aimed to describe the safety and efficacy of continuing ICIs beyond first progress disease (PD) in non-small cell lung cancer (NSCLC).MethodsPatients with NSCLC previously treated with first-line anti-PD-1 antibody plus platinum-doublet chemotherapy and hence had PD as per Response Evaluation Criteria in Solid Tumors v1.1 were enrolled. For the subsequent line, patients received physician’s choice (PsC) with or without an anti-PD-1 antibody. The primary outcome was progression-free survival after second-line treatment (PFS2). Secondary outcomes included overall survival (OS) from the initiation of first-line treatment, post-second-progression survival (P2PS), overall response rate (ORR), disease control rate (DCR), and safety during second-line treatment.ResultsBetween July 2018 and January 2021, 59 patients were included. A total of 33 patients received a physician-decided second-line regimen plus ICIs (PsC plus ICIs group), and 26 patients did not continue ICIs (PsC group). There was no significant difference in PFS2 between the PsC plus ICIs group and the PsC group (median, 6.5 vs. 5.7 months, p = 0.46). median OS (28.8 vs. 29.2 months), P2PS (13.4 vs. 18.7 months), ORR (18.2% vs. 19.2%), and DCR (78.8% vs, 84.6%) were also similar between the two groups. No new safety signals were observed.ConclusionIn this real-world setting, patients treated with continued ICIs beyond their first disease progression did not experience clinical benefit but without compromising safety.

Immune checkpoint inhibitors (ICIs) target the negative regulatory pathway of T cells and effectively reactive the anti-tumor immune function of T cells by blocking the key pathway of the immune escape mechanism of the tumor—PD-1/PD-L1, and fundamentally changing the prospect of immunotherapy for non-small cell lung cancer patients. However, such promising immunotherapy is overshadowed by Hyperprogressive Disease, a response pattern associated with unwanted accelerated tumor growth and characterized by poor prognosis in a fraction of treated patients. This review comprehensively provides an overview of Hyperprogressive Disease in immune checkpoint inhibitor-based immunotherapy for non-small cell lung cancer including its definition, biomarkers, mechanisms, and treatment. A better understanding of the black side of immune checkpoint inhibitors therapy will provide a more profound insight into the pros and cons of immunotherapy.

Epigenetic modification is a complex process of reversible and heritable alterations in gene function, and the combination of epigenetic and metabolic alterations is recognized as an important causative factor in diseases such as inflammatory bowel disease (IBD), osteoarthritis (OA), systemic lupus erythematosus (SLE), and even tumors. Mesenchymal stem cell (MSC) and MSC-derived exosome (MSC-EXO) are widely studied in the treatment of inflammatory diseases, where they appear to be promising therapeutic agents, partly through the potent regulation of epigenetic modifications such as DNA methylation, acetylation, phosphorylation, and expression of regulatory non-coding RNAs, which affects the occurrence and development of inflammatory diseases. In this review, we summarize the current research on the role of MSC-EXO in inflammatory diseases through their modulation of epigenetic modifications and discuss its potential application in the treatment of inflammatory diseases.

BackgroundDespite an increasing understanding of chronic obstructive pulmonary disease (COPD) pathogenesis, the mechanisms of diverse cell populations in the human lung remain unknown. Using single-cell RNA sequencing (scRNA-Seq), we can reveal changes within individual cell populations in COPD that are important for disease pathogenesis and characteristics. MethodsWe performed scRNA-Seq on lung tissue obtained from donors with non-COPD and mild-to-moderate COPD to identify disease-related genes within different cell types. We testified the findings using qRT−PCR, immunohistochemistry, immunofluorescence and Western blotting from 25 additional subjects and RAW 264.7 macrophages. Targeting ferroptosis with the ferroptosis inhibitor ferrostatin-1, iron chelator deferoxamine or HO-1 inhibitor zinc protoporphyrin was administered in the experimental cigarette smoke COPD mouse model.ResultsWe identified two populations of alveolar macrophages (AMs) in the human lung that were dysregulated in COPD patients. We discovered that M2-like AMs modulate susceptibility to ferroptosis by disrupting lipid and iron homeostasis both in vivo and in vitro. The discrepancy in sensitivity to ferroptosis can be determined and regulated by HO-1. In contrast, M1-like AMs showed the ability to attenuate oxidative stress and exert resistance to ferroptosis. In addition, the expression of genes within M2-like AMs is also involved in defects in phagocytosis and lysosome distortion. This ferroptotic phenotype was ameliorated by antiferroptotic compounds, iron chelators and HO-1 inhibitors. During COPD, the accumulation of lipid peroxidation drives ferroptosis-sensitive M2-like AMs, while M1-like AMs show characteristics of ferroptosis resistance. Ferroptotic M2 AMs lose their anti-inflammatory and repair functions but provoke inflammatory responses, resulting in consistent inflammation and tissue damage in the presence of M1 AMs in COPD. ConclusionAppropriate interventions in ferroptosis can reduce the occurrence of infections and acute onset, and delay the COPD process.

This study developed and validated the Early Death Risk Score Model for early identification of emergency patients with very severe aplastic anemia (VSAA). All 377 patients with VSAA receiving first-line immunosuppressive therapy (IST) were categorized into training (n=252) and validation (n=125) cohorts. In the training cohort, age >24 years, absolute neutrophil count ≤0.015×109/L, serum ferritin >900ng/mL and times of fever before IST >1 time were significantly associated with early death. Covariates were assigned scores and categorized as: low (score 0-4), medium (score 5-7) and high (score ≥8) risk. Early death rate was significantly different between risk groups and the validation cohort results were consistent with those of the training cohort. The area under the receiver operating characteristic curve for the model was 0.835 (0.734,0.936) in the training cohort and 0.862 (0.730,0.994) in the validation cohort. The calibration plots showed high agreement, and decision curve analysis showed good benefit in clinical applications. The VSAA Early Death Risk Score Model can help with early identification of emergency VSAA and optimize treatment strategies. Emergency VSAA with high risk is associated with high early death rate, and alternative donor hematopoietic stem cell transplantation could be a better treatment than IST even without HLA-matching.

BackgroundProgrammed cell death-ligand 1 (PD-L1) inhibitors plus chemotherapy have made substantial progress in extensive-stage small-cell lung cancer (ES-SCLC), but the survival benefit is still limited. This study aimed to evaluate the preliminary efficacy and safety of camrelizumab plus platinum-irinotecan (IP/IC) followed by maintenance camrelizumab plus apatinib in patients with untreated ES-SCLC.MethodsIn this non-randomized clinical trial (NCT04453930), eligible patients with untreated ES-SCLC received 4-6 cycles of camrelizumab plus IP/IC, followed by maintenance with camrelizumab plus apatinib until disease progression or unmanageable toxicity. The primary endpoint was progression-free survival (PFS). Patients who received PD-L1 inhibitors (atezolizumab or durvalumab) plus platinum-etoposide (EP/EC) were selected as the historical control.ResultsNineteen patients received IP/IC plus camrelizumab and 34 patients received EP/EC plus PD-L1 inhibitor. At a median follow-up time of 12.1 months, the median PFS was 10.25 months (95% CI: 9.40-NA) in the IP/IC plus camrelizumab group and 7.10 months (95% CI 5.79-8.40) in the EP/EC plus PD-L1 inhibitor group, respectively (HR=0.58, 95% CI 0.42-0.81). The objective response rate of IP/IC plus camrelizumab and EP/EC plus PD-L1 inhibitor was 89.6% and 82.4%, respectively. The most common treatment-related adverse events in the IP/IC plus camrelizumab group was neutropenia, followed by reactive cutaneous capillary endothelial proliferation (RCCEP) and diarrhea. The occurrence of immune-related adverse event was found to be associated with a prolonged PFS (HR=4.64, 95% CI 1.92-11.18).ConclusionsIP/IC plus camrelizumab followed by maintenance camrelizumab plus apatinib showed preliminary efficacy and acceptable safety profile in patients with untreated ES-SCLC.

PurposeTo investigate the incidence of immune-related adverse events (irAEs) of immune checkpoint inhibitor (ICI) therapy and to report the clinical features, management, and outcomes of ophthalmic irAEs.MethodsWe retrospectively reviewed the medical records of patients who received ICI therapy from January 2016 to September 2022 at Peking Union Medical College Hospital and analyzed the incidence of systemic and ophthalmic adverse effects of this therapy.ResultsOf 962 patients, 248 (25.8%) experienced irAEs. The first-year incidences of total irAEs and ophthalmic irAEs were 23.5% and 1.1%. The most common ICI received by the patients was pembrolizumab (373; 38.8%). Nearly half of the patients (477; 49.6%) had lung cancer. Combination therapy was associated with an increased incidence of irAEs without statistical significance. Patients with lung cancer presented with an increased incidence of total irAEs (p = 0.003) and ophthalmic irAEs (p = 0.032). Eleven patients had ophthalmic manifestations, including ophthalmoplegia (6/11), conjunctivitis (3/11), reactive cutaneous capillary endothelial proliferation (RCCEP) (1/11), and orbital inflammation (1/11). Eight patients had concomitant extra-ophthalmic irAEs. Furthermore, ICIs were discontinued in nine patients, and most ophthalmic manifestations were well controlled with topical and systemic steroids. Ten patients were treated with intravenous or oral steroids. However, cancer progression occurred in five out of eleven patients after the interruption of ICIs.ConclusionIrAEs are correlated with ICI regimens and underlying neoplasia. In our Chinese cohort, patients have a higher risk of ophthalmoplegia than uveitis. Early recognition and multidisciplinary consultation are crucial for optimal treatment of ophthalmic irAEs.

Hepatitis-associated aplastic anemia (HAAA) is a rare variant of acquired aplastic anemia characterized with a syndrome of bone marrow failure after hepatitis. We retrospectively analyzed the outcomes of consecutive severe HAAA patients who received immunosuppressive therapy (IST, n = 70), matched-sibling donor hematopoietic stem cell transplantation (MSD-HSCT, n = 26) or haploidentical-donor (HID) HSCT (n = 11) as the first-line treatment. In the IST group, the hematologic response (HR) rate was 55.71% at 6 months. In contrast, HSCT recipients exhibited significantly more rapid and sustained hematopoiesis (HR 76.92%, 96.15% and 96.15% at 3, 6 and 12months, respectively). The 5-year overall survival (OS) was not different among IST (83.7 ± 4.9%), MSD-HSCT (93.3 ± 6.4%) and HID-HSCT group (80.8 ± 12.3%). Compared with IST, MSD and HID-HSCT demonstrated a trend of superiority in the estimated 5-year failure-free survival rates (93.3 ± 6.4% vs 64.3 ± 6.0%, p = 0.05; 80.8 ± 12.3% vs 64.3 ± 6.0%, p = 0.57). In subsequent stratified analysis on age, we found that HID-HSCT showed its efficacy and safety among young patients. In sum, MSD-HSCT remains first-line treatment choice for HAAA, whereas HID-HSCT represents an alternative treatment choice in addition to IST for young patients (< 40 years) without a matched sibling donor.

Neutropenia is a common complication in the treatment of hematological diseases and the most common predisposing factor for invasion by fungi, such as Candida krusei. Recent studies have shown that C. krusei, a life-threatening pathogen, has developed resistance to amphotericin B (AMB). However, the mechanisms that led to the rapid emergence of this AMB-resistant phenotype are unclear. In this study, we found the sensitivity for AMB could be promoted by inhibiting histone acyltransferase activity and western blot analysis revealed differences in the succinylation levels of C. krusei isolated from immunocompromised patients and of the corresponding AMB-resistant mutant. By comparative succinyl-proteome analysis, we identified a total of 383 differentially expressed succinylated sites in with 344 sites in 134 proteins being upregulated in the AMB-resistant mutant, compared to 39 sites in 23 proteins in the wild-type strain. These differentially succinylated proteins were concentrated in the ribosome and cell wall. The critical pathways associated with these proteins included those involved in glycolysis, gluconeogenesis, the ribosome, and fructose and mannose metabolism. In particular, AMB resistance was found to be associated with enhanced ergosterol synthesis and aberrant amino acid and glucose metabolism. Analysis of whole-cell proteomes, confirmed by parallel reaction monitoring, showed that the key enzyme facilitating lysine acylation was significantly upregulated in the AMB-resistant strain. Our results suggest that lysine succinylation may play an indispensable role in the development of AMB resistance in C. krusei. Our study provides mechanistic insights into the development of drug resistance in fungi and can aid in efforts to stifle the emergence of AMB-resistant pathogenic fungi.

BackgroundRabies is a lethal zoonotic disease that kills approximately 60,000 people each year. Although inactivated rabies vaccines are available, multiple-dose regimensare recommended for pre-exposure prophylaxis or post-exposure prophylaxis,which cuts down the cost- and time-effectiveness, especially in low- and middle incomecountries.MethodsWe developed a nucleoside-modified Rabies mRNA-lipid nanoparticle vaccine (RABV-G mRNA-LNP) encoding codon-optimized viral glycoprotein and assessed the immunogenicity and protective efficacy of this vaccine in mice comparing to a commercially available inactivated vaccine.ResultsWe first showed that, when evaluated in mice, a single vaccination of RABV-G mRNA with a moderate or high dose induces more potent humoral and T-cell immune responses than that elicited by three inoculations of the inactivated vaccine. Importantly, mice receiving a single immunization of RABV-G mRNA, even at low doses, showed full protection against the lethal rabies challenge. We further demonstrated that the humoral immune response induced by single RABV-G mRNA vaccination in mice could last for at least 25 weeks, while a two-dose strategy could extend the duration of the highly protective response to one year or even longer. In contrast, the three-dose regimen of inactivated vaccine failed to do so.ConclusionOur study confirmed that it is worth developing a single-dose nucleoside-modified Rabies mRNA-LNP vaccine, which could confer much prolonged and more effective protection.

Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD), and the dysregulation of lipid metabolism and oxidative stress are the typical features. Subsequent dyslipidemia and oxygen radical production may render the formation of modified lipids. Macrophage scavenger receptor 1 (MSR1) is responsible for the uptake of modified lipoprotein and is one of the key molecules in atherosclerosis. However, the unrestricted uptake of modified lipoproteins by MSR1 and the formation of cholesterol-rich foamy macrophages also can be observed in NASH patients and mouse models. In this review, we highlight the dysregulation of lipid metabolism and oxidative stress in NASH, the alteration of MSR1 expression in physiological and pathological conditions, the formation of modified lipoproteins, and the role of MSR1 on macrophage foaming and NASH development and progression.

Idiopathic membranous nephropathy is the main cause of chronic kidney disease (CKD). Studies have shown sodium–glucose co-transporter 2 (SGLT2) inhibitors significantly delay renal outcomes in patients with CKD, but the exact mechanism remains unknown. In this study, we investigated the mechanism by which the SGLT2 inhibitor canagliflozin attenuates podocyte injury by reversing the imbalance in Helper T cell 1 (Th1)/Helper T cell 2 (Th2) in peripheral blood of rats with membranous nephropathy (MN). MN rats were gavaged with canagliflozin (10 mg/kg/d) and losartan (10 mg/kg/d), respectively, for eight weeks. Compared with the MN group, the urinary ratio of total protein and the creatinine levels of the canagliflozin group decreased significantly. Canagliflozin improved the glomerulus pathological damage, increased the expression levels of podocyte marker proteins. The protective effect of canagliflozin on kidneys was more obvious than that of losartan. Treatment with canagliflozin increased the proportion of Th1 cells by 2.3 times, decreased the proportion of Th2 cells by 68.5%, and significantly restrained the synthesis of immunoglobulin G1 in B-cells and glomerulus subepithelial immune complex deposition. Co-culture of B-cells derived from MN rats with podocytes triggered the activation of phosphorylation of mTOR and ULK1 of podocytes, inhibited podocyte autophagy and resulted in podocyte injury. B-cells derived from canagliflozin treatment rats reversed these effects above. In conclusion, canagliflozin exerts a protective effect on kidneys by reversing the imbalance in Th1/Th2 cells in MN rats and restoring the autophagy of podocytes inhibited by the abnormal immunoglobulin G secretion from B-cells.

Lung adenocarcinoma (LUAD) is the most common type of lung cancer and the leading cause of cancer incidence and mortality worldwide. Despite the improvement of traditional and immunological therapies, the clinical outcome of LUAD is still far from satisfactory. Patients given the same treatment regimen had different responses and clinical outcomes due to the heterogeneity of LUAD. How to identify the targets based on heterogeneity analysis is crucial for treatment strategies. Recently, the single-cell RNA-sequencing (scRNA-seq) technology has been used to investigate the tumor microenvironment (TME) based on cell-specific changes and shows prominently valuable for biomarker prediction. In this study, we systematically analyzed a meta-dataset from the multiple LUAD scRNA-seq datasets in LUAD, identified 15 main types of cells and 57 cell subgroups, and revealed a series of potential biomarkers in M2b, exhausted CD8+T, endothelial cells, fibroblast, and metabolic patterns in TME, which further validated with immunofluorescence in clinical cohorts of LUAD. In the prognosis analysis, M0 macrophage and T cell activation were shown correlated to a better prognosis (p

BackgroundCT053PTSA is a novel tyrosine kinase inhibitor that targets MET, AXL, VEGFR2, FLT3 and MERTK. Here, we present preclinical data about CT053PTSA, and we conducted the first-in-human (FIH) study to evaluate the use of CT053PTSA in adult patients with pretreated advanced solid tumors.MethodsThe selectivity and antitumor activity of CT053PTSA were assessed in cell lines in vitro through kinase and cellular screening panels and in cell line-derived tumor xenograft (CDX) and patient-derived xenograft (PDX) models in vivo. The FIH, phase I, single-center, single-arm, dose escalation (3 + 3 design) study was conducted, patients received at least one dose of CT053PTSA (15 mg QD, 30 mg QD, 60 mg QD, 100 mg QD, and 150 mg QD). The primary objectives were to assess safety and tolerability, to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and the recommended dose of CT053PTSA for further study. Secondary objectives included pharmacokinetics, antitumor activity.ResultsCT053 (free-base form of CT053PTSA) inhibited MET, AXL, VEGFR2, FLT3 and MERTK phosphorylation and suppressed tumor cell angiogenesis by blocking VEGF and HGF, respectively, in vitro. Moreover, cell lines with high MET expression exhibited strong sensitivity to CT053, and CT053 blocked the MET and AXL signaling pathways. In an in vivo study, CT053 significantly inhibited tumor growth in CDX and PDX models. Twenty eligible patients were enrolled in the FIH phase I trial. The most common treatment-related adverse events were transaminase elevation (65%), leukopenia (45%) and neutropenia (35%). DLTs occurred in 3 patients, 1/6 in the 100 mg group and 2/4 in the 150 mg group, so the MTD was set to 100 mg. CT053PTSA was rapidly absorbed after the oral administration of a single dose, and the Cmax and AUC increased proportionally as the dose increased. A total of 17 patients in this trial underwent tumor imaging evaluation, and 29.4% had stable disease.ConclusionsCT053PTSA has potent antitumor and antiangiogenic activity in preclinical models. In this FIH phase I trial, CT053PTSA was well tolerated and had a satisfactory safety profile. Further trials evaluating the clinical activity of CT053PTSA are ongoing.

Biliary tract cancers (BTCs), including cholangiocarcinoma and gallbladder carcinoma, originate from the biliary epithelium and have a poor prognosis. Surgery is the only choice for cure in the early stage of disease. However, most patients are diagnosed in the advanced stage and lose the chance for surgery. Early diagnosis could significantly improve the prognosis of patients. Bile has complex components and is in direct contact with biliary tract tumors. Bile components are closely related to the occurrence and development of biliary tract tumors and may be applied as biomarkers for BTCs. Meanwhile, arising evidence has confirmed the immunoregulatory role of bile components. In this review, we aim to summarize and discuss the relationship between bile components and biliary tract cancers and their ability as biomarkers for BTCs, highlighting the role of bile components in regulating immune response, and their promising application prospects.

BackgroundProstate cancer (PCa) was one of the most common malignancies among men, while the prognosis for PCa patients was poor, especially for patients with recurrent and advanced diseases.Materials and methodsFive PCa cohorts were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases, and the biochemical recurrence (BCR)-related chemokine genes were identified by LASSO-Cox regression. The chemokine-related prognostic gene signature (CRPGS) was established, and its association with PCa patients’ clinical, pathological and immune characteristics was analyzed. The association between CRPGS and PCa patients’ responses to androgen deprivation therapy (ADT) and immunotherapy was analyzed. The CRPGS was compared with other previously published molecular signatures, and the CRPGS was externally validated in our real-world AHMU-PC cohort.ResultsFour recurrence-free survival (RFS)-related chemokine genes (CXCL14, CCL20, CCL24, and CCL26) were identified, and the CRPGS was established based on the four identified chemokine genes, and TCGA-PRAD patients with high riskscores exhibited poorer RFS, which was validated in the GSE70768 cohort. The CRPGS was associated with the clinical, pathological, and immune characteristics of PCa patients. Low-risk PCa patients were predicted to respond better to ADT and immunotherapy. By comparing with other molecular signatures, the CRPGS could classify PCa patients into two risk groups well, and the CRPGS was associated with the m6A level, as well as TP53 and SPOP mutation status of PCa patients. In the AHMU-PC cohort, the CRPGS was associated with the advanced pathology stage and Gleason score.ConclusionsThe identified chemokine genes and CRPGS were associated with the prognosis of PCa, which could predict PCa patients’ responses to anti-androgen and immunotherapies.

Tumor mutation burden (TMB) is a widely recognized stratification biomarker for predicting the efficacy of immunotherapy; however, the number and universal definition of the categorizing thresholds remain debatable due to the multifaceted nature of efficacy and the imprecision of TMB measurements. We proposed a minimal joint p-value criterion from the perspective of differentiating the comprehensive therapeutic advantages, termed TMBcat, optimized TMB categorization across distinct cancer cohorts and surpassed known benchmarks. The statistical framework applies to multidimensional endpoints and is fault-tolerant to TMB measurement errors. To explore the association between TMB and various immunotherapy outcomes, we performed a retrospective analysis on 78 patients with non-small cell lung cancer and 64 patients with nasopharyngeal carcinomas who underwent anti-PD-(L)1 therapy. The stratification results of TMBcat confirmed that the relationship between TMB and immunotherapy is non-linear, i.e., treatment gains do not inherently increase with higher TMB, and the pattern varies across carcinomas. Thus, multiple TMB classification thresholds could distinguish patient prognosis flexibly. These findings were further validated in an assembled cohort of 943 patients obtained from 11 published studies. In conclusion, our work presents a general criterion and an accessible software package; together, they enable optimal TMB subgrouping. Our study has the potential to yield innovative insights into therapeutic selection and treatment strategies for patients.

Introduction: In spontaneous type 1 diabetes (T1D) non-obese diabetic (NOD) mice, the insulin B chain peptide 9-23 (B:9-23) can bind to the MHC class II molecule (IAg7) in register 3 (R3), creating a bimolecular IAg7/InsulinB:9-23 register 3 conformational epitope (InsB:R3). Previously, we showed that the InsB:R3-specific chimeric antigen receptor (CAR), constructed using an InsB:R3-monoclonal antibody, could guide CAR-expressing CD8 T cells to migrate to the islets and pancreatic lymph nodes. Regulatory T cells (Tregs) specific for an islet antigen can broadly suppress various pathogenic immune cells in the islets and effectively halt the progression of islet destruction. Therefore, we hypothesized that InsB:R3 specific Tregs would suppress autoimmune reactivity in islets and efficiently protect against T1D. Methods: To test our hypothesis, we produced InsB:R3-Tregs and tested their disease-protective effects in spontaneous T1D NOD.CD28-/- mice. Results: InsB:R3-CAR expressing Tregs secrete IL-10 dominated cytokines upon engagement with InsB:R3 antigens. A single infusion of InsB:R3 Tregs delayed the onset of T1D in 95% of treated mice, with 35% maintaining euglycemia for two healthy lifespans, readily home to the relevant target whereas control Tregs did not. Our data demonstrate that Tregs specific for MHC class II: Insulin peptide epitope (MHCII/Insulin) protect mice against T1D more efficiently than polyclonal Tregs lacking islet antigen specificity, suggesting that the MHC II/insulin-specific Treg approach is a promising immune therapy for safely preventing T1D. [ABSTRACT FROM AUTHOR]

Breast cancer has overtaken lung cancer as the most frequently diagnosed cancer type and is the leading cause of death for women worldwide. It has been demonstrated in published studies that long non-coding RNAs (lncRNAs) involved in genomic stability are closely associated with the progression of breast cancer, and remarkably, genomic stability has been shown to predict the response to immune checkpoint inhibitors (ICIs) in cancer therapy, especially colorectal cancer. Therefore, it is of interest to explore somatic mutator-derived lncRNAs in predicting the prognosis and ICI efficacy in breast cancer patients. In this study, the lncRNA expression data and somatic mutation data of breast cancer patients from The Cancer Genome Atlas (TCGA) were downloaded and analyzed thoroughly. Univariate and multivariate Cox proportional hazards analyses were used to generate the genomic instability-related lncRNAs in a training set, which was subsequently used to analyze a testing set and combination of the two sets. The qRT-PCR was conducted in both normal mammary and breast cancer cell lines. Furthermore, the Kaplan–Meier and receiver operating characteristic (ROC) curves were applied to validate the predictive effect in the three sets. Finally, the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to evaluate the association between genomic instability-related lncRNAs and immune checkpoints. As a result, a six-genomic instability-related lncRNA signature (U62317.4, MAPT-AS1, AC115837.2, EGOT, SEMA3B-AS1, and HOTAIR) was identified as the independent prognostic risk model for breast cancer patients. Compared with the normal mammary cells, the qRT-PCR showed that HOTAIR was upregulated while MAPT-AS1, EGOT, and SEMA3B-AS1 were downregulated in breast cancer cells. The areas under the ROC curves at 3 and 5 years were 0.711 and 0.723, respectively. Moreover, the patients classified in the high-risk group by the prognostic model had abundant negative immune checkpoint molecules. In summary, this study suggested that the prognostic model comprising six genomic instability-related lncRNAs may provide survival prediction. It is necessary to identify patients who are suitable for ICIs to avoid severe immune-related adverse effects, especially autoimmune diseases. This model may predict the ICI efficacy, facilitating the identification of patients who may benefit from ICIs.

The Hippo pathway was initially discovered in Drosophila melanogaster and mammals as a key regulator of tissue growth both in physiological and pathological states. Numerous studies depict the vital role of the Hippo pathway in cardiovascular development, heart regeneration, organ size and vascular remodeling through the regulation of YAP (yes-associated protein) translocation. Recently, an increasing number of studies have focused on the Hippo-YAP pathway in inflammation and immunology. Although the Hippo-YAP pathway has been revealed to play controversial roles in different contexts and cell types in the cardiovascular system, the mechanisms regulating tissue inflammation and the immune response remain to be clarified. In this review, we summarize findings from the past decade on the function and mechanism of the Hippo-YAP pathway in CVDs (cardiovascular diseases) such as myocardial infarction, cardiomyopathy and atherosclerosis. In particular, we emphasize the role of the Hippo-YAP pathway in regulating inflammatory cell infiltration and inflammatory cytokine activation.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a very common urological disorder and has been gradually regarded as an immune-mediated disease. Multiple studies have indicated that the gut microflora plays a pivotal part in immune homeostasis and autoimmune disorder development. However, whether the gut microflora affects the CP/CPPS, and the underlying mechanism behind them remain unclear. Here, we built an experimental autoimmune prostatitis (EAP) mouse model by subcutaneous immunity and identified that its Th17/Treg frequency was imbalanced. Using fecal 16s rRNA sequencing and untargeted/targeted metabolomics, we discovered that the diversity and relative abundance of gut microflora and their metabolites were obviously different between the control and the EAP group. Propionic acid, a kind of short-chain fatty acid (SCFA), was decreased in EAP mice compared to that in controls, and supplementation with propionic acid reduced susceptibility to EAP and corrected the imbalance of Th17/Treg cell differentiation in vivo and in vitro. Furthermore, SCFA receptor G-protein-coupled receptor 43 and intracellular histone deacetylase 6 regulated by propionic acid in Th17 and Treg cells were also evaluated. Lastly, we observed that fecal transplantation from EAP mice induced the decrease of Treg cell frequency in recipient mice. Our data showed that gut dysbiosis contributed to a Th17/Treg differentiation imbalance in EAP via the decrease of metabolite propionic acid and provided valuable immunological groundwork for further intervention in immunologic derangement of CP/CPPS by targeting propionic acid.

BackgroundImmunotherapy has become one of the most important breakthroughs in cancer treatment. Consequently, there have been more immuno-oncology (IO) clinical trials for various cancers in recent decades. However, the quality of such trials in reporting adverse events (AE), especially immune-related AE (irAE), has not been comprehensively evaluated.MethodsWe evaluated the harm reporting quality of IO trials. The PubMed, Embase, Cochrane Library, and Web of Science databases were searched to identify all head-to-head phase II and III clinical trials assessing cancer immunotherapy published between January 1, 2010, and December 31, 2021. Publications were assessed using a 16-point harm reporting quality score (HRQS) derived from the 2004 Consolidated Standards of Reporting Trials (CONSORT) extension. The characteristics associated with improved reporting quality were identified with linear regression.ResultsA total of 123 publications were included. The mean HRQS was 11.1 (range, 5-14). The most common poorly reported items were harms addressed in the title (2%), AE collection methodology (3%), the statistical approach for analyzing harms (11%), and the irAE onset patterns and management (adequately reported in 14% and 33% of publications, respectively). The harm information was well described in the publications’ Results and Discussion sections (89-99%). The multivariable regression model revealed that higher impact factor (IF) (30

BackgroundNon–small cell lung cancer (NSCLC) has entered the era of immunotherapy. However, only partial patients were able to benefit from immune checkpoint inhibitors (ICIs). Currently, biomarkers for predicting patients’ response to ICIs are primarily tumor tissue dependent and have limited accuracy. There is an urgent need to explore peripheral blood-based biomarkers to predict the efficacy and safety of ICI therapy.MethodsTo explore the correlation between lymphocyte subsets and the efficacy and safety of ICIs, we retrospectively analyzed peripheral blood lymphocyte subsets and survival prognosis data of 136 patients with stage IV NSCLC treated with ICIs.ResultsThe two factors that had the greatest impact on the prognosis of patients with NSCLC treated with ICIs were CD4+CD45RA− T cell (HR = 0.644, P = 0.047) and CD8+ T/lymphocyte (%) (HR = 1.806, P = 0.015). CD4+CD45RA− T cell showed excellent predictive efficacy (AUC = 0.854) for ICIs monotherapy, with a sensitivity of 75.0% and specificity of 91.7% using CD4+CD45RA− T cell >311.3 × 106/L as the threshold. In contrast, CD8+ T/lymphocyte (%) was only associated with the prognosis but had no predictive role for ICI efficacy. CD4+ T cell and its subsets were significantly higher in patients with mild (grades 1–2) immune-related adverse events (irAEs) than those without irAEs. CD8+CD38+ T cell was associated with total irAEs and severe (grades 3–4) irAEs but was not suitable to be a predictive biomarker.ConclusionPeripheral blood CD4+CD45RA− T cell was associated with the prognosis of patients with NSCLC applying ICIs, whereas CD8+CD38+ T cell was associated with irAEs and severe irAEs.

ObjectiveLow-intensity shockwave therapy (LiST) has been applied in the clinical treatment of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), but few studies have focused on the prediction of its therapeutic effect before treatment.MethodsSeventy-five CP/CPPS patients from our institute between July 2020 and May 2021 were enrolled and received 3 Hz, 0.25 mJ/mm2 LiST once a week over the course of four weeks. The scores of the NIH-CPSI, IPSS questionnaire and demographic features before treatment were recorded. The plasma before LiST treatment was also collected, while liquid chromatography-tandem mass spectrometry was used to detect the metabolites. Least absolute shrinkage and selection operator (LASSO) regression analysis was employed to identify the prediction metabolites and generate the metabolism score. Receiver operating characteristic curves and calibration curves were drawn to assess the prediction accuracy of the nomogram.ResultsTwelve metabolites were identified at incomparable levels before and after LiST treatment. The metabolism score generated by LASSO analysis presented a perfect prediction value (AUC: 0.848, 95% CI: 0.719-0.940) in the training cohort and further increased to 0.892 (95% CI: 0.802-0.983) on the nomogram, which accompanied with the NIH-CPSI scores and age. Similar results of the metabolism score (AUC: 0.732, 95% CI: 0.516-0.889) and total nomogram (AUC: 0.968, 95% CI: 0.909-1.000) were obtained in the testing cohort. Further enrichment of the 12 metabolites indicated that the glycine and serine metabolism pathway was involved in the LiST treatment.ConclusionWe used our system to accurately and quantitatively measure plasma metabolites and establish a predictive model to identify suitable patients for LiST treatment.

Gut microbiota is a microecosystem composed of various microorganisms. It plays an important role in human metabolism, and its metabolites affect different tissues and organs. Intestinal flora maintains the intestinal mucosal barrier and interacts with the immune system. The liver is closely linked to the intestine by the gut-liver axis. As the first organ that comes into contact with blood from the intestine, the liver will be deeply influenced by the gut microbiota and its metabolites, and the intestinal leakage and the imbalance of the flora are the trigger of the pathological reaction of the liver. In this paper, we discuss the role of gut microbiota and its metabolites in the pathogenesis and development of autoimmune liver diseases((including autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis), metabolic liver disease such as non-alcoholic fatty liver disease, cirrhosisits and its complications, and liver cancer from the perspective of immune mechanism. And the recent progress in the treatment of these diseases was reviewed from the perspective of gut microbiota.

ObjectiveSystemic Lupus Erythematosus (SLE) is a systemic autoimmune disease that displays a significant gender difference in terms of incidence and severity. However, the underlying mechanisms accounting for sexual dimorphism remain unclear. The aim of this work was to reveal the heterogeneity in the pathogenesis of SLE between male and female patients.MethodsPBMC were collected from 15 patients with SLE (7 males, 8 females) and 15 age-matched healthy controls (7 males, 8 females) for proteomic analysis. The proteins of interest were validated in independent samples (6 male SLE, 6 female SLE). Biomarkers for neutrophil activation (calprotectin), neutrophil extracellular traps (cell-free DNA and elastase), and reactive oxygen species (glutathione) were measured, using enzyme-linked immunosorbent assay, in plasma obtained from 52 individuals.ResultsEnrichment analysis of proteomic data revealed that type I interferon signaling and neutrophil activation networks mapped to both male and female SLE, while male SLE has a higher level of neutrophil activation compared with female SLE. Western blot validated that PGAM1, BST2, and SERPINB10 involved in neutrophil activation are more abundant in male SLE than in female SLE. Moreover, biomarkers of neutrophil activation and reactive oxygen species were increased in male SLE compared with female SLE.ConclusionType I interferon activation is a common signature in both male and female SLE, while neutrophil activation is more prominent in male SLE compared with female SLE. Our findings define gender heterogeneity in the pathogenesis of SLE and may facilitate the development of gender-specific treatments.

CD44 partcipates in multiple inflammatory reactions. Here, we aimed to investigate the role of CD44 and the ligand, hyaluronan (HA), on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) pathogenesis. We found that CD44 was universally expressed in CD4+ lymphocytes in the peripheral blood of CP/CPPS patients. After silencing CD44 expression or delivering 4-methylumbelliferone (4-MU), the pain severity and prostatic inflammation were significantly relieved. In vitro assay found that HA/CD44 was able to regulate T helper 1 (Th1) cells differentiation, the deficiency of which diminished experimental autoimmune prostatitis (EAP) susceptibility. Bioinformatic analysis suggested that after HA or 4-MU treatment, mTOR signaling was significantly altered, and these results were confirmed by subsequent Western blotting assay. Besides, mass spectrometry and co-immunoprecipitation assays found that CD44 was able to interact with Annexin A1 (ANX A1), and this kind of interaction stabilized ANX A1 protein and maintained the activation of Akt/mTOR pathway. Meanwhile, HA-treatment-enhanced prostatic inflammation, Th1 cell differentiation, and Akt/mTOR pathway activation were reversed after silencing the expression of ANX A1 using shANX A1-lentivirus. The present study systematically investigates the functional role of HA/CD44 in CP/CPPS and identifies novel mechanisms for HA/CD44 promoting Th1 cell differentiation. Targeting the HA/CD44/ANX A1/Akt/mTOR signaling represents novel potential therapeutic strategies for patients with CP/CPPS.

In this study, we have investigated the influence of vitamin A on gill barrier function of grass carp (Ctenopharyngodon idella) infected with Flavobacterium columnare. The fish were fed different concentrations of vitamin A diets for 10 weeks and then infected with F. columnare by immersion. We observed that optimal vitamin A significantly prevented gill rot morbidity in fish infected with F. columnare. Further investigations revealed that vitamin A boosted the gill immunity by increasing the contents of complements (C3 and C4), activities of acid phosphatase (ACP) and lysozyme, mRNAs of β-defensin-1, liver-expressed antimicrobial peptide 2A and 2B (LEAP-2A and LEAP-2B), hepcidin, and anti-inflammatory cytokines like transforming growth factor β1 (TGF-β1), TGF-β2, interleukin-10 (IL-10), and IL-11. It also enhanced the levels of various related signaling molecules including inhibitor protein κBα (IκBα), target of rapamycin (TOR), and ribosome protein S6 kinase 1 (S6K1) but downregulated the expression of pro-inflammatory cytokines including IL-1β, IL-8, tumor necrosis factor α (TNF-α), and interferon γ2 (IFN-γ2) and related signaling molecules including nuclear factor κB p65 (NF-κB p65) (rather than NF-κB p52), IκB kinase β (IKKβ), IKKγ (rather than IKKα), eIF4E-binding protein 1 (4E-BP1), and 4E-BP2 mRNA levels in fish gills. In addition, dietary vitamin A markedly lowered the concentrations of reactive oxygen species (ROS), malondialdehyde (MDA), and protein carbonyl (PC), increased both the activities and mRNAs of copper/zinc superoxide dismutase (Cu/ZnSOD), MnSOD, glutathione transferases (GSTs), glutathione peroxidase (GPx), and glutathione reductase (GR) associated with upregulation of NF-E2-related factor 2 (Nrf2) mRNAs and downregulation of Kelch-like-ECH-associated protein (Keap1a) and Keap1b mRNAs. Moreover, vitamin A decreased the mRNAs of different apoptotic mediators [caspases 8, 9, 3 (rather than 7)] associated with downregulation of signaling molecule p38 mitogen-activated protein kinase (p38MAPK) mRNAs in fish gills. Besides, vitamin A promoted tight junction (TJ) complex mRNAs [including claudin-b, -c, -3, -7, -12, occludin, and zonula occludens-1 (ZO-1)] that have been linked to the downregulation of myosin light chain kinase (MLCK) signaling. Taken together, the current study demonstrated for the first time that vitamin A markedly enhanced gill health associated with immune modulation and physical barrier protection. Based on protecting fish against gill rot morbidity, ACP activity, and against lipid peroxidation, optimum vitamin A concentrations in on-growing grass carp (262–997 g) were found to be 1,991, 2,188, and 2,934 IU/kg diet, respectively.