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Nasopharyngeal carcinoma (NPC) is one of the most prevalent head and neck cancer in southeast Asia. It is necessary to proceed further studies on the mechanism of occurrence and development of NPC. In this study, we employed the microarray dataset GSE12452 and GSE53819 including 28 normal samples and 49 nasopharyngeal carcinoma samples downloaded from the Gene Expression Omnibus(GEO) to analysis. R software, STRING, CMap, and various databases were used to screen differentially expressed genes (DEGs), construct the protein–protein interaction (PPI) network, and proceed small molecule compounds analysis, among others. Totally, 424 DEGs were selected from the dataset. DEGs were mainly enriched in extracellular matrix organization, cilium organization, PI3K-Akt signaling pathway, collagen-containing extracellular matrix, and extracellular matrix-receptor interaction, among others. Top 10 upregulated and top 10 downregulated hub genes were identified as hub DEGs. Piperlongumine, apigenin, menadione, 1,4-chrysenequinone, and chrysin were identified as potential drugs to prevent and treat NPC. Besides, the effect of genes CDK1, CDC45, RSPH4A, and ZMYND10 on survival of NPC was validated in GEPIA database. The data revealed novel aberrantly expressed genes and pathways in NPC by bioinformatics analysis, potentially providing novel insights for the molecular mechanisms governing NPC progression. Although further studies needed, the results demonstrated that the expression levels of CDK1, CDC45, RSPH4A, and ZMYND10 probably affected survival of NPC patients.

Previous reports indicate that Cdc42-interacting protein-4 (CIP4) has previously been reported to plays an important role in the progression of various cancers. However, its correlation with laryngeal cancer (LC) remains unreported. Data from TCGA and GEO databases were used to evaluate the role of CIP4 in LC. Based on GEO and TCGA datasets, we analyzed the differences in CIP4 expression between normal and tumor samples. The Wilcoxon signed-rank test was used to analyze the relationship between clinical features and CIP4. Cox regression and the Kaplan-Meier analyses were used to identify the clinical characteristics associated with the overall survival. Also, the GEPIA database was used to confirm the relationship between CIP4 and overall survival. Lastly, Gene Set Enrichment Analysis (GSEA) was performed based on the TCGA dataset. CIP4 expression in LC was significantly associated with gender and tumor stage (p-values<0.05). Similar to GEPIA validation, Kaplan-Meier survival analysis demonstrated that LC with CIP4-low exhibited a worse prognosis than that with CIP4-high. Univariate analysis revealed that CIP4-high significantly correlated with better overall survival (HR: 0.522, 95% CI: 0.293–0.830, P = 0.026). Besides, multivariate analysis revealed that CIP4 remained independently associated with the overall survival (HR: 0.61, 95% CI: 0.326–0.912, P = 0.012). GSEA showed that the p53, WNT signaling, TGF-β signaling pathways, etc. were enriched in a phenotype high CIP4 expression. In summary, the CIP4 gene is a potential prognostic molecular marker for patients diagnosed with laryngeal cancer. Moreover, the p53, WNT signaling, and TGF-β signaling pathways are potentially associated with CIP4 in LC.

Rationale: T-cell-redirecting bispecific antibodies (bsAbs) and trispecific antibodies (tsAbs) designed to recognize different epitopes or antigens have emerged as promising cancer therapies. Current approaches are all designed to include another antibody specific to the site of the primary antibody, and the molecular structures are generally established. However, the dimensions of target molecule and epitope location play a key role in the efficiency of the immunological synapse (IS) formation and subsequent T-cell-redirecting activities, therefore the connection flexibility of these antibodies determines the geometries of different formats of these molecules and will have a major impact on the efficacy. Methods: We describe a novel recombination strategy using various linker designs to site-specifically fuse anti-Her2 (2Rs15) or anti-VEGFR2 (3VGR19) nanobodies to different positions of the anti-CD3 antibody fragment (Fab, SP34). Based on the comparison among the various antigen-specific bsAbs, we could determine the desired fusion site of each nanobody to SP34, and further ensure the optimal structure of tsAbs with synergistic dual-antigen enhanced T-cell-redirecting activities. Results: This approach allows precise control of the formation of IS between Her2- and/or VEGFR2-expressing cancer cells and T cells, to obtain the optimal structure of the Her2/VEGFR2/CD3 tsAb without the need to map antibody-binding epitopes. Optimization of Her2/VEGFR2/CD3 tsAb results in enhanced T-cell-redirecting in vitro and in vivo antitumor efficacy compared with the corresponding bsAbs alone or in combination, and the potency to overcome tumor relapse due to antigen escape or resistance to Herceptin and Cyramza therapy. Conclusion: The novel design strategy for developing tsAbs using a site-specific recombination approach represents a promising platform for immuno-oncology and in applications other than cancer therapy.

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