Ferroptosis is a form of programmed cell death characterized by overwhelmed lipid oxidation, and it has emerged as a promising strategy for cancer therapy. Enhanced ferroptosis could overcome the limitations of conventional therapeutic modalities, particularly in difficult-to-treat tumors. In this study, we developed a dual-modality therapy in nanomedicine by combining paclitaxel (PTX) chemotherapy and pyropheophorbide-a (Ppa) phototherapy. Heparin (HP) was grafted with poly(N-(2'-hydroxy) propyl methacrylamide) (pHPMA) using reversible addition-fragmentation chain transfer polymerization to form HP-pHPMA (HH), which was utilized to deliver Ppa and PTX, yielding HP-pHPMA-Ppa (HH-Ppa) and HP-pHPMA-PTX (HH-PTX), respectively. The prodrug-based combinational nanomedicine (HH-PP) was formed by co-assembly of HH-PTX and HH-Ppa. It was found that HH-PP treatment significantly disrupted lipid metabolism in triple-negative breast cancer (TNBC) cells, induced extensive lipid oxidation, and promoted ferroptosis. In vivo, HH-PP intervention achieved a tumor growth inhibition rate of 86.63% and activated adaptive immunity with an elevated CD8⁺ cytotoxic T cell infiltration level. This combinational nanomedicine offers a promising platform for co-delivery of multiple therapeutic agents. It exerts a promising anti-tumor effect via enhanced ferroptosis and ferroptosis-induced immune activation by disrupting lipid metabolism in TNBC cancer cells.

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 investigate the executive condition of Enhanced Recovery After Surgery(ERAS)measures among the hospitalized surgical patients in secondary and tertiary medical institutions of Chongqing City.Methods Using a multicenter cross-sectional survey approach,patients undergoing elective surgeries admitted and treated in 40 member units under the Chongqing Anesthesiology and Perioperative Medicine Specialized Alliance from July 11 to 30,2024 were selected as the survey subjects.Adherence to and completion of ERAS measures were calculated.Factors influencing measures with low completion rates were analyzed.Results A total of 2 100 questionnaires were issued,1 708 effective questionnaires were recovered with an effective recovery rate of 81.33％.Among them,there were 1 017 questionnaires in the tertiary medi-cal institutions and 691 questionnaires in the secondary medical institutions.The age of 1 708 patients ranged from 19-78 years old with a median age of 52 years old.Females were dominant.The proportion of patients from gastrointestinal surgery and those with secondary school education or above was high.Hypertension and diabetes were the main complication types.The surgical grade was concentrated at grades Ⅲ and Ⅳ.The ASA grading was concentrated at the grade Ⅰ/Ⅱ.The NYHA heart function grade was mainly the grade Ⅰ/Ⅱ.The ERAS measures compliance rate ranged from 36.36％to 95.45％,averaged 73.47％.The compliance rate of ERAS measures in the tertiary hospitals was higher than that in the secondary hospitals(75.82％vs.70.01％),and the difference was statistically significant(P<0.05).The average completion rate of ERAS measures was 74.08％.The top three in the completion rate were preoperative education(95.78％),preven-tive antibiotics and skin preparation(92.62％),and preoperative interview and evaluation(88.58％).The completion rates of Prehabilitation(55.27％)and preoperative fasting(57.67％)urgently needed to be in-creased.The completion rate of other measures was lower than 60％.Conclusion The compliance rate of ERAS measures needs to be increased,moreover there are significant differences among various hospitals.Fu-ture practices should focus on two measures:preoperative pre-rehabilitation exercises and preoperative oral intake of carbohydrates.

Objective: To explore the neuroprotective effects of the Shaoyao Gancao decoction (SGD) against excitatory damage in PC12 cells and the role of the Src-NR2-nNOS pathway mediation by SGD in regulating γ-aminobutyric acid (GABA)-glutamate (Glu) homeostasis. Methods: N-Methyl-d-aspartic acid (NMDA) was used to establish a PC12 cell excitability injury model. To investigate the neuroprotective effect of SGD, a cell counting kit-8 (CCK-8) assay was used to determine PC12 cell viability, Annexin V/Propidium Iodide (Annexin V/PI) double staining was used to determine PC12 cell apoptosis, and Ca2+ concentration was observed using laser confocal microscopy. GABA receptor agonists and antagonists were used to analyze the neuroprotective interactions between γ-aminobutyric acid (GABA) and NMDA receptors. Additionally, molecular biology techniques were used to determine mRNA and protein expression in the Src-NR2-nNOS pathway. We analyzed the correlations between the regulatory sites of GABA and NMDA interactions, excitatory neurotoxicity, and brain damage at the molecular level. Results: NMDA excitotoxic injury manifested as a significant decrease in cell activity, increased apoptosis and caspase-3 protein expression, and a significant increase in intracellular Ca2+ concentration. Administration of SGD, a GABAA receptor agonist (muscimol), or a GABAB receptor agonist (baclofen) decreased intracellular Ca2+ concentrations, attenuated apoptosis, and reversed NMDA-induced upregulation of caspase-3, Src, NMDAR2A, NMDAR2B, and nNOS. Unexpectedly, a GABAA receptor antagonist (bicuculline) and a GABAB receptor antagonist (saclofen) failed to significantly increase excitatory neurotoxicity. Conclusions Taken together, these results not only provide an experimental basis for SGD administration in the clinical treatment of central nervous system injury diseases, but also suggest that the Src-NR2A-nNOS pathway may be a valuable target in excitotoxicity treatment.

Objective We aimed to study the protective effect of total glucosides of paeony (TGP) on chemical liver injury with pattern of liver yin deficiency in rats and determine whether it exerts these effects through the phosphoinositide 3-kinase(PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway.Methods Forty male Sprague-Dawley rats were randomly divided into the following four groups: (i) the blank group, (ii) the model group, (iii) the Yiguan Jian group, and (iv) the TGP group (10 rats per group). For 6 weeks, rats in all groups except for the blank group were injected intraperitoneally with 20％ carbon tetrachloride olive oil solution and were given thyroid tablets (30mg/kg) by gavage in order to establish the model of chemical liver injury with pattern of liver yin deficiency. During the modeling period, rats in the blank and model groups were gavaged daily with distilled water, while rats in the Yiguan Jian group and the TGP group were gavaged with 635mg/kg of Yiguan Jian decoction and 50mg/kg of TGP suspension, respectively. During the administration period, the body weight and rectal temperature of rats were measured every 2 weeks. After the administration, 24-hour food intake, 24-hour water intake, and moisture capacity in tongue surface were recorded. Serum cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), and interleukin-1 receptor antagonist (IL-1Ra) contents were measured by ELISA and the cAMP/cGMP ratio was calculated. Changes in the serum levels of alanine aminotransferase (ALT), alanine transaminase (AST), gamma-glutamyl transpeptidase (γ-GT), alkaline phosphatase (ALP), total bilirubin (TBIL), and total bile acids (TBA) were detected using colorimetric method. Masson staining was performed to observe the degree of liver fibrosis and to calculate the relative collagen area. Real-time PCR and Western blotting were conducted to determine the PI3K, AKT, and mTOR mRNA and protein expression levels in rat liver.Results Compared with the blank group, rats in the model group had a lower body weight at weeks 2, 4, and 6, a higher rectal temperature at weeks 2, 4, and 6, and a higher 24-hour food intake; the cAMP level was elevated, the cGMP level was decreased, and the cAMP/cGMP ratio was elevated; the contents of IL-1, IL-6, and TNF-α were elevated, and the contents of IL-10 and IL-1Ra were decreased; ALT, AST, γ-GT, ALP, TBIL, and TBA levels were elevated; the percentage of collagen area in the liver was increased; and the mRNA and protein phosphorylation levels of PI3K, AKT, and mTOR were elevated ( P<0.05). Compared with the model group, rats in the TGP group showed a decrease in rectal temperature at weeks 2, 4, and 6, a decrease in 24-hour food intake and water intake, and an increase in the moisture capacity in tongue surface; rats in the Yiguan Jian and TGP groups showed a decrease in cAMP, an increase in cGMP, and a decrease in the cAMP/cGMP, the contents of IL-1, IL-6, and TNF-α were decreased and the content of IL-10 was increased, the percentage of collagen area in the liver was decreased; ALT, AST, γ-GT, ALP, and TBIL levels were decreased in the TGP group, and PI3K, AKT, and mTOR were downregulated at the mRNA and protein levels(P<0.05).Conclusion TGP has a good protective effect on chemical liver injury with pattern of liver yin deficiency in rats. TGP may regulate the balance of yin and yang by inhibiting the PI3K/AKT/mTOR pathway, reducing the secretion of pro-inflammatory cytokines, and increasing the release of anti-inflammatory cytokines.

Purpose To study the safety and clinical value of adenosine stress myocardial perfusion imaging(MPI)in evaluating myocardial ischemia in children with Kawasaki disease.Materials and Methods A total of 78 children with a history of Kawasaki disease and coronary artery aneurysm confirmed by echocardiography and coronary angiography were prospectively studied in Children's Hospital of Fudan University from August 2019 to February 2021.Adenosine stress MPIs were performed to analyze the safety of adenosine stress test and its sensitivity and specificity in detecting significant coronary artery stenosis(≥75%),and the positive rate of adenosine stress MPIs in different groups of coronary artery stenosis were further compared.Results All 78 children completed adenosine stress test without serious side effects.Among 78 children with adenosine stress imaging,44 patients with negative adenosine stress imaging did not undergo rest imaging,which reduced radiation exposure by 56.4%(44/78).The sensitivity and specificity of adenosine stress MPIs in detecting significant coronary artery stenosis were 66.7%and 60.6%(40/66),respectively.Adenosine stress MPIs were positive in 21 cases(21/52,40.3%)in non-stenosis group,5 cases(35.7%)in mild to moderate stenosis group,and 8 cases(66.7%)in significant stenosis group.There was no significant difference in the positive rate among the three groups(χ2=3.169,P=0.205).Conclusion Adenosine stress test is safe and feasible in children.The stress-first imaging strategy can reduce radiation exposure.Adenosine stress MPI has important clinical value in evaluating and monitoring myocardial ischemia in children with Kawasaki disease complicated with coronary aneurysm.

Objective:To investigate the value of soluble interleukin-6 (IL-6) receptor (sIL-6R) level in predicting ultrafiltration insufficiency in peritoneal dialysis (PD) patients.Methods:It was a prospective cohort study. The patients who received continuous ambulatory PD and regular follow-up between November 2016 and July 2018 in the PD Center of Renji Hospital, School of Medicine, Shanghai Jiao Tong University were enrolled. Enzyme-linked immunosorbent assay was used to determine dialysate sIL-6R and its appearance rate (AR) was calculated. Patients were divided into high sIL-6R AR group and low sIL-6R AR group according to median value of sIL-6R AR and prospectively followed up until death, PD cessation, or the end of the study (December 31, 2022). Multiple linear regression was used to analyze the related factors of sIL-6R AR. Kaplan-Meier method and log-rank test were used to compare the survival rate difference of ultrafiltration insufficiency between high sIL-6R AR group and low sIL-6R AR group. Multivariate Cox regression and multivariate competing risk models were used to assess the risk factors associated with occurrence of ultrafiltration insufficiency.Results:A total of 198 PD patients were enrolled, including 115 (58.1%) males, with age of (54.9±13.7) years old and PD duration of 22.5 (6.6, 65.0) months. The sIL-6R AR of the cohort was 2 094.7 (1 672.4, 2 920.9) pg/min. Compared with low sIL-6R AR（<2 094.7 pg/min）group, high sIL-6R AR（>2 094.7 pg/min）group had older age ( t=-3.269, P=0.001), higher body mass index ( t=-3.248, P=0.001), proportion of combined diabetes mellitus ( χ2=8.890, P=0.003), 24 h glucose exposure ( Z=-2.257, P=0.024), 24 h ultrafiltration capacity ( Z=-2.515, P=0.012), 4 h dialysate creatinine to serum creatinine ratio ( t=-2.609, P=0.010), mass transfer area coefficient of creatinine ( Z=-2.308, P=0.021), IL-6 AR ( Z=-3.533, P<0.001) and solute glycoprotein 130 AR ( Z=-8.670, P<0.001), and lower serum albumin ( t=2.595, P=0.010) and residual renal function ( t=2.133, P=0.033). Multiple linear regression analysis showed that body mass index ( β=0.194, P=0.005), serum albumin ( β=-0.215, P=0.002) and dialysate lg[IL-6 AR] ( β=0.197, P=0.011) were independently correlated with sIL-6R AR. By the end of the study, 57 (28.8%) patients developed ultrafiltration insufficiency. Kaplan-Meier analysis showed that high sIL-6R AR group had a significantly inferior ultrafiltration insufficiency-free survival rate than that in low sIL-6R AR group (log-rank χ 2=5.375, P=0.020). Multivariate Cox regression analysis and multivariate competing risk models showed that high dialysate sIL-6R AR (>2 094.7 pg/min) was an independent influencing factor of ultrafiltration insufficiency ( HR=2.286 , 95% CI 1.254-4.165 , P=0.007 ; SHR=2.074, 95% CI 1.124-3.828, P=0.020) in PD patients. Conclusions:Dialysate sIL-6R level was associated with body mass index, serum albumin and dialysate IL-6 level. Dialysate sIL-6R may be a predictive factor of ultrafiltration insufficiency in PD patients.

Objective To analyze the risk factors for non-sentinel lymph node (NSLN) metastasis in patients with sentinel lymph node (SLN)-negative breast cancer. Methods Patients with breast cancer who underwent mastectomy and SLN biopsy at our center between January 2009 and August 2024 were retrospectively included. Univariate and multivariate analyses were performed in SLN-negative populations underwent low axillary lymph node dissection to identify risk factors for NSLN metastasis. Results A total of 2 387 SLN-negative patients were included, including 2 288 (95.9%) without NSLN metastasis and 99 (4.1%) with NSLN metastasis. Univariate and multivariate analyses showed that lymphovascular invasion (LVI) was an independent risk factor for NSLN metastasis in SLN-negative patients (13.5% versus 3.5%; OR=4.14，95% CI: 2.27-7.56，P<0.001). Patients with multicentric breast cancer showed a trend towards higher risk of NSLN metastasis compared to other types of breast cancer (9.5% versus 4.1%; OR=2.08，95% CI： 0.90-4.81，P=0.089). Conclusions Patients with SLN-negative biopsy who have LVI or multicentric breast cancer are at higher risk for NSLN metastasis.

Pain is an uncomfortable and emotional experience associated with,or similar to,real or po-tential tissue damage.However,far from being a purely physiological sensation,pain involves complex emo-tional and neuromodulatory mechanisms.The pain neural circuit is a complex biological system,covering the multi-level structure of the central nervous system from peripheral neurons to the cerebral cortex,thalamus,a-mygdala and dorsal horn of the spinal cord,participating in the perception,conduction,and regulation of pain signals,involves multiple molecular and cellular interactions to build a comprehensive pain perception process.In recent years,the field of pain neural circuit research has used a variety of scientific and technological tools to provide the theoretical and technical support for the in-depth understanding and treatment of pain.This article aims to provide a comprehensive research status quo for the scholars in related fields and new ideas for clinical pain research and treatment by combing the application of different technologies in the study of pain neural circuits.

Sacral tumors are surgically challenging and at a high risk of complications. In recent years, robotic-assisted resection has been gradually applied in sacral tumors, but it is difficult to remove bone tissue by present robotic instruments, which limits the application of surgical robot in sacral tumor. The present study aimed to explore the application range and therapeutic effect of minimally invasive ultrasonic osteotome in robotic-assisted sacral tumor resection. Eighteen patients underwent robotic-assisted sacral tumor resection in the First Affiliated Hospital of Sun Yat-Sen University from May 2015 to March 2021 by the Da Vinci robotic surgical system. Among them three patients who underwent osteotomy with minimally invasive ultrasonic osteotome were enrolled. There were 2 males and 1 female, aged 24, 32, 71 years, respectively. The tumors included 2 schwannomas and 1 ganglioneuroma. The operation time, bleeding volume and postoperative hospitalization days were recorded. The recurrence and complications were evaluated during follow-up. The operative time of the 3 patients was 80, 240 and 300 minutes, and the intraoperative bleeding volume was 30, 30 and 100 ml. Complete resection was performed in 2 cases and intralesional resection in 1 case. The postoperative hospital stay was 5, 3 and 7 days respectively. The follow-up time was 58, 17 and 31 months respectively. No tumor recurrence was found during the follow-up. As regards complications, only one patient had left foot pain after operation, and there were no other intraoperative or postoperative complications. The therapeutic advantages of ultrasonic osteotome combined with the Da Vinci robotic surgical system can achieve precise osteotomy, reduce intraoperative bleeding and accelerate postoperative recovery for certain patients with sacral tumors.