ObjectiveStudies have shown that nuciferine has anti-cerebral ischemia effect， but the specific mechanism of action has not been elaborated. Based on the transcriptome results， the pharmacological mechanism of nuciferine against cerebral ischemia was analyzed from multiple dimensions including tissue， cell， pathological process， biological process and signaling pathway. MethodsThirty SD rats were randomly divided into the sham group， model group and nuciferine group（40 mg·kg^-1） according to weight. Except for the sham group， the model of middle cerebral artery occlusion（MCAO） was established by thread embolization method after 30 min of administration in the other two groups. Twenty-four hours after surgery， transcriptome sequencing was used to detect the gene expression profiles in the cortex penumbra of rat cerebral tissue， and gene ontology（GO） and kyoto encyclopedia of genes and genomes（KEGG） pathway enrichment analysis were performed for differentially expressed genes. The mechanismof nuciferine against cerebral ischemia was analyzed from 5 dimensions of tissue， cell， pathological process， biological process and signaling pathway by the transcriptome-based multi-scale network pharmacology platform（TMNP）. ResultsTranscriptome sequencing and gene quantitative analysis showed that 667 genes were significantly reversed by nuciferine. Further enrichment analysis of KEGG and GO suggested that the pathways of nuciferine involved regulating stress response， ion transport， cell proliferation and differentiation， and synaptic function. TMNP research found that at the tissue level， nuciferine could significantly improve the cerebral tissue injury caused by ischemia. At the cellular and pathological levels， nuciferine could play an anti-cerebral ischemia role by improving the state of various nerve cells， mobilizing immune cells， regulating inflammation. And at the level of biological processes and signaling pathways， nuciferine mainly acted on the processes such as vascular remodeling， inflammation-related signaling pathways， and synaptic signaling. ConclusionCombined with the results of transcriptome sequencing， gene quantitative analysis and TMNP， the mechanism of nuciferine against cerebral ischemia may be related to processes such as intervening in stress response and inflammation， affecting vascular remodeling and regulating synaptic function. These results can provide a basis and reference for further study of the pharmacological mechanism of nuciferine against cerebral ischemia.

Background and purpose:For patients with human epidermal growth factor receptor 2(HER2)-positive metastatic breast cancer,trastuzumab treatment can prolong the overall survival and significantly improve the prognosis of patients.However,the reference original research trastuzumab(Herceptin?)is more expensive.Biosimilars have comparable efficacy and safety profiles while increasing patient access to treatment.This clinical trial aimed to evaluate the efficacy,pharmacokinetics,safety and immunogenicity of the trastuzumab biosimilar AK-HER2 compared to trastuzumab(Herceptin?)in patients with HER2-positive metastatic breast cancer.Methods:This multi-center,randomised,double-blind phase Ⅲ clinical trial was conducted in 43 subcenters in China.This study complied with the research protocol,the ethical principles stated in the Declaration of Helsinki and the quality management standards for drug clinical trials.It was approved by the hospital's medical ethics committee.The clinical trial registration agency is the State Food and Drug Administration(clinical trial approval number:2015L04224;clinical trial registration number:CTR20170516).Written informed consent was obtained from subjects before enrollment.Enrolled patients were randomly assigned to the AK-HER2 group and the control group,respectively receiving AK-HER2 or trastuzumab(initial loading dose 8 mg/kg,maintenance dose 6 mg/kg,every 3 weeks as a treatment cycle,total treatment time is 16 cycles)in combination with docetaxel(75 mg/m2,treatment duration is at least 9 cycles).The primary endpoint of this clinical trial was the objective response rate(ORR9)between the AK-HER2 group and the control group in the 9th cycle.Secondary efficacy endpoints included ORR16,disease control rate(DCR),clinical benefit rate(CBR),progression-free survival(PFS)and 1-year survival rate.In this study,100 subjects(AK-HER2 group to control group=1:1)were randomly selected for blood sample collection after the 6th cycle of medication,The collection time points were 45 minutes after infusion(the end of administration),4,8,24,72,120,168,336,and 504 hours after the end of administration.After collection,blood samples were analyzed by PK parameter set(PKPS).Other evaluation parameters included safety and immunogenicity assessment.Results:A total of 550 patients with HER2-positive metastatic breast cancer were enrolled in this clinical trial between Sep.2017 and Mar.2021.In the AK-HER2 group(n=237),129 subjects in the experimental group achieved complete response(CR)or partial response(PR),and the ORR9 was 54.4%.There were 134 subjects in the control group(n=241)who achieved CR or PR,and the ORR9 was 55.6%.The ORR9 ratio between the AK-HER2 group and the control group was 97.9%[90%confidence interval(CI):85.4%-112.2%,P=0.784],which was not statistically significant.In all secondary efficacy endpoints,no statistically significant differences were observed between the two groups.We conducted a mean ratio analysis of pharmacokinetics(PK)parameters between the AK-HER2 group and the control group,and the results suggested that the pharmacokinetic characteristics of the two drugs are similar.The incidence of treatment emergent adverse event(TEAE)leading to drug reduction or suspension during trastuzumab treatment was 3.6%(10 cases)in the AK-HER2 group and 8.1%(22 cases)in the control group.There was statistically significant difference between the two groups(P=0.027).The incidence rate was significantly lower in the AK-HER2 group than in the control group,and there was no statistically significant difference among the other groups.The differences in the positive rates of anti-drug antibodies(ADA)and neutralizing antibodies(NAB)between groups were of no statistical significance(P=0.385 and P=0.752).Conclusion:In patients with HER2-positive metastatic breast cancer,AK-HER2 was comparable to the trastuzumab(Herceptin?)in terms of drug efficacy,pharmacokinetics,safety and immunogenicity.

Objective:To compare the efficacy of conventional open ankle fusion and three dimensional(3D) printed guide plate assisted arthroscopic ankle fusion.Methods:A retrospective cohort study was performed on 256 patients with advanced traumatic ankle arthritis, who were admitted to the Department of Orthopaedics, Shanghai Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from May 2018 to February 2023 and underwent ankle fusion procedures. The study cohort comprised 119 males and 137 females, with an age of (59.6±9.5) years (range: 37 to 83 years). Among them, 175 cases underwent internal fixation with plates and screws (58 cases through the combined medial and lateral approach, and 117 cases through the simple lateral approach), 48 cases underwent internal fixation with screws through the anterior approach (conventional open group), and 33 cases underwent minimally invasive arthroscopic ankle fusion assisted by 3D printed guide plate (3D printed guide plate arthroscopy group). Propensity score matching was employed to achieve a 1∶1 match(caliper value=0.02) between the baseline characteristics of patients in the 3D printed guide plate arthroscopy group and the conventional open group. Perioperative and follow-up data between the two groups were compared using the t-test, Mann-Whitney U test, Wilcoxon signed rank test, χ2 test or corrected χ2 test as appropriate. Results:Matching was successfully achieved with 20 cases in both the 3D printed guide plate arthroscopy group and the conventional open group, and there were no statistically significant differences in baseline characteristics between the two groups (all P>0.05). The operation time in the 3D printed guide plate arthroscopy group was significantly longer than that in the conventional open group ((88.9±5.6) minutes vs. (77.9±11.7) minutes; t=-2.392, P=0.022), while the frequency of intraoperative fluoroscopies ((1.7±0.8) times vs. (5.2±1.2) times; t=10.604, P<0.01) and length of hospitalization ((5.5±0.9) days vs. (6.4±1.5) days; t=2.480, P=0.018) were significantly lower in the 3D printed guide plate arthroscopy group compared to the conventional open group. The fusion rate was 95.0% (19/20) in the 3D printed guide plate arthroscopy group and 85.0% (17/20) in the conventional open group, with no statistically significant difference between the two groups ( χ2=0.278, P=0.598). The fusion time was (12.1±2.0) weeks in the conventional open group and (11.1±1.7) weeks in the 3D printed guide plate arthroscopy group, with no statistically significant difference between the two groups ( t=1.607, P=0.116). At the final follow-up, the American Orthopedic Foot and Ankle Society ankle hindfoot scale was (72.6±5.5)points in the 3D printed guide plate arthroscopy group and (70.5±5.8)points in the conventional open group, with no statistically significant difference between the two groups ( t=-1.003, P=0.322). The pain visual analogue score of the 3D printed guide plate arthroscopy group was ( M(IQR)) 1.50 (1.00) points, lower than that of the conventional open group by 3.00 (1.00) points, with statistically significant differences ( Z=-3.937, P<0.01). There was no significant difference in complication rate between the conventional open group and the 3D printed guide plate arthroscopy group (25.0%(5/20) vs. 5.0%(1/20), χ2=1.765， P=0.184). Conclusion:3D printed guide plate assisted arthroscopic ankle fusion exhibited several advantages, including reduced frequency of fluoroscopies, alleviation of postoperative pain, and decreased complications and length of hospitalization.

Objective:To compare the efficacy of conventional open ankle fusion and three dimensional(3D) printed guide plate assisted arthroscopic ankle fusion.Methods:A retrospective cohort study was performed on 256 patients with advanced traumatic ankle arthritis, who were admitted to the Department of Orthopaedics, Shanghai Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from May 2018 to February 2023 and underwent ankle fusion procedures. The study cohort comprised 119 males and 137 females, with an age of (59.6±9.5) years (range: 37 to 83 years). Among them, 175 cases underwent internal fixation with plates and screws (58 cases through the combined medial and lateral approach, and 117 cases through the simple lateral approach), 48 cases underwent internal fixation with screws through the anterior approach (conventional open group), and 33 cases underwent minimally invasive arthroscopic ankle fusion assisted by 3D printed guide plate (3D printed guide plate arthroscopy group). Propensity score matching was employed to achieve a 1∶1 match(caliper value=0.02) between the baseline characteristics of patients in the 3D printed guide plate arthroscopy group and the conventional open group. Perioperative and follow-up data between the two groups were compared using the t-test, Mann-Whitney U test, Wilcoxon signed rank test, χ2 test or corrected χ2 test as appropriate. Results:Matching was successfully achieved with 20 cases in both the 3D printed guide plate arthroscopy group and the conventional open group, and there were no statistically significant differences in baseline characteristics between the two groups (all P>0.05). The operation time in the 3D printed guide plate arthroscopy group was significantly longer than that in the conventional open group ((88.9±5.6) minutes vs. (77.9±11.7) minutes; t=-2.392, P=0.022), while the frequency of intraoperative fluoroscopies ((1.7±0.8) times vs. (5.2±1.2) times; t=10.604, P<0.01) and length of hospitalization ((5.5±0.9) days vs. (6.4±1.5) days; t=2.480, P=0.018) were significantly lower in the 3D printed guide plate arthroscopy group compared to the conventional open group. The fusion rate was 95.0% (19/20) in the 3D printed guide plate arthroscopy group and 85.0% (17/20) in the conventional open group, with no statistically significant difference between the two groups ( χ2=0.278, P=0.598). The fusion time was (12.1±2.0) weeks in the conventional open group and (11.1±1.7) weeks in the 3D printed guide plate arthroscopy group, with no statistically significant difference between the two groups ( t=1.607, P=0.116). At the final follow-up, the American Orthopedic Foot and Ankle Society ankle hindfoot scale was (72.6±5.5)points in the 3D printed guide plate arthroscopy group and (70.5±5.8)points in the conventional open group, with no statistically significant difference between the two groups ( t=-1.003, P=0.322). The pain visual analogue score of the 3D printed guide plate arthroscopy group was ( M(IQR)) 1.50 (1.00) points, lower than that of the conventional open group by 3.00 (1.00) points, with statistically significant differences ( Z=-3.937, P<0.01). There was no significant difference in complication rate between the conventional open group and the 3D printed guide plate arthroscopy group (25.0%(5/20) vs. 5.0%(1/20), χ2=1.765， P=0.184). Conclusion:3D printed guide plate assisted arthroscopic ankle fusion exhibited several advantages, including reduced frequency of fluoroscopies, alleviation of postoperative pain, and decreased complications and length of hospitalization.

BACKGROUND: LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer. METHODS: We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels. RESULTS: On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]). CONCLUSION: LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile. TRIAL REGISTRATION ClinicalTrials.gov, NCT04563936.
Humans ; Male ; Antineoplastic Agents, Hormonal/therapeutic use* ; East Asian People ; Gonadotropin-Releasing Hormone/agonists* ; Goserelin/therapeutic use* ; Prostate-Specific Antigen ; Prostatic Neoplasms/drug therapy* ; Testosterone

As an essential trace element in living organisms, copper is actively involved in normal physiological processes in various systems and is maintained at low level to achieve copper homeostasis. Copper homeostasis, once being disrupted, would induce cell death, and this new form of cell death is known as copper death. In recent years, copper death has been increasingly recognized as an important factor mediating the onset and progression of central nervous system (CNS) diseases. Therefore, we review the pathogenic mechanism of copper death in CNS diseases, as well as its therapeutic strategies so as to deepen the understanding of researchers.

Objective:To investigate the efficacy of osteochondral fragment fixation using bioabsorbable pins for Hepple Ⅱ osteochondral lesions of the talus (OLT) in adolescents.Methods:Retrospective case analysis was used. The clinical data and follow-up results of 13 adolescent patients (13 feet) with Hepple Ⅱ OLT were all treated with osteochondral fragment fixation using bioabsorbable pins admitted to Shanghai Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2017 to December 2021 were retrospectively analyzed. There were 7 males and 6 females, with 13 right feet. The age was (14.85±2.23) years old, ranged from 12 to 18 years old. According to the American orthopedic foot and ankle society (AOFAS) ankle-hindfoot score, visual analogue scale (VAS) and SF-36 score before operation and at the last follow-up were used to evaluate the efficacy and function of the patients. Measurement data with normal distribution were represented as mean ± standard deviation( ± s), and the comparison between groups was conducted using the t-test; The mearsurement data with skewness distribution were expressed by M( Q1, Q3), and rank-sum test was used for inter-group comparison. Results:Thirteen adolescent patients (13 feet) with Hepple Ⅱ OLT underwent surgery successfully and were followed up for (25.54±9.95) months. All wounds healed by first intention, and no complications such as wound infection and delayed healing occurred. Preoperative AOFAS ankle-posterior foot score, VAS and SF-36 score were 58.62±3.55, 7.00 (6.50, 8.00) and 68.38±4.81, respectively. At the last follow-up, the scores were 97.38±2.73, 1.00 (0.00, 1.00), 91.15±4.28, respectively, and the results were significantly improved at the last follow-up, with the difference between the two groups statistically significant( P<0.05). Conclusion:Osteochondral fragment fixation using bioabsorbable pins which can promote cartilage repair, significantly improve symptoms, and achieve better clinical satisfaction with fewer complications, is a safe and effective surgical treatment option for Hepple Ⅱ OLT in adolescents with satisfactory short-term clinical outcomes.

Implantable left ventricular assist device (LVAD) has become an essential treatment for end-stage heart failure, and its effect has been continuously improved. In the world, magnetic levitation LVAD has become mainstream and is increasingly used as a destination treatment. China has also entered the era of ventricular assist device. The continuous improvement of the ventricular assist device will further improve the treatment effect. This article reviews the current situation and development trend of LVAD treatment in China and abroad.

Objective:To evaluate the short-term outcome of arthroscopic modified Brostr?m procedure plus minimally invasive calcaneal osteotomy for the treatment of chronic lateral ankle instability combined with subtle cavus foot.Methods:A retrospective cohort study was conducted to analyze the clinical data of 12 patients suffering chronic lateral ankle instability combined with subtle cavus foot admitted to Shanghai Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University from November 2016 to November 2020, including 5 males and 7 females, aged 16-62 years [(40.3±15.1)years]. All patients were treated with arthroscopic modified Brostr?m procedure plus minimally invasive calcaneal osteotomy. The calcaneal pitch angle, Meary′s angle and medial cuneiform height on the foot weight-bearing lateral view plus calcaneus valgus angle on the hindfoot long axial view were compared to evaluate the improvement of bony structure and foot alignment preoperatively and at 3 months and 1 year postoperatively. At the same time, American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot score and visual analogue scale (VAS) were used to evaluate the improvement of ankle function and pain. Postoperative complications were also observed and recorded.Results:All patients were followed up for 1-3 years [(1.6±0.6)years]. The calcaneal pitch angle was decreased from (24.6±5.3)° preoperatively to (22.5±4.9)° at postoperative 3 months and (22.3±5.0)° at postoperative 1 year; the Meary′s angle was decreased from 6.6°(5.2°,7.6°) preoperatively to 2.5°(0.5°,3.8°) at postoperative 3 months and 2.1°(0.5°,3.2°) at postoperative 1 year; the medial cuneiform height was decreased from (24.3±5.3)mm preoperatively to (22.3±4.8)mm at postoperative 3 months and (22.3±4.6)mm at postoperative 1 year; the calcaneus valgus angle was increased from -7.1°(-10.3°,-5.9°) preoperatively to 2.3°(-2.5°,4.5°) at postoperative 3 months and 2.4°(-1.6°,3.8°) at postoperative 1 year (all P<0.01). However, there were no significant differences in the calcaneal pitch angle, Meary′s angle, medial cuneiform height, and calcaneus valgus angle at postoperative 3 months and 1 year (all P>0.05). AOFAS ankle-hindfoot score was increased from (66.8±8.7)points preoperatively to (81.0±5.9)points at postoperative 3 months and (88.6±3.6)points at postoperative 1 year (all P<0.01). According to AOFAS ankle-hindfoot score, the results were excellent in four patients and good in eight patients at postoperative 1 year, with the excellent and good rate of 100%. VAS was decreased from 2.5(2.0,4.0)points preoperatively to 2.0(1.3,2.8)points at postoperative 3 months and 1.0(0,2.0)points at postoperative 1 year (all P<0.01). There were significant differences in the AOFAS ankle-hindfoot score and VAS at postoperative 3 months and 1 year (all P<0.05). Wound malunion was seen in one patient, and healed with a dress changing. All patients had no complications such as vascular or nerve injury. There was no recurrence of malformation or joint instability during 1-year follow-up. Conclusion:For chronic lateral ankle instability combined with subtle cavus foot, arthroscopic modified Brostr?m procedure plus minimally invasive calcaneal osteotomy can stabilize ankle joint, correct hindfoot alignment, improve function and relieve pain.

Objective:To investigate the efficacy of posterior ankle arthroscopic microfracture with platelet-rich plasma (PRP) injection for the treatment of posterior osteochondral lesions of the talus (OLT).Methods:A retrospective case series study was conducted on clinical data of 13 patients with posterior OLT admitted to Shanghai Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University from September 2019 to October 2020. There were 10 males and 3 females, aged 10-65 years [(38.2±15.9)years]. According to Hepple′s classification, four patients were with type II, three with type IV, and six with type V. According to Elias′ grid scheme, nine patients were in zone 7 and four patients in zone 9. The disease duration was 13-51 months [(26.2±11.4)months]. All patients underwent posterior ankle arthroscopic microfracture with PRP injection. The operation time was recorded. The visual analogue scale (VAS), American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot score, and ankle range of motion (ROM) were compared before operation and at 3 months and 1 year after operation. The magnetic resonance observation of cartilage repair tissue (MOCART) score was used to evaluate the repair of cartilage injury at 1 year after operation. Complications were recorded.Results:All patients were followed up for 12-25 months [(15.7±3.7)months]. The operation time ranged from 50 to 90 minutes [(63.8±13.3)minutes]. The VAS improved from 3.0(3.0, 4.0)points before operation to 1.0(0, 2.0)points at 3 months after operation and 1.0(0,1.5)points at 1 year after operation; the AOFAS ankle-hindfoot score was improved from (66.1±11.8)points before operation to (84.8±9.5)points at 3 months after operation and (92.9±8.6)points at 1 year after operation; the ankle ROM was improved from (48.5±7.5)° before operation to (61.9±10.3)° at 3 months after operation and (65.4±11.8)° at 1 year after operation (all P<0.05). There was no significant difference in VAS at 3 months and 1 year after operation ( P>0.05). There were significant differences in AOFAS ankle-hindfoot score and ankle ROM at 3 months and 1 year after operation (all P<0.05). According to AOFAS ankle-hindfoot score, the results were excellent in 11 patients, good in one, and fair in one, with the excellent and good rate of 92%. The MOCART score was 40-85 points [(70.4±14.2)points] at 1 year after operation. There was no postoperative necrosis, infection or neurovascular injury. Two patients had slight transient pain during rehabilitation training and were improved after non-surgical treatment. Conclusion:For posterior OLT, posterior ankle arthroscopic microfracture with PRP injection can effectively alleviate pain, improve ankle function and repair cartilage damage, with satisfactory short-term efficacy.