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*

Objective To explore the effects of chronic stress and stress cessation on hypothalamic appetite regulators in mice,and to explore the stress-dependent mechanism of appetite change.Methods A total of 32 male C57BL/6 mice were randomly divided into control(Ctrl)group(n=16)and chronic unpredictable mild stress(CUMS)group(n=16).The mice in the CUMS group were given CUMS to establish the stress model,and those in the Ctrl group were fed normally.The food intake and weight of mice were recorded.The CUMS model was verified through tail suspension experiments and forced swimming experiments.Eight mice in the Ctrl group and 8 mice in the CUMS group were randomly sacrificed at the 12th week.The Ctrl group was re-grouped into the cessation-control(C-Ctrl)group(n=8),the CUMS group was re-grouped into the cessation-stress(C-CUMS)group(n=8),and the mice were sacrificed at the 15th week.The mRNA and protein levels of appetite-regulating factors,including orexin 1 receptor(OX1R),leptin receptor(LEPR)and agouti-related protein(AgRP)in the hypothalamus,were detected by quantitative polymerase chain reaction and immunochemistry.Results From week 2 to week 11 of stress,the food intake of the mice in the CUMS group was significantly higher than that in the Ctrl group(all P＜0.05),while there was no significant difference in body weight between the 2 groups within 11 weeks(all P＞0.05).Compared with the Ctrl group,the immobility durations of forced swimming and tail suspension of the CUMS group were markedly longer after 11 weeks(both P＜0.01),indicating successful modeling.AgRP and OX1R mRNA expression in the hypothalamus of the CUMS group was significantly increased(both P＜0.01),while LEPR mRNA expression was significantly decreased(P＜0.01);AgRP protein in the hypothalamic arcuate nucleus of the CUMS group was significantly higher than that of the Ctrl group(P＜0.05),and LEPR protein was markedly lower than that of the Ctrl group(P＜0.01).However,after 3 weeks of stress cessation,the C-CUMS group had less food intake and lower body weight than the C-Ctrl group(both P＜0.05).The LEPR mRNA of the C-CUMS group was significantly increased(P＜0.01),while AgRP and OX1R mRNA were not significantly different(both P＞0.05).There was no significant difference in AgRP protein levels between the C-CUMS group and the C-Ctrl group(P＞0.05),while LEPR protein level of the C-CUMS group was significantly higher than that of the C-Ctrl group(P＜0.01).Conclusion CUMS can lead to increased appetite in mice,which may involve the functional regulation of LEPR and AgRP.After the stress cessation,the appetite decreases,which may involve the functional regulation of LEPR.

Objective To explore the role of serum N-terminal peptide of type Ⅲ procollagen(PⅢNP),insulin-like growth factor(IGF-1),and N-terminal pro-B-type natriuretic peptide(NTpro-BNP)in the disease evaluation and prognostic prediction in elderly patients with chronic left heart failure(CLHF).Methods A total of 92 elderly patients with CLHF who were admitted to Liyang People's Hospital from March 2020 to March 2023 were selected as research objects.There were 34 cases of Class Ⅱ,29 cases of Class Ⅲ,and 29 cases of Class Ⅳ according to the New York Heart Association(NYHA)functional classification.The patients were assignedto good prognosis group(n=62)and poor prognosis group(n=30).The general information and the levels of PⅢNP,IGF-1,and NTpro-BNP were compared between the two groups.Logistic regression analysis was used to identify the factors influencing the prognosis of elderly patients with CLHF,and a nomogram was constructed.Spearman correlation analysis was employed to examine the relationships between these indicators.Receiver operating characteristic(ROC)curves were constructed to analyze the predictive efficiency for the prognosis of elderly patients with CLHF.Results The diastolic pressure,systolic pressure,LVEDD,LVSDD,PⅢNP,and NTpro-BNP increased by the increase of NYHA classification,while the LVEF and IGF-1 decreased by the increase of NYHA classification(P<0.05).The levels of PⅢNP and NTpro-BNP in the good prognosis group were lower than those in the poor prognosis group,while IGF-1 in the good prognosis group was higher than that in the poor prognosis group(P<0.05).Logistic analysis indicated that PⅢNP,IGF-1,and NTpro-BNP were the factors affecting the prognosis of elderly patients with CLHF(P<0.05).Spearman correlation analysis revealed that PⅢNP and NTpro-BNP levels were positively correlated with NYHA functional classification,while IGF-1 was negatively correlated with NYHA functional classification(P<0.05).ROC curve results showed that the combined predictive value of PⅢNP,IGF-1,and NTpro-BNP was significantly superior to each parameter.Conclusion Serum levels of PⅢNP,IGF-1,and NTpro-BNP provide valuable assessment for the condition and prediction for prognosis of elderly CLHF patients.

Objective To investigate the mechanism and optimal concentration of anrotinib on ovarian clear cell carcinoma.Methods Ovarian clear cell carcinoma cells were cultured in vitro,by using renal clear cell carcinoma cells and renal papillary cell carcinoma cells as control cancer cells,and the effects of different concentrations of anlotinib(5,10,15,20μmol/L)on the proliferation,migration,and invasion capabilities of three cancer cell lines were investigated.Compared with the experimental results of renal clear cell carcinoma cells and renal papillary cell carcinoma cells,the advantages of anlotinib on ovarian clear cell carcinoma cells were investigated and advanced its position in clinical practice.Results Anlotinib at the concentrations of 5,10,15,and 20μmol/L can effectively inhibit the proliferation,migration,and invasion ability of ovarian clear cell carcinoma cells,renal clear cell carcinoma cells,and renal papillary cell carcinoma cells.Among them,the optimal action concentration of anlotinib on all three cancer cells fell in the range of 5-10 μmol/L.However,in the three cancer cells,anlotinib was more potent in ovarian clear cell carcinoma cells.Conclusion The effect of anlotinib on ovarian clear cell carcinoma cells has obvious advantages over renal clear cell carcinoma cells and renal papillary cell carcinoma cells,with the optimal concentration of 5-10 μmol/L.

Objective To scan and accurately reconstruct mandible models printed via fused deposition modeling(FDM)that contain screw path information,using cone-beam CT(CBCT),to achieve the digital transfer of preoperative model screw paths.Methods CBCT scans were conducted on 12 FDM-printed mandibular models(Model1 group)intended for prebending reconstruction plates.Mim-ics software was employed to reconstruct scanned data into mandibular models(Model2 group)and extract digital screw path informa-tion.Model2 was then compared with original models(Model0 group)in three dimensions,evaluating reconstruction accuracy through root mean square(RMS).Reconstruction parameters were optimized to enable automatic matching of Model2 with Model0,facilitating precise digital transfer of screw paths.In clinical application,this method was utilized to produce digital short-segment drilling guides,assisting in the reduction surgery of three mandibular fracture patients.Results Model2 demonstrated automatic matching with Model0,exhibiting detailed surface characteristics and clear screw path position and orientation information.The RMS was measured at(0.32±0.09)mm.Utilization of digital segmented screw path transfer guides assisted in the satisfactory reduction surgery of three pa-tients with comminuted mandibular fractures.Conclusion CBCT scanning of FDM-printed preoperative models accurately captures screw path position and orientation information,enabling digital transfer of screw paths and providing a novel method for precise design of digital surgical guides.

Objective:To analyze the efficacy and prognosis of surgical patients with traumatic epidural hematoma straddling the transverse sinus (TEHSTS).Methods:Clinical data of 4 360 patients with epidural hematoma admitted to the First Affiliated Hospital of Henan University of Science and Technology from January 2010 to April 2024 were collected. Among them, 109 cases (2.5%) were diagnosed with TEHSTS. Based on the rapid progression criteria for posterior fossa epidural hematoma [sudden deterioration of Glasgow Coma Scale (GCS) score within hours (a decrease of ≥1 point in the best motor response and/or a decrease of ≥2 points in GCS score), and progressive enlargement of TEHSTS on repeat CT scan], the timing and method of surgery were determined. Two surgical approaches were compared: combined supratentorial and infratentorial craniotomy (craniotomy group) and modified supratentorial burr-hole drainage (burr-hole group). Clinical data, surgical timing, surgical outcomes, and prognosis were compared between the two groups.Results:There were 57 cases (52.3%) in the craniotomy group and 52 cases (47.7%) in the modified burr-hole group. The proportion of patients presenting with vomiting upon admission was higher in the craniotomy group than in the burr-hole group [77.2%(44/57) vs 59.6%(31/52), P=0.048], and the proportion of patients with linear occipital fractures on CT was also higher in the craniotomy group [91.2%(52/57) vs 75.0%(39/52), P=0.023]. No significant differences were observed in other admission symptoms or CT findings between the two groups (all P>0.05). The GCS score upon admission was significantly lower in the craniotomy group [(11.0±1.0)points] than in the modified burr-hole group [(13.0±1.0)points] ( P<0.05). Four cases in the burr-hole group developed delayed hematomas, including two cases of bilateral delayed epidural hematomas. The preoperative GCS score in the craniotomy group [(9.0±0.5)points] was significantly lower than upon admission [(11.0±1.0)points] ( P<0.05), and the surgical timing was (6.5±1.5)hours after injury. The preoperative GCS score in the burr-hole group [(11.5±0.5)points] was also significantly lower than upon admission [(13.0±1.0)points] ( P<0.05), with surgical timing at (19.5±5.5)hours after injury. Preoperative CT scans showed no significant difference in hematoma volume between the burr-hole group [(35.5±7.5)ml] and the craniotomy group [(36.5±9.5)ml] ( P>0.05). The preoperative GCS score was significantly lower in the craniotomy group than in the burr-hole group ( P<0.05). The GCS scores at 24 hours postoperatively were significantly improved compared to preoperative scores in both groups (all P<0.05). The burr-hole group had significantly shorter operative time, less intraoperative blood loss, shorter intensive care unit (ICU) stay, and shorter hospital stay than the craniotomy group (all P<0.01). The incidence of postoperative pulmonary infection was lower in the burr-hole group than in the craniotomy group ( P<0.05). At 3-month follow-up, the rate of good recovery [Glasgow Outcome Scale (GOS) score≥4 points] was significantly higher in the burr-hole group (98.1%) than in the craniotomy group (93.0%) ( P<0.01). Conclusions:TEHSTS should be managed with different surgical approaches based on admission symptoms, GCS score, and the speed of disease progression. The modified burr-hole drainage procedure is convenient, safe, and associated with better prognosis.

Objective To scan and accurately reconstruct mandible models printed via fused deposition modeling(FDM)that contain screw path information,using cone-beam CT(CBCT),to achieve the digital transfer of preoperative model screw paths.Methods CBCT scans were conducted on 12 FDM-printed mandibular models(Model1 group)intended for prebending reconstruction plates.Mim-ics software was employed to reconstruct scanned data into mandibular models(Model2 group)and extract digital screw path informa-tion.Model2 was then compared with original models(Model0 group)in three dimensions,evaluating reconstruction accuracy through root mean square(RMS).Reconstruction parameters were optimized to enable automatic matching of Model2 with Model0,facilitating precise digital transfer of screw paths.In clinical application,this method was utilized to produce digital short-segment drilling guides,assisting in the reduction surgery of three mandibular fracture patients.Results Model2 demonstrated automatic matching with Model0,exhibiting detailed surface characteristics and clear screw path position and orientation information.The RMS was measured at(0.32±0.09)mm.Utilization of digital segmented screw path transfer guides assisted in the satisfactory reduction surgery of three pa-tients with comminuted mandibular fractures.Conclusion CBCT scanning of FDM-printed preoperative models accurately captures screw path position and orientation information,enabling digital transfer of screw paths and providing a novel method for precise design of digital surgical guides.

Objective To investigate the mechanism and optimal concentration of anrotinib on ovarian clear cell carcinoma.Methods Ovarian clear cell carcinoma cells were cultured in vitro,by using renal clear cell carcinoma cells and renal papillary cell carcinoma cells as control cancer cells,and the effects of different concentrations of anlotinib(5,10,15,20μmol/L)on the proliferation,migration,and invasion capabilities of three cancer cell lines were investigated.Compared with the experimental results of renal clear cell carcinoma cells and renal papillary cell carcinoma cells,the advantages of anlotinib on ovarian clear cell carcinoma cells were investigated and advanced its position in clinical practice.Results Anlotinib at the concentrations of 5,10,15,and 20μmol/L can effectively inhibit the proliferation,migration,and invasion ability of ovarian clear cell carcinoma cells,renal clear cell carcinoma cells,and renal papillary cell carcinoma cells.Among them,the optimal action concentration of anlotinib on all three cancer cells fell in the range of 5-10 μmol/L.However,in the three cancer cells,anlotinib was more potent in ovarian clear cell carcinoma cells.Conclusion The effect of anlotinib on ovarian clear cell carcinoma cells has obvious advantages over renal clear cell carcinoma cells and renal papillary cell carcinoma cells,with the optimal concentration of 5-10 μmol/L.