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BackgroundDisulfidptosis, a newly defined type of programmed cell death, has emerged as a significant regulatory process in the development and advancement of malignant tumors, such as lower-grade glioma (LGG). Nevertheless, the precise biological mechanisms behind disulfidptosis in LGG are yet to be revealed, considering the limited research conducted in this field.MethodsWe obtained LGG data from the TCGA and CGGA databases and performed comprehensive weighted co-expression network analysis, single-sample gene set enrichment analysis, and transcriptome differential expression analyses. We discovered nine genes associated with disulfidptosis by employing machine learning methods like Cox regression, LASSO regression, and SVM-RFE. These were later used to build a predictive model for patients with LGG. To confirm the expression level, functional role, and impact on disulfidptosis of ABI3, the pivotal gene of the model, validation experiments were carried out in vitro.ResultsThe developed prognostic model successfully categorized LGG patients into two distinct risk groups: high and low. There was a noticeable difference in the time the groups survived, which was statistically significant. The model’s predictive accuracy was substantiated through two independent external validation cohorts. Additional evaluations of the immune microenvironment and the potential for immunotherapy indicated that this risk classification could function as a practical roadmap for LGG treatment using immune-based therapies. Cellular experiments demonstrated that suppressing the crucial ABI3 gene in the predictive model significantly reduced the migratory and invasive abilities of both SHG44 and U251 cell lines while also triggering cytoskeletal retraction and increased cell pseudopodia.ConclusionThe research suggests that the prognostic pattern relying on genes linked to disulfidptosis can provide valuable insights into the clinical outcomes, tumor characteristics, and immune alterations in patients with LGG. This could pave the way for early interventions and suggests that ABI3 might be a potential therapeutic target for disulfidptosis.

BackgroundsDisulfidptosis, a newly discovered mechanism of programmed cell death, is believed to have a unique role in elucidating cancer progression and guiding cancer therapy strategies. However, no studies have yet explored this mechanism in glioma.MethodsWe downloaded data on glioma patients from online databases to address this gap. Subsequently, we identified disulfidptosis-related genes from published literature and verified the associated lncRNAs.ResultsThrough univariate, multivariate, and least absolute shrinkage and selection operator (LASSO) regression algorithms analyses, we identified 10 lncRNAs. These were then utilized to construct prognostic prediction models, culminating in a risk-scoring signature. Reliability and validity tests demonstrated that the model effectively discerns glioma patients’ prognosis outcomes. We also analyzed the relationship between the risk score and immune characteristics, and identified several drugs that may be effective for high-risk patients. In vitro experiments revealed that LINC02525 could enhances glioma cells’ migration and invasion capacities. Additionally, knocking down LINC02525 was observed to promote glioma cell disulfidptosis.ConclusionThis study delves into disulfidptosis-related lncRNAs in glioma, offering novel insights into glioma therapeutic strategies.

IntroductionThe prevalence of ischemic heart disease has reached pandemic levels worldwide. Early revascularization is currently the most effective therapy for ischemic heart diseases but paradoxically induces myocardial ischemia/reperfusion (MI/R) injury. Cardiac inflammatory reaction and oxidative stress are primarily involved in the pathology of MI/R injury. Low-intensity pulsed ultrasound (LIPUS) has been demonstrated to reduce cell injury by protecting against inflammatory reaction and oxidative stress in many diseases, including cardiovascular diseases, but rarely on MI/R injury.MethodsThis study was designed to clarify whether LIPUS alleviates MI/R injury by alleviating inflammatory reaction and oxidative stress. Simultaneously, we have also tried to confirm which intensity of the LIPUS might be more suitable to ameliorate the MI/R injury, as well as to clarify the signaling mechanisms. MI/R and simulated ischemia/reperfusion (SI/R) were respectively induced in Sprague Dawley rats and human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). LIPUS treatment, biochemical measurements, cell death assay, estimation of cardiac oxidative stress and inflammatory reaction, and protein detections by western blotting were performed according to the protocol.ResultsIn our study, both in vivo and in vitro, LIPUS of 0.1 W/cm2 (LIPUS0.1) and 0.5 W/cm2 (LIPUS0.5) make no significant difference in the cardiomyocytes under normoxic condition. Under the hypoxic condition, MI/R injury, inflammatory reaction, and oxidative stress were partially ameliorated by LIPUS0.5 but were significantly aggravated by LIPUS of 2.5 W/cm2 (LIPUS2.5) both in vivo and in vitro. The activation of the apoptosis signal-regulating kinase 1 (ASK1)/c-Jun N-terminal kinase (JNK) pathway in cardiomyocytes with MI/R injury was partly rectified LIPUS0.5 both in vivo and in vitro.ConclusionOur study firstly demonstrated that LIPUS of different intensities differently affects MI/R injury by regulating cardiac inflammatory reaction and oxidative stress. Modulations on the ASK1/JNK pathway are the signaling mechanism by which LIPUS0.5 exerts cardioprotective effects. LIPUS0.5 is promising for clinical translation in protecting against MI/R injury. This will be great welfare for patients suffering from MI/R injury.

BackgroundSialic acid-binding immunoglobulin-like lectin-15 (Siglec-15) was reported to be a novel immune checkpoint molecule comparable to programmed cell death 1 ligand 1 (PD-L1). However, its expression profile and immunosuppressive mechanisms in the glioma tumor microenvironment have not yet been fully explored.ObjectivesTo identify the expression profile and potential function of Siglec-15 in glioma tumor microenvironment.MethodsWe investigated Siglec-15 and PD-L1 expression in tumor tissues from 60 human glioma patients and GL261 tumor models. Next, Siglec-15 knockout macrophages and mice were used to elucidate the immunosuppressive mechanism of Siglec-15 impacting macrophage function.ResultsOur results demonstrated that high levels of Siglec-15 in tumor tissues was positively correlated with poor survival in glioma patients. Siglec-15 was predominantly expressed on peritumoral CD68+ tumor-associated macrophages, which accumulated to the highest level in grade II glioma and then declined as grade increased. The Siglec-15 expression pattern was mutually exclusive with that of PD-L1 in glioma tissues, and the number of Siglec-15+PD-L1- samples (n = 45) was greater than the number of Siglec-15-PD-L1+ samples (n = 4). The dynamic change in and tissue localization of Siglec-15 expression were confirmed in GL261 tumor models. Importantly, after Siglec15 gene knockout, macrophages exhibited enhanced capacities for phagocytosis, antigen cross-presentation and initiation of antigen-specific CD8+ T-lymphocyte responses.ConclusionOur findings suggested that Siglec-15 could be a valuable prognostic factor and potential target for glioma patients. In addition, our data first identified dynamic changes in Siglec-15 expression and distribution in human glioma tissues, indicating that the timing of Siglec-15 blockade is critical to achieve an effective combination with other immune checkpoint inhibitors in clinical practice.

IntroductionGlioblastoma is a malignant brain tumor with poor prognosis. Lactate is the main product of tumor cells, and its secretion may relate to immunocytes’ activation. However, its role in glioblastoma is poorly understood. MethodsThis work performed bulk RNA-seq analysis and single cell RNA-seq analysis to explore the role of lactate in glioblastoma progression. Over 1400 glioblastoma samples were grouped into different clusters according to their expression and the results were validated with our own data, the xiangya cohort. Immunocytes infiltration analysis, immunogram and the map of immune checkpoint genes’ expression were applied to analyze the potential connection between the lactate level with tumor immune microenvironment. Furthermore, machine learning algorithms and cell-cell interaction algorithm were introduced to reveal the connection of tumor cells with immunocytes. By co-culturing CD8 T cells with tumor cells, and performing immunohistochemistry on Xiangya cohort samples further validated results from previous analysis.DiscussionIn this work, lactate is proved that contributes to glioblastoma immune suppressive microenvironment. High level of lactate in tumor microenvironment can affect CD8 T cells’ migration and infiltration ratio in glioblastoma. To step further, potential compounds that targets to samples from different groups were also predicted for future exploration.

BackgroundGlioma is one of the most common, primary, and lethal adult brain tumors because of its extreme aggressiveness and poor prognosis. Several recent studies relevant to the immune function of CD44, a transmembrane glycoprotein as a significant hyaluronic acid receptor, have achieved great success, revealing the critical role of CD44 in immune infiltration in gliomas. The overexpression of CD44 has been verified to correlate with cancer aggressiveness and migration, while the clinical and immune features of CD44 expression have not yet been thoroughly characterized in gliomas.MethodsMolecular and clinical data of glioma collected from publicly available genomic databases were analyzed.ResultsCD44 was up-expressed in malignant gliomas, notably in the 1p/19q non-codeletion cases, isocitrate dehydrogenase (IDH) wild-type, and mesenchymal subtypes in GBM samples. CD44 expression level strongly correlates with stromal and immune cells, mainly infiltrating the glioma microenvironment by single-cell sequencing analysis. Meanwhile, CD44 can be a promising biomarker in predicting immunotherapy responses and mediating the expression of PD-L1. Finally, RUNX1/CD44 axis could promote the proliferation and migration of gliomas.ConclusionsTherefore, CD44 was responsible for glioma growth and progression. It could potentially lead to a novel target for glioma immunotherapy or a prognostic biomarker.

BackgroundCD161 has been linked to the appearance and development of various cancers.MethodsThe mutation map and the variation of CNVs and SNVs of CD161 were displayed according to cBioportal and GSCALite. We also evaluated the pathway enrichment and drug sensitivity of CD161 according to GSCALite. We performed a single-cell sequencing analysis of cancer cells and T cells in melanoma. The cell communication patterns related to CD161 were further explored. Multiplex immunofluorescence staining of tissue microarrays was used to detect the association between CD161 expression and macrophages and T cells.ResultsA high CD161 level was related to neoantigens expression, pathway enrichment, and drug sensitivity. In addition, single-cell sequencing analysis showed that CD161 was mainly expressed in T cells, M1 and M2 Macrophages, neoplastic, microglial cells, neurons, and cancer cells in many tumor types. Further study on pseudotime trajectories and functional annotation of CD161 proved the critical role of CD161 in tumor progression and T cell immunity in melanoma. Multiplex immunofluorescence revealed that CD161 is closely correlated with the immune infiltration of T cells and macrophages in multiple cancers. In addition, high CD161 expression predicted a favorable immunotherapy response.ConclusionCD161 is involved in the immune infiltration of T cells and macrophages and might be a promising target for tumor immunotherapy.

BackgroundThe mechanism of copper-induced cellular death was newly discovered and termed cuproptosis. Inducing cuproptosis in cancer cells is well anticipated for its curative potential in treating tumor diseases. However, ferredoxin 1 (FDX1), the core regulatory gene in cuproptosis, is rarely studied, and the regulation of FDX1 in tumor biology remains obscure. A comprehensive pan-cancer analysis of FDX1 is needed.MethodsThirty-three types of tumors were included with paired normal tissues in The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets. The interaction between transcription, protein, phosphorylation, and promoter methylation levels was analyzed. Survival, immune infiltration, single-cell FDX1 expression, FDX1-related tumor mutational burden (TMB), microsatellite instability (MSI), stemness, tumor immune dysfunction and exclusion (TIDE), and immunotherapy-related analyses were performed. FDX1 protein expression was assessed by kidney renal clear cell carcinoma (KIRC) tissue microarray immunohistochemistry. The function of FDX1 in KIRC was further explored by experiments in 786-O cell lines in vitro.ResultsFDX1 is highly expressed in 15 tumor types and lowly expressed in 11 tumor types. The corresponding changes in protein expression, phosphorylation, and promoter methylation level of FDX1 have been described in several tumors. Survival analysis showed that FDX1 was related to favorable or poor overall survival in eight tumors and progression-free survival in nine tumors. Immune infiltration and single-cell analysis indicated the indispensable role of FDX1 expression in macrophages and monocytes. Multiple established immunotherapy cohorts suggested that FDX1 may be a potential predictor of treatment effects for tumor patients. Tissue microarray analysis showed decreased FDX1 expression in KIRC patients’ tumor tissues. Knockdown of FDX1 resulted in the downregulation of cuproptosis in kidney renal clear tumor cells. Mechanistically, the FDX1-associated gene expression signature in KIRC is related to the enrichment of genes involved in the tricarboxylic acid (TCA) cycle, NOTCH pathway, etc. Several NOTCH pathway genes were differentially expressed in the high- and low-FDX1 groups in KIRC.ConclusionOur analysis showed that the central regulatory gene of cuproptosis, FDX1, has differential expression and modification levels in various tumors, which is associated with cellular function, immune modulation, and disease prognosis. Thus, FDX1-dependent cuproptosis may serve as a brand-new target in future therapeutic approaches against tumors.

Gliomas, originating from the glial cells, are the most lethal type of primary tumors in the central nervous system. Standard treatments like surgery have not significantly improved the prognosis of glioblastoma patients. Recently, immune therapy has become a novel and effective option. As a conserved group of transcriptional regulators, the Sry-type HMG box (SOX) family has been proved to have a correlation with numerous diseases. Based on the large-scale machine learning, we found that the SOX family, with significant immune characteristics and genomic profiles, can be divided into two distinct clusters in gliomas, among which SOX10 was identified as an excellent immune regulator of macrophage in gliomas. The high expression of SOX10 is related to a shorter OS in LGG, HGG, and pan-cancer groups but benefited from the immunotherapy. It turned out in single-cell sequencing that SOX10 is high in neurons, M1 macrophages, and neural stem cells. Also, macrophages are found to be elevated in the SOX10 high-expression group. SOX10 has a positive correlation with macrophage cytokine production and negative regulation of macrophages’ chemotaxis and migration. In conclusion, our study demonstrates the outstanding cluster ability of the SOX family, indicating that SOX10 is an immune regulator of macrophage in gliomas, which can be an effective target for glioma immunotherapy.

CD93 is a transmembrane receptor that is mainly expressed on endothelial cells. A recent study found that upregulated CD93 in tumor vessels is essential for tumor angiogenesis in several cancers. However, the underlying mechanisms are largely unexplored. Our present research systematically analyzed the characteristics of CD93 in tumor immunotherapy among 33 cancers. CD93 levels and co-expression of CD93 on cancer and stromal cells were detected using public databases and multiple immunofluorescence staining. The Kaplan-Meier (KM) analysis identified the predictive role of CD93 in these cancer types. The survival differences between CD93 mutants and WT, CNV groups, and methylation were also investigated. The immune landscape of CD93 in the tumor microenvironment was analyzed using the SangerBox, TIMER 2.0, and single-cell sequencing. The immunotherapy value of CD93 was predicted through public databases. CD93 mRNA and protein levels differed significantly between cancer samples and adjacent control tissues in multiply cancer types. CD93 mRNA expression associated with patient prognosis in many cancers. The correlation of CD93 levels with mutational status of other gene in these cancers was also analyzed. CD93 levels significantly positively related to three scores (immune, stromal, and extimate), immune infiltrates, immune checkpoints, and neoantigen expression.. Additionally, single-cell sequencing revealed that CD93 is predominantly co-expressed on tumor and stromal cells, such as endothelial cells, cancer-associated fibroblasts (CAFs), neutrophils, T cells, macrophages, M1 and M2 macrophages. Several immune-related signaling pathways were enriched based on CD93 expression, including immune cells activation and migration, focal adhesion, leukocyte transendothelial migration, oxidative phosphorylation, and complement. Multiple immunofluorescence staining displayed the relationship between CD93 expression and CD8, CD68, and CD163 in these cancers. Finally, the treatment response of CD93 in many immunotherapy cohorts and sensitive small molecules was predicted from the public datasets. CD93 expression is closely associated with clinical prognosis and immune infiltrates in a variety of tumors. Targeting CD93-related signaling pathways in the tumor microenvironment may be a novel therapeutic strategy for tumor immunotherapy.

Immunogenic cell death (ICD) is a type of cell death that leads to the regulation and activation of the immune response, which is marked by the exposure and delivery of damage‐associated molecular patterns (DAMPs) in the tumor microenvironment. Accumulating evidence has revealed the significance of ICD-related genes in tumor progression and therapeutic response. In this study, we obtained two ICD-related clusters for glioblastoma (GBM) by applying consensus clustering, and further constructed a risk signature on account of the prognostic ICD genes. Based on the risk signature, we found that higher risk scores were associated with worse patient prognosis. Besides, the results illustrated that ferroptosis regulators/markers were highly enriched the high-risk group, and ferroptosis were correlated with cytokine signaling pathway and other immune-related pathways. We also discovered that high-risk scores were correlated to specific immune infiltration patterns and good response to immune checkpoint blockade (ICB) treatment. In conclusion, our study highlights the significance of ICD-related genes as prognostic biomarkers and immune response indicators in GBM. And the risk signature integrating prognostic genes possessed significant potential value to predict the prognosis of patients and the efficacy of ICB treatment.

Accumulating evidence has demonstrated that the immune cells have an emerging role in controlling anti-tumor immune responses and tumor progression. The comprehensive role of mast cell in glioma has not been illustrated yet. In this study, 1,991 diffuse glioma samples were collected from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). xCell algorithm was employed to define the mast cell-related genes. Based on mast cell-related genes, gliomas were divided into two clusters with distinct clinical and immunological characteristics. The survival probability of cluster 1 was significantly lower than that of cluster 2 in the TCGA dataset, three CGGA datasets, and the Xiangya cohort. Meanwhile, the hypoxic and metabolic pathways were active in cluster 1, which were beneficial to the proliferation of tumor cells. A potent prognostic model based on mast cell was constructed. Via machine learning, DRG2 was screened out as a characteristic gene, which was demonstrated to predict treatment response and predict survival outcome in the Xiangya cohort. In conclusion, mast cells could be used as a potential effective prognostic factor for gliomas.

The aberrant protein disulfide isomerase A5 (PDIA5) expression was relevant to the poor prognosis of patients with human cancers. However, its relationship with the epigenetic and genetic alterations and its effect on tumor immunity is still lacking. In the present study, we comprehensively analyzed the immune infiltration role of PDIA5 in human cancers based on large-scale bioinformatics analyses and in vitro experiments. Obvious DNA methylation and moderate alteration frequency of PDIA5 were observed in human cancers. The expression level of PDIA5 was significantly correlated with infiltrated immune cells, immune pathways, and other immune signatures. We found that cancer cells and macrophages exhibited high PDIA5 expression in human cancers using the single-cell RNA sequencing analysis. We also demonstrated the interaction between PDIA5 and immune cells in glioblastoma multiforme (GBM). Multiplex immunofluorescence staining showed the upregulated expression level of PDIA5 and the increased number of M2 macrophage markers-CD163 positive cells in pan-cancer samples. Notably, PDIA5 silencing resulted in upregulated expression of PD-L1 and SPP1 in U251 cells. Silencing of PDIA5 in hepG2 cells, U251 cells, and PC3 cells contributed to a decline in their ability of proliferation, clone formation, and invasion and inhibited the migration of cocultured M2 macrophages. Additionally, PDIA5 also displayed predictive value in the immunotherapy response of both murine and human cancer cohorts. Overall, our findings indicated that PDIA5 might be a potential target for immunotherapies in cancers.

BackgroundCLEC5A is a member of the C-type lectin superfamily. It can activate macrophages and lead to a series of immune-inflammation reactions. Previous studies reveal the role of CLEC5A in infection and inflammation diseases.MethodWe acquire and analyze data from The Cancer Genome Atlas (TCGA) database, Genotype-Tissue Expression (GTEx) database, and other comprehensive databases via GSCALite, cBioPortal, and TIMER 2.0 platforms or software. Single-cell sequencing analysis was performed for quantifying the tumor microenvironment of several types of cancers.ResultsCLEC5A is differentially expressed in a few cancer types, of which overexpression accompanies low overall survival of patients. DNA methylation mainly negatively correlates with CLEC5A expression. Moreover, CLEC5A is positively related to immune infiltration, including macrophages, cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs). Immune checkpoint genes are significantly associated with CLEC5A expression in diverse cancers. In addition, CLEC5A expression correlates with mismatch repair (MMR) in several cancers. Tumor mutation burden (TMB), microsatellite instability (MSI), and neoantigens show a positive association with CLEC5A expression in several cancers. Furthermore, CLEC5A in cancer correlates with signal transduction, the immune system, EMT, and apoptosis process. The drug sensitivity analysis screens out potential therapeutic agents associated with CLEC5A expression, including FR-180204, Tivozanib, OSI-930, Linifanib, AC220, VNLG/124, Bexarotene, omacetaxine mepesuccinate, narciclasine, leptomycin B, PHA-793887, LRRK2-IN-1, and CR-1-31B.ConclusionCLEC5A overexpresses in multiple cancers in contrast to normal tissues, and high CLEC5A expression predicts poor prognosis of patients and immune infiltration. CLEC5A is a potential prognostic biomarker of diverse cancers and a target for anti-tumor therapy.

BackgroundJMJD8 has recently been identified as a cancer-related gene, but current studies provide limited information. We aimed to clarify its roles and the potential mechanisms in pan-cancer.MethodsPan-cancer bulk sequencing data and online web tools were applied to analyze JMJD8’s correlations with prognosis, genome instability, cancer stemness, DNA repair, and immune infiltration. Moreover, single-cell datasets, SpatialDB database, and multiple fluorescence staining were used to validate the association between JMJD8 expression and M2 macrophages. Further, we utilized ROCplotter and cMap web tool to analyze the therapeutic responses and screened JMJD8-targeted compounds, respectively, and we used AlphaFold2 and Discovery Studio to conduct JMJD8 homology modeling and molecular docking.ResultsWe first noticed that JMJD8 was an oncogene in many cancer types. High JMJD8 was associated with lower genome stability. We then found that high JMJD8 correlated with high expression of mismatch repair genes, stemness, homologous repair gene signature in more than 9 cancers. ESTIMATE and cytokine analyses results presented JMJD8’s association with immunosuppression. Also, immune checkpoint CD276 was positively relevant to JMJD8. Subsequently, we validated JMJD8 as the M2 macrophage marker and showed its connection with other immunosuppressive cells and CD8+ T-cell depression. Finally, potential JMJD8-targeted drugs were screened out and docked to JMJD8 protein.ConclusionWe found that JMJD8 was a novel oncogene, and it correlated with immunosuppression and DNA repair. JMJD8 was highly associated with immune checkpoint CD276 and was an M2 macrophage biomarker in many cancers. This study will reveal JMJD8’s roles in pan-cancer and its potential as a novel therapeutic target.

BackgroundLung adenocarcinoma (LUAD) is a fatal malignancy in the world. Growing evidence demonstrated that autophagy-related genes regulated the immune cell infiltration and correlated with the prognosis of LUAD. However, the autophagy-based signature that can predict the prognosis and the efficiency of checkpoint immunotherapy in LUAD patients is yet to be discovered.MethodsWe used conventional autophagy-related genes to screen candidates for signature construction in TCGA cohort and 9 GEO datasets (tumor samples, n=2181; normal samples, n=419). An autophagy-based signature was constructed, its correlation with the prognosis and the immune infiltration of LUAD patients was explored. The prognostic value of the autophagy-based signature was validated in an independent cohort with 70 LUAD patients. Single-cell sequencing data was used to further characterize the various immunological patterns in tumors with different signature levels. Moreover, the predictive value of autophagy-based signature in PD-1 immunotherapy was explored in the IMvigor210 dataset. At last, the protective role of DRAM1 in LUAD was validated by in vitro experiments.ResultsAfter screening autophagy-related gene candidates, a signature composed by CCR2, ITGB1, and DRAM1 was established with the ATscore in each sample. Further analyses showed that the ATscore was significantly associated with immune cell infiltration and low ATscore indicated poor prognosis. Meanwhile, the prognostic value of ATscore was validated in our independent LUAD cohort. GSEA analyses and single-cell sequencing analyses revealed that ATscore was associated with the immunological status of LUAD tumors, and ATscore could predict the efficacy of PD-1 immunotherapy. Moreover, in vitro experiments demonstrated that the inhibition of DRAM1 suppressed the proliferation and migration capacity of LUAD cells.ConclusionOur study identified a new autophagy-based signature that can predict the prognosis of LUAD patients, and this ATscore has potential applicative value in the checkpoint therapy efficiency prediction.

CD147 plays an important role in promoting tumor proliferation and inhibiting cancer cell apoptosis in the tumor microenvironment. However, the mechanisms by which CD147 is involved in tumorigenesis remains unclear. This study systematically analyzed the prognostic value and immune characteristics of CD147 in 31 cancer types. The expression levels and mutant landscapes of CD147 in pan-cancer were explored. The Kaplan-Meier (KM) analysis was applied to analyze the prognostic value of CD147. The immune characteristics of CD147 in the tumor microenvironment were evaluated via TIMER 2.0 and R package (immunedeconv). We also explored the expression of CD147 on tumor cells and stromal cells through Gene Set Variation Analysis and single-cell sequencing analysis. The co-expression of CD147 and macrophage markers CD68 and CD163 in pan-cancer was detected using multiplex immunofluorescence staining on tissue microarrays. CD147 was found to be overexpressed in almost all cancer types, which was related to poor outcome. CD147 expression exhibited a strong association with immune infiltrates, immune checkpoint molecules, and neoantigen levels in the tumor microenvironment. In addition, CD147 was expressed on various cell types in the tumor microenvironment, including tumor cells, macrophages, T cells, monocytes, fibroblasts, etc. Furthermore, multiplex immunofluorescence revealed the co-expression pattern of CD147 and macrophage markers CD68 and CD163 in many tumor types. Finally, the immunotherapy response and sensitive small molecule drugs based on CD147 expression were predicted. In sum, CD147 has a significant relationship with the clinical outcome and immune infiltrates in multiple cancer types. Inhibiting the CD147-dependent signaling pathways might be a promising therapeutic strategy for tumor immunotherapy.

Immunogenicity, influenced by tumor antigenicity and antigen presenting efficiency, critically determines the effectiveness of immune checkpoint inhibitors. The role of immunogenicity has not been fully elucidated in gliomas. In this study, a large-scale bioinformatics analysis was performed to analyze the prognostic value and predictive value of antigen presentation machinery (APM) signature in gliomas. ssGSEA algorithm was used for development of APM signature and LASSO regression analysis was used for construction of APM signature-based risk score. APM signature and risk score showed favorable performance in stratifying survival and predicting tumorigenic factors of glioma patients. APM signature and risk score were also associated with different genomic features in both training cohort TCGA and validating cohort CGGA. Furthermore, APM signature-based risk score was independently validated in three external cohorts and managed to predict immunotherapy response. A prognostic nomogram was constructed based on risk score. Risk score-derived CALR was found to mediate the invasion and polarization of macrophages based on the coculture of HMC3 and U251 cells. CALR could significantly predict immunotherapy response. In conclusion, APM signature and APM signature-based risk score could help promote the clinical management of gliomas.

Gliomas are malignant tumors that originate from the central nervous system. The aldehyde dehydrogenase family has been documented to affect cancer progression; however, its role in gliomas remains largely unexplored. Bulk RNA-seq analysis and single-cell RNA-Seq analysis were performed to explore the role of the aldehyde dehydrogenases family in gliomas. Training cohort contained The Cancer Genome Atlas data, while data from Chinese Glioma Genome Atlas and Gene Expression Omnibus were set as validation cohorts. Our scoring system based on the aldehyde dehydrogenases family suggested that high-scoring samples were associated with worse survival outcomes. The enrichment score of pathways were calculated by AUCell to substantiate the biofunction prediction results that the aldehyde dehydrogenases family affected glioma progression by modulating tumor cell proliferation, migration, and immune landscape. Tumor immune landscape was mapped from high-scoring samples. Moreover, ALDH3B1 and ALDH16A1, two main contributors of the scoring system, could affect glioblastoma cell proliferation and migration by inducing cell-cycle arrest and the epithelial-mesenchymal transition. Taken together, the aldehyde dehydrogenases family could play a significant role in the tumor immune landscape and could be used to predict patient prognosis. ALDH3B1 and ALDH16A1 could influence tumor cell proliferation and migration.

Gliomas are aggressive tumors in the central nervous system and glioblastoma is the most malignant type. Ferroptosis is a programmed cell death that can modulate tumor resistance to therapy and the components of tumor microenvironment. However, the relationship between ferroptosis, tumor immune landscape, and glioblastoma progression is still elusive. In this work, data from bulk RNA-seq analysis, single cell RNA-seq analysis, and our own data (the Xiangya cohort) are integrated to reveal their relationships. A scoring system is constructed according to ferroptosis related gene expression, and high scoring samples resistant to ferroptosis and show worse survival outcome than low scoring samples. Notably, most of the high scoring samples are aggressive glioblastoma subtype, mesenchymal, and classical, by calculating RNA velocity. Cross-talk between high scoring glioblastoma cells and immunocytes are explored by R package ‘celltalker’. Ligand–receptor pairs like the TRAIL or TWEAK signaling pathway are identified as novel bridges implying how ferroptosis modulate immunocytes’ function and shape tumor microenvironment. Critically, potential drugs target to high scoring samples are predicted, namely, SNX2112, AZ628, and bortezomib and five compounds from the CellMiner database. Taken together, ferroptosis associates with glioblastoma aggressiveness, cross-talk with immunocytes and offer novel chemotherapy strategy.

DNA methylation patterns are essential in understanding carcinogenesis. However, the relationship between DNA methylation and the immune process has not been clearly established—this study aimed at elucidating the interaction between glioma and DNA methylation, consolidating glioma classification and prognosis. A total of 2,483 immune-related genes and 24,556 corresponding immune-related methylation probes were identified. From the Cancer Genome Atlas (TCGA) glioma cohort, a total of 683 methylation samples were stratified into two different clusters using unsupervised clustering, and eight types of other cancer samples from the TCGA database were shown to exhibit excellent distributions. A total of 3,562 differentially methylated probes (DMPs) were selected and used for machine learning. A five-probe signature was established to evaluate the prognosis of glioma as well as the potential benefits of radiotherapy and Procarbazine, CCNU, Vincristine (PCV) treatment. Other prognostic clinical models, such as nomogram and decision tree, were also evaluated. Our findings confirmed the interactions between immune-related methylation patterns and glioma. This novel approach for cancer molecular characterization and prognosis should be validated in further studies.

Existing therapeutic strategies for gliomas are restricted; hence, exploration for novel diagnostic indicator and treatment is essential. Here, we performed bioinformatic analyses for TNFSF13 (also known as APRIL), a proliferation-inducing ligand of the tumor necrosis factor (TNF) superfamily, aiming to assess its potential for predicting glioma patient’s prognosis and targeted therapy. TNFSF13 expression was upregulated in the increase of tumor grades based on Xiangya cohort. In high TNFSF13 gliomas, somatic mutation was proved to correlate with amplification of EGFR and deletion of CDKN2A; while mutation of IDH1 was more frequently observed in low TNFSF13 group. We also confirmed the positive correlation between TNFSF13 and infiltrating immune and stromal cells in glioma microenvironment. Further, TNFSF13 was found to be involved in immunosuppression via diverse immunoregulation pathways and was associated with other immune checkpoints and inflammation. Single-cell sequencing revealed an abundant expression of TNFSF13 in neoplastic cells and M2 macrophages, which TNFSF13 might potentially regulate the cell communication via IL-8, C3, and CD44. Lastly, TNFSF13 mediated the activities of transcription factors including FOXO3, MEIS2, and IRF8. Our analyses demonstrated the relevance between TNFSF13 and glioma progress and indicated the potential of TNFSF13 as a novel diagnostic onco-inflammatory biomarker and immunotherapy target of gliomas.

Tumor-infiltrating immune cells (TIICs) have become an important source of markers for predicting the clinical outcomes of cancer patients. However, measurements of cellular heterogeneity vary due to the frequently updated reference genomes and gene annotations. In this study, we systematically collected and evaluated the infiltration pattern of 65 immune cells. We constructed the Immune Cell Pair (ICP) score based on the cell pair algorithm in 3,715 samples and across 12 independent cancer types, among which, the ICP score from six cancer types was further validated in 2,228 GEO samples. An extensive tumorigenic and immunogenomic analysis was subsequently conducted. As a result, the ICP score showed a robust reliability and efficacy in predicting the survival of patients with gliomas, in pan-cancer samples, and six independent cancer types. Notably, the ICP score was correlated with the genomic alteration features in gliomas. Moreover, the ICP score exhibited a remarkable association with multiple immunomodulators that could potentially mediate immune escape. Finally, the ICP score predicted immunotherapeutic responses with a high sensitivity, allowing a useful tool for predicting the overall survival and guiding immunotherapy for cancer patients.

Gliomas are a type of malignant central nervous system tumor with poor prognosis. Molecular biomarkers of gliomas can predict glioma patient’s clinical outcome, but their limitations are also emerging. C-X-C motif chemokine ligand family plays a critical role in shaping tumor immune landscape and modulating tumor progression, but its role in gliomas is elusive. In this work, samples of TCGA were treated as the training cohort, and as for validation cohort, two CGGA datasets, four datasets from GEO database, and our own clinical samples were enrolled. Consensus clustering analysis was first introduced to classify samples based on CXCL expression profile, and the support vector machine was applied to construct the cluster model in validation cohort based on training cohort. Next, the elastic net analysis was applied to calculate the risk score of each sample based on CXCL expression. High-risk samples associated with more malignant clinical features, worse survival outcome, and more complicated immune landscape than low-risk samples. Besides, higher immune checkpoint gene expression was also noticed in high-risk samples, suggesting CXCL may participate in tumor evasion from immune surveillance. Notably, high-risk samples also manifested higher chemotherapy resistance than low-risk samples. Therefore, we predicted potential compounds that target high-risk samples. Two novel drugs, LCL-161 and ADZ5582, were firstly identified as gliomas’ potential compounds, and five compounds from PubChem database were filtered out. Taken together, we constructed a prognostic model based on CXCL expression, and predicted that CXCL may affect tumor progression by modulating tumor immune landscape and tumor immune escape. Novel potential compounds were also proposed, which may improve malignant glioma prognosis.

BackgroundHypoxia-related genes are demonstrated to correlate with the prognosis of various cancers. However, the role of hypoxia-related long non-coding RNAs (HRLs) in lower-grade glioma (LGG) remains unclear.MethodsA total of 700 LGG samples were extracted from TCGA and CGGA databases. Pearson correlation analysis was used to identify HRLs. Lasso analysis was adopted to construct the HRL signature. TIDE algorithm was used to predict responses to immune checkpoint inhibitors. Cell proliferation was estimated by cell counting kit-8 assay, colony formation assay, and EdU assay.ResultsWe identified 340 HRLs and constructed a novel risk signature composed of 19 HRLs. The risk score exhibited potent value in predicting the prognosis of LGG patients and was significantly associated with the prognosis of LGG patients. Moreover, HRL signature could distinguish patients with similar expression levels of immune checkpoints and might predict the efficacy of immune checkpoint inhibitors. Additionally, hypoxia-related pathways and immune pathways were enriched in high-risk group, and high risk score indicated low tumor purity and high immune infiltration. Two major HRLs, LINC00941 and BASP1-AS1, could significantly affect the proliferation of glioma cells.ConclusionsOur study constructed a novel HRL signature that could predict the prognosis and immunotherapy response of LGG patients. HRLs could be novel biomarkers to predict the prognosis of LGG patients and potential targets for LGG treatment.

The glioma tumor microenvironment (TME), composed of several noncancerous cells and biomolecules is known for its complexity of cancer-immune system interaction. Given that, novel risk signature is required for predicting glioma patient responses to immunotherapy. In this study, we systematically evaluated the TME infiltration pattern of 2877 glioma samples. TME phenotypes were determined using the Partitioning Around Medoid method. Machine learning including SVM-RFE and Principal component analysis (PCA) were used to construct a TME scoring system. A total of 857 glioma samples from four datasets were used for external validation of the TME-score. The correlation of TME phenotypes and TME-scores with diverse clinicopathologic characteristics, genomic features, and immunotherapeutic efficacy in glioma patients was determined. Immunohistochemistry staining for the M2 macrophage marker CD68 and CD163, mast cell marker CD117, neutrophil marker CD66b, and RNA sequencing of glioma samples from the XYNS cohort were performed. Two distinct TME phenotypes were identified. High TME-score correlated with a high number of immune infiltrating cells, elevated expression of immune checkpoints, increased mutation rates of oncogenes, and poor survival of glioma patients. Moreover, high TME-score exhibited remarkable association with multiple immunomodulators that could potentially mediate immune escape of cancer. Thus, the TME-score showed the potential to predict the efficacy of anti-PD-1 immunotherapy. Univariate and multivariate analyses demonstrated the TME-score to be a valuable prognostic biomarker for gliomas. Our study demonstrated that TME could potentially influence immunotherapy efficacy in melanoma patients whereas its role in immunotherapy of glioma patients remains unknown. Therefore, a better understanding of the TME landscape in gliomas would promote the development of novel immunotherapy strategies against glioma.

Gliomas are primary malignant brain tumors. Monocytes have been proved to actively participate in tumor growth. Weighted gene co-expression network analysis was used to identify meaningful monocyte-related genes for clustering. Neural network and SVM were applied for validating clustering results. Somatic mutation and copy number variation were used for defining the features of identified clusters. Differentially expressed genes (DEGs) between the stratified groups after performing elastic regression and principal component analyses were used for the construction of risk scores. Monocytes were associated with glioma patients’ survival and exhibited high predictive value. The prognostic value of risk score in glioma was validated by the abundant expression of immune checkpoint and metabolic profile. Additionally, high risk score was positively associated with the expression of immunogenic and antigen presenting factors, which indicated high immune infiltration. A prognostic model based on risk score demonstrated high accuracy rate of receiver operating characteristic curves. Compared with previous studies, our research dissected functional roles of monocytes from large-scale analysis. Findings of our analyses strongly support an immune modulatory and prognostic role of monocytes in glioma progression. Notably, monocyte could be an effective predictor for therapy responses of glioma patients.

Gliomas are the most common and lethal primary malignant tumor of the brain. Routine treatment including surgical resection, chemotherapy, and radiotherapy produced limited therapeutic effect, while immunotherapy targeting the glioma microenvironment has offered a novel therapeutic option. PDIA5 protein is the member of PDI family, which is highly expressed in glioma and participates in glioma progression. Based on large-scale bioinformatics analysis, we discovered that PDIA5 expression level is upregulated in aggressive gliomas, with high PDIA5 expression predicting poor clinical outcomes. We also observed positive correlation between PDIA5 and immune infiltrating cells, immune related pathways, inflammatory activities, and other immune checkpoint members. Patients with high PDIA5 high-expression benefited from immunotherapies. Additionally, immunohistochemistry revealed that PDIA5 and macrophage biomarker CD68 were upregulated in high-grade gliomas, and patients with low PDIA5 level experienced favorable outcomes among 33 glioma patients. Single cell RNA sequencing exhibited that PDIA5 was in high level presenting in neoplastic cells and macrophages. Cell transfection and co-culture of glioma cells and macrophages revealed that PDIA5 in tumor cells mediated macrophages exhausting. Altogether, our findings indicate that PDIA5 overexpression is associated with immune infiltration in gliomas, and may be a promising therapeutic target for glioma immunotherapy.

The pentraxin is a superfamily of proteins with the same domain known as the pentraxin domain at C-terminal. This family has two subgroups, namely; short pentraxins (C-reactive protein and serum amyloid P component) and long pentraxins (neuronal pentraxin 1, neuronal pentraxin 2, neuronal pentraxin receptor, pentraxin 3 and pentraxin 4). Each group shares a similar structure with the pentameric complexes arranged in a discoid shape. Previous studies revealed the functions of different pentraxin family members. Most of them are associated with human innate immunity. Inflammation has commonly been associated with tumor progression, implying that the pentraxin family might also participate in tumor progression. Therefore, we reviewed the basic characteristics and functions of the pentraxin family and their role in tumor progression.

The possible protective effect of interleukin-32 (IL-32) in Mycobacterium tuberculosis ( Mtb ) infection has been indicated. However, few studies have been focused on IL-32 in tuberculosis patients. Additionally, the regulation of IL-32 production has rarely been reported. In the present study, the production, regulation, and role of IL-32 in tuberculous pleurisy (TBP) were investigated. We found that the content of IL-32 in tuberculous pleural effusion (TPE) was higher than the level in the malignant pleural effusion and transudative pleural effusion. The level of IL-32 mRNA in pleural fluid mononuclear cells (PFMCs) was higher than that in peripheral blood mononuclear cells (PBMCs) of patients with TBP, and this difference was mainly reflected in the splice variants of IL-32α, IL-32β, and IL-32γ. Compared with the PBMCs, PFMCs featured higher IL-32β/IL-32γ and IL-32α/IL-32γ ratios. In addition, lipopolysaccharide (LPS), Bacillus Calmette-Guérin (BCG), and H37Ra stimulation could induce IL-32 production in the PFMCs. IL-32 production was positively correlated with the TNF-α, IFN-γ, and IL-1Ra levels in TPE, whereas IFN-γ, but not TNF-α or IL-1Ra, could induce the production of IL-32 in PFMCs. Furthermore, IL-32γ could induce the TNF-α production in PFMCs. Monocytes and macrophages were the main sources of IL-32 in PFMCs. Nevertheless, direct cell-cell contact between lymphocytes and monocytes/macrophages plays an important role in enhancing IL-32 production by monocyte/macrophage cells. Finally, compared with the non-tuberculous pleural effusion, the purified CD4 + and CD8 + T cells in TPE expressed higher levels of intracellular IL-32. Our results suggested that, as a potential biomarker, IL-32 may play an essential role in the protection against Mtb infection in patients with TBP. However, further studies need to be carried out to clarify the functions and mechanisms of the IFN-γ/IL-32/TNF-α axis in patients with TBP., 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 Wang, Yang, Quan, Li, Hu, Liu, Guan and Li.)

Objectives: The aims of this study were to report the effectiveness and safety of teriflunomide in Chinese patients with relapsing-remitting multiple sclerosis (RRMS) and to explore the association of paramagnetic rim lesion (PRL) burden with patient outcome in the context of teriflunomide treatment and the impact of teriflunomide on PRL burden., Methods: This is a prospective observational study. A total of 100 RRMS patients treated with teriflunomide ≥3 months were included in analyzing drug persistence and safety. Among them, 96 patients treated ≥6 months were included in assessing drug effectiveness in aspects of no evidence of disease activity (NEDA) 3. The number and total volume of PRL were calculated in 76 patients with baseline susceptibility-weighted imaging (SWI), and their association with NEDA3 failure during teriflunomide treatment was investigated., Results: Over a treatment period of 19.7 (3.1-51.7) months, teriflunomide reduced annualized relapse rate (ARR) from 1.1 ± 0.8 to 0.3 ± 0.5, and Expanded Disability Status Scale (EDSS) scores remained stable. At month 24, the NEDA3% and drug persistence rate were 43.8% and 65.1%, respectively. In patients with a baseline SWI, 81.6% had at least 1 PRL, and 42.1% had ≥4 PRLs. The total volume of PRL per patient was 0.3 (0.0-11.5) mL, accounting for 2.3% (0.0%-49.0%) of the total T2 lesion volume. Baseline PRL number ≥ 4 (OR = 4.24, p = 0.009), younger onset age (OR = 0.94, p = 0.039), and frequent relapses in initial 2 years of disease (OR = 13.40, p = 0.026) were associated with NEDA3 failure. The PRL number and volume were not reduced ( p = 0.343 and 0.051) after teriflunomide treatment for more than 24 months. No new safety concerns were identified in this study., Conclusion: Teriflunomide is effective in reducing ARR in Chinese patients with RRMS. Patients with less PRL burden, less frequent relapses, and relatively older age are likely to benefit more from teriflunomide, indicating that PRL might be a valuable measurement to inform clinical treatment decision., 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 Tan, Li, Li, He, ZhangBao, Zhou, Yang, Zhao, Lu, Dong, Li and Quan.)

DEK protein is highly expressed in asthma. However, the mechanism of DEK on mitophagy in asthma has not been fully understood. This study aims to investigate the role and mechanism of DEK in asthmatic airway inflammation and in regulating PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. PINK1-Parkin mitophagy, NLRP3 inflammasome, and apoptosis were examined after gene silencing or treatment with specific inhibitors (MitoTEMPO, MCC950, and Ac-DEVD-CHO) in house dust mite (HDM) or recombinant DEK (rmDEK)-induced WT and DEK-/- asthmatic mice and BEAS-2B cells. The regulatory role of DEK on ATAD3A was detected using ChIP-sequence and co-immunoprecipitation. rmDEK promoted eosinophil recruitment, and co-localization of TOM20 and LC3B, MFN1 and mitochondria, LC3B and VDAC, and ROS generation, reduced protein level of MnSOD in HDM induced-asthmatic mice. Moreover, rmDEK also increased DRP1 expression, PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. These effects were partially reversed in DEK -/- mice. In BEAS-2B cells, siDEK diminished the Parkin, LC3B, and DRP1 translocation to mitochondria, mtROS, TOM20, and mtDNA. ChIP-sequence analysis showed that DEK was enriched on the ATAD3A promoter and could positively regulate ATAD3A expression. Additionally, ATAD3A was highly expressed in HDM-induced asthma models and interacted with DRP1, and siATAD3A could down-regulate DRP1 and mtDNA-mediated mitochondrial oxidative damage. Conclusively, DEK deficiency alleviates airway inflammation in asthma by down-regulating PINK1-Parkin mitophagy, NLRP3 inflammasome activation, and apoptosis. The mechanism may be through the DEK/ATAD3A/DRP1 signaling axis. Our findings may provide new potential therapeutic targets for asthma 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 © 2024 Bai, Liu, Quan, Han, Wang, Wang, Wang, Li, Li, Piao, Song and Yan.)

Purpose: Chlamydia psittaci ( C. psittaci ) has caused sporadic, but recurring, fatal community-acquired pneumonia outbreaks worldwide, posing a serious threat to public health. Our understanding of host inflammatory responses to C. psittaci is limited, and many bronchitis cases of psittaci have rapidly progressed to pneumonia with deterioration., Methods: To clarify the host inflammatory response in psittacosis, we analyzed clinical parameters, and compared transcriptomic data, concentrations of plasma cytokines/chemokines, and changes of immune cell populations in 17 laboratory-confirmed psittacosis cases, namely, 8 pneumonia and 9 bronchitis individuals, in order to assess transcriptomic profiles and pro-inflammatory responses., Results: Psittacosis cases with pneumonia were found to have abnormal routine blood indices, liver damage, and unilateral pulmonary high-attenuation consolidation. Transcriptome sequencing revealed markedly elevated expression of several pro-inflammatory genes, especially interleukins and chemokines. A multiplex-biometric immunoassay showed that pneumonia cases had higher levels of serum cytokines (G-CSF, IL-2, IL-6, IL-10, IL-18, IP-10, MCP-3, and TNF-α) than bronchitis cases. Increases in activated neutrophils and decreases in the number of lymphocytes were also observed in pneumonia cases., Conclusion: We identified a number of plasma biomarkers distinct to C. psittaci pneumonia and a variety of cytokines elevated with immunopathogenic potential likely inducing an inflammatory milieu and acceleration of the disease progression of psittaci pneumonia. This enhances our understanding of inflammatory responses and changes in vascular endothelial markers in psittacosis with heterogeneous symptoms and should prove helpful for developing both preventative and therapeutic strategies., 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 Zhang, Wang, Ma, Wang, Li, Quan, Cao, Guo, Wang, Yan, Carr, Meng and Shi.)

Background and Aims: Radiation-induced lung injury (RILI) is the most common complication associated with chest tumors, such as lung and breast cancers, after radiotherapy; however, the pathogenic mechanisms are unclear. Single-cell RNA sequencing has laid the foundation for studying RILI at the cellular microenvironmental level. This study focused on changes during the acute pneumonitis stage of RILI at the cellular microenvironmental level and investigated the interactions between different cell types., Methods: An acute RILI model in mice and a single-cell transcriptional library were established. Intercellular communication networks were constructed to study the heterogeneity and intercellular interactions among different cell types., Results: A single-cell transcriptome map was established in a mouse model of acute lung injury. In total, 18,500 single-cell transcripts were generated, and 10 major cell types were identified. The heterogeneity and radiosensitivity of each cell type or subtype in the lung tissues during the acute stage were revealed. It was found that immune cells had higher radiosensitivity than stromal cells. Immune cells were highly heterogeneous in terms of radiosensitivity, while some immune cells had the characteristics of radiation resistance. Two groups of radiation-induced Cd8 + Mki67 + T cells and Cd4 + Cxcr6 + helper T cells were identified. The presence of these cells was verified using immunofluorescence. The ligand-receptor interactions were analyzed by constructing intercellular communication networks. These explained the origins of the cells and revealed that they had been recruited from endothelial cells to the inflammatory site., Conclusions: This study revealed the heterogeneity of in vivo radiosensitivity of different cell types in the lung at the initial stage post irradiation., 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 Ma, Ye, Lu, Xing, Zhao, Quan, Jia, Lu, Li and Zhou.)

Background: Recognizing the predictors of disease relapses in patients with anti-aquaporin-4 antibody (AQP4-ab)-positive neuromyelitis optica spectrum disorder (NMOSD) is essential for individualized treatment strategy. We aimed to identify the factors that predicted relapses among patients with AQP4-ab-positive NMOSD, develop outcome prediction models, and validate them in a multicenter validation cohort., Methods: Between January 2015 and December 2020, 820 patients with NMOSD were registered at Huashan Hospital. We retrospectively reviewed their medical records, and included 358 AQP4-ab-positive patients with 1135 treatment episodes. Univariate and multivariate analyses were used to explore the predictors of relapse, severe visual or motor disability during follow-up. A model predicting the 1- and 2-year relapse-free probability was developed and validated in an external validation cohort of 92 patients with 213 treatment episodes., Results: Lower serum AQP4-ab titer (< 1:100), higher Expanded Disability Status Scale (EDSS) score at onset (≥ 2.5), and use of intravenous methylprednisolone (IVMP) at the first attack predicted an overall lower annualized relapse rate. Older age (> 48 years), optic neuritis at onset, and higher onset EDSS score (≥ 2.5) significantly increased the risk for blindness, while IVMP at the first attack and maintenance therapy reduced the risk for blindness. Myelitis at onset increased the possibility of motor disability (EDSS ≥ 6.0), severe motor disability or death (EDSS ≥ 8.0), while maintenance therapy reduced these possibilities. Anderson and Gill model identified that the risk factors predicting recurrent relapses under certain treatment status were female gender, high AQP4-ab titer (≥ 1:100), previous attack under same therapy, lower EDSS score at treatment initiation (< 2.5), and no maintenance therapy or oral prednisone lasting less than 6 months. A nomogram using the above factors showed good discrimination and calibration abilities. The concordance indexes in the primary and validation cohort were 0.66 and 0.65, respectively., Conclusion: This study reports the demographic, clinical and therapeutic predictors of relapse, and severe visual or motor disability in NMOSD. Early identification of patients at risk of unfavorable outcomes is of paramount importance to inform treatment decisions., 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 Wang, Du, Li, Li, Wang, Zhao, Meng, Li, Pan, Xia, Wu, Yang, Li, Ma, ZhangBao, Huang, Chang, Tan, Yu, Zhou, Lu, Wang, Dong, Lu, Zhao and Quan.)

N 6 -methylation of adenosine (m 6 A), a post-transcriptional regulatory mechanism, is the most abundant nucleotide modification in almost all types of RNAs. The biological function of m 6 A in regulating the expression of oncogenes or tumor suppressor genes has been widely investigated in various cancers. However, recent studies have addressed a new role of m 6 A modification in the anti-tumor immune response. By modulating the fate of targeted RNA, m 6 A affects tumor-associated immune cell activation and infiltration in the tumor microenvironment (TME). In addition, m 6 A-targeting is found to affect the efficacy of classical immunotherapy, which makes m 6 A a potential target for immunotherapy. Although m 6 A modification together with its regulators may play the exact opposite role in different tumor types, targeting m 6 A regulators has been shown to have wide implications in several cancers. In this review, we discussed the link between m 6 A modification and tumor with an emphasis on the importance of m 6 A in anti-tumor immune response and immunotherapy., 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 © 2021 Quan, Belaydi, Hu, Li, Yu, Liu, Yi, Qiu, Ren, Ma, Gong, Ou, Chen, Sun, Chen and Zu.)

Objective: To evaluate the potential of serum neurofilament light (sNfL) and serum glial fibrillary acidic protein (sGFAP) as disease biomarkers in neuromyelitis optica spectrum disorder (NMOSD) with aquaporin-4 antibody (AQP4-ab) or myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD). Methods: Patients with AQP4-ab-positive NMOSD ( n = 51), MOGAD ( n = 42), and relapsing-remitting multiple sclerosis (RRMS) ( n = 31 for sNfL and n = 22 for sGFAP testing), as well as healthy controls (HCs) ( n = 28), were enrolled prospectively. We assessed sNfL and sGFAP levels using ultrasensitive single-molecule array assays. Correlations of sNfL and sGFAP levels with clinical parameters were further examined in AQP4-ab-positive NMOSD and MOGAD patients. Results: sNfL levels were significantly higher in patients with AQP4-ab-positive NMOSD (median 17.6 pg/mL), MOGAD (27.2 pg/mL), and RRMS (24.5 pg/mL) than in HCs (7.4 pg/mL, all p < 0.001). sGFAP levels were remarkably increased in patients with AQP4-ab-positive NMOSD (274.1 pg/mL) and MOGAD (136.7 pg/mL) than in HCs (61.4 pg/mL, both p < 0.001). Besides, sGFAP levels were also significantly higher in patients with AQP4-ab-positive NMOSD compared to those in RRMS patients (66.5 pg/mL, p < 0.001). The sGFAP/sNfL ratio exhibited good discrimination among the three disease groups. sNfL levels increased during relapse in patients with MOGAD ( p = 0.049) and RRMS ( p < 0.001), while sGFAP levels increased during relapse in all three of the disease groups (all p < 0.05). Both sNfL and sGFAP concentrations correlated positively with Expanded Disability Status Scale scores in AQP4-ab-positive NMOSD (β = 1.88, p = 0.018 and β = 2.04, p = 0.032) and MOGAD patients (β = 1.98, p = 0.013 and β = 1.52, p = 0.008). Conclusion: sNfL and sGFAP levels are associated with disease severity in AQP4-ab-positive NMOSD and MOGAD patients, and the sGFAP/sNfL ratio may reflect distinct disease pathogenesis., 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 © 2021 Chang, Huang, Wang, ZhangBao, Zhou, Lu, Wang, Yu, Li, Li, Zhao, Lu and Quan.)