A meta-validated immune infiltration-related gene model predicts prognosis and immunotherapy sensitivity in HNSCC.

BACKGROUND: Tumor microenvironment (TME) is of great importance to regulate the initiation and advance of cancer. The immune infiltration patterns of TME have been considered to impact the prognosis and immunotherapy sensitivity in Head and Neck squamous cell carcinoma (HNSCC). Whereas, specific molecular targets and cell components involved in the HNSCC tumor microenvironment remain a twilight zone. METHODS: Immune scores of TCGA-HNSCC patients were calculated via ESTIMATE algorithm, followed by weighted gene co-expression network analysis (WGCNA) to filter immune infiltration-related gene modules. Univariate, the least absolute shrinkage and selection operator (LASSO), and multivariate cox regression were applied to construct the prognostic model. The predictive capacity was validated by meta-analysis including external dataset GSE65858, GSE41613 and GSE686. Model candidate genes were verified at mRNA and protein levels using public database and independent specimens of immunohistochemistry. Immunotherapy-treated cohort GSE159067, TIDE and CIBERSORT were used to evaluate the features of immunotherapy responsiveness and immune infiltration in HNSCC. RESULTS: Immune microenvironment was significantly associated with the prognosis of HNSCC patients. Total 277 immune infiltration-related genes were filtered by WGCNA and involved in various immune processes. Cox regression identified nine prognostic immune infiltration-related genes (MORF4L2, CTSL1, TBC1D2, C5orf15, LIPA, WIPF1, CXCL13, TMEM173, ISG20) to build a risk score. Most candidate genes were highly expressed in HNSCC tissues at mRNA and protein levels. Survival meta-analysis illustrated high prognostic accuracy of the model in the discovery cohort and validation cohort. Higher proportion of progression-free outcomes, lower TIDE scores and higher expression levels of immune checkpoint genes indicated enhanced immunotherapy responsiveness in low-risk patients. Decreased memory B cells, CD8+ T cells, follicular helper T cells, regulatory T cells, and increased activated dendritic cells and activated mast cells were identified as crucial immune cells in the TME of high-risk patients. CONCLUSIONS: The immune infiltration-related gene model was well-qualified and provided novel biomarkers for the prognosis of HNSCC.

Identification of the shared genes and immune signatures between systemic lupus erythematosus and idiopathic pulmonary fibrosis.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disorder which could lead to inflammation and fibrosis in various organs. Pulmonary fibrosis is a severe complication in patients with SLE. Nonetheless, SLE-derived pulmonary fibrosis has unknown pathogenesis. Of pulmonary fibrosis, Idiopathic pulmonary fibrosis (IPF) is a typicality and deadly form. Aiming to investigate the gene signatures and possible immune mechanisms in SLE-derived pulmonary fibrosis, we explored common characters between SLE and IPF from Gene Expression Omnibus (GEO) database. RESULTS: We employed the weighted gene co-expression network analysis (WGCNA) to identify the shared genes. Two modules were significantly identified in both SLE and IPF, respectively. The overlapped 40 genes were selected out for further analysis. The GO enrichment analysis of shared genes between SLE and IPF was performed with ClueGO and indicated that p38MAPK cascade, a key inflammation response pathway, may be a common feature in both SLE and IPF. The validation datasets also illustrated this point. The enrichment analysis of common miRNAs was obtained from the Human microRNA Disease Database (HMDD) and the enrichment analysis with the DIANA tools also indicated that MAPK pathways' role in the pathogenesis of SLE and IPF. The target genes of these common miRNAs were identified by the TargetScan7.2 and a common miRNAs-mRNAs network was constructed with the overlapped genes in target and shared genes to show the regulated target of SLE-derived pulmonary fibrosis. The result of CIBERSORT showed decreased regulatory T cells (Tregs), naïve CD4+ T cells and rest mast cells but increased activated NK cells and activated mast cells in both SLE and IPF. The target genes of cyclophosphamide were also obtained from the Drug Repurposing Hub and had an interaction with the common gene PTGS2 predicted with protein-protein interaction (PPI) and molecular docking, indicating its potential treatment effect. CONCLUSIONS: This study originally uncovered the MAPK pathway, and the infiltration of some immune-cell subsets might be pivotal factors for pulmonary fibrosis complication in SLE, which could be used as potentially therapeutic targets. The cyclophosphamide may treat SLE-derived pulmonary fibrosis through interaction with PTGS2, which could be activated by p38MAPK.

CX3CR1 regulates the development of renal interstitial fibrosis through macrophage polarization. / CX3CR1通过调控巨噬细胞极化影响肾间质纤维化.

OBJECTIVES: The binding of CX3C chemokine receptor 1 (CX3CR1) and its unique ligand CX3C chemokine ligand 1 (CX3CL1) can promote the migration of inflammatory cells to the lesion and affect the progression of renal interstitial fibrosis, but the underlying mechanisms remain unclear. This study aims to investigate whether CX3CR1 affects renal interstitial fibrosis by macrophage polarization. METHODS: A mouse model of renal interstitial fibrosis was established by unilateral ureteral obstruction (UUO). C57/B6 mice were divided into a CX3CR1 inhibitor group (injected with CX3CR1 inhibitor AZD8797) and a model group (injected with physiological saline). After continuous intraperitoneal injection for 5 days, the ligated lateral kidneys of mice were obtained on the 7th day. Hematoxylin and eosin (HE) staining and Masson staining were used to observe the infiltration of inflammatory cells and the collagen fiber deposition in renal interstitium, respectively. The mRNA and protein expressions of CX3CR1, alpha-smooth muscle actin (α-SMA) and fibronectin (FN) in the kidneys were detected by reverse transcription PCR (RT-PCR) and Western blotting, respectively. Differentially expressed genes in kidney of the 2 groups were identified by whole genome sequencing and the differential expression of arginase-1 (Arg-1) was verified by RT-PCR. Flow cytometry was used to detect the proportion of M2 type macrophages in kidneys of the 2 groups. RESULTS: The infiltration of inflammatory cells and the collagen fiber deposition in renal interstitium were significantly reduced in the CX3CR1 inhibitor group. The mRNA and protein levels of CX3CR1 and the mRNA levels of α-SMA and FN in the CX3CR1 inhibitor group were significantly lower than those of the model group (all P<0.05). Whole genome sequencing showed that the top 5 differentially expressed genes in kidney of the 2 groups were Ugt1a6b, Serpina1c, Arg-1, Retnla, and Nup62. RT-PCR verified that the expression level of Arg-1 in kidney of the CX3CR1 inhibitor group was significantly higher than that of the model group (P<0.001). Flow cytometry showed that the proportion of Arg1+CD206+M2 macrophages in kidney of the CX3CR1 inhibitor group was significantly higher than that of the model group (P<0.01). CONCLUSIONS: Inhibiting CX3CR1 can effectively prevent the progression of renal interstitial fibrosis. The mechanism may be related to macrophage polarization towards M2 type and upregulation of Arg-1 expression.

Impact of Cardiovascular Diseases on COVID-19: A Systematic Review.

In December 2019, pneumonia of unknown cause broke out, and currently more than 150 countries around the world have been affected. Globally, as of 5: 46 pm CET, 6 November 2020, the World Health Organization (WHO) had reported 48 534 508 confirmed cases of COVID-19, including 1 231 017 deaths. The novel coronavirus disease (COVID-19) outbreak, caused by the SARS-CoV-2 virus, is the most important medical challenge in decades. Previous research mainly focused on the exploration of lung changes. However, with development of the disease and deepening research, more and more patients showed cardiovascular diseases, even in those without respiratory symptoms, and some researchers have found that underlying cardiovascular diseases increase the risk of infection. Although the related mechanism is not thoroughly studied, based on existing research, we speculate that the interaction between the virus and its receptor, inflammatory factors, various forms of the stress response, hypoxic environment, and drug administration could all induce the development of cardiac adverse events. Interventions to control these pathogenic factors may effectively reduce the occurrence of cardiovascular complications. This review summarizes the latest research on the relationship between COVID-19 and its associated cardiovascular complications, and we also explore possible mechanisms and treatments.

Immunological Indicators of Recurrent Pregnancy Loss: A Mendelian Randomization Study.

Recurrent pregnancy loss (RPL) is thought to be related to maternal-fetal immune tolerance disorders. Immune monitoring of RPL patients mainly involves two aspects: inflammatory factors and immune cells. However, most observational studies have reported controversial findings. This study aimed to confirm whether abnormal inflammatory factors and immune cells in peripheral blood may lead to RPL, and guide clinical immune monitoring. We demonstrated causality using two-sample Mendelian randomization. Sensitivity analysis, reverse Mendelian randomization and meta-analysis were used to enhance the effectiveness of the results. There was a causal relationship between the level of IL-12 (OR = 1.78, 95% CI = 1.25-2.55; P = 0.00149) and RPL for 41 inflammatory factors. We screened 5 groups of immune cell subtypes that were causally associated with RPL: switched memory B-cell absolute count (OR = 0.66, 95% CI = 0.49-0.87, P = 0.00406), IgD + CD24 + B-cell absolute count (OR = 0.69, 95% CI = 0.53-0.88, P = 0.00319), CD39 + resting CD4 regulatory T-cell %CD4 regulatory T-cell (OR = 0.86, 95% CI = 0.78-0.95, P = 0.00252), activated & resting CD4 regulatory T-cell %CD4 regulatory T-cell (OR = 0.89, 95% CI = 0.82-0.97, P = 0.00938) and CD45 RA + CD28-CD8 + T-cell %CD8 + T-cell (OR = 0.99, 95% CI = 0.98-1.00, P = 0.01231). In terms of inflammatory factors, a causal relationship between IL-12 and RPL in peripheral blood was confirmed. We also identified five immune cell phenotypes that play a protective role. This suggests that there may be protective B cells and CD8 + T-cell subsets in peripheral blood, and the protective effect of Tregs was proved again. Immune monitoring of peripheral blood in patients with RPL seems to be necessary and the foundation for precision medicine.

An analysis of reported cases of hemophagocytic lymphohistiocytosis (HLH) after COVID-19 vaccination.

Although COVID-19 vaccines are an effective public health tool to combat the global pandemic, serious adverse events, such as hemophagocytic lymphohistiocytosis (HLH), caused by them are a concern. In this systematic review, cases of HLH reported after COVID-19 vaccination have been examined to understand the relationship between the two and propose effective therapeutic strategies. Furthermore, ruxolitinib's potential as a cytokine inhibitor and its affinity for CD25 were initially assessed through molecular docking, aiming to aid targeted HLH therapy. PubMed and Web of Science databases were searched for published individual case reports on the occurrence of HLH after the administration of any COVID-19 vaccine. A total of 17 articles (25 patients) were included in this qualitative analysis. Furthermore, molecular docking was employed to investigate the therapeutic potential of ruxolitinib for HLH after COVID-19 vaccination. The mean age of patients who developed HLH after COVID-19 vaccination was 48.1 years. Most HLH episodes occurred after the BNT162b2 mRNA COVID-19 vaccination (14/25 cases) and to an extent after the ChAdOx1 nCov-19 vaccination (5/25 cases). Almost all affected patients received steroid and antibiotic therapy. Three patients died despite treatment because of esophagus rupture, neutropenic fever, bacteroides bacteremia, refractory shock, and encephalopathy and shock. Visual docking results of IL-2 Rα and ruxolitinib using the Discovery Studio 2019 Client software yielded a model score of 119.879. The findings highlight the importance of considering and identifying the adverse effects of vaccination and the possibility of using ruxolitinib for treating HLH after COVID-19 vaccination.

Knowledge mapping of students' mental health status in the COVID-19 pandemic: A bibliometric study.

Objective: The purpose of this study was to investigate the international scientific output on mental health of students during COVID-19 from 2020 to 2022 through a bibliometric analysis and to explore trend and research hotspots in this field. Methods: We searched the Web of Science Core Collection for publications and used a variety of software to analyze and visualize the data such as R, CiteSpace, VOSviewer and Scimago. Results: A total of 2,734 publications were retrieved as of June 4, 2022, published by 3,894 institutions from 120 countries/regions. China and the United States lead in the quantity and quality of publications in this field. According to Bradford's Law, 16 journals are considered core journals in the field. Co-cited references indicate the main psychological problems of students under the epidemic revolve around anxiety, poor sleep and financial difficulty. Their behavior might also be influenced by increased internet and alcohol use. Conclusion: Mental health of students during COVID-19 is attracting increasing attention. It is identified that the research hotspots in this field continue to revolve around emotional anxiety and unhealthy behaviors. Due to the different troubles faced by different groups under COVID-19, further exploration of the relevant factors specific for students are needed, with a hopeful view to providing ideas for intervention measures.

Ferroptosis-related gene signatures in neuroblastoma associated with prognosis.

Background: Ferroptosis, a form of regulatory cell death, has been linked to the development of various tumors. Peripheral neuroblastoma (NB) is one of the most common extracranial solid tumors in children, and it has been proposed that regulating tumor cell ferroptosis may be a future treatment for NB. However, it is unclear how ferroptosis contributes to NB development. Methods: Expression data were collected from two independent cohorts (GEO and Arrayexpress databases). Univariate Cox analysis, multivariate Cox analysis, and the least absolute shrinkage and selection operator (Lasso) algorithm were applied to create a prognostic signature, whose performance was quantified using the area under the receiver operating characteristic curve (AUC) and Kaplan-Meier curves. A prognostic meta-analysis was used to test the suitability and stability of the FRG signature. Drug sensitivity analyses were performed using the data collected from Cell Miner™. Results: PROM2, AURKA, STEAP3, CD44, ULK2, MAP1LC3A, ATP6V1G2, and STAT3 are among the eight genes in the FRG prognostic signature, all of which were highly expressed in stage 1 NB, except AURKA. Furthermore, the high-risk group, which was stratified by signature, had a lower overall survival rate than the low-risk group. GSEA revealed that high-risk groups have more biological processes related to ferroptosis. Conclusion: Ferroptosis-related genes are expressed differently between stages 1 and 4 NB. The FRG signature successfully stratified NB patients into two risk groups and can accurately predict the overall survival in NB. In addition, we found that the gene AURKA might have the potential to be a prognostic marker in NB.

Investigation of an FGFR-Signaling-Related Prognostic Model and Immune Landscape in Head and Neck Squamous Cell Carcinoma.

Background: There is accumulating evidence on the clinical importance of the fibroblast growth factor receptor (FGFR) signal, hypoxia, and glycolysis in the immune microenvironment of head and neck squamous cell carcinoma (HNSCC), yet reliable prognostic signatures based on the combination of the fibrosis signal, hypoxia, and glycolysis have not been systematically investigated. Herein, we are committed to establish a fibrosis-hypoxia-glycolysis-related prediction model for the prognosis and related immune infiltration of HNSCC. Methods: Fibrotic signal status was estimated with microarray data of a discovery cohort from the TCGA database using the UMAP algorithm. Hypoxia, glycolysis, and immune-cell infiltration scores were imputed using the ssGSEA algorithm. Cox regression with the LASSO method was applied to define prognostic genes and develop a fibrosis-hypoxia-glycolysis-related gene signature. Immunohistochemistry (IHC) was conducted to identify the expression of specific genes in the prognostic model. Protein expression of several signature genes was evaluated in HPA. An independent cohort from the GEO database was used for external validation. Another scRNA-seq data set was used to clarify the related immune infiltration of HNSCC. Results: Six genes, including AREG, THBS1, SEMA3C, ANO1, IGHG2, and EPHX3, were identified to construct a prognostic model for risk stratification, which was mostly validated in the independent cohort. Multivariate analysis revealed that risk score calculated by our prognostic model was identified as an independent adverse prognostic factor (p < .001). Activated B cells, immature B cells, activated CD4+ T cells, activated CD8+ T cells, effector memory CD8+ T cells, MDSCs, and mast cells were identified as key immune cells between high- and low-risk groups. IHC results showed that the expression of SEMA3C, IGHG2 were slightly higher in HNSCC tissue than normal head and neck squamous cell tissue. THBS1, ANO1, and EPHX3 were verified by IHC in HPA. By using single-cell analysis, FGFR-related genes and highly expressed DEGs in low-survival patients were more active in monocytes than in other immune cells. Conclusion: A fibrosis-hypoxia-glycolysis-related prediction model provides risk estimation for better prognoses to patients diagnosed with HNSCC.

Mitochondrial dysfunction in fibrotic diseases.

Although fibrosis is a common pathological feature of most end-stage organ diseases, its pathogenesis remains unclear. There is growing evidence that mitochondrial dysfunction contributes to the development and progression of fibrosis. The heart, liver, kidney and lung are highly oxygen-consuming organs that are sensitive to mitochondrial dysfunction. Moreover, the fibrotic process of skin and islet is closely related to mitochondrial dysfunction as well. This review summarized emerging mechanisms related to mitochondrial dysfunction in different fibrotic organs and tissues above. First, it highlighted the important elucidation of mitochondria morphological changes, mitochondrial membrane potential and structural damage, mitochondrial DNA (mtDNA) damage and reactive oxidative species (ROS) production, etc. Second, it introduced the abnormality of mitophagy and mitochondrial transfer also contributed to the fibrotic process. Therefore, with gaining the increasing knowledge of mitochondrial structure, function, and origin, we could kindle a new era for the diagnostic and therapeutic strategies of many fibrotic diseases based on mitochondrial dysfunction.

Tolerogenic Dendritic Cells: The Pearl of Immunotherapy in Organ Transplantation.

Over a half century, organ transplantation has become an effective method for the treatment of end-stage visceral diseases. Although the application of immunosuppressants (IS) minimizes the rate of allograft rejection, the common use of IS bring many adverse effects to transplant patients. Moreover, true transplant tolerance is very rare in clinical practice. Dendritic cells (DCs) are thought to be the most potent antigen-presenting cells, which makes a bridge between innate and adaptive immunity. Among their subsets, a small portion of DCs with immunoregulatory function was known as tolerogenic DC (Tol-DC). Previous reports demonstrated the ability of adoptively transferred Tol-DC to approach transplant tolerance in animal models. In this study, we summarized the properties, ex vivo generation, metabolism, and clinical attempts of Tol-DC. Tol-DC is expected to become a substitute for IS to enable patients to achieve immune tolerance in the future.