Chemotherapy resistance plays a pivotal role in the prognosis and therapeutic failure of patients with colorectal cancer(CRC).Cisplatin(DDP)-resistant cells exhibit an inherent ability to evade the toxic chemotherapeu...Chemotherapy resistance plays a pivotal role in the prognosis and therapeutic failure of patients with colorectal cancer(CRC).Cisplatin(DDP)-resistant cells exhibit an inherent ability to evade the toxic chemotherapeutic drug effects which are characterized by the activation of slow-cycle programs and DNA repair.Among the elements that lead to DDP resistance,O^(6)-methylguanine(O^(6)-MG)-DNA-methyltransferase(MGMT),a DNA-repair enzyme,performs a quintessential role.In this study,we clarify the significant involvement of MGMT in conferring DDP resistance in CRC,elucidating the underlying mechanism of the regulatory actions of MGMT.A notable upregulation of MGMT in DDP-resistant cancer cells was found in our study,and MGMT repression amplifies the sensitivity of these cells to DDP treatment in vitro and in vivo.Conversely,in cancer cells,MGMT overexpression abolishes their sensitivity to DDP treatment.Mechanistically,the interaction between MGMT and cyclin dependent kinase 1(CDK1)inducing slow-cycling cells is attainted via the promotion of ubiquitination degradation of CDK1.Meanwhile,to achieve nonhomologous end joining,MGMT interacts with XRCC6 to resist chemotherapy drugs.Our transcriptome data from samples of 88 patients with CRC suggest that MGMT expression is co-related with the Wnt signaling pathway activation,and several Wnt inhibitors can repress drug-resistant cells.In summary,our results point out that MGMT is a potential therapeutic target and predictive marker of chemoresistance in CRC.展开更多
Green and low carbon promote the application and development of light-weight materials in body-in-white. Large-scale die-casting Al alloy (DCAA) and high-strength thermo-formed steel sheet (TFSS) have put forward high...Green and low carbon promote the application and development of light-weight materials in body-in-white. Large-scale die-casting Al alloy (DCAA) and high-strength thermo-formed steel sheet (TFSS) have put forward higher requirements for the application of joining technology of high-strength steel/Al dissimilar materials. Taking the new die-casting Al alloy body as an example, this paper systematically studies the progress of the latest joining methods of steel/Al dissimilar material with combination of two-layer plate and three-layer plate. By analyzing the joining technologies such as FSPR, RES, FDS and SPR, the technology and process characteristics of steel/Al dissimilar material joining are studied, and the joining technical feasibility and realization means of different material combination of the body are analyzed. The conditions of material combination, material thickness, material strength, flange height, preformed holes and joint spacing for achieving high-quality joining are given. The FSPR joining technology is developed and tested in order to meet with the joining of parts with DCAA and TFSS, especially for the joining of three-layer plates with them. It finds the method and technical basis for the realization of high quality joining of dissimilar materials, provides the early conditions for the application of large DCAA and TFSS parts in body-in-white, and meets the design requirements of new energy body. .展开更多
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.:82003807,82173394)the Shaanxi Province Science Foundation,China(Grant No.:2023-GHZD-19)+1 种基金the Medical Foundation-Clinical Integration Program of Xi'an Jiaotong University,China(Grant No.:YXJLRH2022043)the Xi'an Jiaotong University Free Exploration and Innovation-Teacher Project Foundation,China(Grant No.:xzy012023104).
文摘Chemotherapy resistance plays a pivotal role in the prognosis and therapeutic failure of patients with colorectal cancer(CRC).Cisplatin(DDP)-resistant cells exhibit an inherent ability to evade the toxic chemotherapeutic drug effects which are characterized by the activation of slow-cycle programs and DNA repair.Among the elements that lead to DDP resistance,O^(6)-methylguanine(O^(6)-MG)-DNA-methyltransferase(MGMT),a DNA-repair enzyme,performs a quintessential role.In this study,we clarify the significant involvement of MGMT in conferring DDP resistance in CRC,elucidating the underlying mechanism of the regulatory actions of MGMT.A notable upregulation of MGMT in DDP-resistant cancer cells was found in our study,and MGMT repression amplifies the sensitivity of these cells to DDP treatment in vitro and in vivo.Conversely,in cancer cells,MGMT overexpression abolishes their sensitivity to DDP treatment.Mechanistically,the interaction between MGMT and cyclin dependent kinase 1(CDK1)inducing slow-cycling cells is attainted via the promotion of ubiquitination degradation of CDK1.Meanwhile,to achieve nonhomologous end joining,MGMT interacts with XRCC6 to resist chemotherapy drugs.Our transcriptome data from samples of 88 patients with CRC suggest that MGMT expression is co-related with the Wnt signaling pathway activation,and several Wnt inhibitors can repress drug-resistant cells.In summary,our results point out that MGMT is a potential therapeutic target and predictive marker of chemoresistance in CRC.
文摘Green and low carbon promote the application and development of light-weight materials in body-in-white. Large-scale die-casting Al alloy (DCAA) and high-strength thermo-formed steel sheet (TFSS) have put forward higher requirements for the application of joining technology of high-strength steel/Al dissimilar materials. Taking the new die-casting Al alloy body as an example, this paper systematically studies the progress of the latest joining methods of steel/Al dissimilar material with combination of two-layer plate and three-layer plate. By analyzing the joining technologies such as FSPR, RES, FDS and SPR, the technology and process characteristics of steel/Al dissimilar material joining are studied, and the joining technical feasibility and realization means of different material combination of the body are analyzed. The conditions of material combination, material thickness, material strength, flange height, preformed holes and joint spacing for achieving high-quality joining are given. The FSPR joining technology is developed and tested in order to meet with the joining of parts with DCAA and TFSS, especially for the joining of three-layer plates with them. It finds the method and technical basis for the realization of high quality joining of dissimilar materials, provides the early conditions for the application of large DCAA and TFSS parts in body-in-white, and meets the design requirements of new energy body. .
