Most cancers are currently incurable, partly due to abnormal post-translational modifications (PTMs). In this study, we initially used multiple myeloma (MM) as a working model and found that SUMOylation activating enzyme subunit 1 (SAE1) promotes the malignancy of MM. Through proteome microarray analysis, SAE1 was identified as a potential target for bioactive colcemid or its derivative colchicine. Elevated levels of SAE1 were associated with poor clinical survival and increased MM proliferation in vitro and in vivo. Additionally, SAE1 directly SUMOylated and upregulated the total protein expression of p27, leading to LLPS-mediated nuclear export of p27. Our study also demonstrated the involvement of SAE1 in other types of cancer cells, and provided the first monomer crystal structure of SAE1 and its key binding model with colchicine. Colchicine also showed promising results in the Patient-Derived Tumor Xenograft (PDX) model. Furthermore, a controlled clinical trial with 56 MM patients demonstrated the clinical efficacy of colchicine. Our findings reveal a novel mechanism by which tumor cells evade p27-induced cellular growth arrest through p27 SUMOylation-mediated nuclear export. SAE1 may serve as a promising therapeutic target, and colchicine may be a potential treatment option for multiple types of cancer in clinical settings.

BACKGROUND:Overactive osteoclasts disrupt bone homeostasis and play a bad role in the pathological mechanisms of related skeletal diseases,such as osteoporosis,fragility fractures,and osteoarthritis.Studies have confirmed that ellagic acid and ellagtannin have the potential to inhibit osteoclast differentiation.As their natural metabolites,urolithin A has antioxidant,anti-inflammatory,anti-proliferative and anti-cancer effects,but its effect on osteoclast differentiation and its underlying molecular mechanisms remain unclear. OBJECTIVE:To explore the effect of urolithin A on osteoclast differentiation induced by receptor activator for nuclear factor-κB ligand and its mechanism. METHODS:Mouse mononuclear macrophage leukemia cells(RAW264.7)that grew stably were cultured in vitro.Toxicity of urolithin A(0,0.1,0.5,1.5,2.5 μmol/L)to RAW264.7 cells were detected by cytotoxic MTS assay to screen out the safe concentration.Different concentrations of urolithin A were used again to intervene with receptor activator for nuclear factor-κB ligand-induced differentiation of RAW264.7 cells in vitro.Then,tartrate-resistant acid phosphatase staining and F-actin ring and nucleus staining were performed to observe its effect on the formation and function of osteoclasts.Finally,the expressions of urolithin A on upstream and downstream genes and proteins in the MAPK signaling pathway were observed by western blot and RT-qPCR assays. RESULTS AND CONCLUSION:Urolithin A inhibited osteoclast differentiation and F-actin ring formation in a concentration-dependent manner and 2.5 μmol/L had the strongest inhibitory effect.Urolithin A inhibited the mRNA expression of Nfatc1,Ctsk,Mmp9 and Atp6v0d2 and the protein synthesis of Nfatc1 and Ctsk,related to osteoclast formation and bone resorption.Urolithin A inhibited the activity of osteoclasts by downregulating the phosphorylation of p38 protein to inhibit the mitogen-activated protein kinase signaling pathway.

Objective To explore the clinicopathological and immunohistochemical features of nephrogenic adenoma(NA).Methods Clinical data of NA patients diagnosed in the Department of Pathology,Zhongshan Hospital,Fudan University from July 2016 to October 2022 were collected and analyzed to explore their clinicopathological features.Results A total of 13 NA cases were enrolled.There were 11 males and 2 females.Organs involved:ureter(n=7),bladder(n=5),bladder and ureter(n=1),renal pelvis(n=2).NA patients performed as ureteral stenosis(6/7),rough bladder wall(3/5),and renal pelvis polyp(2/2).The typical microscopical features of NA were tubular(13/13)and papillary(4/13)structures,covered with cuboidal or columnar epithelium(13/13),or a mixed hobnail-spike eosinophilic epithelium(12/13);the interstitium was loose,containing varied amounts of vasculature and inflammatory cells(13/13).Immunohistochemistry revealed specific expressions of CK7,PAX-8,CK19 and CK8.Conclusions NA is a rare neoplasm of the urinary system with unique histological features.NA has the risk of misdiagnosis and over-treatment,and the potential of recurrence and malignant conversion.The diagnosis of NA depends on pathology,and the immunohistochemistry can be helpful for its pathological diagnosis.

Objective:To introduce the health insurance fund supervision model in Japan,compare the current situation of health insurance fund supervision in China,learn from experiences,and propose suggestions for improvement.Methods:By combining cases and regulatory effects,it introduces Japan's"guidance-inspection"based health insurance fund supervision model.Results:Japan's"guidance-inspection"based health insurance fund supervision model is relatively effective.Compared with China,it has a higher level of organizational hierarchy,focuses on education in its supervisory approach,clarifies the direction of patients'self-paid expences,and has a well-developed dual-way communication mechanism.Conclusion:China should establish a comprehensive health insurance fund supervision pathway,clearly define the resolution pathway for self-paid expenses caused by violations,and improve the mechanisms for negotiation and dispute resolution during the process.

Objective:To introduce the health insurance fund supervision model in Japan,compare the current situation of health insurance fund supervision in China,learn from experiences,and propose suggestions for improvement.Methods:By combining cases and regulatory effects,it introduces Japan's"guidance-inspection"based health insurance fund supervision model.Results:Japan's"guidance-inspection"based health insurance fund supervision model is relatively effective.Compared with China,it has a higher level of organizational hierarchy,focuses on education in its supervisory approach,clarifies the direction of patients'self-paid expences,and has a well-developed dual-way communication mechanism.Conclusion:China should establish a comprehensive health insurance fund supervision pathway,clearly define the resolution pathway for self-paid expenses caused by violations,and improve the mechanisms for negotiation and dispute resolution during the process.

Objective:To introduce the health insurance fund supervision model in Japan,compare the current situation of health insurance fund supervision in China,learn from experiences,and propose suggestions for improvement.Methods:By combining cases and regulatory effects,it introduces Japan's"guidance-inspection"based health insurance fund supervision model.Results:Japan's"guidance-inspection"based health insurance fund supervision model is relatively effective.Compared with China,it has a higher level of organizational hierarchy,focuses on education in its supervisory approach,clarifies the direction of patients'self-paid expences,and has a well-developed dual-way communication mechanism.Conclusion:China should establish a comprehensive health insurance fund supervision pathway,clearly define the resolution pathway for self-paid expenses caused by violations,and improve the mechanisms for negotiation and dispute resolution during the process.

Objective:To introduce the health insurance fund supervision model in Japan,compare the current situation of health insurance fund supervision in China,learn from experiences,and propose suggestions for improvement.Methods:By combining cases and regulatory effects,it introduces Japan's"guidance-inspection"based health insurance fund supervision model.Results:Japan's"guidance-inspection"based health insurance fund supervision model is relatively effective.Compared with China,it has a higher level of organizational hierarchy,focuses on education in its supervisory approach,clarifies the direction of patients'self-paid expences,and has a well-developed dual-way communication mechanism.Conclusion:China should establish a comprehensive health insurance fund supervision pathway,clearly define the resolution pathway for self-paid expenses caused by violations,and improve the mechanisms for negotiation and dispute resolution during the process.

Objective:To introduce the health insurance fund supervision model in Japan,compare the current situation of health insurance fund supervision in China,learn from experiences,and propose suggestions for improvement.Methods:By combining cases and regulatory effects,it introduces Japan's"guidance-inspection"based health insurance fund supervision model.Results:Japan's"guidance-inspection"based health insurance fund supervision model is relatively effective.Compared with China,it has a higher level of organizational hierarchy,focuses on education in its supervisory approach,clarifies the direction of patients'self-paid expences,and has a well-developed dual-way communication mechanism.Conclusion:China should establish a comprehensive health insurance fund supervision pathway,clearly define the resolution pathway for self-paid expenses caused by violations,and improve the mechanisms for negotiation and dispute resolution during the process.

Objective:To introduce the health insurance fund supervision model in Japan,compare the current situation of health insurance fund supervision in China,learn from experiences,and propose suggestions for improvement.Methods:By combining cases and regulatory effects,it introduces Japan's"guidance-inspection"based health insurance fund supervision model.Results:Japan's"guidance-inspection"based health insurance fund supervision model is relatively effective.Compared with China,it has a higher level of organizational hierarchy,focuses on education in its supervisory approach,clarifies the direction of patients'self-paid expences,and has a well-developed dual-way communication mechanism.Conclusion:China should establish a comprehensive health insurance fund supervision pathway,clearly define the resolution pathway for self-paid expenses caused by violations,and improve the mechanisms for negotiation and dispute resolution during the process.

Objective:To introduce the health insurance fund supervision model in Japan,compare the current situation of health insurance fund supervision in China,learn from experiences,and propose suggestions for improvement.Methods:By combining cases and regulatory effects,it introduces Japan's"guidance-inspection"based health insurance fund supervision model.Results:Japan's"guidance-inspection"based health insurance fund supervision model is relatively effective.Compared with China,it has a higher level of organizational hierarchy,focuses on education in its supervisory approach,clarifies the direction of patients'self-paid expences,and has a well-developed dual-way communication mechanism.Conclusion:China should establish a comprehensive health insurance fund supervision pathway,clearly define the resolution pathway for self-paid expenses caused by violations,and improve the mechanisms for negotiation and dispute resolution during the process.