Zoledronic acid (ZA), a nitrogen-containing bisphosphonate with established clinical utility in osteoporosis management, exhibits emerging antitumor potential in estrogen receptor-positive breast cancer. However, the molecular mechanisms underlying its nonapoptotic anticancer effects remain poorly characterized. This study revealed that ZA induced ferroptosis in ER+ breast cancer cells through dual suppression of cystine-glutamate antiporter SLC7A11 and glutathione peroxidase 4 (GPX4), key repressors of ferroptosis. Pharmacological inhibition of ferroptosis using Ferrostatin-1 significantly attenuated ZA-induced cytotoxicity, while combinatorial treatment with the GPX4 inhibitor RSL3 synergistically enhanced lipid peroxidation and cell death. Mechanistically, ZA activated the Hippo-YAP signaling pathway, promoting YAP phosphorylation, proteasomal degradation, and cytoplasmic retention, thereby silencing SLC7A11 and GPX4. We established a novel metabolic vulnerability in hormone-responsive malignancies.These findings position ZA as a bifunctional ferroptosis inducer in ER+ breast cancer, offering a promising strategy to overcome endocrine resistance.

Objective:To explore the application of the flipped classroom teaching method in pediatric internship, evaluate the feedback from both students and faculty, and provide evidence for optimizing clinical medical education strategies.Methods:Fourth-year students ( n=174) enrolled in 2019 in the eight-year clinical medicine program at Peking University Health Science Center and instructors ( n=42) participated in this study. Questionnaire survey and exit examination scores were used to assess the effectiveness of the flipped classroom method. A statistical analysis was performed using SPSS 26.0. Kruskal-Wallis test and Dunn's multiple comparisons were used to evaluate the differences in satisfaction across teaching components. Chi-square test and Fisher's exact test were applied to compare satisfaction between high-score (top 30%) and low-score (bottom 30%) student groups. Results:①Overall student satisfaction with the flipped classroom reached 91.33% ("very satisfied" + "satisfied"). High satisfaction was reported for pre-class self-learning videos (80.35%), recommended clinical guidelines (82.80%), and English literature (71.10%), while satisfaction with the flipped classroom lectures was comparatively low (52.60%), with significant differences compared to other components ( P<0.05). ②High-score students exhibited significantly lower satisfaction than low-score students across all components (overall evaluation, 84.61% vs. 98.08%, Fisher's exact test, P=0.031; pre-class videos, 53.85% vs. 76.92%, χ2=6.12, P=0.013; preparatory assignments, 61.54% vs. 80.77%, χ2=4.68, P=0.030; English literature, 53.85% vs. 75.00%, χ2=5.80, P=0.016; and flipped class lectures, 36.54% vs. 59.62%, χ2=5.55, P=0.019). ③Enhanced competency in ≥2 core areas was reported in 71.68% of students, including theoretical knowledge acquisition (49.71%), self-directed learning (35.84%), clinical thinking (31.21%), research capabilities (25.43%), and communication skills (22.54%). ④Faculty feedback indicated that 83.33% of instructors perceived the flipped classroom as equivalent or superior to traditional teaching, particularly in cultivating clinical thinking (90.48%), self-directed learning (85.71%), theoretical knowledge acquisition (76.19%), and communication skills (76.19%). ⑤Student participation willingness was primarily influenced by pre-class time investment (46.51% reported excessive effort in preparing discussion materials), while faculty engagement depended on implementation effectiveness (42.86%) and curriculum design (35.71%). Conclusions:The flipped classroom method demonstrated promising initial outcomes in pediatric internship, with high satisfaction among both students and faculty. However, further exploration and practice are required in optimizing teaching components, implementing differentiated instructional strategies, and managing time investment.

Objective To investigate the effect of fumigation decoction on the expression of aggrecan(AGG)and type Ⅱ collagen(COL2A1)in an intervertebral disc degeneration(IDD)model,and to gain an in-depth understanding of the cellular and molecular mechanisms underlying traditional Chinese medicine fumigation therapy.Methods An IDD model was established using Sprague-Dawley rats by inducing disc injury via needle puncture.The rats were divided into three groups:normal control(CON),model(PUN),and fumigation(CHF).Only the CHF group received treatment with fumigation decoction for 4 weeks.Imaging analysis was conducted to assess the relative height of intervertebral discs,while Masson's trichrome staining was used to observe structural changes in the discs.The expression of NLRP3 inflammasome was detected by immunohistochemistry.Quantitative RT-PCR and Western blotting were employed to evaluate the expression levels of AGG and COL2A1 genes and proteins.Results A total of 12 rats were randomly divided into 3 groups,with 4 rats in each group.Compared with the CON group,disc height was significantly lost in the PUN group(P＜0.05),and disc height could be partially restored in the CHF group(P＜0.05).In the PUN group,the expression levels of AGG mRNA and COL2A1 mRNA and protein in the nucleus pulposus tissue were significantly lower than those in the CON group(P＜0.05).Compared with the PUN group,the CHF group showed significantly increased expression levels of AGG mRNA and COL2A1 mRNA and protein in the nucleus pulposus tissue(P＜0.05).Histological analysis revealed that,compared with the PUN group,the CHF group exhibited partial restoration of the gel-like properties of the nucleus pulposus and an increase in proteoglycan content.Additionally,NLRP3 expression in the nucleus pulposus tissue of the CHF group was markedly reduced.Conclusion Fumigation decoction treatment can enhance the expression of AGG and COL2A1 and decrease the expression of NLRP3 in IDD models,which may be one of its mechanisms for treating lumbar degenerative diseases.This research provides new insights into the treatment of IDD.

Objective To evaluate the efficacy and safety of high-power,short-duration radiofrequency catheter ablation for the treatment of persistent atrial fibrillation.Methods This retrospective study included 392 patients diagnosed with persistent atrial fibrillation who underwent catheter radiofrequency ablation at Suzhou Kowloon Hospital,Shanghai Jiao Tong University School of Medicine,from January 2019 to December 2023.Of these,256 patients were treated with high-power,short-duration ablation,and 136 patients with low-power,long-duration ablation.The following parameters were compared:radiofrequency ablation time,total procedure time,single-circle pulmonary vein isolation rate,immediate procedural success rate,number of ablation points,and perioperative complications(including pericardial tamponade,pseudoaneurysm,arteriovenous fistula,stroke,etc.).Follow-up assessments were conducted at 3,6,and 12 months post-surgery to evaluate the 12-month sinus rhythm maintenance rate.Results The ablation time in the high-power group was significantly shorter than that in the low-power group[(14.6±2.3)min vs.(30.3±4.2)min,P＜0.001],as was the total procedure time[(113.8±24.8)min vs.(128.5±26.7)min,P=0.001].There were no significant differences between the two groups in terms of pulmonary vein isolation rate(97.7％vs.94.9％,P=0.823),number of ablation points[(71.2±8.0)vs.(74.3±14.3),P=0.168],or perioperative complications(3.1％vs.4.4％,P=0.571).Regarding the maintenance rate of sinus rhythm at 12 months post-operation,the high-power group showed a higher rate than the low-power group,but no statistically significant difference was observed(82.8％vs.79.4％,P=0.399).Conclusions High-power,short-duration radiofrequency catheter ablation can improve procedural efficiency in the treatment of persistent atrial fibrillation.Its efficacy and safety are similar to those of the low-power,long-duration technique.

Objectives:To investigate the effect and mechanism of mitochondrial targeting peptide SS-31 on senescence and pyroptosis of nucleus pulposus(NP)cells induced by inflammation.Methods:NP cells were isolated and cultured in vitro from 6-week-old male SD rats,and were divided into control group,lipopolysaccharide(LPS)group,and LPS+SS-31 group;And the control group of cells received no treatment,LPS group of cells were treated with 100μg/mL LPS for 24h,and LPS+SS-31 group of cells were pre-treated with SS-31 30min before LPS intervention.The levels of cellular senescence and pyroptosis were assessed in each group using β-galactosidase(SA-β-Gal)staining and westem blot(WB)assay;Transmission electron mi-croscopy and oxygen consumption rate(OCR)assay were used to analyze the mitochondrial function of NP cells in each group;The expressions of phosphorylated nuclear factor-κB-p65(p-NF-κB-p65),cyclic GMP-AMP synthase(cGAS),and interferon stimulating gene(STING)in each group were detected by WB and im-munofluorescence;Hematoxylin-eosin(HE)staining,immunohistochemistry(IHC)staining and WB assay were performed to analyze the effects of in vivo injection of SS-31 on intervertebral disc degeneration,senescence,and pyroptosis.Results:The positive SA-β-Gal staining of NP cells,expression of senescence marker pro-teins(p53,p21),and pyroptosis-related molecules(NLRP3,Caspase-1 p20)were significantly lower in the LPS+SS-31 group compared with the LPS group(P＜0.05);Transmission electron microscopy(TEM)showed that the mitochondrial swelling of NP cells was round,the matrix was translucent,and the interstitial lumen of the mitochondrial cristae was dilated in the LPS group,while the mitochondrial swelling was subsided,and the morphology of mitochondria tended to be normalized in the LPS+SS-31 group.Meanwhile,the maximum respi-ration level of NP cells was significantly enhanced in the LPS+SS-31 group compared with the LPS group(P＜0.05).The results of WB and immunofluorescence showed that LPS significantly up-regulated the expression of p-NF-κB-p65,cGAS,and STING(P＜0.05),while SS-31 pretreatment significantly inhibited the expression of p-NF-κB-p65,cGAS and STING in NP cells induced by LPS(P＜0.05).Finally,in vivo experiments con-firmed that local injection of SS-31 reduced the senescence and pyroptosis of NP cells,and alleviated the degeneration of intervertebral disc induced by annulus fibropuncture.Conclusions:SS-31 alleviates inflamma-tion-induced senescence and pyroptosis of NP cells,which is related to the inhibition of NF-κB signaling pathway and cGAS/STING signaling pathway.

Objective To investigate the effect of fumigation decoction on the expression of aggrecan(AGG)and type Ⅱ collagen(COL2A1)in an intervertebral disc degeneration(IDD)model,and to gain an in-depth understanding of the cellular and molecular mechanisms underlying traditional Chinese medicine fumigation therapy.Methods An IDD model was established using Sprague-Dawley rats by inducing disc injury via needle puncture.The rats were divided into three groups:normal control(CON),model(PUN),and fumigation(CHF).Only the CHF group received treatment with fumigation decoction for 4 weeks.Imaging analysis was conducted to assess the relative height of intervertebral discs,while Masson's trichrome staining was used to observe structural changes in the discs.The expression of NLRP3 inflammasome was detected by immunohistochemistry.Quantitative RT-PCR and Western blotting were employed to evaluate the expression levels of AGG and COL2A1 genes and proteins.Results A total of 12 rats were randomly divided into 3 groups,with 4 rats in each group.Compared with the CON group,disc height was significantly lost in the PUN group(P＜0.05),and disc height could be partially restored in the CHF group(P＜0.05).In the PUN group,the expression levels of AGG mRNA and COL2A1 mRNA and protein in the nucleus pulposus tissue were significantly lower than those in the CON group(P＜0.05).Compared with the PUN group,the CHF group showed significantly increased expression levels of AGG mRNA and COL2A1 mRNA and protein in the nucleus pulposus tissue(P＜0.05).Histological analysis revealed that,compared with the PUN group,the CHF group exhibited partial restoration of the gel-like properties of the nucleus pulposus and an increase in proteoglycan content.Additionally,NLRP3 expression in the nucleus pulposus tissue of the CHF group was markedly reduced.Conclusion Fumigation decoction treatment can enhance the expression of AGG and COL2A1 and decrease the expression of NLRP3 in IDD models,which may be one of its mechanisms for treating lumbar degenerative diseases.This research provides new insights into the treatment of IDD.

Objective To evaluate the efficacy and safety of high-power,short-duration radiofrequency catheter ablation for the treatment of persistent atrial fibrillation.Methods This retrospective study included 392 patients diagnosed with persistent atrial fibrillation who underwent catheter radiofrequency ablation at Suzhou Kowloon Hospital,Shanghai Jiao Tong University School of Medicine,from January 2019 to December 2023.Of these,256 patients were treated with high-power,short-duration ablation,and 136 patients with low-power,long-duration ablation.The following parameters were compared:radiofrequency ablation time,total procedure time,single-circle pulmonary vein isolation rate,immediate procedural success rate,number of ablation points,and perioperative complications(including pericardial tamponade,pseudoaneurysm,arteriovenous fistula,stroke,etc.).Follow-up assessments were conducted at 3,6,and 12 months post-surgery to evaluate the 12-month sinus rhythm maintenance rate.Results The ablation time in the high-power group was significantly shorter than that in the low-power group[(14.6±2.3)min vs.(30.3±4.2)min,P＜0.001],as was the total procedure time[(113.8±24.8)min vs.(128.5±26.7)min,P=0.001].There were no significant differences between the two groups in terms of pulmonary vein isolation rate(97.7％vs.94.9％,P=0.823),number of ablation points[(71.2±8.0)vs.(74.3±14.3),P=0.168],or perioperative complications(3.1％vs.4.4％,P=0.571).Regarding the maintenance rate of sinus rhythm at 12 months post-operation,the high-power group showed a higher rate than the low-power group,but no statistically significant difference was observed(82.8％vs.79.4％,P=0.399).Conclusions High-power,short-duration radiofrequency catheter ablation can improve procedural efficiency in the treatment of persistent atrial fibrillation.Its efficacy and safety are similar to those of the low-power,long-duration technique.

Objectives:To investigate the effect and mechanism of mitochondrial targeting peptide SS-31 on senescence and pyroptosis of nucleus pulposus(NP)cells induced by inflammation.Methods:NP cells were isolated and cultured in vitro from 6-week-old male SD rats,and were divided into control group,lipopolysaccharide(LPS)group,and LPS+SS-31 group;And the control group of cells received no treatment,LPS group of cells were treated with 100μg/mL LPS for 24h,and LPS+SS-31 group of cells were pre-treated with SS-31 30min before LPS intervention.The levels of cellular senescence and pyroptosis were assessed in each group using β-galactosidase(SA-β-Gal)staining and westem blot(WB)assay;Transmission electron mi-croscopy and oxygen consumption rate(OCR)assay were used to analyze the mitochondrial function of NP cells in each group;The expressions of phosphorylated nuclear factor-κB-p65(p-NF-κB-p65),cyclic GMP-AMP synthase(cGAS),and interferon stimulating gene(STING)in each group were detected by WB and im-munofluorescence;Hematoxylin-eosin(HE)staining,immunohistochemistry(IHC)staining and WB assay were performed to analyze the effects of in vivo injection of SS-31 on intervertebral disc degeneration,senescence,and pyroptosis.Results:The positive SA-β-Gal staining of NP cells,expression of senescence marker pro-teins(p53,p21),and pyroptosis-related molecules(NLRP3,Caspase-1 p20)were significantly lower in the LPS+SS-31 group compared with the LPS group(P＜0.05);Transmission electron microscopy(TEM)showed that the mitochondrial swelling of NP cells was round,the matrix was translucent,and the interstitial lumen of the mitochondrial cristae was dilated in the LPS group,while the mitochondrial swelling was subsided,and the morphology of mitochondria tended to be normalized in the LPS+SS-31 group.Meanwhile,the maximum respi-ration level of NP cells was significantly enhanced in the LPS+SS-31 group compared with the LPS group(P＜0.05).The results of WB and immunofluorescence showed that LPS significantly up-regulated the expression of p-NF-κB-p65,cGAS,and STING(P＜0.05),while SS-31 pretreatment significantly inhibited the expression of p-NF-κB-p65,cGAS and STING in NP cells induced by LPS(P＜0.05).Finally,in vivo experiments con-firmed that local injection of SS-31 reduced the senescence and pyroptosis of NP cells,and alleviated the degeneration of intervertebral disc induced by annulus fibropuncture.Conclusions:SS-31 alleviates inflamma-tion-induced senescence and pyroptosis of NP cells,which is related to the inhibition of NF-κB signaling pathway and cGAS/STING signaling pathway.

Objective To investigate the clinical efficacy and safety of facilitated percutaneous coronary intervention(PCI)with half-dose recombinant staphylokinase(r-SAK)in patients with ST-segment elevation myocardial infarction(STEMI)who are expected to undergo PCI within 120 minutes.Methods From October 2021 to August 2022,a total of 200 STEMI patients in eight centers were included and randomly assigned in a 1﹕1 ratio to either r-SAK group or control group.Patients received loading doses of aspirin and ticagrelor and intravenous heparin and were randomized to receive an intravenous bolus of either 5 mg r-SAK or normal saline prior to PCI.The outcomes were set as ST-segment resolution(STR)at 60-90 minutes after PCI,the proportion and transition of pathological Q waves on the 5th day after PCI,and the proportion of high-sensitivity cardiac troponin T(hs-cTnT)peaking within 12 hours of onset.The safety outcome was major bleeding events defined as Bleeding Academic Research Consortium(BARC)≥type 3 bleeding during hospitalization.Results Compared with the control group,the r-SAK group had a higher proportion of STR≥70%within 60-90 minutes after PCI(58.3%vs.40.3%,P=0.009);a lower proportion of pathological Q waves(59.1%vs.74.1%,P=0.040);a lower rate of Q wave progression(14.8%vs.43.2%,P＜0.001);a higher rate of Q wave disappearance(12.5%vs.3.7%,P=0.027);and a higher proportion of hs-cTnT peaking within 12 hours of symptom onset[31/40(77.5%)vs.17/33(51.5%),P=0.027].Regarding the safety outcome,no significant difference in BARC≥type 3 bleeding was found between the two groups during hospitalization(P＞0.05).Conclusions For STEMI patients who were expected to undergo primary PCI within 120 minutes of symptom onset,the facilitated PCI with half-dose r-SAK significantly increased the proportion of STR≥70%at 60-90 minutes after PCI,reduced the formation of pathological Q waves,and shortened the time to peak hs-cTnT,without increasing the risk of bleeding,which should be an alternative reperfusion strategy worthy of further study.

Objective To investigate the clinical efficacy and safety of facilitated percutaneous coronary intervention(PCI)with half-dose recombinant staphylokinase(r-SAK)in patients with ST-segment elevation myocardial infarction(STEMI)who are expected to undergo PCI within 120 minutes.Methods From October 2021 to August 2022,a total of 200 STEMI patients in eight centers were included and randomly assigned in a 1﹕1 ratio to either r-SAK group or control group.Patients received loading doses of aspirin and ticagrelor and intravenous heparin and were randomized to receive an intravenous bolus of either 5 mg r-SAK or normal saline prior to PCI.The outcomes were set as ST-segment resolution(STR)at 60-90 minutes after PCI,the proportion and transition of pathological Q waves on the 5th day after PCI,and the proportion of high-sensitivity cardiac troponin T(hs-cTnT)peaking within 12 hours of onset.The safety outcome was major bleeding events defined as Bleeding Academic Research Consortium(BARC)≥type 3 bleeding during hospitalization.Results Compared with the control group,the r-SAK group had a higher proportion of STR≥70%within 60-90 minutes after PCI(58.3%vs.40.3%,P=0.009);a lower proportion of pathological Q waves(59.1%vs.74.1%,P=0.040);a lower rate of Q wave progression(14.8%vs.43.2%,P＜0.001);a higher rate of Q wave disappearance(12.5%vs.3.7%,P=0.027);and a higher proportion of hs-cTnT peaking within 12 hours of symptom onset[31/40(77.5%)vs.17/33(51.5%),P=0.027].Regarding the safety outcome,no significant difference in BARC≥type 3 bleeding was found between the two groups during hospitalization(P＞0.05).Conclusions For STEMI patients who were expected to undergo primary PCI within 120 minutes of symptom onset,the facilitated PCI with half-dose r-SAK significantly increased the proportion of STR≥70%at 60-90 minutes after PCI,reduced the formation of pathological Q waves,and shortened the time to peak hs-cTnT,without increasing the risk of bleeding,which should be an alternative reperfusion strategy worthy of further study.