Background: In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes. Methods: The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments. Results: RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice. Conclusion RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.

Background: In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes. Methods: The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments. Results: RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice. Conclusion RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.

Background: In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes. Methods: The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments. Results: RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice. Conclusion RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.

Background: In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes. Methods: The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments. Results: RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice. Conclusion RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.

Objective:To investigate the efficacy and safety of trastuzumab deruxtecan (T-DXd) in the treatment of metastatic breast cancer.Methods:A retrospective case series study was conducted. The clinical data of 38 breast cancer patients with metastasis in other parts who received T-DXd treatment in Xi'an International Medical Center Hospital from August 2021 to August 2024 were analyzed. The clinical efficacy and incidence of adverse reactions in patients were recorded, comparison of clinical efficacy in stratified patients based on clinical characteristics was performed, and the progression-free survival (PFS) was analyzed using Kaplan-Meier method.Results:All 38 patients were female, with a median age [ M ( Q1, Q3)] of 55 (42, 60) years; according to the guidelines of the American Society of Clinical Oncology/College of American Pathologists, 13 cases (34.2%) were positive for human epidermal growth factor receptor 2 (HER2) and 25 cases (65.8%) were low in HER2 expression; the Eastern Cooperative Oncology Group (ECOG) physical status scores of 23 cases (60.5%) were 0-2 points and 15 cases (39.5%) were 3-4 points; the median number of T-DXd treatment lines was 4 (2,16) lines. According to the Response Evaluation Criteria in Solid Tumors 1.1, the objective response rate (ORR) of T-DXd treatment was 34.2% (13/38), and the disease control rate (DCR) was 78.9% (30/38); the ORR of patients aged ≤ 50 years old was higher than that of patients aged >50 years old [56.3% (9/16) vs. 18.2% (4/22)], patients with HER2 positive was lower than that of patients with low HER2 expression [100.0 (13/13) vs. 68.0% (17/25)], patients with previous tyrosine kinase inhibitor (TKI) treatment was higher than that of patients without TKI treatment [100.0% (12/12) vs. 69.2% (18/26)], and the DCR of patients with T-DXd treatment for ≥ 4 cycles was higher than that of patients with T-DXd treatment for 1-3 cycles [100.0% (25/25) vs. 38.5% (5/13)], and the differences were statistically significant (all P < 0.05). Among the 38 patients, 19 (50.0%) stopped medication due to disease progression, 11 (28.9%) stopped medication due to economic reasons, 1 (0.8%) stopped medication due to grade 3 nausea and vomiting, and 1 (0.8%) stopped medication due to grade 2 interstitial lung disease (ILD), while the remaining 6 (15.8%) were undergoing T-DXd treatment. The median follow-up time was 9.5 (3.9, 17.8) months, and 16 cases (42.1%) progressed and died; the median PFS time was 5.9 months (95% CI: 3.1-8.7 months). Adverse reactions were mostly grade 1-2; common hematological adverse reactions included leukopenia [18 cases (47.3%)], neutropenia [16 cases (42.1%)], thrombocytopenia [11 cases (28.9%)], and anemia [15 cases (39.5%)]. Non-hematological adverse reactions included nausea [28 cases (73.7%)], vomiting [15 cases (39.5%)], decreased appetite [20 cases (52.6%)], fatigue [22 cases (57.9%)], alopecia [22 cases (57.5%)], elevated aspartate aminotransferase [20 cases (52.6%)], and elevated alanine aminotransferase [15 cases (39.5%)] were more common. Two cases developed interstitial lung disease (ILD), classified as grade 1 and grade 2, respectively. After discontinuation of medication and treatment with methylprednisolone, they returned to normal. Conclusions:T-DXd ≥ 2 line therapy has good efficacy and safety in the treatment of HER2 positive or low expression metastatic breast cancer. Bone marrow suppression and gastrointestinal adverse reactions are the most common, and the occurrence of ILD should be noted in the treatment.

Deflazacort,as a glucocorticoid medication,is conductive to improving motor function and muscle strength,delaying the loss of ambulation,enhancing pulmonary function,reducing the risk of scoliosis,slowing the progression of cardiomyopathy,and increasing survival rates in patients with Duchenne muscular dystrophy(DMD).In February 2017,the U.S.Food and Drug Administration(FDA)approved deflazacort for the treatment of DMD.In May 2024,deflazacort entered Peking Union Medical College Hospital for desig-nated use through the ＂ temporary import＂ pathway.This article provides an overview of deflazacort from the perspectives of its mechanism of action,pharmacokinetics,clinical efficacy,and adverse effects,aiming to offer a reference for its rational and safe application in clinical practice.