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Objective of this study was to systematically analyze and identify genetic characteristics associated with immune infiltration in UC.Patients and Methods: Gene expression data from three independent datasets obtained from the Gene Expression Omnibus (GEO) were utilized. By employing the ssGSEA and CIBERSORT algorithms, we estimated the extent of immune cell infiltration in UC samples. Subsequently, Weighted Correlation Network Analysis (WGCNA) was performed to identify gene modules exhibiting significant associations with immune infiltration, and further identification of hub genes associated with immune infiltration was accomplished using least absolute shrinkage and selection operator (LASSO) regression analysis. The relationship between the identified hub genes and clinical information was subsequently investigated.Results: Our findings revealed significant activation of both innate and adaptive immune cells in UC. Notably, the expression levels of CD44, IL1B, LYN, and ITGA5 displayed strong correlations with immune cell infiltration within the mucosa of UC patients. Immunohistochemical analysis confirmed the significant upregulation of CD44, LYN, and ITGA5 in UC samples, and their expression levels were found to be significantly associated with common inflammatory markers, including the systemic immune inflammation indices, C-reactive protein, and erythrocyte sedimentation rate.Conclusion: CD44, LYN, and ITGA5 are involved in the immune infiltration pathogenesis of UC and may be potential therapeutic targets for UC. [ABSTRACT FROM AUTHOR]

The association between specific genetic mutations and immunotherapy benefits has been widely known, while such studies in pan-cancer are still limited. SPEN, mainly involved in X chromosome inactivation (XCI), plays an essential in tumorigenesis and sex differences in cancer. Thus, we firstly analyzed the potential role of SPEN in the TCGA pan-cancer cohort and clinical samples. Bioinformatics analysis and immunohistochemistry (IHC) staining confirm that the expression of SPEN is significantly different in various cancers and may involve RNA splicing and processing via enrichment analysis. Then, our data further revealed that those patients with SPEN mutation could predict a better prognosis in pan-cancer and had distinct immune signatures, higher tumor mutation burden (TMB), and microsatellite instability (MSI) in common cancer types. Finally, the cancer patients from 9 studies treated with immune checkpoint inhibitors were included to investigate the efficacy of immunotherapy. The results further showed that SPEN mutation was associated with better clinical outcomes (HR, 0.74; 95%CI, 0.59–0.93, P = 0.01), and this association remained existed in female patients (HR, 0.60; 95%CI, 0.38–0.94 P = 0.024), but not in male patients (HR, 0.82; 95%CI, 0.62–1.08 P = 0.150). Our findings demonstrated that SPEN mutation might strongly predict immunotherapy efficacy in pan-cancer. [ABSTRACT FROM AUTHOR]

Background: Head and neck squamous cell carcinoma (HNSCC) is highly aggressive with a significant tropism of lymph nodes, which restricts treatment options and negatively impacts patient outcomes. Although progress has been made in understanding the molecular mechanisms underlying lymphatic metastasis (LM), these mechanisms remain elusive. ANXA6 is a scaffold protein that participates in tumor pathogenesis and autophagy regulation; however, how ANXA6 affects autophagy and LM in HNSCC cells remains unknown. Methods: RNA sequencing was performed on HNSCC clinical specimens with or without metastasis as well as on The Cancer Genome Atlas dataset to investigate ANXA6 expression and survival. Both in vitro and in vivo studies were performed to investigate the role of ANXA6 in the regulation of LM in HNSCC. The molecular mechanism by which ANXA6 interacts with TRPV2 was examined at the molecular level. Results: ANXA6 expression was significantly upregulated in HNSCC patients with LM and higher expression was associated with poor prognosis. ANXA6 overexpression promoted the proliferation and mobility of FaDu and SCC15 cells in vitro; however, ANXA6 knockdown retarded LM in HNSCC in vivo. ANXA6 induced autophagy by inhibiting the AKT/mTOR signaling pathway in HNSCC, thereby regulating the metastatic capability of the disease. Furthermore, ANXA6 expression positively correlated with TRPV2 expression both in vitro and in vivo. Lastly, TRPV2 inhibition reversed ANXA6-induced autophagy and LM. Conclusions: These results indicate that the ANXA6/TRPV2 axis facilitates LM in HNSCC by stimulating autophagy. This study provides a theoretical basis for investigating the ANXA6/TRPV2 axis as a potential target for the treatment of HNSCC, as well as a biomarker for predicting LM. [ABSTRACT FROM AUTHOR]

This study aimed to test cinobufacini therapeutic potential for pancreatic cancer, verify its potential molecular mechanism, and evaluate the cinobufacini impact on pancreatic cancer microenvironment. First, the effect of cinobufacini-treated pancreatic stellate cells (PSCs) supernatant on the value-added ability of pancreatic cancer (PCCs) was tested. The results show that cinobufacini can effectively reduce the ability of PSCs supernatant to promote the value-added PCCs. Further results show that cinobufacini can effectively reduce the concentration of TGFβ in the supernatant of PSCs. Subsequently, the impact of cinobufacini on the transcription and translation levels of key genes in the TGFβ/Smads pathway was examined. The results showed that the impact of cinobufacini on the transcription levels of Smad2, Smad3, and Smad7 was in a concentration-dependent manner, while the transcriptional activity of collagen I mRNA was decreased with the increase of cinobufacini concentration. The results of protein expression showed that cinobufacini could upregulate the expression of inhibitory protein Smad7, inhibit the phosphorylation level of p-Smad2/3, and then suppress the expression of type I collagen (collagen I). On the one hand, this study shows that cinobufacini can inhibit the promotion of PSCs on the proliferation of PCCs. On the other hand, cinobufacini can upregulate the expression of the inhibitory molecule, Smad7, through the TGFβ/Smads pathway and reduce the phosphorylation level of p-Smad2/3, thereby inhibiting the expression of collagen I and pancreatic fibrosis. cinobufacin can inhibit the proliferation of SW1900 cells by blocking the TGFβ/Smads pathway of pancreatic stellate cells. These results provide a clinical basis for the treatment of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: Low-intensity pulsed ultrasound (LIPUS) is a safe and noninvasive rehabilitative physical therapy with anti-inflammatory effects. The current study investigated the effect of LIPUS on the inflammation of nucleus pulposus (NP) cells and its underlying mechanism. Methods: Human NP cells were acquired from lumbar disc herniation tissue samples and cultured for experiments. Human NP cells were treated with LPS and then exposed to LIPUS (15 mW/cm2, 30 mW/cm2 and 60 mW/cm2) for 20 min daily for 3 days to determine the appropriate intensity to inhibit the expression of the inflammatory factors TNF-α and IL-1β. The gene and protein expression of aggrecan, collagen II, MMP-3 and MMP-9 was measured by real‐time PCR and western blotting, respectively. The activity of the nuclear factor‐kappa B (NF‐κB) pathway was examined by western blotting and immunofluorescence. After pretreatment with the NF-κB inhibitor PDTC, the expression of TNF-α, IL-1β, MMP-3 and MMP-9 was measured by real‐time PCR. Results: LIPUS at intensities of 15 mW/cm2, 30 mW/cm2 and 60 mW/cm2 inhibited LPS-induced NP cell expression of the inflammatory factors TNF-α and IL-1β, especially at 30 mW/cm2. LIPUS significantly upregulated the gene and protein expression of aggrecan and collagen II and downregulated the gene and protein expression of MMP-3 and MMP-9 in LPS-induced NP cells. The NF‐κB signaling pathway was inhibited by LIPUS through inhibiting the protein expression of p-P65 and the translocation of P65 into the nucleus in LPS-induced NP cells. In addition, LIPUS had similar effects as the NF-κB inhibitor PDTC by inhibiting the NF-κB signaling pathway, inflammation and catabolism in LPS-induced human degenerative nucleus pulposus cells. Conclusion: LIPUS inhibited inflammation and catabolism through the NF‐κB pathway in human degenerative nucleus pulposus cells. [ABSTRACT FROM AUTHOR]

Background: Copy number variation (CNVs) is a key factor in breast cancer development. This study determined prognostic molecular characteristics to predict breast cancer through performing a comprehensive analysis of copy number and gene expression data. Methods: Breast cancer expression profiles, CNV and complete information from The Cancer Genome Atlas (TCGA) dataset were collected. Gene Expression Omnibus (GEO) chip data sets (GSE20685 and GSE31448) containing breast cancer samples were used as external validation sets. Univariate survival COX analysis, multivariate survival COX analysis, least absolute shrinkage and selection operator (LASSO), Chi square, Kaplan-Meier (KM) survival curve and receiver operating characteristic (ROC) analysis were applied to build a gene signature model and assess its performance. Results: A total of 649 CNV related-differentially expressed gene obtained from TCGA-breast cancer dataset were related to several cancer pathways and functions. A prognostic gene sets with 9 genes were developed to stratify patients into high-risk and low-risk groups, and its prognostic performance was verified in two independent patient cohorts (n = 327, 246). The result uncovered that 9-gene signature could independently predict breast cancer prognosis. Lower mutation of PIK3CA and higher mutation of TP53 and CDH1 were found in samples with high-risk score compared with samples with low-risk score. Patients in the high-risk group showed higher immune score, malignant clinical features than those in the low-risk group. The 9-gene signature developed in this study achieved a higher AUC. Conclusion: The current research established a 5-CNV gene signature to evaluate prognosis of breast cancer patients, which may innovate clinical application of prognostic assessment. [ABSTRACT FROM AUTHOR]

Objective: It has been reported that ADAMTS‐12 is a susceptibility gene for rheumatoid arthritis (RA) development, and its level is significantly increased in RA patients. In addition, ADAMTS‐12 is reported to be required for inflammation in otherwise healthy subjects. This study was undertaken to determine the role of ADAMTS‐12 and the underlying mechanisms in the pathogenesis of inflammatory arthritis. Methods: The collagen‐induced arthritis (CIA) model was established in ADAMTS‐12–deficient mice and their control littermates to determine the role of ADAMTS‐12 in vivo. Micro–computed tomography scanning was used to demonstrate the destruction of the ankle joint; histologic analysis illustrated synovitis, pannus formation, and bone and cartilage destruction; enzyme‐linked immunosorbent assay was performed to measure serum levels of inflammatory cytokines; and protein–protein interaction assays were performed to detect the interactions of ADAMTS‐12 and its various deletion mutants with connective tissue growth factor (CTGF). Results: Deficiency of ADAMTS‐12 led to accelerated inflammatory arthritis in the CIA mouse model. Loss of ADAMTS‐12 caused enhanced osteoclastogenesis. In vitro and in vivo protein–protein interaction assays demonstrated that ADAMTS‐12 bound and processed CTGF, a previously unrecognized substrate of ADAMTS‐12. In addition, deletion of ADAMTS‐12 enhanced, while overexpression of ADMATS‐12 reduced, CTGF‐mediated inflammation. Furthermore, ADAMTS‐12 regulation of inflammation was largely lost in CTGF‐deficient macrophages. Importantly, blocking of CTGF attenuated elevated inflammatory arthritis seen in the ADAMTS‐12–deficient CIA mouse model. Conclusion: This study provides evidence that ADAMTS‐12 is a critical regulator of inflammatory arthritis and that this is mediated, at least in part, through control of CTGF turnover. [ABSTRACT FROM AUTHOR]

The article discusses tumor necrosis factor receptor (TNFR), death receptor 3 (DR-3), and progranulin (PGRN) pathways in bone remodeling and arthritis. Topics include interactions between PGRN and TNFR in bone remodeling and arthritis, cellular expression of death domain with tumor necrosis factor receptor superfamily (TNFRSF) members, and interactions between DR-3 and tumor necrosis factor-like molecule 1A (TL1A) in bone remodeling and arthritis.

Numerous clinical conditions have been linked to ectopic mineralization (EM). This process of pathological biomineralization is complex and not fully elucidated, but thought to be started within matrix vesicles (MVs). We hypothesized that high mobility group box 1 (HMGB1), a cytokine associated with biomineralizing process under physiological and pathological conditions, induces EM via promoting MVs secretion from macrophages. In this study, we found that HMGB1 significantly promoted secretion of MVs from macrophages and subsequently led to mineral deposition in elevated Ca/Pi medium in vitro. Transmission electron microscopy of calcifying MVs showed formation of hydroxyapatite crystals in the vesicle interior. Subcutaneous injection into mice with MVs derived from HMGB1-treated cells showed a greater potential to initiate regional mineralization. Mechanistic experiments revealed that HMGB1 activated neutral sphingomyelinase2 (nSMase2) that involved the receptor for advanced glycation end products (RAGE) and p38 MAPK (upstream of nSMase2). Inhibition of nSMase2 with GW4869 or p38 MAPK with SB-239063 prevented MVs secretion and mineral deposition. Collectively, HMGB1 induces MVs secretion from macrophages at least in part, via the RAGE/p38 MAPK/nSMase2 signaling pathway. Our findings thus reveal a novel mechanism by which HMGB1 induces ectopic mineralization. [ABSTRACT FROM AUTHOR]

The progranulin (PGRN) is known to protect regulatory T cells (Tregs) from a negative regulation by TNF-α, and its levels are elevated in various kinds of autoimmune diseases. Whether PGRN directly regulates the conversion of CD4+CD25-T cells into Foxp3-expressing regulatory T cells (iTreg), and whether PGRN affects the immunosuppressive function of Tregs, however, remain unknown. In this study we provide evidences demonstrating that PGRN is able to stimulate the conversion of CD4+CD25-T cells into iTreg in a dose-dependent manner in vitro. In addition, PGRN showed synergistic effects with TGF-β1 on the induction of iTreg. PGRN was required for the immunosuppressive function of Tregs, since PGRN-deficient Tregs have a significant decreased ability to suppress the proliferation of effector T cells (Teff). In addition, PGRN deficiency caused a marked reduction in Tregs number in the course of inflammatory arthritis, although no significant difference was observed in the numbers of Tregs between wild type and PGRN deficient mice during development. Furthermore, PGRN deficiency led to significant upregulation of the Wnt receptor gene Fzd2. Collectively, this study reveals that PGRN directly regulates the numbers and function of Tregs under inflammatory conditions, and provides new insight into the immune regulatory mechanism of PGRN in the pathogenesis of inflammatory and immune-related diseases. [ABSTRACT FROM AUTHOR]

Background: Immune-related genes (IRGs) have been confirmed to have an important role in tumorigenesis and tumor microenvironment formation. Nevertheless, a systematic analysis of IRGs and their clinical significance in soft tissue sarcoma (STS) patients is lacking.Methods: Gene expression files from The Cancer Genome Atlas (TCGA) database and Genotype-Tissue Expression (GTEx) were used to select differentially expressed genes (DEGs). Differentially expressed immune-related genes (DEIRGs) were determined by matching the DEG and ImmPort gene sets, which were evaluated by functional enrichment analysis. Unsupervised clustering of the identified DEIRGs was conducted, and associations with prognosis, the tumor microenvironment (TME), immune checkpoints, and immune cells were analyzed simultaneously. Two prognostic signatures, one for overall survival (OS) and one for progression free survival (PFS), were established and validated in an independent set. Finally, two transcription factor (TF)-IRG regulatory networks were constructed, and a crucial regulatory axis was validated.Results: In total, 364 DEIRGs and four clusters were identified. OS, TME scores, five immune checkpoints, and 12 types of immune cells were found to be significantly different among the four clusters. The two prognostic signatures incorporating 20 DEIRGs showed favorable discrimination and were successfully validated. Two nomograms combining signature and clinical variables were generated. The C-indexes were 0.879 (95%CI 0.832 ~ 0.926) and 0.825 (95%CI 0.776 ~ 0.874) for the OS and PFS signatures, respectively. Finally, TF-IRG regulatory networks were established, and the MYH11-ADM regulatory axis was verified in three independent datasets.Conclusion: This comprehensive analysis of the IRG landscape in soft tissue sarcoma revealed novel IRGs related to carcinogenesis and the immune microenvironment. These findings have implications for prognosis and therapeutic responses, which reveal novel potential prognostic biomarkers, promote precision medicine, and provide potential novel targets for immunotherapy. [ABSTRACT FROM AUTHOR]