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ObjectiveSeveral studies have demonstrated the impacts of GTPases of immunity-associated proteins (GIMAPs) on malignant cells. However, the mechanisms through which Gimap5 regulates lung cancer cells are yet to be thoroughly investigated in the literature. Our study aimed to investigate the function of Gimap5 in the development of lung cancer.MethodsThe expression levels of the GIMAP family were analyzed in lung cancer patients of various cancer databases and lung cancer cell lines. After the survival rates of the cells were analyzed, we constructed Gimap5 over-expressed lung cancer cell lines and assessed the effects of Gimap5 on cell migration, cell invasion, cell proliferation and the epithelial-mesenchymal transition (EMT). We later screened the interacting proteins of Gimap5 using Co-IP combined with mass spectrometry and then analyzed the expression and distribution of M6PR, including its impacts on protein-arginine deiminase type-4 (PADI4).ResultsFindings indicated that GIMAP family expression decreased significantly in lung cancer cell lines. We also noticed that the downregulation of the GIMAP family was related to the poor prognosis of lung cancer patients. Our experimental results showed that Gimap5 could inhibit the migration, invasion, proliferation and EMT of lung cancer cell lines. Moreover, we found that Gimap5 promoted the transport of M6PR from the cytoplasm to the cell membrane, thereby inhibiting the enhancement of EMT-related PADI4.ConclusionOur research suggested that Gimap5 could inhibit the growth of lung cancer by interacting with M6PR and that it could be a potential biomarker for the diagnosis and prognosis of lung cancer.

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Respiratory syncytial virus (RSV) is one of the main pathogens of viral pneumonia and bronchiolitis in infants and young children and life‐threatening diseases among infants and young children. GTPases of the immune‐associated protein family (GIMAP) are new family members of immune‐associated GTPases. In recent years, much attention has been paid to the function of the GIMAP family in coping with infection and stress. Gimap5 is a member of the GIMAP family, which may be correlated with anti‐infectious immunity. RT‐qPCR, Western blot, and indirect immunofluorescence (IFA) were used to detect the expression of Gimap5, M6PR and IGF1R(the major RSV receptor). Transmission electron microscopy (TEM) was used to detect the degradation of RSV in Gimap5‐overexpressed or ‐silent cell lines. Computer virtual screening was used to screen small molecule compounds targeting Gimap5 and the anti‐RSV effects were explored through in vivo and in vitro experiments. GIMAP5 and M6PR were significantly downregulated after RSV infection. Gimap5 accelerated RSV degradation in lysosomes by interacting with M6PR, and further prevented RSV invasion by downregulating the expression of RSV surface receptor IGF1R. Three small molecule compounds targeting Gimap5 were confirmed to be the agonists of Gimap5. The three compounds effectively inhibited RSV infection and RSV‐induced complications. Gimap5 promotes the degradation of RSV and its receptor through interacting with M6PR. Gimap5 agonists can effectively reduce RSV infection and RSV‐induced complication in vivo and in vitro, which provides a new choice for the treatment of RSV.

Background: Thymic epithelial tumors (TETs) are uncommon neoplasms with poor prognosis and limited effective therapeutic options. This study aims to investigate the prognosis of tumor mutation burden (TMB) and the potential association with immune infiltrates in TETs. Methods: Tumor mutation burden (TMB) was calculated using Maftools package and the samples were classified into high-TMB and low- TMB groups. Differentially expressed genes (DEGs) combined with immune cell infiltration and survival rate were analyzed between the low-TMB and high-TMB groups.Results: Single nucleotide polymorphism (SNP) occurred more frequently than insertion or deletion, and C>T was the most common single nucleotide variants (SNV) in TETs. The results of Kaplan–Meier curve indicated that a high TMB was associated with worse clinical outcomes of TETs. Moreover, 3 hub immune genes associated with immune infiltration were significantly associated with prognosis. Besides, the TMB-related signature (TMBRS) model based on the three hub immune genes possessed good predictive value with area under curve (AUC) 0.729, and patients with higher TMBRS scores showed worse TETs outcomes. In addition, infiltration levels of native CD4+ T cell, activated memory CD4+ T cell and follicular helper T cells in low-TMB group were higher than those in high-TMB group, which were correlated positively with prognosis of TETs. Conclusion: TETs patients with low TMB have better prognosis than those with high TMB, and TMB might affect the development of TETs by regulating immune infiltration.

Backgroud:The study was designed to explore the role of GIMAP family in non-small cell lung cancer (NSCLC) and its possible expression regulation mechanisms using existing biological databases including encyclopedia of DNA elements (ENCODE), gene expression omnibus (GEO), and the cancer genome atlas (TCGA). Methods: Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) were used to evaluate the expression of GIMAPs in TCGA.Five NSCLC datasets were then selected from GEO for validation. RNA-seq and Chip-seq data from ENCODE and GEO were used to observe epigenetic modifications on the chromosomes of GIAMPs in NSCLC. We constructed protein-protein interaction (PPI) network to reveal the main interacting proteins of GIMAPs. We then analyzed the correlation and regulatory mechanism between TAL1 and the expression of GIMAP family. We also used Kaplan-Meier for survival analysis. Results: All 7 genes in the GIMAP family were down-regulated in NSCLC.H3K4me3 and H3K27ac disappeared, while H3K27me3 increased on the chromosome of this family. The expression of TAL1 was positively correlated with the expression of GIMAPs. sh-TAL1 significantly down-regulated the expression of GIMAP family through epigenetic modification. High expression of GIMAPs and TAL1 was found to be associated with a good prognosis of NLCSC. Conclusion: The downregulation of TAL1 caused the disappearance of H3K27ac and H3K4me3. It also caused an increase in H3K27me3 on the GIMAPs gene, eventually leading to the overall downregulation of the GIMAP family genes.

Background Insulin-like growth factor 1 receptor (IGF1R) is a newly discovered key receptor that allows RSV to enter cells. RSV and IGF1R fusion triggers PKCζ activation, promoting cell signaling by recruiting nucleolin from the nucleus to the plasma membrane. It is tempting to speculate that other pneumoviruses, including bovine RSV, bind to the IGF1R. Methods Natural products that are effective against IGF1R protein were screened from TargetMol drugs datas by virtual screening. Virtual screening and in vivo and in vitro experiments were carried out. Results The results showed that Tannic acid and Daptomycin had anti-RSV potential through reducing viral loads, inflammation, airway resistance and protecting alveolar integrity. And the IC50 values of tannic acid and daptomycin were the 6 nM and 0.45 µM, respectively. Conclusions Novel small-molecule inhibitors targeting the IGF1R, Tannic acid or Daptomycin, may be effective anti-RSV therapy agents.

Objectives Respiratory syncytial virus (RSV) infection is one of the three most common causes of death in the infants, pre-schoolers, immunocompromised patients and elderly individuals due to many complications and lack of specific treatment. During RSV infection, the fusion protein (F protein) mediates the fusion of the virus envelope with the host cell membrane. Therefore, the F protein is an effective target for viral inhibition. Methods We identified potential small-molecule inhibitors against RSV-F protein for the treatment of RSV infection using virtual screening and molecular dynamics (MD) simulations. The CCK8 assay was used to determine the cytotoxicity and quantitative RT–PCR and indirect fluorescence assay (IFA) were used to determine the viral replication and RSV-induced inflammation in vitro. An RSV-infected mouse model was established, and viral replication was assayed using real-time quantitative PCR and IFA. Virus-induced complications were also examined using histopathological analysis, airway resistance and the levels of IL-1β, IL-6 and TNF-α. Results The top three potential inhibitors against the RSV-F protein were screened from the FDA-approved drug database. Z65, Z85 and Z74 significantly inhibited viral replication and RSV-induced inflammation. They also significantly alleviated RSV infection and RSV-induced complications in vivo. Z65 and Z85 had no cytotoxicity and better anti-RSV effects than Z74. Conclusions Z65 and Z85 may be suitable candidates for the treatment of RSV and serve as the basis for the development of new drugs.