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: This study aimed to determine whether surgery followed by adjuvant chemoradiotherapy has superior survival outcomes for node-positive patients with T1b1-T2a1 stage cervical cancer compared with those who undergo chemoradiation. Methods: We investigated the Surveillance, Epidemiology, and End Results database for 12,701 patients diagnosed between 2000 and 2018. Patients were stratified according to different T stages and different treatment strategies. Surgery included radical hysterectomy (RH) or total hysterectomy (TH). Radiotherapy (RT) included adjuvant chemoradiation or chemoradiation alone. Cox analyses were performed to select the clinically important factors of survival outcomes. Survival analysis was used to compare those who received different treatment methods. Results: A total of 12,701 International Federation of Gynecology and Obstetrics 2018 stage IIIC cervical cancer patients were identified. The risk of overall survival (OS) was significantly different between patients who received and did not receive chemoradiotherapy in the T categories. In the propensity-score matched dataset, early-T stage (T1b1 and T1b2) and node-positive patients in the “RH+RT” and “TH+RT” groups had better disease-specific survival (DSS) than those in the RT group. No difference in DSS was observed between the “surgery following RT” group and the RT group in locally advanced stage (T1b3 and T2a1, node positive) patients. Regarding T1b1-T2a1 node-positive patients, the RH+RT group had a similar survival outcome to that in the TH+RT group. Conclusion We showed that surgery following RT benefits early-T stage (T1b1 and T1b2) cervical cancer patients with lymph node metastasis. For locally advanced stages (T1b3 and T2a1), surgery and RT had similar survival outcomes.

Objective: This study aimed to determine whether surgery followed by adjuvant chemoradiotherapy has superior survival outcomes for node-positive patients with T1b1-T2a1 stage cervical cancer compared with those who undergo chemoradiation. Methods: We investigated the Surveillance, Epidemiology, and End Results database for 12,701 patients diagnosed between 2000 and 2018. Patients were stratified according to different T stages and different treatment strategies. Surgery included radical hysterectomy (RH) or total hysterectomy (TH). Radiotherapy (RT) included adjuvant chemoradiation or chemoradiation alone. Cox analyses were performed to select the clinically important factors of survival outcomes. Survival analysis was used to compare those who received different treatment methods. Results: A total of 12,701 International Federation of Gynecology and Obstetrics 2018 stage IIIC cervical cancer patients were identified. The risk of overall survival (OS) was significantly different between patients who received and did not receive chemoradiotherapy in the T categories. In the propensity-score matched dataset, early-T stage (T1b1 and T1b2) and node-positive patients in the “RH+RT” and “TH+RT” groups had better disease-specific survival (DSS) than those in the RT group. No difference in DSS was observed between the “surgery following RT” group and the RT group in locally advanced stage (T1b3 and T2a1, node positive) patients. Regarding T1b1-T2a1 node-positive patients, the RH+RT group had a similar survival outcome to that in the TH+RT group. Conclusion We showed that surgery following RT benefits early-T stage (T1b1 and T1b2) cervical cancer patients with lymph node metastasis. For locally advanced stages (T1b3 and T2a1), surgery and RT had similar survival outcomes.

Objective: This study aimed to determine whether surgery followed by adjuvant chemoradiotherapy has superior survival outcomes for node-positive patients with T1b1-T2a1 stage cervical cancer compared with those who undergo chemoradiation. Methods: We investigated the Surveillance, Epidemiology, and End Results database for 12,701 patients diagnosed between 2000 and 2018. Patients were stratified according to different T stages and different treatment strategies. Surgery included radical hysterectomy (RH) or total hysterectomy (TH). Radiotherapy (RT) included adjuvant chemoradiation or chemoradiation alone. Cox analyses were performed to select the clinically important factors of survival outcomes. Survival analysis was used to compare those who received different treatment methods. Results: A total of 12,701 International Federation of Gynecology and Obstetrics 2018 stage IIIC cervical cancer patients were identified. The risk of overall survival (OS) was significantly different between patients who received and did not receive chemoradiotherapy in the T categories. In the propensity-score matched dataset, early-T stage (T1b1 and T1b2) and node-positive patients in the “RH+RT” and “TH+RT” groups had better disease-specific survival (DSS) than those in the RT group. No difference in DSS was observed between the “surgery following RT” group and the RT group in locally advanced stage (T1b3 and T2a1, node positive) patients. Regarding T1b1-T2a1 node-positive patients, the RH+RT group had a similar survival outcome to that in the TH+RT group. Conclusion We showed that surgery following RT benefits early-T stage (T1b1 and T1b2) cervical cancer patients with lymph node metastasis. For locally advanced stages (T1b3 and T2a1), surgery and RT had similar survival outcomes.

Objective:To assess the value of amide proton transfer weighted (APTw) imaging in the evaluation of pH changes in infarct core (IC) and ischemic penumbra (IP) in subacute cerebral infarction.Methods:The data of twenty-three subacute cerebral infarction patients with unilateral steno-occlusive disease of the middle cerebral artery (subacute infarction group) from April to November 2019 in the First Affiliated Hospital of Dalian Medical University were prospectively analyzed. Fifteen healthy volunteers were enrolled in this study as the control group. All subjects underwent conventional MRI, DWI, 3D-pseudo continuous arterial spin labeling (3D-pCASL) and APTw sequences. Based on DWI images, relative cerebral blood flow (rCBF) and APTw images to determine the region of IC, blood flow penumbra [cerebral blood flow(CBF)-DWI mismatch area, IP CBF] and metabolic penumbra (APTw-DWI mismatched area, IP APT). 3D ROIs were used to semi-automatically measure the APTw signals and the volume of IC and IP CBF of the patients in subacute infarction group. The comparison of APTw signals between the infarct side and the contralateral side in the subacute infarction group, the comparison of bilateral APTw signals in the control group, and the comparison of APTw signals in the IC and IP CBF regions were performed by paired-sample t test or Wilcoxon signed-rank test. The paired-sample t test or Mann-Whitney U test was used to compare the APTw signals between the two groups. The Friedman test was applied to compare the difference of volumes among IP CBF1.5, IP CBF2.5 and IP APT . Results:There was no significant difference of the APTw signals among the IC, the contralateral side in the subacute infarction group and the control group ( P>0.05). The APTw signals of IP CBF and IC of the infarction group were statistically different ( P<0.05). Compared with the contralateral side of IP CBF1.5 (3.7±1.7, -1.84±1.48, 5.57±2.75), the APTwmax (3.07±1.41, t=-3.012, P=0.006), APTw min [-1.30 (-1.74, -0.57), Z=-2.099, P=0.036], and APTwmax-min(4.51±2.58, t=-3.273, P=0.003) signals in the IP CBF1.5 were decreased ( P<0.05). Compared with the contralateral side of IP CBF2.5 [-1.53 (-2.80, -0.91), 5.31±2.61], the APTw min [-1.08 (-1.60, -0.49), Z=-2.616, P=0.009] and APTwmax-min (4.41±2.72, t=-3.228, P=0.004) signals in the IP CBF2.5 were decreased. The volumes of IP CBF1.5 [107.51(50.08, 138.61)mm 3], IP APT [99.00 (53.27, 121.335) mm 3] and IP CBF2.5 [89.91 (51.53, 139.87) mm 3] were successively reduced (χ2=7.913, P=0.019), and the volume of IP CBF2.5 was significantly smaller than that of IP CBF1.5 ( P=0.037). Conclusion:The acid-base metabolism in the IC of subacute cerebral infarction is not obvious, but the blood flow penumbra has local acid-base metabolism imbalance, and the range of metabolic penumbra coincides with the blood flow penumbra.

Objective:To understand the training needs of basic food and drug supervision personnel to provide guidance for the future textbook compiling and training. Methods:The work, training and learning needs of basic food and drug supervision personnel were investigated using the questionnaire survey in the director of the county bureau. Results:The difference in the professional back-ground among the supervision persons and the training were significant in different areas. Conclusion: By strengthening training and textbook construction, the ability of basic food and drug supervision personnel can be enhanced and the supervision and regulation level can be improved as well.