Diffuse-type tenosynovial giant cell tumor(dTGCT)is a destructive but rare benign proliferative synovial neoplasm.Although surgery is currently the main treatment modality for dTGCT,the recurrence risk is up to 50%.Th...Diffuse-type tenosynovial giant cell tumor(dTGCT)is a destructive but rare benign proliferative synovial neoplasm.Although surgery is currently the main treatment modality for dTGCT,the recurrence risk is up to 50%.Therefore,there is a great need for effective drugs against dTGCT with minor side effects.The Janus kinase(JAK)/signal transducer and activator of transcription(STAT)signaling plays a central role in rheumatoid arthritis(RA),a disease with similar characteristics as dTGCT,but its function in dTGCT remains unknown.dTGCT fibroblast-like synoviocytes(FLS)and macrophages were isolated from 10 synovial tissue samples from dTGCT patients for the screening and validation of the five clinically approved JAK inhibitors to treat RA against dTGCT.Cell viability,cell death,inflammation and the activity of the JAK family members of cultured dTGCT FLS(both 2-D and 3-D)and macrophages were investigated for the efficacy of the JAK inhibitors.Here,we found that similar to RA,JAK/STAT signaling was markedly activated in the dTGCT synovium.Of the 5 JAK inhibitors,peficitinib was shown to have the most potency in addressing some of the pathological responses of dTGCT FLS and macrophages.The potency of peficitinib was much higher than pexidartinib,which is the only FDA-approved drug for dTGCT.Mechanistically,peficitinib inhibited tyrosine kinase 2(TYK2),a JAK family member necessary for the pathological progression of dTGCT FLS and macrophages.In summary,we not only revealed JAK/STAT(especially TYK2)signaling as the major mechanism underlying dTGCT,but also identified peficitinib as a promising drug against dTGCT.展开更多
Ulcerative colitis(UC), a chronic, relapsing, remitting disease of the colon and rectum, is characterized by inflammatory ulceration of the mucosa. Current UC therapy relies on controlling acute episodes and preventin...Ulcerative colitis(UC), a chronic, relapsing, remitting disease of the colon and rectum, is characterized by inflammatory ulceration of the mucosa. Current UC therapy relies on controlling acute episodes and preventing relapse. To predict modifications in the natural course of UC, mucosal healing(MH) has emerged as a major treatment goal. Endoscopic evaluation is considered the gold standard for assessing MH, which can be achieved by conventional drugs and biologics in many, but not all, patients. Consequently, interest is focusing on the development of new substances for UC therapy, and new oral agents are in the pipeline. This review will focus on the ability of newly developed oral drugs to induce and maintain MH in UC patients.展开更多
基金supported by grants from the National Key R&D Program of China(2021YFF0501401,2018YFA0800501)National Natural Science Foundation of China(82325004,92168114,82172447)Haihe Laboratory of Cell Ecosystem Innovation Fund(HH22KYZX0047).
文摘Diffuse-type tenosynovial giant cell tumor(dTGCT)is a destructive but rare benign proliferative synovial neoplasm.Although surgery is currently the main treatment modality for dTGCT,the recurrence risk is up to 50%.Therefore,there is a great need for effective drugs against dTGCT with minor side effects.The Janus kinase(JAK)/signal transducer and activator of transcription(STAT)signaling plays a central role in rheumatoid arthritis(RA),a disease with similar characteristics as dTGCT,but its function in dTGCT remains unknown.dTGCT fibroblast-like synoviocytes(FLS)and macrophages were isolated from 10 synovial tissue samples from dTGCT patients for the screening and validation of the five clinically approved JAK inhibitors to treat RA against dTGCT.Cell viability,cell death,inflammation and the activity of the JAK family members of cultured dTGCT FLS(both 2-D and 3-D)and macrophages were investigated for the efficacy of the JAK inhibitors.Here,we found that similar to RA,JAK/STAT signaling was markedly activated in the dTGCT synovium.Of the 5 JAK inhibitors,peficitinib was shown to have the most potency in addressing some of the pathological responses of dTGCT FLS and macrophages.The potency of peficitinib was much higher than pexidartinib,which is the only FDA-approved drug for dTGCT.Mechanistically,peficitinib inhibited tyrosine kinase 2(TYK2),a JAK family member necessary for the pathological progression of dTGCT FLS and macrophages.In summary,we not only revealed JAK/STAT(especially TYK2)signaling as the major mechanism underlying dTGCT,but also identified peficitinib as a promising drug against dTGCT.
文摘Ulcerative colitis(UC), a chronic, relapsing, remitting disease of the colon and rectum, is characterized by inflammatory ulceration of the mucosa. Current UC therapy relies on controlling acute episodes and preventing relapse. To predict modifications in the natural course of UC, mucosal healing(MH) has emerged as a major treatment goal. Endoscopic evaluation is considered the gold standard for assessing MH, which can be achieved by conventional drugs and biologics in many, but not all, patients. Consequently, interest is focusing on the development of new substances for UC therapy, and new oral agents are in the pipeline. This review will focus on the ability of newly developed oral drugs to induce and maintain MH in UC patients.
