Ovarian cancer is the most lethal malignancy affecting the female reproductive system. Pharmacological inhibitors targeting CDK4/6 have demonstrated promising efficacy across various cancer types. However, their clinical benefits in ovarian cancer patients fall short of expectations, with only a subset of patients experiencing these advantageous effects. This study aims to provide further clinical and biological evidence for antineoplastic effects of a CDK4/6 inhibitor (TQB4616) in ovarian cancer and explore underlying mechanisms involved. Patient-derived ovarian cancer organoid models were established to evaluate the effectiveness of TQB3616. Potential key genes related to TQB3616 sensitivity were identified through RNA-seq analysis, and TRIM4 was selected as a candidate gene for further investigation. Subsequently, co-immunoprecipitation and GST pull-down assays confirmed that TRIM4 binds to hnRNPDL and promotes its ubiquitination through RING and B-box domains. RIP assay demonstrated that hnRNPDL binded to CDKN2C isoform 2 and suppressed its expression by alternative splicing. Finally, in vivo studies confirmed that the addition of siTRIM4 significantly improved the effectiveness of TQB3616. Overall, our findings suggest that TRIM4 modulates ubiquitin-mediated degradation of hnRNPDL and weakens sensitivity to CDK4/6 inhibitors in ovarian cancer treatment. TRIM4 may serve as a valuable biomarker for predicting sensitivity to CDK4/6 inhibitors in ovarian cancer.
Humans ; Female ; Ovarian Neoplasms/pathology* ; Animals ; Tripartite Motif Proteins/genetics* ; Mice ; Cyclin-Dependent Kinase 4/antagonists & inhibitors* ; Cell Line, Tumor ; Cyclin-Dependent Kinase 6/antagonists & inhibitors* ; Protein Kinase Inhibitors/pharmacology* ; Ubiquitin/metabolism* ; Xenograft Model Antitumor Assays ; Ubiquitination ; Antineoplastic Agents/pharmacology*

Idiopathic pulmonary fibrosis （IPF）， as a progressive lung disease， has a poor prognosis and no reliable and effective therapies. IPF is mainly treated by organ transplantation and administration of chemical drugs， which are ineffective and induce side effects， failing to meet the clinical needs. Therefore， developing safer and more effective drugs has become an urgent task， which necessitates clear understanding of the pathogenesis of IPF. The available studies about the pathogenesis of IPF mainly focus on macrophage polarization， epithelial-mesenchymal transition （EMT）， oxidative stress， and autophagy， while few studies systematically explain the principles and links of the pathogeneses. According to the traditional Chinese medicine theory， Qi deficiency and blood stasis and Qi-Yang deficiency are the key pathogeneses of IPF. Therefore， the Chinese medicines or compound prescriptions with the effects of replenishing Qi and activating blood， warming Yang and tonifying Qi， and eliminating stasis and resolving phlegm are often used to treat IPF. Modern pharmacological studies have shown that such medicines play a positive role in inhibiting macrophage polarization， restoring redox balance， inhibiting EMT， and regulating cell autophagy. However， few studies report how Chinese medicines regulate the pathways in the treatment of IPF. By reviewing the latest articles in this field， we elaborate on the pathogenesis of IPF and provide a comprehensive overview of the mechanism of the active ingredients or compound prescriptions of Chinese medicines in regulating IPF. Combining the pathogenesis of IPF with the modulating effects of Chinese medicines， we focus on exploring systemic treatment options for IPF， with a view to providing new ideas for the in-depth study of IPF and the research and development of related drugs.

Objective:To evaluate the nutritional status of patients with decompensated liver cirrhosis and explore the correlation with malnutrition and the risk factors of depressed mood.Methods:190 cirrhotic patients admitted to the Department of Gastroenterology of the First Hospital of Shanxi Medical University from June to September 2023 were selected according to the inclusion and exclusion criteria. Eligible patients were divided into subgroups based on the presence or absence of malnutrition as determined by subjective global assessment (SGA). The Center for Epidemiological Studies Depression (CES-D) scale was used to assess patients' propensity for depressed mood. Relevant clinical data were also collected and analyzed.Results:A total of 185 patients were included, of which 126 were in the non-malnutrition group and 59 malnutrition group. There were significant between-group differences in terms of CES-D results, age, body mass index, platelets, D-dimer, serum sodium, third lumbar skeletal muscle index, grip strength, triceps skinfold thickness, and upper arm muscle circumference (all P<0.05). Correlation analysis showed that grip strength, triceps skinfold thickness, upper arm muscle circumference, serum sodium, and depressed mood tendency status were correlated with the development of cirrhotic malnutrition ( P<0.05). The diagnostic model for malnutrition in cirrhosis using these five indicators showed the area under the curve of 81.9%. Conclusions:Depression is closely related to the development of malnutrition in patients with liver cirrhosis. Independent risk factors for malnutrition in cirrhosis include serum sodium≤135 mmol/L, grip strength, triceps skinfold thickness, lower-than-normal upper arm circumference , and the tendency of depression , which demonstrate the combined contribution to the diagnosis of malnutrition in cirrhosis.

Background::The potential impact of pre-existing coronary artery stenosis (CAS) on acute pulmonary embolism (PE) episodes remains underexplored. This study aimed to investigate the association between pre-existing CAS and the elevation of high-sensitivity cardiac troponin I (hs-cTnI) levels in patients with PE.Methods::In this multicenter, prospective case-control study, 88 cases and 163 controls matched for age, sex, and study center were enrolled. Cases were patients with PE with elevated hs-cTnI. Controls were patients with PE with normal hs-cTnI. Coronary artery assessment utilized coronary computed tomographic angiography or invasive coronary angiography. CAS was defined as ≥50% stenosis of the lumen diameter in any coronary vessel >2.0 mm in diameter. Conditional logistic regression was used to evaluate the association between CAS and hs-cTnI elevation.Results::The percentage of CAS was higher in the case group compared to the control group (44.3% [39/88] vs. 30.1% [49/163]; P = 0.024). In multivariable conditional logistic regression model 1, CAS (adjusted odds ratio [OR], 2.680; 95% confidence interval [CI], 1.243–5.779), heart rate >75 beats/min (OR, 2.306; 95% CI, 1.056–5.036) and N-terminal pro-B type natriuretic peptide (NT-proBNP) >420 pg/mL (OR, 12.169; 95% CI, 4.792–30.900) were independently associated with elevated hs-cTnI. In model 2, right CAS (OR, 3.615; 95% CI, 1.467–8.909) and NT-proBNP >420 pg/mL (OR, 13.890; 95% CI, 5.288–36.484) were independently associated with elevated hs-cTnI. Conclusions::CAS was independently associated with myocardial injury in patients with PE. Vigilance towards CAS is warranted in patients with PE with elevated cardiac troponin levels.

Atrial septal defect（ASD）is one of the most common congenital heart diseases in children. Although most children with this condition may not exhibit clinical symptoms，persistent left-to-right shunting can increase the burden on the right heart and compromise cardiac function as they age. Therefore，early intervention is crucial for these children. Percutaneous intervention has superseded conventional surgery as the primary mode of treatment for secondary atrial septal defect in children. The procedure has a low rate of postoperative complications，but carries a substantial risk. Serious complications include unsatisfactory device position or embolization，cardiac erosion，atrioventricular block，thrombosis or thromboembolism，air embolism，and hemolysis. Common complications include headache or migraine，residual shunt，and vascular-related complications. This review focuses on the pathogenesis，clinical presentations，prevention and treatment of complications related to percutaneous intervention of atrial septal defect in children.

Aim To investigate the effects of naringenin on atherosclerotic plaque extracellular matrix remodeling and plaque stability.Methods Murine vascular smooth muscle cells were isolated and treated with various doges of naringenin.ApoE-/-mice were fed with high-fat diet and received naringenin by lavage for 16 weeks.Intraplaque nec-rotic core,contents of collagen and fibrous cap thickness were measured by Sirius red-Haematoxylin staining.Elastin was detected by Van Gieson staining.Matrix metalloproteinase(MMP)activity was determined by gelatin zymography and fluorescence-gelatin staining.Results Naringenin(50 μmol/L)increased signal tansducer and activator of transciption 6(STAT6)phosphorylation and promoted tissue inhibitor of metalloproteinase-3(TIMP-3)expression by 3.1-fold(P＜0.001).After naringenin(80 mg/kg)treatment,compared with the control group,the area of plaque necrotic core in aor-tic root decreased by 53％(P＜0.01),the thickness of fibrous caps increased by nearly 50％(P＜0.05),and the degree of elastic fiber degradation decreased.At the same time,naringenin promoted the expression of TIMP-3 in plaques,and corre-spondingly reduced the activity of MMP in plaques.Lentivirus mediated inhibition of TIMP-3 expression in vivo could reduce the protective effect of naringenin on plaque stability.Conclusion Naringin can increase the expression of TIMP-3 in smooth muscle cells,improve the composition of extracellular matrix,and promote the stability of atherosclerotic plaque.

Aim To study the effect of maternal high-fat diet during pregnancy on endothelial to mesenchymal transition of aortic vessels in adult offspring.Methods The pregnant mice were randomly divided into normal diet group and high-fat diet group,and the offspring mice were fed normally for 16 weeks after the mother gave birth.Western blot and RT-qPCR were used to detect the expression and transcription of related proteins,and immunofluorescence and im-munohistochemical staining were used for pathological analysis.Results Compared with the offspring of maternal nor-mal diet during pregnancy,the expressions of vascular inflammatory factors,macrophage infiltration,monocyte-endothelium adhesion were significantly increased in the offspring of maternal high-fat diet(OHF)during pregnancy(P＜0.05).Vas-cular endothelial nitric oxide synthase(eNOS)activity,nitric oxide(NO)level were dramatically reduced(P＜0.05).Immunofluorescence results showed reduced endothelial cell marker CD31 and increased mesenchymal marker α-smooth muscle actin(α-SMA)in OHF.Western blot analysis further confirmed the results,which showed that maternal high fat diet reduced vascular endothelial-cadherin(VE-cadherin)and CD31 and increased α-SMA and Vimentin in the offspring(P＜0.05).The maternal high fat diet increased the extracellular matrix protein disposition and transforming growth factor beta(TGF-β)/Smad signaling in endothelium(P＜0.05).Moreover,the maternal high fat diet reduced Kruppel-like factor 2(KLF2)expression by 76％in mRNA level and 59％in protein level(P＜0.05).Conclusion Maternal high-fat diet during pregnancy lead to a transition of endothelial to mesenchyme in the offspring aorta.The results provide a clue for prevention of vascular disease in early stage.

Objective:To analyze the efficacy of laparoscopic radical surgery, compared to open surgery, for incidental gallbladder cancer following cholecystectomy.Methods:Clinical data of 106 patients with incidental gallbladder cancer treated at the Second Affiliated Hospital Zhejiang University School of Medicine from April 2010 to February 2018 were retrospectively analyzed, including 66 males and 40 females, aged (64.7±7.9) years old. According to surgical approach, patients were divided into the laparoscopic group ( n=45) and open group ( n=61). Perioperative data, including intraoperative blood loss, postoperative hospital stay, and postoperative complications, were compared between the groups. Follow-ups were conducted via outpatient visits or telephone reviews. Survival analysis was performed using the Kaplan-Meier method, and the survival rates were compared using the log-rank test. Results:All 45 patients in the laparoscopic group successfully underwent the surgery without conversion to open surgery. Compared to the open group, the laparoscopic group had a reduced intraoperative blood loss [(100±25) ml vs. (200±46) ml] and a shortened postoperative hospital stay [3(2, 5) d vs. 5(4, 7) d] (both P<0.05). The postoperative complication rates were 6.7% (3/45) in the laparoscopic group and 13.1% (8/61) in the open group ( χ2=4.16, P=0.041). The cumulative survival rate after radical surgery for incidental gallbladder cancer was better in the laparoscopic group ( χ2=4.58, P=0.032). Conclusion:Compared to open surgery, laparoscopic radical surgery for incidental gallbladder cancer showed benefits in intraoperative blood loss, postoperative hospital stay, complication rates, and cumulative survival.