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*

Due to patient compliance and convenience, oral medication is likely the most common and acceptable method of drug administration. However, traditional dosage forms such as tablets or capsules may lead to low drug bioavailability and poor therapeutic efficiency. Therefore, with advancements in material science and micro/nano manufacturing technology, various carriers have been developed to enhance drug absorption in the gastrointestinal tract. In this context, we initially discuss the key biological factors that hinder drug transport and absorption (including anatomical, physical, and biological factors). Building on this foundation, recent progress in both conventional and innovative oral drug delivery routes aimed at improving drug bioavailability and targeting is reviewed. Finally, we explore future prospects for oral drug delivery systems as well as potential challenges in clinical translation.

OBJECTIVES: To assess the preliminary efficacy and safety of a dose-intensified C5VD regimen (cisplatin, 5-fluorouracil, vincristine, and doxorubicin) in children with locally advanced hepatoblastoma. METHODS: This prospective study enrolled 24 children with newly diagnosed, locally advanced hepatoblastoma who received the dose-intensified C5VD regimen at Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, and Shanghai Children's Hospital between January 2020 and December 2023. Clinical characteristics, treatment outcomes, and chemotherapy-related toxicities were analyzed. RESULTS: Of the 24 patients, 13 were male and 11 were female, with a median age at diagnosis of 18.7 months (range: 3.5-79.4 months). All patients achieved complete macroscopic resection of hepatic lesions without liver transplantation. Serum alpha-fetoprotein levels decreased significantly after two chemotherapy cycles. During a median follow-up of 38.4 months (range: 15.8-50.7 months), all patients maintained continuous complete remission, with 3-year event-free survival and overall survival rates of 100%. Across 144 chemotherapy cycles, the incidence rates of grade 3-4 neutropenia, thrombocytopenia, and infections were 97%, 77%, and 71%, respectively; no treatment-related deaths occurred. Notably, 5 patients (21%) developed Brock grade ≥3 hearing loss, of whom 1 required a hearing aid. CONCLUSIONS The dose-intensified C5VD regimen demonstrates significant efficacy with an overall favorable safety profile in the treatment of newly diagnosed, locally advanced pediatric hepatoblastoma. Grade 3-4 myelosuppression and infection are the predominant toxicities. However, high‑dose cisplatin-induced ototoxicity remains a concern, highlighting the need for improved otoprotective strategies.
Humans ; Hepatoblastoma/pathology* ; Male ; Female ; Infant ; Liver Neoplasms/pathology* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Child, Preschool ; Prospective Studies ; Doxorubicin/adverse effects* ; Child ; Cisplatin/adverse effects* ; Vincristine/adverse effects* ; Fluorouracil/adverse effects*

Purpose To explore the relationship between semi-quantitative parameters maximum standard uptake value(SUVmax)and target-background ratio(TBR)of 18F-FDG PET/CT imaging and the activity of Takayasu arteritis.Materials and Methods A total of 110 patients with Takayasu arteritis from February 2016 to December 2022 in the First Affiliated Hospital of Zhengzhou University who underwent 18F-FDG PET/CT images were retrospectively reviewed.All Takayasu arteritis patients were divided into active(92 cases)and inactive groups(18 cases)according to Kerr score.The region of interest technique was used to measure the SUVmax of the arterial wall,and compares the SUVmax with the average SUV in the center of the inferior vena cava and the maximum SUV measured in the right lobe of the liver to obtain TBRblood pool and TBRliver.The diagnostic efficacy of SUVmax,TBRblood pool and TBRliver in Takayasu arteritis activity was compared using the receiver operating characteristic curve.The relationship between PET/CT parameters and Kerr score,erythrocyte sedimentation rate and C-reactive protein was evaluated.Results SUVmax,TBRblood pool and TBRliver in the active group were higher than those in the inactive group[3.70(3.03,5.18)vs.1.45(1.38,1.53),2.50(1.93,3.88)vs.0.91(0.79,1.16)and 1.37(1.00,1.96)vs.0.44(0.39,0.63);Z=5.510-5.900,all P<0.001],respectively.A SUVmax level of 2.65 was shown to be the best predictive cut-off value for Takayasu arteritis disease activity(sensitivity 83.7%,specificity 100%and area under the curve 0.91).A TBRblood pool level of 1.63 was shown to be the best predictive cut-off value for Takayasu arteritis disease activity(sensitivity 83.7%,specificity 94.4%and area under the curve 0.93).A TBRliver level of 0.81 was shown to be the best predictive cut-off value for Takayasu arteritis disease activity(sensitivity 87.0%,specificity 100%and area under the curve 0.94).SUVmax,TBRblood pool,TBRliver were all positively correlated with the Kerr score(r=0.88,0.89.0.90,all P<0.001),among which the correlation coefficient between TBRliver and the Kerr score was the highest.Conclusion SUVmax,TBRblood pool and TBRliver can evaluate disease activity in Takayasu arteritis patients,with TBRliver being the best.

Objective:To explore the effect of nursing scheme based on self-regulation theory (SRT) on self-efficacy and quality of life of patients with chronic pancreatitis, and to provide basis for better promoting patients′ rehabilitation.Methods:Using a non-random historical control study, 55 patients with chronic pancreatitis admitted to The Fifth Affiliated Hospital of Southern Medical University from November 2021 to October 2022 were classified as the control group, and 55 patients with chronic pancreatitis admitted from November 2022 to October 2023 were classified as the research group. The control group received routine nursing intervention, while the research group received SRT-based nursing intervention. Both groups received a 3-month intervention. The General Self-Efficacy Scale, Exercise of Self-Care Agency Scale, Self Rated Abilities for Health Practices Scale, and Gastrointestinal Quality of Life Index were used to evaluate the self-efficacy, self-care ability, health behavior, and quality of life of two groups before and after the intervention, and statistical comparisons were made.Results:Both groups of patients completed the study. There were 28 males and 27 females in the control group. The age was (45.33 ± 12.26) years old. There were 30 males and 25 females in the research group. The age was (45.48 ± 12.61) years old. After the intervention, the score of the self-efficacy in the research group was (29.32 ± 2.88) points, which was higher than that in the control group (19.28 ± 1.95) points, the difference was significant ( t=21.41, P<0.05). The scores of self-care skills, self-responsibility, self-concept, health knowledge and the total score of the self-care ability in the research group were (35.32 ± 2.31), (22.85 ± 1.42), (25.88 ± 1.93), (64.32 ± 5.22), (148.34 ± 8.33) points respectively. They were all higher than those of the control group (28.66 ± 1.77), (17.22 ± 1.23), (18.67 ± 1.86), (60.08 ± 4.52), (124.56 ± 8.92) points. The differences were significant ( t values were 4.55-22.23, all P<0.05). The scores of exercise, nutrition, health responsibility, psychological comfort and the total score of the health behavior in the research group were (25.58 ± 1.41), (25.02 ± 2.03), (24.31 ± 2.34), (25.16 ± 1.63), (100.05 ± 7.36) points respectively. They were all higher than those of the control group (22.31 ± 2.03), (20.15 ± 2.82), (20.16 ± 2.89), (21.15 ± 2.17), (83.79 ± 7.84) points. The differences were significant ( t values were 8.28-11.21, all P<0.05). The scores of social activity, psychological state, physiological function, self-conscious symptoms and the total score of the quality of life in the research group were (16.78 ± 1.26), (17.03 ± 1.85), (22.43 ± 1.96), (17.09 ± 0.88), (73.41 ± 4.22) points respectively. They were all higher than those of the control group (15.32 ± 1.15), (15.34 ± 1.76), (20.86 ± 1.59), (16.03 ± 0.75), (67.52 ± 4.18) points. The differences were significant ( t values were 4.61-7.35, all P<0.05). Conclusions:SRT-based nursing scheme can effectively improve the self-efficacy and self-care ability of patients with chronic pancreatitis, and improve their health behavior and quality of life.

BACKGROUND: Doxorubicin hydrochloride (DOX) is extensively used in the treatment of various tumors. However, its clinical application is limited due to dose-dependent cardiotoxicity. Currently, few effective strategies exist to mitigate or eliminate DOX-induced cardiomyopathy (DIC). Although ferroptosis is implicated in DIC and its inhibition partially alleviates the condition, the direct targets of DOX in the progression of cardiotoxicity remain unclear. This study aimed to discover the direct targets of DOX in ferroptosis-mediated DIC. METHODS: A DOX pulldown assay was performed to identify proteins specifically binding to DOX in murine hearts, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify candidate proteins. A cardiac injury mouse model was established by DOX treatment. Based on this, multiple ferroptosis biomarkers were detected by flow cytometry, quantitative real-time polymerase chain reaction, western blotting, immunochemistry, etc. Besides, specific activator and inhibitor of signaling pathways were applied to illuminate molecular mechanisms. RESULTS: Glutathione S-transferase P1 (GSTP1) was identified as a DOX target. GSTP1 activity was inhibited in DOX-treated cardiomyocytes, while its overexpression significantly alleviated DIC. Moreover, GSTP1 overexpression inhibited acyl-CoA synthetase long-chain family member 4 (ACSL4)-dependent ferroptosis. Mechanistically, GSTP1 overexpression suppressed c-Jun N-terminal kinase (JNK) phosphorylation, thereby reducing reactive oxygen species (ROS) production and inhibiting ferroptosis in DIC. CONCLUSIONS This study identifies the DOX/GSTP1/JNK axis as a critical pathway mediating ACSL4-dependent ferroptosis in DIC. GSTP1 is highlighted as a potential key mediator of ferroptosis and a promising therapeutic target for DIC.

Objective:To explore the effect of nursing scheme based on self-regulation theory (SRT) on self-efficacy and quality of life of patients with chronic pancreatitis, and to provide basis for better promoting patients′ rehabilitation.Methods:Using a non-random historical control study, 55 patients with chronic pancreatitis admitted to The Fifth Affiliated Hospital of Southern Medical University from November 2021 to October 2022 were classified as the control group, and 55 patients with chronic pancreatitis admitted from November 2022 to October 2023 were classified as the research group. The control group received routine nursing intervention, while the research group received SRT-based nursing intervention. Both groups received a 3-month intervention. The General Self-Efficacy Scale, Exercise of Self-Care Agency Scale, Self Rated Abilities for Health Practices Scale, and Gastrointestinal Quality of Life Index were used to evaluate the self-efficacy, self-care ability, health behavior, and quality of life of two groups before and after the intervention, and statistical comparisons were made.Results:Both groups of patients completed the study. There were 28 males and 27 females in the control group. The age was (45.33 ± 12.26) years old. There were 30 males and 25 females in the research group. The age was (45.48 ± 12.61) years old. After the intervention, the score of the self-efficacy in the research group was (29.32 ± 2.88) points, which was higher than that in the control group (19.28 ± 1.95) points, the difference was significant ( t=21.41, P<0.05). The scores of self-care skills, self-responsibility, self-concept, health knowledge and the total score of the self-care ability in the research group were (35.32 ± 2.31), (22.85 ± 1.42), (25.88 ± 1.93), (64.32 ± 5.22), (148.34 ± 8.33) points respectively. They were all higher than those of the control group (28.66 ± 1.77), (17.22 ± 1.23), (18.67 ± 1.86), (60.08 ± 4.52), (124.56 ± 8.92) points. The differences were significant ( t values were 4.55-22.23, all P<0.05). The scores of exercise, nutrition, health responsibility, psychological comfort and the total score of the health behavior in the research group were (25.58 ± 1.41), (25.02 ± 2.03), (24.31 ± 2.34), (25.16 ± 1.63), (100.05 ± 7.36) points respectively. They were all higher than those of the control group (22.31 ± 2.03), (20.15 ± 2.82), (20.16 ± 2.89), (21.15 ± 2.17), (83.79 ± 7.84) points. The differences were significant ( t values were 8.28-11.21, all P<0.05). The scores of social activity, psychological state, physiological function, self-conscious symptoms and the total score of the quality of life in the research group were (16.78 ± 1.26), (17.03 ± 1.85), (22.43 ± 1.96), (17.09 ± 0.88), (73.41 ± 4.22) points respectively. They were all higher than those of the control group (15.32 ± 1.15), (15.34 ± 1.76), (20.86 ± 1.59), (16.03 ± 0.75), (67.52 ± 4.18) points. The differences were significant ( t values were 4.61-7.35, all P<0.05). Conclusions:SRT-based nursing scheme can effectively improve the self-efficacy and self-care ability of patients with chronic pancreatitis, and improve their health behavior and quality of life.

Objective:To assess the preliminary efficacy and safety of modified Société Internationale d′Oncologie Pédiatrique Epithelial Liver Tumor Study Group (SIOPEL)-4 protocol for pediatric hepatoblastoma (HB) with lung metastases.Methods:This prospective cohort study enrolled 27 newly diagnosed pediatric HB with lung metastases who received the modified SIOPEL-4 protocol at Shanghai Children′s Medical Center, Shanghai Jiao Tong University School of Medicine, and Shanghai Children′s Hospital between January 2020 to December 2023. Clinical characteristics, lung response rates to induction chemotherapy, treatment outcomes, prognostic factors and sever chemotherapy toxicities at different stages were analyzed. Survival analysis was performed by Kaplan-Meier method. Univariate prognostic analysis was conducted by Log-Rank test.Results:Of the 27 patients, there were 17 males and 10 females, with the age of 21 (15, 33) months. During the follow-up of 31 (12, 45) months for 17 continuous complete remission patients, 4 cases disease progression (2 cases death) and 6 cases relapse were observed. The 2-year event free survival (EFS) and overall survival (OS) rate was (58±11)% and (89±7)%, respectively. All the 27 patients had response to block 1-3 induction chemotherapy (cisplatin+doxorubicin), with 14 cases (52%) achieving complete response and 13 cases (48%) achieving partial response of lung metastatic lesions, the 2-year EFS rate was (81±12)% and (34±14)%, respectively ( χ 2=6.76, P=0.009), the 2-year OS rate was 100% and (79±13)%, respectively ( χ2=2.12, P=0.145). Patients with caudate lobe tumors or ≥10 pulmonary metastatic nodules had significantly lower EFS rates ( χ2=5.36, 7.84, P=0.021, 0.005, respectively). The incidence of grade 3/4 neutropenia after block 1-3 induction chemotherapy, CD (carboplatin+doxorubicin), and VI (vincristine+irinotecan) consolidation chemotherapy was 90% (73/81), 75% (58/77), and 31% (11/35), respectively. The incidence of grade 3/4 thrombocytopenia was 77% (62/81), 69% (53/77), and 14% (5/35), respectively. The incidence of grade 3/4 infections was 64% (52/81), 25% (19/77), and 20% (7/35), respectively. The differences between the groups were statistically significant ( χ2=43.51, 42.69, 33.00, all P<0.001). Two patients (10%) of the 20 evaluable patients for ototoxicity occurred grade 3 and higher hearing impairment, with 1 patient requiring a hearing aid. Conclusions:The modified SIOPEL-4 regimen shows good preliminary efficacy and safety in treating pediatric HB with lung metastases. The prognosis for patients with residual lesions in the lungs after induction chemotherapy needs to be improved. Attention should be given to the ototoxicity induced by high-dose cisplatin chemotherapy.

Purpose To explore the relationship between semi-quantitative parameters maximum standard uptake value(SUVmax)and target-background ratio(TBR)of 18F-FDG PET/CT imaging and the activity of Takayasu arteritis.Materials and Methods A total of 110 patients with Takayasu arteritis from February 2016 to December 2022 in the First Affiliated Hospital of Zhengzhou University who underwent 18F-FDG PET/CT images were retrospectively reviewed.All Takayasu arteritis patients were divided into active(92 cases)and inactive groups(18 cases)according to Kerr score.The region of interest technique was used to measure the SUVmax of the arterial wall,and compares the SUVmax with the average SUV in the center of the inferior vena cava and the maximum SUV measured in the right lobe of the liver to obtain TBRblood pool and TBRliver.The diagnostic efficacy of SUVmax,TBRblood pool and TBRliver in Takayasu arteritis activity was compared using the receiver operating characteristic curve.The relationship between PET/CT parameters and Kerr score,erythrocyte sedimentation rate and C-reactive protein was evaluated.Results SUVmax,TBRblood pool and TBRliver in the active group were higher than those in the inactive group[3.70(3.03,5.18)vs.1.45(1.38,1.53),2.50(1.93,3.88)vs.0.91(0.79,1.16)and 1.37(1.00,1.96)vs.0.44(0.39,0.63);Z=5.510-5.900,all P<0.001],respectively.A SUVmax level of 2.65 was shown to be the best predictive cut-off value for Takayasu arteritis disease activity(sensitivity 83.7%,specificity 100%and area under the curve 0.91).A TBRblood pool level of 1.63 was shown to be the best predictive cut-off value for Takayasu arteritis disease activity(sensitivity 83.7%,specificity 94.4%and area under the curve 0.93).A TBRliver level of 0.81 was shown to be the best predictive cut-off value for Takayasu arteritis disease activity(sensitivity 87.0%,specificity 100%and area under the curve 0.94).SUVmax,TBRblood pool,TBRliver were all positively correlated with the Kerr score(r=0.88,0.89.0.90,all P<0.001),among which the correlation coefficient between TBRliver and the Kerr score was the highest.Conclusion SUVmax,TBRblood pool and TBRliver can evaluate disease activity in Takayasu arteritis patients,with TBRliver being the best.

Objective:To assess the preliminary efficacy and safety of modified Société Internationale d′Oncologie Pédiatrique Epithelial Liver Tumor Study Group (SIOPEL)-4 protocol for pediatric hepatoblastoma (HB) with lung metastases.Methods:This prospective cohort study enrolled 27 newly diagnosed pediatric HB with lung metastases who received the modified SIOPEL-4 protocol at Shanghai Children′s Medical Center, Shanghai Jiao Tong University School of Medicine, and Shanghai Children′s Hospital between January 2020 to December 2023. Clinical characteristics, lung response rates to induction chemotherapy, treatment outcomes, prognostic factors and sever chemotherapy toxicities at different stages were analyzed. Survival analysis was performed by Kaplan-Meier method. Univariate prognostic analysis was conducted by Log-Rank test.Results:Of the 27 patients, there were 17 males and 10 females, with the age of 21 (15, 33) months. During the follow-up of 31 (12, 45) months for 17 continuous complete remission patients, 4 cases disease progression (2 cases death) and 6 cases relapse were observed. The 2-year event free survival (EFS) and overall survival (OS) rate was (58±11)% and (89±7)%, respectively. All the 27 patients had response to block 1-3 induction chemotherapy (cisplatin+doxorubicin), with 14 cases (52%) achieving complete response and 13 cases (48%) achieving partial response of lung metastatic lesions, the 2-year EFS rate was (81±12)% and (34±14)%, respectively ( χ 2=6.76, P=0.009), the 2-year OS rate was 100% and (79±13)%, respectively ( χ2=2.12, P=0.145). Patients with caudate lobe tumors or ≥10 pulmonary metastatic nodules had significantly lower EFS rates ( χ2=5.36, 7.84, P=0.021, 0.005, respectively). The incidence of grade 3/4 neutropenia after block 1-3 induction chemotherapy, CD (carboplatin+doxorubicin), and VI (vincristine+irinotecan) consolidation chemotherapy was 90% (73/81), 75% (58/77), and 31% (11/35), respectively. The incidence of grade 3/4 thrombocytopenia was 77% (62/81), 69% (53/77), and 14% (5/35), respectively. The incidence of grade 3/4 infections was 64% (52/81), 25% (19/77), and 20% (7/35), respectively. The differences between the groups were statistically significant ( χ2=43.51, 42.69, 33.00, all P<0.001). Two patients (10%) of the 20 evaluable patients for ototoxicity occurred grade 3 and higher hearing impairment, with 1 patient requiring a hearing aid. Conclusions:The modified SIOPEL-4 regimen shows good preliminary efficacy and safety in treating pediatric HB with lung metastases. The prognosis for patients with residual lesions in the lungs after induction chemotherapy needs to be improved. Attention should be given to the ototoxicity induced by high-dose cisplatin chemotherapy.