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Background: Afatinib, a second-generation tyrosine kinase inhibitor (TKI), exerts its radiosensitive effects in nasopharyngeal carcinoma (NPC). However, the detailed mechanism of afatinib-mediated sensitivity to radiation is still obscure in NPC. Methods: Quantitative phosphorylated proteomics and bioinformatics analysis were performed to illustrate the global phosphoprotein changes. The activity of the CD44-Stat3 axis and Epithelial-Mesenchymal Transition (EMT)-linked markers were evaluated by Western blotting. Wound healing and transwell assays were used to determine the levels of cell migration upon afatinib combined IR treatment. Cell proliferation was tested by CCK-8 assay. A pharmacological agonist by IL-6 was applied to activate Stat3. The xenograft mouse model was treated with afatinib, radiation or a combination of afatinib and radiation to detect the radiosensitivity of afatinib in vivo. Results: In the present study, we discovered that afatinib triggered global protein phosphorylation alterations in NPC cells. Further, bioinformatics analysis indicated that afatinib inhibited the CD44-Stat3 signaling and subsequent EMT process. Moreover, functional assays demonstrated that afatinib combined radiation treatment remarkably impeded cell viability, migration, EMT process and CD44-Stat3 activity in vitro and in vivo. In addition, pharmacological stimulation of Stat3 rescued radiosensitivity and biological functions induced by afatinib in NPC cells. This suggested that afatinib reversed the EMT process by blocking the activity of the CD44-Stat3 axis. Conclusion: Collectively, this work identifies the molecular mechanism of afatinib as a radiation sensitizer, thus providing a potentially useful combination treatment and drug target for NPC radiosensitization. Our findings describe a new function of afatinib in radiosensitivity and cancer treatment. [ABSTRACT FROM AUTHOR]

The anti-derailment guard rail is the key accessory equipment of track safety in elevated rail transit line. The existing anti-derailment guard rail for urban rail transit has some disadvantages, such as poor engineering adaptability, large quality, difficult maintenance, complex process and poor reliability, etc., which are not conducive to the continued use of urban rail transit elevated lines. Therefore, it is necessary to study a new type of anti-derailment guard rail with better safety, versatility, construction convenience and economy. Combined with the existing experiences of anti-derailment guard rail, a new type of anti-derailment guard rail applicable to 60 kg / m rail in urban rail transit line is designed from the aspects of better safety, structural strength, engineering adaptability and maintainability. The simulation analysis shows that the middle part and joint part of the new anti-derailment guard rail are not damaged under different lateral force loads. The lateral thrust test shows that the middle part and joint position of anti-derailment guard rail are not damaged under the lateral thrust of 100 kN. The fatigue test with 3 million cyclic loads shows no looseness in the assembled anti-derailment guard rail. The new anti- derailment guard rail has good durability, stability, safety and reliability, meets the requirements of urban rail transit, and can replace the existing anti-derailment guard rails. [ABSTRACT FROM AUTHOR]

As one of commonly used platforms for BIM design of urban rail transit, Revit has built-in rich design tools in professional engineering such as architecture and structure, which can realize efficient BIM modeling. The urban rail transit track project is belt-shaped under a spatial curve, and the existing Revit platform cannot meet the efficient modeling needs of professional designers. In response to this problem, based on the professional design experience of the track, combined with the characteristics of the software of the Revit platform, this paper proposed a method to quickly realize the BIM modeling of the track under the Revit platform. Through the Dynamo visual programming tool under the Revit platform, a special tool was developed to read the basic data of the horizontal and vertical section of the line and directly calculate the line space position and direction, and then automatically called various rail Revit adaptive components for rails and sleepers. The arrangement of fasteners and track bed realizes the efficient modeling of track BIM, which can a provide reference for the BIM design of similar projects. [ABSTRACT FROM AUTHOR]

Aerobic glycolysis is a pivotal hallmark of cancers, including colorectal cancer. Evidence shows glycolytic enzymes are regulated by post-translational modifications (PTMs), thereby affecting the Warburg effect and reprograming cancer metabolism. Lysine lactylation is a PTM reported in 2019 in histones. In this study, we identified protein lactylation in FHC cells and SW480 colon cancer cells through mass spectrometry. Totally, 637 lysine lactylation sites in 444 proteins were identified in FHC and SW480 cells. Lactylated proteins were enriched in the glycolysis pathway, and we identified lactylation sites in phosphofructokinase, platelet (PFKP) lysine 688 and aldolase A (ALDOA) lysine 147. We also showed that PFKP lactylation directly attenuated enzyme activity. Collectively, our study presented a resource to investigate proteome-wide lactylation in SW480 cells and found PFKP lactylation led to activity inhibition, indicating that lactic acid and lactylated PFKP may form a negative feedback pathway in glycolysis and lactic acid production., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

To investigate the global proteomic profiles of vascular endothelial cells (VECs) in the tumor microenvironment and antiangiogenic therapy for colorectal cancer (CRC), matched pairs of normal (NVECs) and tumor-associated VECs (TVECs) were purified from CRC tissues by laser capture microdissection and subjected to iTRAQ-based quantitative proteomics analysis. Here, 216 differentially expressed proteins (DEPs) were identified and used for bioinformatics analysis. Interestingly, these proteins were implicated in epithelial mesenchymal transition (EMT), ECM-receptor interaction, focal adhesion, PI3K-Akt signaling pathway, angiogenesis and HIF-1 signaling pathway, which may play important roles in CRC angiogenesis. Among these DEPs we found that Tenascin-C (TNC) was upregulated in TVECs of CRC and correlated with CRC multistage carcinogenesis and metastasis. Furthermore, the reduction of tumor-derived TNC could attenuate human umbilical vein endothelial cell (HUVEC) proliferation, migration and tube formation through ITGB3/FAK/Akt signaling pathway. Based on the present work, we provided a large-scale proteomic profiling of VECs in CRC with quantitative information, a certain number of potential antiangiogenic targets and a novel vision in the angiogenesis bio-mechanism of CRC., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2019. Published by The Company of Biologists Ltd.)