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:Hydroxyapatite is the main inorganic component of bone tissue.The polymer has the structure and function of a biomimetic extracellular matrix.The composites of hydroxyapatite and polymer have been widely studied. OBJECTIVE:To summarize the research status of hydroxyapatite composite polymer materials for bone tissue repair. METHODS:The articles collected in PubMed,Web of Science,CNKI and WanFang databases were searched from January 2010 to April 2023.The Chinese and English search terms were"hydroxyapatite,polymer,composites,degradability,bone defect,bone repair".Finally,75 articles were included for review. RESULTS AND CONCLUSION:Polymers often used in composite with hydroxyapatite for bone tissue repair include natural polymers(collagen,chitosan,alginate,serine protein,cellulose,hyaluronic acid,and polyhydroxybutyrate)and synthetic polymers[polylactic acid,polylactic acid-hydroxyacetic acid copolymer,poly(has-lactide),poly(amino acid)and poly(vinyl alcohol)].The mechanical properties and osteoinductivity of hydroxyapatite/polymer composites were improved compared with pure hydroxyapatite.Hydroxyapatite composite with polymers can be made into porous scaffolds,hydrogels,and coatings for bone repair.Hydroxyapatite/polymer composites can accelerate bone reconstruction with a slow release of loaded drugs and cytokines due to their bionic extracellular matrix structure and function.Based on the diversity of causes of bone defects and the fact that bone repair is a complex continuous process involving multiple biological factors and proteins,repair materials with mechanical properties matching bone tissue,degradation processes synchronized with bone repair,and efficient osteogenesis and vascularization need to be further investigated.

BACKGROUND:As a leading technique in the treatment of primary stenosis by posterior spinal endoscopy through unilateral approach and bilateral decompression using single channel endoscopy,the long-term efficacy needs to be further observed.There are few reports on the scope of intraoperative resection and few relevant studies on biomechanics and finite element analysis. OBJECTIVE:A three-dimensional finite element model was established to evaluate the effects of bilateral lumbar canal decompression under a one-hole split endoscope on lumbar range of motion and intradiscal pressure,to provide suggestions for clinical operation and theoretical basis for further clinical research. METHODS:A complete L3-L5 vertebral body model was reconstructed by CT images of nine healthy volunteers,which was used as the preoperative model M1.The simulated surgical resection range of L4-L5 was performed,and 1/4,1/3 and 1/2 of bilateral facet joints were removed respectively to obtain models M2,M3 and M4.The range of motion and the maximum Von Mises stress of the four models were compared in the six directions of forward bending,backward extension,left and right bending,and left and right rotation. RESULTS AND CONCLUSION:(1)The L3-L5 finite element model established in this study was effective,and the range of motion was within the range of previous solid studies under six motion states.(2)Compared with the M1 model,the L4-L5 lumbar spine range of motion increased with the increase of resection range in M2 with M3 and M4 models under forward bending,left and right bending and left and right rotation loading,and the difference was significant(P＜0.05).Under posterior extension loading,there was no significant difference in lumbar range of motion between M1 and M2(P＞0.05),but there was a significant difference of M1,M3 and M4(P＜0.05).(3)The range of motion of the L3-L4 lumbar spine had no significant change with the increase of bilateral facet arthrotomy(P＞0.05).(4)There was a significant difference in the maximum value of L4-L5 Von Mises between M1 and M2(P＜0.05),and there was a significant difference in the maximum value of L4-L5 Von Mises between M1 and M3,M4(P＜0.01),and the maximum value of L4-L5 lumbar von Mises increased with the increasing range of bilateral facet joint resection.Resection of more than 1/3 was particularly obvious.(5)The maximum value of Von Mises in the L3-L4 lumbar spine was increased with the increase of the resection range under forward bending,left and right bending and left and right rotation loading and the difference was significant(P＜0.05).(6)The results exhibited that the L4-L5 lumbar motion and intervertebral disc pressure increased with the increase of the excision range.Intervertebral disc pressure at L3-L4 increased with the increased extent of excision,but the lumbar range of motion was not significantly affected.In conclusion,the stability of the operative segment may be affected by the increase in the scope of facet joint resection.Although the immediate stability of adjacent segments is not affected,it may accelerate disc degeneration.

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 investigate the effect of five-element music therapy combined with meridian-based acupoint massage timed according to qi circulationon on negative emotions and sleep quality in older adults with chronic heart failure. Methods:A total of 112 older adult patients with chronic heart failure who received treatment at The Affiliated Hospital of Hangzhou Normal University between January 2022 and June 2023 were included in this study. They were randomly divided into a control group ( n = 56) and a study group ( n = 56) using the random number table method. Based on conventional treatment, the control group received five-element music therapy, while the intervention group underwent a combination of five-element music therapy and meridian-based acupoint massage timed according to qi circulation. Before and after the intervention, a comparison was made between the two groups in terms of the scores of the Hamilton Anxiety Scale (HAMA), Hamilton Depression Scale (HAMD), Pittsburgh Sleep Quality Index (PSQI), and various dimensions of the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Additionally, the sleep outcome and patient satisfaction were also compared between the two groups. Results:After intervention, the scores of the HAMA and HAMD in the study group were (11.29 ± 2.48) points and (12.48 ± 3.36) points, respectively. In contrast, the control group had scores of (15.93 ± 3.35) points and (16.50 ± 4.32) points, respectively. After intervention, the scores of the HAMA and HAMD scales in both the study and control groups demonstrated a significant reduction in comparison with their respective pre-intervention scores [study group: (20.13 ± 5.18) points, (23.95 ± 8.97) points, control group: (19.36 ± 5.45) points, (23.79 ± 7.61) points, t = 15.35, 10.24, 5.65, 8.93, all P < 0.001). After intervention, the scores of the HAMA and HAMD scales in the study group were significantly lower than those in the control group ( t = -8.34, -5.49, both P < 0.001). After intervention, the scores of the PSQI in the study and control groups were (7.05 ± 0.96) points and (9.91 ± 1.28) points, respectively. After intervention, the scores of PSQI in both the study and control groups demonstrated a significant reduction compared with their respective pre-intervention scores [study group: (12.98 ± 2.21) points, control group: (12.50 ± 2.48) points, t = 24.68, 9.79, both P < 0.05]. After intervention, the score of the PSQI in the study group was significantly lower than that in the control group ( t = 13.34, P < 0.05). Based on the scores across various dimensions of the MLHFQ, it was observed that after intervention, the scores of emotional, physical, and other domains in both the study and control groups [study group: (9.36 ± 2.29) points, (16.95 ± 3.80) points, (18.50 ± 2.33) points; control group: (12.93 ± 2.00) points, (19.98 ± 3.98) points, (20.04 ± 2.24) points] decreased significantly compared with their pre-intervention scores [study group: (15.57 ± 1.55) points, (26.23 ± 4.63) points, (21.18 ± 2.50) points, control group: (16.09 ± 1.87) points, (25.32 ± 4.40) points, (21.57 ± 2.69) points, t = 21.66, 18.55, 8.44, 11.29, 11.73, 4.61, all P < 0.001]. After intervention, the scores of emotional, physical, and other domains in the study group were significantly lower than those in the control group ( t = -8.79, -4.13, -3.56, all P < 0.05). Patient satisfaction in the study group was superior to that that in the control group [98.21% (55/56) vs. 87.50% (49/56), χ2 = -3.09, P < 0.05]. Total effective rate of intervention on sleep in the study group was significantly higher than that in the control group [92.86% (52/56) vs. 78.57% (44/56), χ2 = -2.09, P < 0.05]. Conclusion:Five-element music therapy combined with meridian-based acupoint massage timed according to qi circulationon in the treatment of chronic heart failure in older adults can effectively alleviate negative emotions, improve the quality of life and sleep, and increase patient satisfaction with nursing care.

Objective:To explore potential predictors of refractory Mycoplasma pneumoniae pneumonia (RMPP) in early stage. Methods:The prospective multicenter study was conducted in Zhejiang, China from May 1 st, 2019 to January 31 st, 2020. A total of 1 428 patients with fever >48 hours to <120 hours were studied. Their clinical data and oral pharyngeal swab samples were collected; Mycoplasma pneumoniae DNA in pharyngeal swab specimens was detected. Patients with positive Mycoplasma pneumoniae DNA results underwent a series of tests, including chest X-ray, complete blood count, C-reactive protein, lactate dehydrogenase (LDH), and procalcitonin. According to the occurrence of RMPP, the patients were divided into two groups, RMPP group and general Mycoplasma pneumoniae pneumonia (GMPP) group. Measurement data between the 2 groups were compared using Mann-Whitney U test. Logistic regression analyses were used to examine the associations between clinical data and RMPP. Receiver operating characteristic (ROC) curves were used to analyse the power of the markers for predicting RMPP. Results:A total of 1 428 patients finished the study, with 801 boys and 627 girls, aged 4.3 (2.7, 6.3) years. Mycoplasma pneumoniae DNA was positive in 534 cases (37.4%), of whom 446 cases (83.5%) were diagnosed with Mycoplasma pneumoniae pneumonia, including 251 boys and 195 girls, aged 5.2 (3.3, 6.9) years. Macrolides-resistant variation was positive in 410 cases (91.9%). Fifty-five cases were with RMPP, 391 cases with GMPP. The peak body temperature before the first visit and LDH levels in RMPP patients were higher than that in GMPP patients (39.6 (39.1, 40.0) vs. 39.2 (38.9, 39.7) ℃, 333 (279, 392) vs. 311 (259, 359) U/L, both P<0.05). Logistic regression showed the prediction probability π=exp (-29.7+0.667×Peak body temperature (℃)+0.004×LDH (U/L))/(1+exp (-29.7+0.667×Peak body temperature (℃)+0.004 × LDH (U/L))), the cut-off value to predict RMPP was 0.12, with a consensus of probability forecast of 0.89, sensitivity of 0.89, and specificity of 0.67; and the area under ROC curve was 0.682 (95% CI 0.593-0.771, P<0.01). Conclusion:In MPP patients with fever over 48 to <120 hours, a prediction probability π of RMPP can be calculated based on the peak body temperature and LDH level before the first visit, which can facilitate early identification of RMPP.

Objective To explore the feasibility of predicting expression level of Ki-67 in lung adenocarcinoma via multi-parameter of spectral CT.Methods The data of 226 patients with lung adenocarcinoma confirmed by pathology were analyzed retrospectively.The conventional and spectral CT parameters of the lesions were analyzed.According to Ki-67 expression level,all patients were divided into low expression group and high expression group.The parameters with statistical significance were identified as independent variables for multivariate logistic regression analysis to establish a logistic regression model for predicting the expression level of Ki-67.Receiver operating characteristic(ROC)curve was used to assess the diagnostic performance for each model,respectively.Results There were significant differences in the clinical factors of gender,smoking and chest pain between high and low Ki-67 expression groups.In spectral CT parameters,CT40 keV,CT100 keV,Z-effective(Zeff)and iodine concentration(IC)in the high expression group in arterial phase were significantly higher than those in the low expression group.Logistic regression analysis showed that CT100 keV was the independent risk factor for Ki-67 expression level.Both the spectral CT model and the combined model had high value in predicting the expression level of Ki-67 in lung adenocarcinoma,and the combined model had better diagnostic efficacy.Conclusion Spectral CT parameters combined with clinical factors have a certain value in predicting the expression level of Ki-67 in lung adenocarcinoma.

Objective:To explore the metabolic basis and related molecular mechanism of oral squamous cell carcinoma(OSCC)path-ogenesis.Methods:20 Chinese hamsters were divided into 2 groups(n=10).OSCC models were induced by dimethylbenzanthracene(DMBA)in 10 of the animals and the other 10 were used as the controls.LC-MS chromatography-mass spectrometry was used to iden-tify the metabolites in the buccal pouch,and multidimensional statistical analysis of the metabolites was performed with the orthogonal partial least squares discriminant analysis model.Variable Importance for the Projection(VIP)＞1 and P＜0.05 were used as the criteria to screen the differential metabolites between the 2 groups.KEGG pathway annotation and enrichment analysis for the metabolites were performed to screen the significantly differential pathways.Results:The hamster cheek pouches painted with 0.5％DMBA for 18 weeks were diffused with leukoplakia and loaded obvious papillary protrusions,which were diagnosed as OSCC by pathological examination.Lipids and lipid-like molecules were the main differential metabolites.Reprogramming of unsaturated fatty acid biosynthesis,cholesterol accumulation,enhanced catabolism of tryptophan,up-regulation of aspartate,increased synthesis of pyrimidine and purine,etc.were important metabolic features in the occurrence and development of OSCC.Conclusion:Molecular intervention targeting the related met-abolic pathways is expected to inhibit OSCC pathogenesis and progression.

Objective:To explore the effects of fecal microbiota transplantation (FMT) on SAE in rats through the modulation of the gut microbiome.Methods:Total of 30 Sprague-Dawley rats were divided(random number) into sham surgery, SAE, SAE+FMT, SAE+FMT+ NF-κB agonist, and SAE+FMT+NLRP3 agonist groups. The gut microbiome, neurological function, and inflammatory responses in rats were analyzed using 16S rRNA sequencing, neurological behavioral scoring, water maze testing, Nissl staining, quantitative reverse transcription polymerase chain reaction, and western blot assays. Univariate analysis of variance for multiple samples among groups was conducted using SPSS software, with further pairwise comparisons using Tukey's test.Results:(1) Compared with the sham surgery group, a reduction in α-diversity was observed in the SAE rats ( P<0.01), whereas an increase in α-diversity was noted in the SAE rats after FMT treatment ( P<0.05). A decrease in beneficial bacteria such as Bacteroidete and Clostridiales was seen in the SAE group compared to the sham group, which increased after FMT. (2) A decrease in mNSS, learning and memory abilities, and the number of neurons in the hippocampal CA1 region was noted in SAE rats compared with the sham group ( P<0.01), whereas an improvement in mNSS scores, learning and memory abilities, and neuron count was observed in SAE rats treated with FMT ( P<0.05). (3) Compared with the sham group, increased liver and kidney function indicators, inflammatory factors, blood-brain barrier proteins, NLRP3 pathway proteins, and NF-κB pathway proteins were observed in the SAE group ( P<0.05), which were reduced by FMT ( P<0.05). (4) The effects of FMT were negated after the intervention with NF-κB and NLRP3 agonists ( P<0.05). Conclusions:FMT regulate the gut microbiome and inhibit the NF-κB/NLRP3 signaling pathway in the brain. This provides new insights into the treatment of SAE, emphasizing the importance of considering the gut microbiota in clinical therapy.

Objective:To explore the value of the Nomogram model established by CT radiomics combined with clinical indicators for prediction of the severity of early acute pancreatitis (AP).Methods:From January 2016 to March 2023, the AP patients in the Second Affiliated Hospital of Soochow University were retrospectively collected. According to the revised Atlanta classification and definition of acute pancreatitis in 2012, all patients were divided into the severe group and the non-severe group. All patients were first diagnosed, and abdominal CT plain scan and enhanced scan were completed within 1 week. Patients were randomly (random number) divided into training and validation groups at a ratio of 7:3. The pancreatic parenchyma was delineated as the region of interest on each phase CT images, and the radiomics features were extracted by python software. LASSO regression and 10-fold cross-validation were used to reduce the dimension and select the optimal features to establish the radiomics signature. Multivariate Logistic regression was used to select the independent predictors of severe acute pancreatitis (SAP), and a clinical model was established. A Nomogram model was established by combining CT radiomics signature and clinical independent predictors. Receiver operating characteristic (ROC) curve and decision curve analysis (DCA) were used to evaluate the predictive efficacy of each model.Results:Total of 205 AP patients were included (59 cases in severe group, 146 cases in non-severe group). 3, 5, 5 and 5 optimal radiomics features were selected from the plain CT scan, arterial phase, venous phase and delayed phase images of all patients, and the radiomics models were established. Among them, the arterial phase radiomics model had relatively better performance in predicting SAP, with an area under curve (AUC) of 0.937 in the training group and 0.913 in the validation group. Multivariate Logistic regression showed that C-reactive protein (CRP) and lactate dehydrogenase (LDH) were independent predictors of SAP, and they were used to establish a clinical model. The AUC in the training and validation groups were 0.879 and 0.889, respectively. The Nomogram model based on arterial phase CT radiomics signature, CRP and LDH was established, and the AUC was 0.956 and 0.947 in the training group and validation group, respectively. DCA showed that the net benefit of Nomogram model was higher than that of clinical model or radiomics model alone.Conclusions:The Nomogram model established by CT radiomics combined with clinical indicators has high application value for early prediction of the severity of AP, which is conducive to the formulation of clinical treatment plans and prognosis evaluation.