Objective:To discuss the clinical features of lymphoma of the male urogentioal system.Methods:The clinical data of 9 patients in Beijing Friendship Hospital from August 2014 to August 2019 reviewed, including 5 males and 4 females. The mean age of those patients was 62 years, range from 50 to 69.3 cases were diagnosed as renal tumor, 2 cases were diagnosed as bladder tumor and 4 cases were testicular tumor. 2 cases of the renal tumor presented with fever primarily(1 case with abdominal pain and weight loss) , 1 case was found renal pelvis tumor in medical checkup. 1 case of bladder lesions suffered from gross hematuria with abdominal pain and the other case with urinary frequency and urgency. All of the 4 testicular tumor cases were admitted to hospital with painless testicle mass. 5 cases were examined by CT showed low density mass with mild to moderate enhanced. Testicular tumors were detected by ultrasound showed irregular and heterogeneous mass with blood flow signals in them. 4 cases received operation and chemotherapy, 2 cases only received chemotherapy, 2 cases only received operation and 1 case didn’t receive further treatment. 1 case of 3 renal tumor cases received ultrasound-guided tumor biopsy and accepted rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone(R-CHOP) chemotherapy. 1 renal pelvis tumor patient received laparoscopic nephroureterectomy and R-CHOP chemotherapy. 1 case received ultrasound-guided tumor biopsy and refused further treatment. Both of two bladder tumor patients accepted TURBT and refused radiotherapy and chemotherapy. For 4 testicular tumor cases, 3 patients received orchiectomy and 1 patient received ultrasound-guided tumor biopsy. 3 cases accepted R-CHOP chemotherapy, 1 case received chemotherapy and contralateral testis irradiation(specific proposals unknown). All of 4 cases received CNS prophylaxis by intrathecal injection(methotrexate 15mg, cytarabine 50 mg and dexamethasone 5 mg).Results:All 9 cases who received surgery or biopsy recovered favorably, no complications were found. The histological type of them were non-Hodgkin lymphomas. 8 of 9 cases were diffuse large B-cell lymphomas, 1 case was anaplastic large cell lymphoma. Belonged to Ann Arbor staging system, 4 cases staged Ⅰ-ⅡE and 5 cases staged ⅢE-ⅣE. 6 cases had international prognostic index(IPI) scores 0-2, 2 cases ≥3. The average follow-up time was 18 months (6-66 months). 7 cases still alive, 3 of them completed chemotherapy, 2 cases achieved complete remission(1 case was testicular lymphoma stage ⅡE IPI score 1 point and 1 case was testicular lymphoma stage ⅣE IPI score 2 points), 1 case achieved partial remission(renal pelvis lymphoma stage ⅣE IPI score 3 points). 3 cases which refused chemotherapy didn’t relapse or progress(2 cases were bladder lymphomas stage ⅠIE IPI score 1 point and 1 case was renal pelvis lymphoma stage ⅠIE IPI score 1 point). 1 case developed bacterial combine fungal pneumonia after 2 chemotherapy periods and stopped chemotherapy. 1 case of renal lymphoma( stage ⅢE IPI score 3 points) and 1 case of testicular lymphoma( stage ⅢE IPI score 2 point) died of the tumor progression of 6 months and 17 months after diagnoses.Conclusions:The main histological type of the male urogentioal system lymphoma is diffuse large B-cell lymphoma which clinical feature of it is nonspecific. Differential diagnosis should be done with other genitourinary system tumor according to clinical symptom and imaging findings. Histological diagnosis is the gold standard and R-CHOP chemotherapy is recommended as the primary treatment.

Objective:Assessing the prognosis of patients with bladder urothelial carcinoma by using multiple molecular markers [epithelial-cadherin (E-cadherin), fibroblast growth factor receptor 3 (FGFR3), Jagged2, Survivin and stromal antigen 2 (STAG2)] in combination method, and compared it with the traditional method of evaluating prognosis by clinical pathological parameters.Methods:Retrospective analysis of 128 cases of bladder urothelial carcinoma patients admitted to Beijing Friendship Hospital, Capital Medical University from January 2010 to December 2016, including 102 males and 26 females; the median age was 70.5 years, ranged from 41 to 93 years. E-cadherin, FGFR3, Jagged2, Survivin and STAG2 alterations by immunohistochemistry during the first surgical treatment. The Kaplan-Meier survival curve was used to evaluate the relationship between the above markers and overall survival (OS), recurrence-free survival (RFS), progression-free survival (PFS), and clinicopathological indicators of tumors. Use Cox regression model to find the most suitable molecular markers for judging the prognosis of bladder urothelial carcinoma, and compare it with the traditional clinical staging + pathological grading method to evaluate OS to detect its sensitivity and specificity.Results:After 36.4 months of follow-up, it was found that the expressions of E-cadherin, FGFR3, Jagged2 and Survivin were all related to the OS, RFS and PFS of bladder urothelial carcinoma (all P<0.05). The expression of STAG2 was related to the TMN stage of bladder urothelial carcinoma ( P=0.047) and pathological grade ( P=0.015). Cox regression analysis showed that Survivin ( P=0.001) and Jagged2 ( P=0.037) were independent risk factors for evaluating the OS of bladder urothelial carcinoma, and Survivin ( P<0.001) and Jagged2 ( P=0.006) were independent risk factors for RFS, Survivin ( P=0.001) was also an independent risk factor for PFS. Multivariate analysis of the above molecular markers showed that the prognosis of patients with more than 3 molecular markers was better than that of independent application or the use of two of them to evaluate the prognosis ( P<0.001). The combined application of Survivin and Jagged2 to evaluate the 5-year survival rate was not less sensitive and specific than the clinical and pathological indicators (93.5% vs 77.2%, 84.7% vs 81.3%). Conclusions:Five molecular markers of E-cadherin, FGFR3, Jagged2, Survivin and STAG2 have an evaluation effect on the prognosis of bladder urothelial carcinoma, and some can independently predict the OS and RFS of patients with bladder urothelial carcinoma, however, the combined application is better than the single molecular marker to evaluate the prognosis. Compared with the traditional method of evaluating the prognosis by clinical pathological parameters, the combined application of Jagged2 and Survivin may be a better choice for evaluating the prognosis of patients with bladder urothelial carcinoma.

Hepatic stellate cells(HSCs)are essential drivers of fibrogenesis.Inducing activated-HSC apoptosis is a promising strategy for treating hepatic fibrosis.18beta-glycyrrhetinic acid(18β-GA)is a natural com-pound that exists widely in herbal medicines,such as Glycyrrhiza uralensis Fisch,which is used for treating multiple liver diseases,especially in Asia.In the present study,we demonstrated that 18β-GA decreased hepatic fibrosis by inducing the apoptosis in activated HSCs.18β-GA inhibited the expression of α-smooth muscle actin and collagen type Ⅰ alpha-1.Using a chemoproteomic approach derived from activity-based protein profiling,together with cellular thermal shift assay and surface plasmon reso-nance,we found that 18β-GA covalently targeted peroxiredoxin 1(PRDX1)and peroxiredoxin 2(PRDX2)proteins via binding to active cysteine residues and thereby inhibited their enzymatic activities.18β-GA induced the elevation of reactive oxygen species(ROS),resulting in the apoptosis of activated HSCs.PRDX1 knockdown also led to ROS-mediated apoptosis in activated HSCs.Collectively,our findings revealed the target proteins and molecular mechanisms of 18β-GA in ameliorating hepatic fibrosis,highlighting the future development of 18β-GA as a novel therapeutic drug for hepatic fibrosis.

The composition of serum is extremely complex,which complicates the discovery of new pharmaco-dynamic biomarkers via serum proteome for disease prediction and diagnosis.Recently,nanoparticles have been reported to efficiently reduce the proportion of high-abundance proteins and enrich low-abundance proteins in serum.Here,we synthesized a silica-coated iron oxide nanoparticle and devel-oped a highly efficient and reproducible protein corona(PC)-based proteomic analysis strategy to improve the range of serum proteomic analysis.We identified 1,070 proteins with a median coefficient of variation of 12.56％using PC-based proteomic analysis,which was twice the number of proteins iden-tified by direct digestion.There were also more biological processes enriched with these proteins.We applied this strategy to identify more pharmacodynamic biomarkers on collagen-induced arthritis(CIA)rat model treated with methotrexate(MTX).The bioinformatic results indicated that 485 differentially expressed proteins(DEPs)were found in CIA rats,of which 323 DEPs recovered to near normal levels after treatment with MTX.This strategy can not only help enhance our understanding of the mechanisms of disease and drug action through serum proteomics studies,but also provide more pharmacodynamic biomarkers for disease prediction,diagnosis,and treatment.

Tripterygium glycosides tablet(TGT),the classical commercial drug of Tripterygium wilfordii Hook.F.has been effectively used in the treatment of rheumatoid arthritis,nephrotic syndrome,leprosy,Behcet's syndrome,leprosy reaction and autoimmune hepatitis.However,due to its narrow and limited treatment window,TGT-induced organ toxicity(among which liver injury accounts for about 40％of clinical reports)has gained increasing attention.The present study aimed to clarify the cellular and molecular events underlying TGT-induced acute liver injury using single-cell RNA sequencing(scRNA-seq)technology.The TGT-induced acute liver injury mouse model was constructed through short-term TGT exposure and further verified by hematoxylin-eosin staining and liver function-related serum indicators,including alanine aminotransferase,aspartate aminotransferase,alkaline phosphatase and total bilirubin.Using the mouse model,we identified 15 specific subtypes of cells in the liver tissue,including endothelial cells,hepatocytes,cholangiocytes,and hepatic stellate cells.Further analysis indicated that TGT caused a significant inflammatory response in liver endothelial cells at different spatial locations;led to marked inflammatory response,apoptosis and fatty acid metabolism dysfunction in hepatocytes;activated he-patic stellate cells;brought about the activation,inflammation,and phagocytosis of liver capsular macrophages cells;resulted in immune dysfunction of liver lymphocytes;disturbed the intercellular crosstalk in liver microenvironment by regulating various signaling pathways.Thus,these findings elaborate the mechanism underlying TGT-induced acute liver injury,provide new insights into the safe and rational applications in the clinic,and complement the identification of new biomarkers and ther-apeutic targets for liver protection.

Ferroptosis is a form of regulated cell death, characterized by excessive membrane lipid peroxidation in an iron- and ROS-dependent manner. Celastrol, a natural bioactive triterpenoid extracted from Tripterygium wilfordii, shows effective anti-fibrotic and anti-inflammatory activities in multiple hepatic diseases. However, the exact molecular mechanisms of action and the direct protein targets of celastrol in the treatment of liver fibrosis remain largely elusive. Here, we discover that celastrol exerts anti-fibrotic effects via promoting the production of reactive oxygen species (ROS) and inducing ferroptosis in activated hepatic stellate cells (HSCs). By using activity-based protein profiling (ABPP) in combination with bio-orthogonal click chemistry reaction and cellular thermal shift assay (CETSA), we show that celastrol directly binds to peroxiredoxins (PRDXs), including PRDX1, PRDX2, PRDX4 and PRDX6, through the active cysteine sites, and inhibits their anti-oxidant activities. Celastrol also targets to heme oxygenase 1 (HO-1) and upregulates its expression in activated-HSCs. Knockdown of PRDX1, PRDX2, PRDX4, PRDX6 or HO-1 in HSCs, to varying extent, elevated cellular ROS levels and induced ferroptosis. Taken together, our findings reveal the direct protein targets and molecular mechanisms via which celastrol ameliorates hepatic fibrosis, thus supporting the further development of celastrol as a promising therapeutic agent for liver fibrosis.