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Inhaled glucocorticoids form the mainstay of asthma treatment because of their anti-inflammatory effects in the lung. Exposure to the air pollutant ozone (O3) exacerbates chronic airways disease. We and others showed that presence of the epithelial-derived surfactant protein-D (SP-D) is important in immunoprotection against inflammatory changes including those induced by O3 inhalation in the airways. SP-D synthesis requires glucocorticoids. We hypothesized here that O3 exposure impairs glucocorticoid responsiveness (including SP-D production) in allergic airway inflammation. The effects of O3 inhalation and glucocorticoid treatment were studied in a mouse model of allergic asthma induced by sensitization and challenge with Aspergillus fumigatus (Af) in vivo. The role of O3 and glucocorticoids in regulation of SP-D expression was investigated in A549 and primary human type II alveolar epithelial cells in vitro. Budesonide inhibited airway hyperreactivity, eosinophil counts in the lung and bronchoalveolar lavage (BAL) and CCL11, IL-13, and IL-23p19 release in the BAL of mice sensitized and challenged with Af (p < 0.05). The inhibitory effects of budesonide were attenuated on inflammatory changes and were completely abolished on airway hyperreactivity after O3 exposure of mice sensitized and challenged with Af. O3 stimulated release of pro-neutrophilic mediators including CCL20 and IL-6 into the airways and impaired the inhibitory effects of budesonide on CCL11, IL-13 and IL-23. O3 also prevented budesonide-induced release of the immunoprotective lung collectin SP-D into the airways of allergen-challenged mice. O3 had a bi-phasic direct effect with early (48 h) activation of SP-D mRNA (sftpd) in vitro. Dexamethasone and budesonide induced sftpd transcription and translation in human type II alveolar epithelial cells in a glucocorticoid receptor and STAT3 (an IL-6 responsive transcription factor) dependent manner. Our study indicates that O3 exposure counteracts the effects of budesonide on airway inflammation, airway hyperreactivity, and SP-D production. We speculate that impairment of SP-D expression may contribute to the acute O3-induced airway inflammation. Asthmatics exposed to high ambient O3 levels may become less responsive to glucocorticoid treatment during acute exacerbations.

BackgroundA high-fat diet (HFD) contributes to various metabolic disorders and obesity, which are major contributors to cardiovascular disease. As an essential regulator for heart homeostasis, cardiac resident macrophages may go awry and contribute to cardiac pathophysiology upon HFD. Thus, to better understand how HFD induced cardiac dysfunction, this study intends to explore the transcriptional and functional changes in cardiac resident macrophages of HFD mice.MethodsC57BL/6J female mice that were 6 weeks old were fed with HFD or normal chow diet (NCD) for 16 weeks. After an evaluation of cardiac functions by echocardiography, mouse hearts were harvested and cardiac resident CCR2- macrophages were sorted, followed by Smart sequencing. Bioinformatics analysis including GO, KEGG, and GSEA analyses were employed to elucidate transcriptional and functional changes.ResultsHyperlipidemia and obesity were observed easily upon HFD. The mouse hearts also displayed more severe fibrosis and diastolic dysfunction in HFD mice. Smart sequencing and functional analysis revealed metabolic dysfunctions, especially lipid-related genes and pathways. Besides this, antigen-presentation-related gene such as Ctsf and inflammation, particularly for NF-κB signaling and complement cascades, underwent drastic changes in cardiac resident macrophages. GO cellular compartment analysis was also performed and showed specific organelle enrichment trends of the involved genes.ConclusionDysregulated metabolism intertwines with inflammation in cardiac resident macrophages upon HFD feeding in mice, and further research on crosstalk among organelles could shed more light on potential mechanisms.

Disulfidptosis, a regulated form of cell death, has been recently reported in cancers characterized by high SLC7A11 expression, including invasive breast carcinoma, lung adenocarcinoma, and hepatocellular carcinoma. However, its role in colon adenocarcinoma (COAD) has been infrequently discussed. In this study, we developed and validated a prognostic model based on 20 disulfidptosis-related genes (DRGs) using LASSO and Cox regression analyses. The robustness and practicality of this model were assessed via a nomogram. Subsequent correlation and enrichment analysis revealed a relationship between the risk score, several critical cancer-related biological processes, immune cell infiltration, and the expression of oncogenes and cell senescence-related genes. POU4F1, a significant component of our model, might function as an oncogene due to its upregulation in COAD tumors and its positive correlation with oncogene expression. In vitro assays demonstrated that POU4F1 knockdown noticeably decreased cell proliferation and migration but increased cell senescence in COAD cells. We further investigated the regulatory role of the DRG in disulfidptosis by culturing cells in a glucose-deprived medium. In summary, our research revealed and confirmed a DRG-based risk prediction model for COAD patients and verified the role of POU4F1 in promoting cell proliferation, migration, and disulfidptosis.

IntroductionLung cancer, with the highest global mortality rate among cancers, presents a grim prognosis, often diagnosed at an advanced stage in nearly 70% of cases. Recent research has unveiled a novel mechanism of cell death termed disulfidptosis, which is facilitated by glucose scarcity and the protein SLC7A11.MethodsUtilizing the least absolute shrinkage and selection operator (LASSO) regression analysis combined with Cox regression analysis, we constructed a prognostic model focusing on disulfidptosis-related genes. Nomograms, correlation analyses, and enrichment analyses were employed to assess the significance of this model. Among the genes incorporated into the model, CHRNA5 was selected for further investigation regarding its role in LUAD cells. Biological functions of CHRNA5 were assessed using EdU, transwell, and CCK-8 assays.ResultsThe efficacy of the model was validated through internal testing and an external validation set, with further evaluation of its robustness and clinical applicability using a nomogram. Subsequent correlation analyses revealed associations between the risk score and infiltration of various cancer types, as well as oncogene expression. Enrichment analysis also identified associations between the risk score and pivotal biological processes and KEGG pathways. Our findings underscore the significant impact of CHRNA5 on LUAD cell proliferation, migration, and disulfidptosis.ConclusionThis study successfully developed and validated a robust prognostic model centered on disulfidptosis-related genes, providing a foundation for predicting prognosis in LUAD patients.

Lymph node (LN) metastasis is a common mode of metastasis in advanced gastric cancer (GC), while axillary LN metastasis infrequently occurs in GC. There are few reports on this rare type of metastasis – especially its clinicopathological features – and systemic treatment are unclear. We describe a case of GC with extensive metastasis, including the rare axillary LN metastasis. The patient achieved partial response of optimal efficacy, who was treated with combination immunotherapy as second-line treatment for nearly two years. The potential mechanisms were revealed by clinical and immune characteristics, such as high expression of PD-L1, high tumor mutational burden (TMB-H), Epstein-Barr virus (EBV) positive and CD8+ tumor-infiltrating lymphocyte positive.

ObjectivesPerform a bibliometric analysis on the role of LAG-3 in the domain of cancer, elucidate the prevailing areas of research, and visually depict the evolutionary trajectory and prospective directions of LAG-3 research over the past twenty-three decades.Materials and methodsBetween 2000 and 2023, a comprehensive review of scholarly articles pertaining to LAG-3 research in the context of cancer was carried out using the Web of Science Core Collection (WoSCC) database. Bibliometric analysis can be conducted by taking advantage of VOSviewer (version 1.6.16) and CiteSpace (version 6.2.R4). Create a network diagram to visually represent various authors, countries, and organizations while assessing the publishing years, journals, references, and keywords.ResultsIn conclusion, 1841 records were identified and published in 587 publications. These records were authored by 12,849 individuals affiliated with 2491 institutes across 74 countries. There has been a substantial surge in publications subsequent to 2013. The USA, China, and Germany gave the majority of records, amounting to 69.69%. American institutions actively engage in collaboration with institutions located in other countries. Triebel, F., Vignali, Dario A. A., Workman, Creg J. Drake, Charles G., and Elkord, Eyad are highly regarded authors in their respective fields. However, it is worth noting that Triebel exhibits limited collaboration with other writers. The examination of the role of LAG-3 in cancer and its potential for use in clinical settings is a discernible trend, as seen by keyword analysis.ConclusionThe scientific interest in and attention towards LAG-3 has experienced a significant rise since 2013. The United States is leading the way, with China following closely behind. Promoting collaboration among writers, nations, and institutions with varied backgrounds is imperative. The discipline of immunotherapy is currently seeing ongoing progress. A thorough investigation of the distinctive cis ligand TCR-CD3 complex of LAG-3 and its signal transduction mechanism is necessary. Additionally, it is worthwhile to explore novel combinations of LAG-3 therapy.

AMG 256 is a bi-specific, heteroimmunoglobulin molecule with an anti-PD-1 antibody domain and a single IL-21 mutein domain on the C-terminus. Nonclinical studies in cynomolgus monkeys revealed that AMG 256 administration led to the development of immunogenicity-mediated responses and indicated that the IL-21 mutein domain of AMG 256 could enhance the anti-drug antibody response directed toward the monoclonal antibody domain. Anti-AMG 256 IgE were also observed in cynomolgus monkeys. A first-in-human (FIH) study in patients with advanced solid tumors was designed with these risks in mind. AMG 256 elicited ADA in 28 of 33 subjects (84.8%). However, ADA responses were only robust and exposure-impacting at the 2 lowest doses. At mid to high doses, ADA responses remained low magnitude and all subjects maintained exposure, despite most subjects developing ADA. Limited drug-specific IgE were also observed during the FIH study. ADA responses were not associated with any type of adverse event. The AMG 256 program represents a unique case where nonclinical studies informed on the risk of immunogenicity in humans, due to the IL-21-driven nature of the response.

Gliomas are one of the most common primary malignant tumours of the central nervous system (CNS), of which glioblastomas (GBMs) are the most common and destructive type. The glioma tumour microenvironment (TME) has unique characteristics, such as hypoxia, the blood-brain barrier (BBB), reactive oxygen species (ROS) and tumour neovascularization. Therefore, the traditional treatment effect is limited. As cellular oxidative metabolites, ROS not only promote the occurrence and development of gliomas but also affect immune cells in the immune microenvironment. In contrast, either too high or too low ROS levels are detrimental to the survival of glioma cells, which indicates the threshold of ROS. Therefore, an in-depth understanding of the mechanisms of ROS production and scavenging, the threshold of ROS, and the role of ROS in the glioma TME can provide new methods and strategies for glioma treatment. Current methods to increase ROS include photodynamic therapy (PDT), sonodynamic therapy (SDT), and chemodynamic therapy (CDT), etc., and methods to eliminate ROS include the ingestion of antioxidants. Increasing/scavenging ROS is potentially applicable treatment, and further studies will help to provide more effective strategies for glioma treatment.

IntroductionDense connective tissues (DCTs) such as tendon, ligament, and cartilage are important stabilizers and force transmitters in the musculoskeletal system. The healing processes after DCT injuries are highly variable, often leading to degenerative changes and poor clinical outcome. Biomarkers in relation to repair quality for human DCTs, especially tendon are lacking. This study expands our previous findings and aimed to characterize the mechanisms by which a potential biomarker of good outcomes, complement factor D (CFD), regulates tendon healing. MethodsQuantitative mass spectrometry (QMS) profiling of tissue biopsies from the inflammatory phase of healing (n = 40 patients) and microdialysates from the proliferative phase of healing (n = 28 patients) were used to identify specific biomarkers for tendon healing. Further bioinformatic and experimental investigations based on primary fibroblasts and fibroblast cell line were used to confirm the identified biomarkers.ResultsThe QMS profiling of tissue biopsies from the inflammatory phase of healing identified 769 unique proteins, and microdialysates from the proliferative phase of healing identified 1423 unique proteins in Achilles tendon rupture patients. QMS-profiling showed that CFD expression was higher during the inflammatory- and lower during the proliferative healing phase in the good outcome patients. Further bioinformatic and experimental explorations based on both inflammatory and proliferative fibroblast models demonstrated that CFD potentially improved repair by regulating cell migration and modulating collagen type I (Col1a1) expression. Moreover, it was shown that the enhanced Col1a1 expression, through increased fibroblast migration, was correlated with the validated clinical outcome. DiscussionThe results of the current studies characterized underlying inflammatory- and proliferative healing mechanisms by which CFD potentially improved tendon repair. These findings may lead to improved individualized treatment options, as well the development of effective therapies to promote good long-term clinical outcomes after tendon and other DCT injuries. Trial registrationhttp://clinicaltrials.gov, identifiers NCT02318472, NCT01317160.

Multiple Sclerosis (MS) is a chronic neurodegenerative disease with limited therapeutic options. Recombinant Fc multimers (rFc), designed to mirror many of the anti-inflammatory activities of Intravenous Immunoglobulin (IVIG), have been shown to effectively treat numerous immune-mediated diseases in rodents. In this study we used the experimental autoimmune encephalomyelitis (EAE) murine model of MS to test the efficacy of a rFc, M019, that consists of multimers of the Fc portion of IgG2, in inhibiting disease severity. We show that M019 effectively reduced clinical symptoms when given either pre- or post-symptom onset compared to vehicle treated EAE induced mice. M019 was effective in reducing symptoms in both SJL model of relapsing remitting MS as well as the B6 model of chronic disease. M019 binds to FcγR bearing-monocytes both in vivo and in vitro and prevented immune cell infiltration into the CNS of treated mice. The lack of T cell infiltration into the spinal cord was not due to a decrease in T cell priming; there was an equivalent frequency of Th17 cells in the spleens of M019 and vehicle treated EAE induced mice. Surprisingly, there was an increase in chemokines in the sera but not in the CNS of M019 treated mice compared to vehicle treated animals. We postulate that M019 interacts with a FcγR rich monocyte intermediary to prevent T cell migration into the CNS and demyelination.

Gene-engineered immune cell therapies have partially transformed cancer treatment, as exemplified by the use of chimeric antigen receptor (CAR)-T cells in certain hematologic malignancies. However, there are several limitations that need to be addressed to target more cancer types. Natural killer (NK) cells are a type of innate immune cells that represent a unique biology in cancer immune surveillance. In particular, NK cells obtained from heathy donors can serve as a source for genetically engineered immune cell therapies. Therefore, NK-based therapies, including NK cells, CAR-NK cells, and antibodies that induce antibody-dependent cellular cytotoxicity of NK cells, have emerged. With recent advances in genetic engineering and cell biology techniques, NK cell-based therapies have become promising approaches for a wide range of cancers, viral infections, and senescence. This review provides a brief overview of NK cell characteristics and summarizes diseases that could benefit from NK-based therapies. In addition, we discuss recent preclinical and clinical investigations on the use of adoptive NK cell transfer and agents that can modulate NK cell activity.

BackgroundLung adenocarcinoma (LUAD) is a major subtype of non-small cell lung cancer (NSCLC) with a highly heterogeneous tumor microenvironment. Immune checkpoint inhibitors (ICIs) are more effective in tumors with a pre-activated immune status. However, the potential of the immune activation-associated gene (IAG) signature for prognosis prediction and immunotherapy response assessment in LUAD has not been established. Therefore, it is critical to explore such gene signatures.MethodsRNA sequencing profiles and corresponding clinical parameters of LUAD were extracted from the TCGA and GEO databases. Unsupervised consistency clustering analysis based on immune activation-related genes was performed on the enrolled samples. Subsequently, prognostic models based on genes associated with prognosis were built using the last absolute shrinkage and selection operator (LASSO) method and univariate Cox regression. The expression levels of four immune activation related gene index (IARGI) related genes were validated in 12 pairs of LUAD tumor and normal tissue samples using qPCR. Using the ESTIMATE, TIMER, and ssGSEA algorithms, immune cell infiltration analysis was carried out for different groups, and the tumor immune dysfunction and rejection (TIDE) score was used to evaluate the effectiveness of immunotherapy.ResultsBased on the expression patterns of IAGs, the TCGA LUAD cohort was classified into two clusters, with those in the IAG-high pattern demonstrating significantly better survival outcomes and immune cell infiltration compared to those in the IAG-low pattern. Then, we developed an IARGI model that effectively stratified patients into different risk groups, revealing differences in prognosis, mutation profiles, and immune cell infiltration within the tumor microenvironment between the high and low-risk groups. Notably, significant disparities in TIDE score between the two groups suggest that the low-risk group may exhibit better responses to ICIs therapy. The IARGI risk model was validated across multiple datasets and demonstrated exceptional performance in predicting overall survival in LUAD, and an IARGI-integrated nomogram was established as a quantitative tool for clinical practice.ConclusionThe IARGI can serve as valuable biomarkers for evaluating the tumor microenvironment and predicting the prognosis of LUAD patients. Furthermore, these genes probably provide valuable guidance for establishing effective immunotherapy regimens for LUAD patients.

BackgroundThe implication of the monocyte-to-high-density lipoprotein ratio (MHR) in Takayasu arteritis (TAK) remains unclear.ObjectiveWe aimed to assess the predictive value of the MHR to identify coronary involvement with TAK and determine the patient prognosis.MethodsIn this retrospective study, 1,184 consecutive patients with TAK were collected and assessed, and those who were initially treated and with coronary angiography were enrolled and classified according to coronary involvement or no involvement. Binary logistic analysis was performed to assess coronary involvement risk factors. Receiver-operating characteristic analysis was used to determine the MHR value to predict coronary involvement in TAK. Major adverse cardiovascular events (MACEs) were recorded in patients with TAK and coronary involvement within a 1-year follow-up, and Kaplan–Meier survival curve analysis was conducted to compare MACEs between them stratified by the MHR.ResultsA total of 115 patients with TAK were included in this study, and 41 of them had coronary involvement. A higher MHR was found for TAK with coronary involvement than for TAK without coronary involvement (P = 0.014). Multivariate analysis showed that the MHR is an independent risk factor for coronary involvement in TAK (odds ratio: 92.718, 95% confidence interval (CI): 2.813–3056.291, P = 0.011). With the best cut-off value of 0.35, the MHR identified coronary involvement with 53.7% sensitivity and 68.9% specificity [area under the curve (AUC): 0.639, 95% CI: 0.544–0.726, P=0.010] and identified left main disease and/or three-vessel disease (LMD/3VD) with 70.6% sensitivity and 66.3% specificity (AUC: 0.704, 95% CI: 0.612–0.786, P = 0.003) in TAK. Combined with other variables, the MHR identified coronary involvement with 63.4% sensitivity and 90.5% specificity (AUC: 0.852, 95% CI: 0.773–0.911, P < 0.001), and identified LMD/3VD with 82.4% sensitivity and 78.6% specificity (AUC: 0.827, 95% CI: 0.720–0.934, P < 0.001) in TAK. A total of 39 patients with TAK and coronary involvement were followed up for 1 year, and 5 patients suffered a MACE. Those with an MHR >0.35 had a higher MACE incidence than their counterparts with an MHR ≤0.35 (χ2 = 4.757, P = 0.029).ConclusionsThe MHR could be a simple, practical biomarker for identifying coronary involvement and LMD/3VD in TAK and predicting a long-term prognosis.

Necroptosis is a type of cell death with excessive inflammation and organ damage in various human diseases. Although abnormal necroptosis is common in patients with neurodegenerative, cardiovascular, and infectious diseases, the mechanisms by which O-GlcNAcylation contributes to the regulation of necroptotic cell death are poorly understood. In this study, we reveal that O-GlcNAcylation of RIPK1 (receptor-interacting protein kinase1) was decreased in erythrocytes of the mouse injected with lipopolysaccharide, resulting in the acceleration of erythrocyte necroptosis through increased formation of RIPK1-RIPK3 complex. Mechanistically, we discovered that O-GlcNAcylation of RIPK1 at serine 331 in human (corresponding to serine 332 in mouse) inhibits phosphorylation of RIPK1 at serine 166, which is necessary for the necroptotic activity of RIPK1 and suppresses the formation of the RIPK1-RIPK3 complex in Ripk1-/- MEFs. Thus, our study demonstrates that RIPK1 O-GlcNAcylation serves as a checkpoint to suppress necroptotic signaling in erythrocytes.

Macrophages are an integral part of the innate immune response in periodontal tissue and play a crucial role in the progression of periodontitis. Here we reported that macrophages also provoke periodontitis-induced gingival destruction through Piezol-mediated collagen degradation. We discovered that the PIEZO1 expression was markedly elevated in patients with periodontitis through transcriptomic profiling. Moreover, Piezo1 promoted macrophage polarization toward the M1 type in response to lipopolysaccharide (LPS) and induced production of proinflammatory cytokines, which in turn stimulated production of matrix metalloproteinases (MMPs) leading to collagen degradation. Our study suggests that Piezol might be a potential therapeutic target for treating periodontitis-induced gingival destruction.

The HIV-1 reservoirs harbor the latent proviruses that are integrated into the host genome. It is a challenging task to eradicate the proviruses in order to achieve an HIV cure. We have described a strategy for the clearance of HIV-1 infection through selective elimination of host cells harboring replication-competent HIV (SECH), by inhibition of autophagy and promotion of apoptosis during viral re-activation. HIV-1 can infect various CD4+ T cell subsets, but it is not known whether the SECH approach is equally effective in targeting HIV-1 reservoirs in these different subsets in vivo. In a humanized mouse model, we found that treatments of HIV-1 infection by suppressive antiretroviral therapy (ART) led to the establishment of latent HIV reservoirs in naïve, central memory and effector memory T cells. Moreover, SECH treatments could clear latent HIV-1 reservoirs in these different T cell subsets of humanized mice. Co-culture studies showed that T cell subsets latently infected by HIV-1, but not uninfected bystander cells, were susceptible to cell death induced by SECH treatments. Our study suggests that the SECH strategy is effective for specific targeting of latent HIV-1 reservoirs in different T cell subsets.

Long noncoding RNAs (lncRNAs) play a critical role in the immune regulation and tumor microenvironment of pancreatic cancer (PaCa). To construct a novel immune-related prognostic risk model for PaCa and evaluate the prognostic prediction of lncRNAs, essential immune-related lncRNAs (IRlncRNAs) were identified by Pearson correlation analysis of differentially expressed immune-related genes (IRGs) and IRlncRNAs in PaCa from The Cancer Genome Atlas (TCGA) and GTEx databases. Least absolute shrinkage and selection operator (LASSO) regression was also applied to construct a prognostic risk model of IRlncRNAs, and gene set enrichment analysis (GSEA) was further applied for functional annotation for these IRlncRNAs. A total of 148 IRlncRNAs were identified in PaCa to construct a prognostic risk model. Among them, lncRNA LINC02325, FNDC1-AS1, and ZEB2-AS1 were significantly upregulated in 69 pairs of PaCa tissues by qRT−PCR. ROC analyses showed that LINC02325 (AUC = 0.80), FNDC1-AS1 (AUC = 0.76), and ZEB2-AS1 (AUC = 0.75) had a good predictive effect on 5-year survival prognosis. We demonstrated that high expression levels of ZEB2-AS1 and LINC02325 were not only positively associated with tumor size and CA199, but elevated levels of ZEB2-AS1 and FNDC1-AS1 were also positively correlated with tumor stage. GSEA further revealed that immune-related pathways were mainly enriched in the high-risk groups. Several immune-related algorithms demonstrated that four IRlncRNAs were related to immune infiltration, immune checkpoints, and immune-related functions. Thus, the prognostic risk model based on IRlncRNAs in Paca indicates that the four IRlncRNA signatures may serve as predictors of survival and potential predictive biomarkers of the pancreatic tumor immune response.

BackgroundAccurate evaluation of the response to neoadjuvant chemotherapy (NAC) provides important information about systemic therapies for breast cancer, which implies pharmacological response, prognosis, and guide further therapy. Gene profiles overcome the shortcomings of the relatively limited detection indicators of the classical pathological evaluation criteria and the subjectivity of observation, but are complicated and expensive. Therefore, it is essential to develop a more accurate, repeatable, and economical evaluation approach for neoadjuvant chemotherapy responses.MethodsWe analyzed the transcriptional profiles of chemo-resistant breast cancer cell lines and tumors of chemo-resistant breast cancer patients in the GSE25066 dataset. We preliminarily screened out common significantly differentially expressed genes and constructed a NAC response risk model using LASSO regression and univariate and multivariate analyses. The differences in bioinformatic features of tumor cells, immune characteristics, and prognosis were compared between high and low-risk group. The potential drugs that could reverse chemotherapy resistance in breast cancer were screened by the CMap database.ResultsThirty-six genes were commonly up/down-regulated in both NAC chemo-resistant tumors and cells compared to the sensitive tumors and wild-type cells. Through LASSO regression, we obtained a risk model composed of 12 genes. The risk model divided patients into high and low-risk groups. Univariate and multivariate Cox regression analyses suggested that the risk score is an independent prognostic factor for evaluating NAC response in breast cancer. Tumors in risk groups exhibited significant differences in molecular biological characteristics, tumor-infiltrating lymphocytes, and immunosuppressive molecule expression. Our results suggested that the risk score was also a good prognostic factor for breast cancer. Finally, we screened potential drugs that could reverse chemotherapy resistance in breast cancer.ConclusionA novel 12 gene-signature could be used to predict NAC response and predict prognosis in breast cancer.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative treatment for patients with myeloid malignancies such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, relapse and graft-versus-host disease (GvHD) still affect the survival of patients who receive allo-HSCT, and more appropriate therapeutic strategies should be applied at all stages of transplantation to prevent these adverse events. The use of epigenetics agents, such as hypomethylating agents (HMAs), has been explored to decrease the risk of relapse by epigenetic modulation, which is especially effective among AML patients with poor mutations in epigenetic regulators. Furthermore, epigenetic agents have also been regarded as prophylactic methods for GvHD management without abrogating graft versus leukemia (GvL) effects. Therefore, the combination of epigenetic therapy and HSCT may optimize the transplantation process and prevent treatment failure. Existing studies have investigated the feasibility and effectiveness of using HMAs in the pretransplant, transplant and posttransplant stages among MDS and AML patients. This review examines the application of HMAs as a bridge treatment to reduce the tumor burden and the determine appropriate dose during allo-HSCT. Within this review, we also examine the efficacy and safety of HMAs alone or HMA-based strategies in posttransplant settings for MDS and AML. Finally, we provide an overview of other epigenetic candidates, which have been discussed in the nontransplant setting.

Ferroptosis is a phospholipid peroxidation-mediated and iron-dependent cell death form, involved in sepsis-induced organ injury and other lung diseases. Yes-associated protein 1 (YAP1), a key regulator of the Hippo signaling pathway, could target multiple ferroptosis regulators. Herein, this study aimed to explore the involvement of ferroptosis in the etiopathogenesis of sepsis-induced acute lung injury (ALI) and demonstrate that YAP1 could disrupt ferritinophagy and moderate sepsis-induced ALI. Cecal ligation and puncture (CLP) models were constructed in wild-type (WT) and pulmonary epithelium-conditional knockout (YAP1f/f) mice to induce ALI, while MLE-12 cells with or without YAP1 overexpression were stimulated by lipopolysaccharide (LPS) in vitro. In-vivo modes showed that YAP1 knockout aggravated CLP-induced ALI and also accelerated pulmonary ferroptosis, as presented by the downregulated expression of GPX4, FTH1, and SLC7A11, along with the upregulated expression of SFXN1 and NCOA4. Transcriptome research identified these key genes and ferroptosis pathways involved in sepsis-induced ALI. In-vitro modes consistently verified that YAP1 deficiency boosted the ferrous iron accumulation and mitochondrial dysfunction in response to LPS. Furthermore, the co-IP assay revealed that YAP1 overexpression could prevent the degradation of ferritin to a mass of Fe2+ (ferritinophagy) via disrupting the NCOA4–FTH1 interaction, which blocked the transport of cytoplasmic Fe2+ into the mitochondria via the mitochondrial membrane protein (SFXN1), further reducing the generation of mitochondrial ROS. Therefore, these findings revealed that YAP1 could inhibit ferroptosis in a ferritinophagy-mediated manner, thus alleviating sepsis-induced ALI, which may provide a new approach to the therapeutic orientation for sepsis-induced ALI.

BackgroundPrimary Sjögren’s syndrome (pSS) and breast cancer are a highly prevalent autoimmune disease and malignancy, respectively, both occurring predominantly in females. Whether there is a link between these two diseases is uncertain. We conducted a systematic review and meta-analysis to investigate the risk, incidence, and mortality of breast cancer in patients with pSS.MethodsWe systematically searched Embase, PubMed, and Web of Science on January 31, 2022 to identify the study that assessed risk, incidence, or mortality of breast cancer in pSS. The fixed or random-effects models were applied to pool the effect estimates based on heterogeneity measured by Cochran’s Q-test and Higgins’ I2.ResultsTen studies involving 725,805 participants and 64,836 pSS patients were included in our analysis. The pooled result showed that, overall, pSS was not associated with the risk (SIR=0.92, 95%CI: 0.66-1.29, P=0.646) and mortality (HR = 0.78, 95%CI: 0.26-2.34, P = 0.664) of breast cancer; however, when stratified by geographic region, we found that patients with pSS in Asian countries (SIR=1.32, 95%CI: 1.10-1.58, P=0.003) and Argentina (SIR=3.76, 95%CI: 1.04-9.45, P=0.019) had an elevated risk of breast cancer, while pSS in Europe was associated with a reduced risk (SIR=0.61, 95%CI: 0.51-0.73, P

For decades, tumor-bearing murine models established using tumor cell lines have been the most commonly used models to study human cancers. Even though there are several studies reported that implant sites caused disparities in tumor behaviors, few of them illuminated the positional effect on immunotherapy. Herein, we describe surgical techniques for a novel orthotopic implantation of syngeneic pancreatic ductal adenocarcinoma (PDAC) tissue slices. This method has a high success modeling rate and stable growth kinetics, which makes it useful for testing novel therapeutics. Pathological examination indicated that the orthotopic tumor displayed poor vascularization, desmoplastic stromal reaction, and a highly immunosuppressive tumor microenvironment. This unique microenvironment resulted in limited response to PD1/CTLA4 blockade therapy and anti-MUC1 (αMUC1) CAR-T transfer treatment. To reverse the suppressive tumor microenvironment, we developed gene modified T-cells bearing a chimeric receptor in which activating receptor NKG2D fused to intracellular domains of 4-1BB and CD3ζ (NKG2D CAR). The NKG2D CAR-T cells target myeloid-derived suppressor cells (MDSCs), which overexpress Rae1 (NKG2D ligands) within the TME. Results indicated that NKG2D CAR-T cells eliminated MDSCs and improved antitumor activity of subsequently infused CAR-T cells. Moreover, we generated a bicistronic CAR-T, including αMUC1 CAR and NKG2D CAR separated by a P2A element. Treatment with the dual targeted bicistronic CAR-T cells also resulted in prolonged survival of orthotopic model mice. In summary, this study describes construction of a novel orthotopic PDAC model through implantation of tissue slices and discusses resistance to immunotherapy from the perspective of a PDAC microenvironment. Based on the obtained results, it is evident that elimination MDSCs by NKG2D CAR could rescue the impaired CAR-T cell activity.

Stroke is a disease with high incidence, mortality and disability rates. It is also the main cause of adult disability in developed countries. Stroke is often caused by small emboli on the inner wall of the blood vessels supplying the brain, which can lead to arterial embolism, and can also be caused by cerebrovascular or thrombotic bleeding. With the exception of recombinant tissue plasminogen activator (rt-PA), which is a thrombolytic drug used to recanalize the occluded artery, most treatments have been demonstrated to be ineffective. Stroke can also induce peripheral organ damage. Most stroke patients have different degrees of injury to one or more organs, including the lung, heart, kidney, spleen, gastrointestinal tract and so on. In the acute phase of stroke, severe inflammation occurs in the brain, but there is strong immunosuppression in the peripheral organs, which greatly increases the risk of peripheral organ infection and aggravates organ damage. Nonneurological complications of stroke can affect treatment and prognosis, may cause serious short-term and long-term consequences and are associated with prolonged hospitalization and increased mortality. Many of these complications are preventable, and their adverse effects can be effectively mitigated by early detection and appropriate treatment with various medical measures. This article reviews the pathophysiological mechanism, clinical manifestations and treatment of peripheral organ injury after stroke.

A ketogenic diet (KD) is known to have beneficial health effects. Various types of KD interventions have been applied to manage metabolic syndrome based on modification of diet parameters such as duration of intervention, macronutrient components, and total calories. Nevertheless, the beneficial health impact of isocaloric KD is largely unknown, especially in healthy subjects. The present study investigated the acute effects of a 3-day isocaloric KD. In this non-randomized intervention study, we recruited 15 healthy volunteers aged 24-38 years (7 men and 8 women) and placed them on an isocaloric KD restricting intake of carbohydrates but not energy (75% fat, 20% protein, 5% carbohydrate) for 3 days. Biochemical profiles and laboratory measurements were performed. Peripheral blood monocular cells were cultured, and measured cell stimulated cytokines. After short-term isocaloric KD, subjects lost body weight and serum free fatty acid levels were increased. These results accompanied elevated serum β-hydroxybutyrate (BHB) concentration and fibroblast growth factor 21 (FGF21) levels and improved insulin sensitivity. Regarding the direct effect of BHB on inflammasome activation, interleukin-1β (IL-1β) and tumor necrosis factor-α secretion in response to adenosine triphosphate or palmitate stimulation in human macrophages decreased significantly after isocaloric KD. In ex-vivo experiments with macrophages, both FGF21 and BHB further reduced IL-1β secretion compared to either BHB or FGF21 alone. The inhibitory effect of FGF21 on IL-1β secretion was blunted with bafilomycin treatment, which blocked autophagy flux. In conclusion, isocaloric KD for 3 days is a promising approach to improve metabolic and inflammatory status.Clinical Trial Registrationclinicaltrials.gov (NCT02964572).

AimWe mainly explored the role and mechanism of double-negative T cells (DNTs) in liver fibrosis.MethodsDNTs were co-cultured with mouse hepatic stellate cells (HSCs). Later, cell viability was detected by Cell Counting Kit-8 (CCK-8) assay; α-SMA expression was measured through fluorescence staining; TNF-α, IL-6, and MMP-9 levels were measured by ELISA; and the expression of Bcl-2, TGF-β1, NLRP3, ASC, and TNFR1 proteins in HSCs was detected by Western blotting (WB) assay. At the same time, HSC-NLRP3−/− and HSC-TNFR1−/− are used to explore the mechanism. In mouse experiments, mice were intraperitoneally injected with DNTs; afterward, the hepatic tissue fibrosis degree was detected by Masson staining, α-SMA expression was measured through immunohistochemistry (IHC) assay, and histopathological changes were detected by sirius-red staining and H&E staining.ResultsThe results suggested that DNTs promoted HSC activation and NLRP3 activation. The effect of DNTs on activating HSC-NLRP3−/− was suppressed, and the difference was significant as compared with HSCs. HSC-TNFR1−/− activation was also inhibited. To explore the mechanism of DNT-secreted TNF-α in TNFR1-NLRP3 activation, we transfected DNTs with TNF-α siRNA; as a result, DNTs with TNF-α silencing did not significantly affect HSC activation. DNTs promoted hepatic tissue fibrosis progression and HSC activation; after treatment with NLRP3 inhibitor, the effect of DNTs on promoting fibrosis was suppressed.ConclusionWe discovered that DNTs played an important role in liver fibrosis and that DNTs promoted HSC activation via the TNF-α–TNFR1-NLRP3 signal axis, thus further promoting liver fibrosis progression.

Recent exposure to seasonal coronaviruses (sCoVs) may stimulate cross-reactive antibody responses against severe acute respiratory syndrome CoV 2 (SARS-CoV-2). However, previous studies have produced divergent results regarding protective or damaging immunity induced by prior sCoV exposure. It remains unknown whether pre-existing humoral immunity plays a role in vaccine-induced neutralization and antibody responses. In this study, we collected 36 paired sera samples from 36 healthy volunteers before and after immunization with inactivated whole-virion SARS-CoV-2 vaccines for COVID-19, and analyzed the distribution and intensity of pre-existing antibody responses at the epitope level pre-vaccination as well as the relationship between pre-existing sCoV immunity and vaccine-induced neutralization. We observed large amounts of pre-existing cross-reactive antibodies in the conserved regions among sCoVs, especially the S2 subunit. Excep t for a few peptides, the IgG and IgM fluorescence intensities against S, M and N peptides did not differ significantly between pre-vaccination and post-vaccination sera of vaccinees who developed a neutralization inhibition rate (%inhibition)

The production of autoantibodies by autoreactive B cells plays a major role in the pathogenesis of lupus. Increases in memory B cells have been observed in human lupus patients and autoimmune lpr mice. Autophagy is required for the maintenance of memory B cells against viral infections; however, whether autophagy regulates the persistence of autoantigen-specific memory B cells and the development of lupus remains to be determined. Here we show that memory B cells specific for autoantigens can be detected in autoimmune lpr mice and a pristane-induced lupus mouse model. Interestingly, B cell-specific deletion of Atg7 led to significant loss of autoreactive memory B cells and reduced autoantibody production in pristane-treated mice. Autophagy deficiency also attenuated the development of autoimmune glomerulonephritis and pulmonary inflammation after pristane treatment. Adoptive transfer of wild type autoreactive memory B cells restored autoantibody production in Atg7-deficient recipients. These data suggest that autophagy is important for the persistence of autoreactive memory B cells in mediating autoantibody responses. Our results suggest that autophagy could be targeted to suppress autoreactive memory B cells and ameliorate humoral autoimmunity.

Osteosarcoma (OSA) is the most common bone malignancy and displays high heterogeneity of molecular phenotypes. This study aimed to characterize the molecular features of OSA by developing a classification system based on the gene expression profile of the tumor microenvironment. Integrative analysis was performed using specimens and clinical information for OSA patients from the TARGET program. Using a matrix factorization method, we identified two molecular subtypes significantly associated with prognosis, S1 (infiltration type) and S2 (escape type). Both subtypes displayed unique features of functional significance features and cellular infiltration characteristics. We determined that immune and stromal infiltrates were abundant in subtype S1 compare to that in subtype S2. Furthermore, higher expression of immune checkpoint PDCD1LG2 and HAVCR2 was associated with improved prognosis, while a preferable chemotherapeutic response was associated with FAP-positive fibroblasts in subtype S1. Alternatively, subtype S2 is characterized by a lack of effective cytotoxic responses and loss of major histocompatibility complex class I molecule expression. A gene classifier was ultimately generated to enable OSA classification and the results were confirmed using the GSE21257 validation set. Correlations between the percentage of fibroblasts and/or fibrosis and CD8+ cells, and their clinical responses to chemotherapy were assessed and verified based on 47 OSA primary tumors. This study established a new OSA classification system for stratifying OSA patient risk, thereby further defining the genetic diversity of OSA and allowing for improved efficiency of personalized therapy.

Post-translational modifications, including O-GlcNAcylation, play fundamental roles in modulating cellular events, including transcription, signal transduction, and immune signaling. Several molecular targets of O-GlcNAcylation associated with pathogen-induced innate immune responses have been identified; however, the direct regulatory mechanisms linking O-GlcNAcylation with antiviral RIG-I-like receptor signaling are not fully understood. In this study, we found that cellular levels of O-GlcNAcylation decline in response to infection with Sendai virus. We identified a heavily O-GlcNAcylated serine-rich region between amino acids 249–257 of the mitochondrial antiviral signaling protein (MAVS); modification at this site disrupts MAVS aggregation and prevents MAVS-mediated activation and signaling. O-GlcNAcylation of the serine-rich region of MAVS also suppresses its interaction with TRAF3; this prevents IRF3 activation and production of interferon-β. Taken together, these results suggest that O-GlcNAcylation of MAVS may be a master regulatory event that promotes host defense against RNA viruses.

Gamma-delta (γδ) T cells are a subset of T cells that promote the inflammatory responses of lymphoid and myeloid lineages, and are especially vital to the initial inflammatory and immune responses. Given the capability to connect crux inflammations of adaptive and innate immunity, γδ T cells are responsive to multiple molecular cues and can acquire the capacity to induce various cytokines, such as GM-CSF, IL-4, IL-17, IL-21, IL-22, and IFN-γ. Nevertheless, the exact mechanisms responsible for γδ T cell proinflammatory functions remain poorly understood, particularly in the context of the central nervous system (CNS) diseases. CNS disease, usually leading to irreversible cognitive and physical disability, is becoming a worldwide public health problem. Here, we offer a review of the neuro-inflammatory and immune functions of γδ T cells, intending to understand their roles in CNS diseases, which may be crucial for the development of novel clinical applications.

In our previous study, we have found increased serum levels of HMGB1 in patients with Henoch– Schonlein purpura (HSP), allergic vasculitis (AV), and urticarial vasculitis (UV) and altered HMGB1 distribution in lesional skin in patients with HSP. HMGB1 plays a pro-inflammatory role in the pathogenesis of HSP. To further investigate the role of HMGB1 in the pathogenic mechanism of vasculitis, we investigated the anti-inflammatory effects of HMGB1 blockades (including anti-HMGB1 mAb and glycyrrhizin) in a mouse model of a cutaneous reverse passive Arthus (RPA) reaction. A total of 36 balb/c mice were randomly divided into four groups: the control group, IC model group, HMGB1 monoclonal antibody (anti-HMGB1-mAb) group and the glycyrrhizin group, with nine mice in each group. A cutaneous RPA reaction mouse model was established by injections of the OVA antibody and the OVA antigen. Mice of the anti-HMGB1-mAb group and glycyrrhizin group were pre-treated with anti-HMGB1 mAb or glycyrrhizin, respectively, before the RPA reaction. Our results indicated that HMGB1 blockades (anti-HMGB1 mAb and glycyrrhizin) obviously extenuated the severity of vasculitis skin damage and improved the histological evolvement of inflammatory cells infiltration, vascular fibroid necrosis, and vasodilation in a cutaneous RPA reaction mouse model. In addition, HMGB1 blockades reduced the infiltration of neutrophils, DCs, and T cells and decreased the mRNA expression of IL-6 and CCL5 in skin lesions in the cutaneous RPA reaction mouse model. We suggest that HMGB1 blockades may represent a new direction for the treatment of cutaneous vasculitis.

CD8+ T cells represent one of the most versatile immune cells critical for clearing away viral infections. Due to their important role, CD8+ T cell activation and memory formation during viral infection have been the focus of several studies recently. Although CD8+ T cell activation and memory formation have been associated with metabolic alterations, the molecular understanding behind T cells choosing one type of metabolism over others based on their differentiation stage is still unclear. This review focuses on how the signaling molecules and cellular processes that are characteristic of CD8+ T cell activation and memory formation also play a critical role in selecting specific type of metabolism during viral infections. In addition, we will summarize the epigenetic factors regulating these metabolic alterations.

The success of Intravenous Immunoglobulin in treating autoimmune and inflammatory processes such as immune thrombocytopenia purpura and Kawasaki disease has led to renewed interest in developing recombinant molecules capable of recapitulating these therapeutic effects. The anti-inflammatory properties of IVIG are, in part, due to the Fc region of the IgG molecule, which interacts with activating or inhibitory Fcγ receptors (FcγRs), the neonatal Fc Receptor, non-canonical FcRs expressed by immune cells and complement proteins. In most cases, Fc interactions with these cognate receptors are dependent upon avidity—avidity which naturally occurs when polyclonal antibodies recognize unique antigens on a given target. The functional consequences of these avid interactions include antibody dependent cell-mediated cytotoxicity, antibody dependent cell phagocytosis, degranulation, direct killing, and/or complement activation—all of which are associated with long-term immunomodulatory effects. Many of these immunologic effects can be recapitulated using recombinant or non-recombinant approaches to induce Fc multimerization, affording the potential to develop a new class of therapeutics. In this review, we discuss the history of tolerance induction by immune complexes that has led to the therapeutic development of artificial Fc bearing immune aggregates and recombinant Fc multimers. The contribution of structure, aggregation and N-glycosylation to human IgG: FcγR interactions and the functional effect(s) of these interactions are reviewed. Understanding the mechanisms by which Fc multimers induce tolerance and attempts to engineer Fc multimers to target specific FcγRs and/or specific effector functions in autoimmune disorders is explored in detail.

Aims: Cardiac dysfunction can be a fatal complication during severe sepsis. The migration of neutrophils is significantly impaired during severe sepsis. We sought to determine the role of trimetazidine (TMZ) in regulation of neutrophil migration to the heart in a mouse model of sepsis and endotoxemia, and to identify the mechanism whereby TMZ confers a survival advantage.Methods and Results: C57/BL6 mice were (1) injected with LPS followed by 24-h TMZ administration, or (2) treated with TMZ (20 mg/kg/day) for 1 week post cecal ligation and puncture (CLP) operation. Echocardiography and Millar system detection showed that TMZ alleviated cardiac dysfunction and histological staining showed the failure of neutrophils migration to heart in both LPS- and CLP-induced mice. Bone marrow transplantation revealed that TMZ-pretreated bone marrow cells improved LPS- and CLP-induced myocardial dysfunction and enhanced neutrophil recruitment in heart. In CXCL2-mediated chemotaxis assays, TMZ increased neutrophils migration via AMPK/Nrf2-dependent up-regulation of CXCR2 and inhibition of GRK2. Furthermore, using luciferase reporter gene and chromatin immunoprecipitation assays, we found that TMZ promoted the binding of the Nrf2 and CXCR2 promoter regions directly. Application of CXCR2 inhibitor completely reversed the protective effects of TMZ in vivo. Co-culture of neutrophils and cardiomyocytes further validated that TMZ decreased LPS-induced cardiomyocyte pyroptosis by targeting neutrophils.Conclusion: Our findings suggested TMZ as a potential therapeutic agent for septic or endotoxemia associated cardiac dysfunction in mice.STUDY HIGHLIGHTS What is the current knowledge on the topic?Migration of neutrophils is significantly impaired during severe sepsis, but the underlying mechanisms remain unknown.What question did this study address?The effects of TMZ on cardiac dysfunction via neutrophils migration.What this study adds to our knowledgeTMZ attenuated LPS-induced cardiomyocyte pyroptosis and cardiac dysfunction by promoting neutrophils recruitment to the heart tissues via CXCR2.How this might change clinical pharmacology or translational scienceOur findings suggested TMZ as a potential therapeutic agent for septic cardiac dysfunction.

Harmful effects of heavy metals are myriad. Lead (Pb) from soil and atmosphere contaminates water bodies and affects the aquatic animals. Our previous study confirmed the in vitro probiotic potential of Lactobacillus reuteri against Pb toxicity, but further investigation is necessary for gaining insights into the related protection mode. Therefore, in this study, we investigated the protective effects of the potential probiotic L. reuteri P16 against waterborne Pb exposure-induced toxicity in the freshwater fish Cyprinus carpio. Fish (average weight: 23.16 ± 0.73 g) were allocated to four groups (control, Pb only, Pb + L. reuteri P16, and L. reuteri P16 only) and Pb groups were exposed to waterborne Pb (1 mg L−1) for 6 weeks. L. reuteri P16 (108 CFU g−1) supplemented diet was provided twice daily. Growth performances, hemato-biochemical parameters, innate immune responses, intestinal microbiota, and Pb accumulation in tissues were measured at the end of the trial. When the fish were exposed to Pb, dietary supplementation of L. reuteri P16 effectively decreased mortality and accumulation of Pb in tissues, and improved the growth performance. Co-treatment with Pb and L. reuteri P16 alleviated Pb exposure-induced oxidative stress, reversed alterations in hemato-biochemical parameters, improved innate immune parameters, and restored intestinal enzymatic activities. Moreover, L. reuteri P16 supplementation reversed the changes in intestinal microbiota in Pb-exposed fish. Furthermore, Pb exposure decreased the expressions of pro-inflammatory cytokines (TNF-α, IL-1β). However, the expression of heat shock proteins (HSP70 and HSP90) increased, which might have increased the cellular stress. Interestingly, the Pb-induced alterations of gene expressions were reversed by L. reuteri P16 supplementation. Thus, dietary administration of the potential probiotic L. reuteri P16 had several beneficial effects on growth performance and immune responses, decreased Pb accumulation in tissues, and reversed alterations in hematological responses of C. carpio. Furthermore, it offered direct protection against Pb-induced oxidative stress. Therefore, L. reuteri P16 may be a novel dietary supplement for enhancing growth performance and preventing Pb-exposure-induced toxicity in fish in aquaculture and aquatic products.

A westernized high-fat diet (HFD) is associated with the development of inflammatory bowel disease (IBD). High level fecal deoxycholic acid (DCA) caused by HFD contributes to the colonic inflammatory injury of IBD, however, the mechanism concerning the initiation of inflammatory response by DCA remains unclear. In this study, we sought to investigate the role and mechanism of DCA in the induction of inflammation via promoting NLRP3 inflammasome activation. Here we for the first time showed that DCA dose-dependently induced NLRP3 inflammasome activation and highly pro-inflammatory cytokine-IL-1β production in macrophages. Mechanistically, DCA triggered NLRP3 inflammasome activation by promoting cathepsin B release at least partially through sphingosine-1-phosphate receptor 2 (S1PR2). Colorectal instillation of DCA significantly increased mature IL-1β level in colonic tissue and exacerbated DSS-induced colitis, while in vivo blockage of NLRP3 inflammasome or macrophage depletion dramatically reduced the mature IL-1β production and ameliorated the aggravated inflammatory injury imposed by DCA. Thus, our findings show that high level fecal DCA may serve as an endogenous danger signal to activate NLRP3 inflammasome and contributes to HFD-related colonic inflammation. NLRP3 inflammasome may represent a new potential therapeutical target for treatment of IBD.

Autoimmune rheumatic diseases comprise a group of immune-related disorders characterized by non-organ-specific inflammation. These diseases include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis (AS), gout, among others. Typically involving the hematologic system, these diseases may also affect multiple organs and systems. The pathogenesis of autoimmune rheumatic immune diseases is complex, with diverse etiologies, all associated with immune dysfunction. The current treatment options for this type of disease are relatively limited and come with certain side effects. Therefore, the urgent challenge remains to identify novel therapeutic targets for these diseases. Sterol regulatory element-binding proteins (SREBPs) are basic helix-loop-helix-leucine zipper transcription factors that regulate the expression of genes involved in lipid and cholesterol biosynthesis. The expression and transcriptional activity of SREBPs can be modulated by extracellular stimuli such as polyunsaturated fatty acids, amino acids, glucose, and energy pathways including AKT-mTORC and AMP-activated protein kinase (AMPK). Studies have shown that SREBPs play roles in regulating lipid metabolism, cytokine production, inflammation, and the proliferation of germinal center B (GCB) cells. These functions are significant in the pathogenesis of rheumatic and immune diseases (Graphical abstract). Therefore, this paper reviews the potential mechanisms of SREBPs in the development of SLE, RA, and gout, based on an exploration of their functions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xu, Jin, Chang and Ding.)

Background: Primary biliary cholangitis (PBC) is a chronic intrahepatic cholestatic autoimmune liver disease characterized by inflammatory injury of small and medium-sized bile ducts in the liver. The pathogenesis of PBC has yet to be entirely understood. CD47/signal-regulatory protein alpha (SIRPα) is closely related to developing autoimmune diseases by promoting inflammatory response. However, the effect of CD47/SIRPα on inflammatory response in PBC patients is still unclear., Objective: We investigated the expression of CD47/SIRPα and the effect of inflammatory cytokines on the CD47 expression, analyzed potential autoantibodies against CD47 and the effect of anti-CD47 antibody on the inflammatory response in PBC, provided laboratory basis for the study of the pathogenesis and targets for non-invasive diagnosis and treatment on PBC., Methods: The expression levels of CD47 and SIRPα on peripheral blood mononuclear cells (PBMC) were measured in 14 patients with PBC (the PBC group) and 13 healthy subjects (the Control group) by flow cytometry (FCM). The PBMC derived from healthy subjects were stimulated with healthy subjects' serum, PBC patients' serum, IFN-α or TNF-α, and the CD47 expression level on CD14 + monocytes was detected by FCM. The level of serum anti-CD47 antibody or IFN-α in PBC patients and healthy subjects was analyzed by ELISA. FCM was used to examine the TNF-α expression level in CD14 + monocytes of healthy subjects stimulated with isotype control antibody, anti-CD47 antibody, LPS or LPS combined with CD47 antibody., Results: The CD47 expression level on the CD14 + monocytes in PBC patients was statistically higher than that in the Control group ( P <0.01). Compared with the Control group (PBMC+healthy serum), the CD47 expression on CD14 + monocyte stimulated with the PBC patients' serum (PBMC+PBC patients' serum) was increased ( P <0.001); the CD47 expression on CD14 + monocyte stimulated with IFN-α (PBMC + IFN-α) increased gradually with the increased concentration of IFN-α ( P <0.05). However, there was no similar trend on CD14 + monocyte stimulated with the TNF-α (PBMC+TNF-α) ( P >0.05). The levels of serum anti-CD47 antibody and IFN-α in the PBC patients were higher than those in healthy subjects ( P <0.05). The TNF-α expression level in CD14 + monocyte stimulated with the LPS (PBMC+LPS) or anti-CD47 antibody+LPS group (PBMC+LPS+anti-CD47 antibody) was significantly increased than that in the Control group (PBMC+isotype control antibody) ( P <0.01 and P <0.001, respectively). The TNF-α expression level in CD14 + monocyte stimulated with the anti-CD47 antibody + LPS was higher than that with the LPS ( P < 0.05)., Conclusion: The CD47 may be related to the pathogenesis of PBC by inflammatory response. The CD47/SIRPα signal were imbalanced in PBC patients. The presence of serum anti-CD47 antibodies in PBC patients provides a laboratory basis for clinical diagnosis and treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Su, Jin, Liu, Zhu and Li.)

Background: Neoadjuvant immunochemotherapy has been increasingly applied to treat non-small cell lung cancer (NSCLC). However, the comparison between robotic-assisted thoracoscopic surgery (RATS) and video-assisted thoracoscopic surgery (VATS) in the feasibility and oncological efficacy following neoadjuvant immunochemotherapy is scarce. This study aims to assess the superiorities of RATS over (VATS) concerning short-term outcomes in treating NSCLC patients with neoadjuvant immunochemotherapy., Methods: NSCLC patients receiving RATS or VATS lobectomy following neoadjuvant immunochemotherapy at Shanghai Chest Hospital from 2019 to 2022 were retrospectively identified. Baseline clinical characteristics, perioperative outcomes, and survival profiles were analyzed., Results: Forty-six NSCLC patients with neoadjuvant immunochemotherapy were included and divided into the RATS (n=15) and VATS (n=31) groups. The baseline clinical characteristics and induction-related adverse events were comparable between the two groups (all p>0.050). The 30-day mortality in the RATS and VATS groups were 0% and 3.23%, respectively (p=1.000). Patients undergoing RATS were associated with reduced surgical-related intensive unit care (ICU) stay than those receiving VATS (0.0 [0.0-0.0] vs. 0.0 [0.0-1.0] days, p=0.026). Moreover, RATS assessed more N1 LNs (6.27 ± 1.94 vs 4.90 ± 1.92, p=0.042) and LN stations (3.07 ± 1.03 vs 2.52 ± 0.57, p=0.038) compared with VATS. By comparison, no difference was found in surgical outcomes, pathological results, and postoperative complications between the RATS and VATS groups (all p>0.050). Finally, RATS and VATS achieved comparable one-year recurrence-free survival (82.96% vs. 85.23%, p=0.821) and the timing of central nervous system, LN, and bone recurrences (all p>0.050)., Conclusion: RATS is safe and feasible for NSCLC patients with neoadjuvant immunochemotherapy, reducing surgical-related ICU stay, assessing increased N1 LNs and stations, and achieving similar survival profiles to VATS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer RJ declared a shared affiliation with the authors to the handling editor at time of review., (Copyright © 2023 Pan, Zou, Tian, Zhu, Zhang, Jin, Gu, Ning, Li, Kong, Jiang, Huang and Luo.)

Objectives: To investigate the associations between the overall burden of comorbidity, inflammatory indicators in plasma and Ct values among the elderly with COVID-19., Methods: We conducted a retrospective observational study. The results of each nucleic acid test of during hospitalization were obtained. Linear regression models assessed the associations between the overall burden of comorbidity, inflammatory indicators in plasma and Ct values among the elderly. A causal mediation analysis was performed to assess the mediation effects of inflammatory indicators on the association between the overall burden of comorbidity and Ct values., Results: A total of 767 COVID-19 patients aged ≥ 60 years were included between April 2022 and May 2022. Patients with a high burden of comorbidity had significantly lower Ct values of the ORF gene than subjects with a low burden of comorbidity (median, 24.81 VS 26.58, P < 0.05). Linear regression models showed that a high burden of comorbidity was significantly associated with higher inflammatory responses, including white blood cell count, neutrophil count and C-reactive protein. Also, white blood cell count, neutrophil count, C-reactive protein and the overall burden of comorbidity assessed by age-adjusted Charlson comorbidity index were independent risk factors for the Ct values. A mediation analysis detected the mediation effect of white blood cells on the association between the burden of comorbidity and Ct values, with the indirect effect estimates of 0.381 (95% CI: 0.166, 0.632, P < 0.001). Similarly, the indirect effect of C-reactive protein was -0.307 (95% CI: -0.645, -0.064, P = 0.034). White blood cells and C-reactive protein significantly mediated the relationship between the burden of comorbidity and Ct values by 29.56% and 18.13% of the total effect size, respectively., Conclusions: Inflammation mediated the association between the overall burden of comorbidity and Ct values among elderly with COVID-19, which suggests that combined immunomodulatory therapies could reduce the Ct values for such patients with a high burden of comorbidity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Mi, Li, Shi, Sun, He, Lin, Jin, Gao, Hu, Su and Pan.)

Introduction: Despite the many benefits immunotherapy has brought to patients with different cancers, its clinical applications and improvements are still hindered by drug resistance. Fostering a reliable approach to identifying sufferers who are sensitive to certain immunotherapeutic agents is of great clinical relevance., Methods: We propose an ELISE (Ensemble Learning for Immunotherapeutic Response Evaluation) pipeline to generate a robust and highly accurate approach to predicting individual responses to immunotherapies. ELISE employed iterative univariable logistic regression to select genetic features of patients, using Monte Carlo Tree Search (MCTS) to tune hyperparameters. In each trial, ELISE selected multiple models for integration based on add or concatenate stacking strategies, including deep neural network, automatic feature interaction learning via self-attentive neural networks, deep factorization machine, compressed interaction network, and linear neural network, then adopted the best trial to generate a final approach. SHapley Additive exPlanations (SHAP) algorithm was applied to interpret ELISE, which was then validated in an independent test set., Result: Regarding prediction of responses to atezolizumab within esophageal adenocarcinoma (EAC) patients, ELISE demonstrated a superior accuracy (Area Under Curve [AUC] = 100.00%). AC005786.3 (Mean [|SHAP value|] = 0.0097) was distinguished as the most valuable contributor to ELISE output, followed by SNORD3D (0.0092), RN7SKP72 (0.0081), EREG (0.0069), IGHV4-80 (0.0063), and MIR4526 (0.0063). Mechanistically, immunoglobulin complex, immunoglobulin production, adaptive immune response, antigen binding and others, were downregulated in ELISE-neg EAC subtypes and resulted in unfavorable responses. More encouragingly, ELISE could be extended to accurately estimate the responsiveness of various immunotherapeutic agents against other cancers, including PD1/PD-L1 suppressor against metastatic urothelial cancer (AUC = 88.86%), and MAGE-A3 immunotherapy against metastatic melanoma (AUC = 100.00%)., Discussion: This study presented deep insights into integrating ensemble deep learning with self-attention as a mechanism for predicting immunotherapy responses to human cancers, highlighting ELISE as a potential tool to generate reliable approaches to individualized treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jin, Yang, Chi, Wei, Zhang, Zhao, Chen, Xia and Li.)

Wound healing is impaired in the diabetic status, largely attributable to diabetes-associated angiopathy. Pericytes play critical roles in the stabilization of the formed vessels. The loss and dysfunction of pericytes have been reported in inflammation during diabetes and associated with the pathology of diabetic angiopathy. However, a practical approach that targets inflammatory pericytes to improve diabetic wound healing is lacking. In the current study, we showed that the inflammatory pericytes from wound skin of diabetic patients were impaired in growth potential and underwent oxidative stress and apoptosis. Expression of antioxidant gene oxidation resistance protein 1 (OXR1) specifically in pericytes through an adenovirus carrying OXR1 under a pericyte-specific neuron glia antigen-2 (NG2) promoter (AV-NG2p-OXR1) relieved the oxidative stress, reduced the apoptosis, and recovered the growth potential in diabetic pericytes. Moreover, expression of OXR1 in diabetic pericytes retrieved their potential of both suppressing the migration of co-cultured HUVECs and inducing cell aggregates at the branching points, indicating a functional recovery. In vivo gene therapy using this AV-NG2p-OXR1 to DB/DB mice, the mouse model for type 2 diabetes, significantly improved wound healing, likely through enhancing blood flow at the wound rather than increasing vessel density. Together, our data suggest that gene therapy targeting inflammatory pericytes may improve diabetes-associated impaired wound healing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jin, Chen, Kong and Huang.)

Triple negative breast cancer (TNBC) remains the worst molecular subtype due to high heterogeneity and lack of effective therapeutic targets. Here we investigated the tumor and immune microenvironment heterogeneity of TNBC using scRNA-seq and bulk RNA-seq data from public databases and our cohort. Macrophage subpopulations accounted for a high proportion of tumor immune microenvironment (TIME), and M1 macrophages were associated with better clinical outcomes. Furthermore, three maker genes including IFI35, PSMB9, and SAMD9L showed a close connection with M1 macrophages. Specifically, IFI35 was positively associated with macrophage activation, chemotaxis, and migration. Also, patients with high IFI35 expression had a better prognosis. In vitro studies subsequently demonstrated that IFI35 was upregulated during the M1 subtype differentiation of macrophages. In summary, our data suggested that IFI35 maybe a promising novel target that helps to reshape macrophage polarization towards the M1 subtype for anti-tumor effects., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Xu, Sun, Song, Liu and Jin.)

Ependymoma (EPN) is a malignant glial tumor occurring throughout central nervous system, which commonly presents in children. Although recent studies have characterized EPN samples at both the bulk and single-cell level, intratumoral heterogeneity across subclones remains a confounding factor that impedes understanding of EPN biology. In this study, we generated a high-resolution single-cell dataset of pediatric ependymoma with a particular focus on the comparison of subclone differences within tumors and showed upregulation of cilium-associated genes in more highly differentiated subclone populations. As a proxy to traditional pseudotime analysis, we applied a novel trajectory scoring method to reveal cellular compositions associated with poor survival outcomes across primary and relapsed patients. Furthermore, we identified putative cell-cell communication features between relapsed and primary samples and showed upregulation of pathways associated with immune cell crosstalk. Our results revealed both inter- and intratumoral heterogeneity in EPN and provided a framework for studying transcriptomic signatures of individual subclones at single-cell resolution., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wu, Fu, Zhang, Liu, Chen, Xu, Tian, Jin, Wong and Wu.)

Background: Colorectal cancer (CRC) is one of the most common malignancies and its incidence and mortality are increasing yearly. 5-Fluorouracil (5-FU) has long been used as a standard first-line treatment for CRC patients. Although 5-FU-based chemotherapy is effective for advanced CRC, the consequent resistance remains a key problem and causes the poor prognosis of CRC patients. Thus, there is an urgent need to identify new biomarkers to predict the response to 5-FU-based chemotherapy., Methods: CRC samples were retrieved from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). The immune-related genes were retrieved from the ImmPort database. Single-cell sequencing results from colorectal cancer were obtained by the ArrayExpress database. 5-FU resistance-related genes were filtered and validated by R packages. ESTIMATE algorithms were used to assess the tumor microenvironment (TME). KEGG and GO analysis were performed to explore the biological signaling pathway for resistant-response patients and sensitive-response patients in the tumor microenvironment. pRRophetic algorithms were used to predict 5-FU sensitivity. GSEA and GSVA analysis was performed to excavate the biological signaling pathway of the RBP7 gene., Results: Nine immune-related genes were identified to be associated with 5-FU resistance and poor disease-free survival (DFS) of CRC patients and the signature of these genes was developed in a DFS-prognostic model. Four immune-related genes were determined to be associated with 5-FU resistance and overall survival (OS) of CRC patients. The signature of these genes was developed an OS-prognostic model. ESTIMATE scores showed a significant difference between 5-FU resistant and 5-FU sensitive CRC patients. Resistant-response patients and sensitive-response patients to 5-FU based chemotherapy showed different GO and KEGG enrichment on the tumor microenvironment. RBP7, as a tumor immune microenvironment (TIME) related gene, was found to have the potential of predicting chemotherapy resistance and poor prognosis of CRC patients. GSEA analysis showed multiple signaling differences between the high and low expression of RBP7 in CRC patients. Hypoxia and TNFα signaling via NFκB gene sets were significantly different between chemotherapy resistant (RBP7 High ) and chemotherapy sensitive (RBP7 Low ) patients. Single-cell RNA-seq suggested RBP7 was centrally distributed in endothelial stalk cells, endothelial tip cells, and myeloid cells., Conclusions: Immune-related genes will hopefully be potential prognostic biomarkers to predict chemotherapy resistance for CRC. RBP7 may function as a tumor microenvironment regulator to induce 5-FU resistance, thereby affecting the prognosis of CRC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Huang, Ke, Jin, Zhu, Zhu, Mei, Zhang, Yu, Shou, Sun, Feng, Duan, Mou, Xie, Wu and Sui.)