Objective To explore the feasibility of radiomics nomogram based on magnetic resonance diffusion weighted imaging for predicting the expression of Ki-67 in breast cancer.Methods A retrospective study was conducted on patients with breast cancer confirmed by surgery and pathology in the Second Affiliated Hospital of Guangdong Medical University.All patients were detected by Ki-67 expression staining,and then divided into group A(n=28,low-level expression of Ki-67)and group B(n=73,high-level expression of Ki-67).The apparent diffusion coefficient(ADC)graph was generated from diffusion weighted images,and the two groups were compared for radiomics features of ADC images and clinical data.The expression level of Ki-67 in breast cancer was predicted using the features of LASSO after dimensionality reduction,and a nomogram model was established,whose diagnostic efficiency was analyzed with receiver operating characteristic curve.Results No significant difference was observed in ADC value,age,carbohydrate antigen 199,carbohydrate antigen 153,carbohydrate antigen 125 and carcinoembryonic antigen between two groups(P>0.05).LASSO regression identified two radiomics features as predictors for the expression level of Ki-67 in breast cancer.The best tuning Lambda of LASSO was-0.125 690 135 478 682,and the included radiomics features for nomogram establishment were MinIntensity and Quantile95.The established nomogram had an area under ROC curve of 0.917,achieving a sensitivity of 91.7%and a specificity of 83.3%.Conclusion The expression of Ki-67 in breast cancer can be predicted based on the radiomics features of ADC images,which can provide a noninvasive detection method for evaluating the proliferation degree and treatment prognosis of breast cancer.

Objective To investigate the efficacy and mechanism of topiramate combined with oxcarbazepine in children with epilepsy.Methods The targeted genes of topiramate and oxcarbazepine were analyzed by pharm GKB database;targeted genes of epilepsy in children were screened by GeneCards database;the drug-disease-target gene network map was constructed using Cytoscape 3.9.1 software.A total of 83 children with epilepsy were enrolled and treated for the first time,which were divided into topiramate group and combined drugs group according to the different drugs used.The level of serum mechanistic target of rapamycin(mTOR),epidermal growth factor receptor(EGFR),nitrogen permease regulator 3-like protein(NPRL3)of two groups were observed by ELISA,and the EEG and therapeutic effect were recorded.Results mTOR,EGFR,NPRL3 were the target genes of topiramate combined with oxcarbazepine in the treatment of epilepsy in children.There was no significant difference in seizure rate between the combined drugs group and topiramate group(x2=3.239,P=0.072).The efficacy of combined drug group was significantly better than that of the topiramate group(x2=5.817,P=0.049).The rate of standing wave ratio(SWR)≤2 in EEG spike in the combined drug group was significantly higher than that in the topiramate group(P=0.018).There was different in spike location between combined drug group and topiramate group(P=0.002),while not different statistically in spike region of two groups(P＞0.05).Compared with those in topiramate group,the number of sharp waves in the combination group was significantly reduced at 1 month,3 months and 6 months after treatment,and the sharp wave clearance rate was significantly increased at 1 month,3 months,5 months and 6 months after treatment(P＜0.05-0.01).There was no significant difference in levels of mTOR,EGFR,NPRL3 between the combination group and topiramate groups before treatment(all P＞0.05).Compared with those in topiramate group,the levels of mTOR,EGFR in combined drug group after treatment were significantly decreased(P=0.028,P=0.006),and the level of NPRL3 was significantly increased(P=0.007).Survival analysis showed the median duration of epilepsy work was 6(5,6)months,the seizure rate was 55.42％.Compared with patients with mTOR ≤9.93(16.7％),patients with mTOR＞9.93(93.1％)had a significantly higher probability of epilepsy(x2=11.430,P＜0.001).Conclusion Topiramate combined with oxcarbazepine may reduce the pike and wave rate of EEG,improve epileptic seizures,the mechanism maybe related to the levels of mTOR,NPRL3 and EGFR.

Objective To explore the feasibility of radiomics nomogram based on magnetic resonance diffusion weighted imaging for predicting the expression of Ki-67 in breast cancer.Methods A retrospective study was conducted on patients with breast cancer confirmed by surgery and pathology in the Second Affiliated Hospital of Guangdong Medical University.All patients were detected by Ki-67 expression staining,and then divided into group A(n=28,low-level expression of Ki-67)and group B(n=73,high-level expression of Ki-67).The apparent diffusion coefficient(ADC)graph was generated from diffusion weighted images,and the two groups were compared for radiomics features of ADC images and clinical data.The expression level of Ki-67 in breast cancer was predicted using the features of LASSO after dimensionality reduction,and a nomogram model was established,whose diagnostic efficiency was analyzed with receiver operating characteristic curve.Results No significant difference was observed in ADC value,age,carbohydrate antigen 199,carbohydrate antigen 153,carbohydrate antigen 125 and carcinoembryonic antigen between two groups(P>0.05).LASSO regression identified two radiomics features as predictors for the expression level of Ki-67 in breast cancer.The best tuning Lambda of LASSO was-0.125 690 135 478 682,and the included radiomics features for nomogram establishment were MinIntensity and Quantile95.The established nomogram had an area under ROC curve of 0.917,achieving a sensitivity of 91.7%and a specificity of 83.3%.Conclusion The expression of Ki-67 in breast cancer can be predicted based on the radiomics features of ADC images,which can provide a noninvasive detection method for evaluating the proliferation degree and treatment prognosis of breast cancer.

Objective To investigate the efficacy and mechanism of topiramate combined with oxcarbazepine in children with epilepsy.Methods The targeted genes of topiramate and oxcarbazepine were analyzed by pharm GKB database;targeted genes of epilepsy in children were screened by GeneCards database;the drug-disease-target gene network map was constructed using Cytoscape 3.9.1 software.A total of 83 children with epilepsy were enrolled and treated for the first time,which were divided into topiramate group and combined drugs group according to the different drugs used.The level of serum mechanistic target of rapamycin(mTOR),epidermal growth factor receptor(EGFR),nitrogen permease regulator 3-like protein(NPRL3)of two groups were observed by ELISA,and the EEG and therapeutic effect were recorded.Results mTOR,EGFR,NPRL3 were the target genes of topiramate combined with oxcarbazepine in the treatment of epilepsy in children.There was no significant difference in seizure rate between the combined drugs group and topiramate group(x2=3.239,P=0.072).The efficacy of combined drug group was significantly better than that of the topiramate group(x2=5.817,P=0.049).The rate of standing wave ratio(SWR)≤2 in EEG spike in the combined drug group was significantly higher than that in the topiramate group(P=0.018).There was different in spike location between combined drug group and topiramate group(P=0.002),while not different statistically in spike region of two groups(P＞0.05).Compared with those in topiramate group,the number of sharp waves in the combination group was significantly reduced at 1 month,3 months and 6 months after treatment,and the sharp wave clearance rate was significantly increased at 1 month,3 months,5 months and 6 months after treatment(P＜0.05-0.01).There was no significant difference in levels of mTOR,EGFR,NPRL3 between the combination group and topiramate groups before treatment(all P＞0.05).Compared with those in topiramate group,the levels of mTOR,EGFR in combined drug group after treatment were significantly decreased(P=0.028,P=0.006),and the level of NPRL3 was significantly increased(P=0.007).Survival analysis showed the median duration of epilepsy work was 6(5,6)months,the seizure rate was 55.42％.Compared with patients with mTOR ≤9.93(16.7％),patients with mTOR＞9.93(93.1％)had a significantly higher probability of epilepsy(x2=11.430,P＜0.001).Conclusion Topiramate combined with oxcarbazepine may reduce the pike and wave rate of EEG,improve epileptic seizures,the mechanism maybe related to the levels of mTOR,NPRL3 and EGFR.

Objective:To investigate the relation between rs2298771 genotype in voltage-gated sodium channels 1A ( SCN1A) polymorphism and antiepileptic drug (AED) response in children with epilepsy. Methods:Sixty-two children with epilepsy admitted to Department of Neurology, Zhangjiakou First Hospital from June 2022 to December 2023 were divided into AED response group and AED resistance group ( n=31) according to their response to AED. In addition, 31 children with pharyngitis or mild gastroenteritis admitted to Department of Pediatrics at the same period were selected as control group. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to analyze the rs2298771 genotype in SCN1A polymorphism, and differences in rs2298771 genotype and allele in SCN1A polymorphism were compared among the 3 groups. Relation between rs2298771 genotype in SCN1A polymorphism and AED response was analyzed. Multivariate Logistic regression was used to analyze the influencing factors for AED response in children with epilepsy. Results:(1) Significant differences in type of first seizure and AEDs were noted between AED response group and AED resistance group ( P<0.05); compared with the AED resistance group, the AED response group had significantly lower seizure frequency, significantly longer duration after last seizure, and statistically higher proportions of children with normal EEG or with one kind of AED ( P?0.05). (2) Compared with the control group and AED response group, the AED resistance group had significantly higher rs2298771 GC genotype and G allele, and statistically lower rs2298771 AA genotype and A allele in SCN1A polymorphism ( P?0.05). (3) In the AED response group, rs2298771 AA and AG genotype in SCN1A polymorphism were positively correlated with levetiracetam ( P?0.05); in AED resistance group, rs2298771 AG genotype in SCN1A polymorphism was positively correlated with topiramate and valproic acid ( P<0.05). (4) Multivariate Logistic regression analysis showed that duration after last seizure ( OR=3.249, 95% CI=1.097-9.621, P=0.033), rs2298771 genotype in SCN1A polymorphism ( OR=9.660, 95% CI=4.680-19.970, P=0.011) and seizure frequency ( OR=0.160, 95% CI=0.032-0.804, P=0.026) were independent influencing factors for AED response in children with epilepsy. Conclusion:Epilepsy children with shorter duration after last seizure, rs2298771 GG genotype in SCN1A polymorphism, and high seizure frequency are susceptible to AED resistance; especially, AG genotype is correlated with topiramate and valproic acid.

AIM:To evaluate the bioequivalence of the two rivaroxaban tablets in Chinese healthy subjects.METHODS:Twenty-eight subjects under fasting status and twenty-eight subjects under fed status were enrolled in the study.This study was designed as a four period,fully repetitive,cross-over study.All subjects were administered test(T)and reference(R)rivaroxaban tablets(10 mg)un-der fasting and fed condition respectively.Liquid chromatography-tandem mass spectrometry was used to detect the concentrations of rivaroxaban in plasma.WinNonlin 7.0 was used to calculate the main pharmacokinetic parameters(PK)and to eval-uate the bioequivalence.RESULTS:In fasting group,the main pharmacokinetic parameters of T and R preparation were as follows:Cmax were(186.57±56.41)and(187.61±50.89)ng/mL;AUC0-t were(1 156.21±335.85)and(1 177.59±343.72)h·ng·mL-1;AUC0-∞ were(1 235.77±384.03)and(1223.53±392.10)ng·h·mL-1.The 90％confidential interval(CI)of the three main parameters were 90.81％-105.67％,92.83％-103.85％and 95.04％-107.13％.The upper limit of the 90％CI for the test-to-reference ratio of the within-subject of Cmax,AUC0-t and AUC0-∞ were 1.56,1.41 and 1.73.In fed group,the main pharmacokinetic parameters of T and R preparation were as follows:Cmax were(207.81±45.26)and(211.04±36.62)ng/mL;AUC0-t were(1 271.26±260.92)and(1 233.23±201.85)h·ng·mL-1;AUC0-∞ were(1 290.76±264.90)and(1251.68±203.73)ng·h·mL-1.The 90％CI of the three main parameters were 92.82％-102.28％,97.68％-106.68％and 97.71％-106.68％.The upper limit of the 90％CI for the test-to-reference ratio of the within-subject of Cmax,AUC0t and AUC0-∞were 1.76,1.47 and 1.47.CONCLUSION:The two preparations of rivaroxaban tablets were bioequiva-lent.

AIM:To evaluate the bioequivalence of the two rivaroxaban tablets in Chinese healthy subjects.METHODS:Twenty-eight subjects under fasting status and twenty-eight subjects under fed status were enrolled in the study.This study was designed as a four period,fully repetitive,cross-over study.All subjects were administered test(T)and reference(R)rivaroxaban tablets(10 mg)un-der fasting and fed condition respectively.Liquid chromatography-tandem mass spectrometry was used to detect the concentrations of rivaroxaban in plasma.WinNonlin 7.0 was used to calculate the main pharmacokinetic parameters(PK)and to eval-uate the bioequivalence.RESULTS:In fasting group,the main pharmacokinetic parameters of T and R preparation were as follows:Cmax were(186.57±56.41)and(187.61±50.89)ng/mL;AUC0-t were(1 156.21±335.85)and(1 177.59±343.72)h·ng·mL-1;AUC0-∞ were(1 235.77±384.03)and(1223.53±392.10)ng·h·mL-1.The 90％confidential interval(CI)of the three main parameters were 90.81％-105.67％,92.83％-103.85％and 95.04％-107.13％.The upper limit of the 90％CI for the test-to-reference ratio of the within-subject of Cmax,AUC0-t and AUC0-∞ were 1.56,1.41 and 1.73.In fed group,the main pharmacokinetic parameters of T and R preparation were as follows:Cmax were(207.81±45.26)and(211.04±36.62)ng/mL;AUC0-t were(1 271.26±260.92)and(1 233.23±201.85)h·ng·mL-1;AUC0-∞ were(1 290.76±264.90)and(1251.68±203.73)ng·h·mL-1.The 90％CI of the three main parameters were 92.82％-102.28％,97.68％-106.68％and 97.71％-106.68％.The upper limit of the 90％CI for the test-to-reference ratio of the within-subject of Cmax,AUC0t and AUC0-∞were 1.76,1.47 and 1.47.CONCLUSION:The two preparations of rivaroxaban tablets were bioequiva-lent.

Objective:To identify the genetic variation in a mucopolysaccharidosis type Ⅱ(MPS Ⅱ)family, and conduct a functional study of iduronate-2-sulfatase(IDS): c.323A>C.Methods:A five-generation MPS Ⅱ family of 83 individuals including 4 patients from northern China was collected. Urine mucopolysaccharide and Alder-Reilly body were tested to assist the clinical diagnosis of MPS Ⅱ. IDS enzyme activity was detected on core family members. By the whole exome sequencing of a MPS Ⅱ patient in this family and bioinformatics analysis, the variant was screened and further identified by PCR-Sanger sequencing. Finally, to validate the function of the variant in vitro, the wild-type IDS overexpression plasmid(pCMV-hIDS-WT)and the IDS overexpression plasmid carrying the mutation site(pCMV-hIDS-c.323A>C)were transfected into COS-7 cells and the IDS activity was detected. Results:The proband(Ⅳ3)and Ⅳ4 were diagnosed as MPS Ⅱ by urine mucopolysaccharide, Alder-Reilly body, and IDS enzyme activity tests. Ⅳ3, Ⅳ4, Ⅲ19, and Ⅲ32 were determined to carry IDS: c.323A>C missense variant through the whole-exome sequencing, and diagnosed as MPS Ⅱ. Meanwhile, Ⅱ2, Ⅱ4, Ⅱ8, Ⅱ12, Ⅱ14, Ⅲ5, Ⅲ7, Ⅳ14 in the MPS Ⅱ family carried IDS: c.323A>C missense variant, and were excluded as MPS Ⅱ. The in vitro experiment in COS-7 cells showed that the missense mutation led to a significant decrease in IDS enzyme activity. Conclusion:The variant IDS: c.323A>C: p.Y108S significantly decreases the activity of IDS enzyme in vivo and in vitro, and it is identified as a pathogenic variant for MPS Ⅱ.

Objective:To explore the latest progress of oncology drug clinical trials in China under COVID-19, as well as to provide decision-making evidence for related stakeholders. Research progress of oncology drug trials and approved cancer drugs in China in 2020 were systematically summarized and compared with 2019.Methods:Information Disclosure Platform for Drug Clinical Studies and China Food and Drug Administration Query System for Domestic and Imported Drug were searched for registered clinical trials and approved oncology drugs, respectively. The trial scope, stage, drug type, effect and mechanism of domestic and global pharmaceutical enterprises were compared between 2019 and 2020.Results:A total of 722 cancer drug trials registered in China in 2020, with an annual growth rate of 52.3%, accounting for 28.3% of all registered trials. Among them, 603 (83.5%) trials were initiated by domestic pharmaceutical enterprises, and 105 (14.5%) were international multicenter trials, phase I trials accounted for 44.5%. For all those trials, there were 458 cancer drug varieties, with an annual growth rate of 36.7%, and 361 (85.8%) were developed by domestic enterprises. Most of the investigational products were therapeutic innovative drugs (77.1%), major in tumor treatment (92.8%). In terms of mechanism, targeted drugs were the most popular, accounting for 76.6%, and programmed cell death-1 (PD-1) and epithelial growth factor receptor (EGFR) were the most common targets. In addition, there were 19 anticancer drugs from 17 companies approved in China in 2019, with 10 drugs from domestic companies. Lung cancer and breast cancer are the most common indications for both registered trials and marketed drugs. No statistically significant differences were found between 2020 and 2019 in terms of the distribution of trial sponsor, scope and stage, as well as the distribution of drug type, effect and mechanism ( P>0.05). Conclusions:During the Covid-19 epidemic period, clinical trials of oncology drugs in China progress smoothly and maintain a high growth rate. Series of innovative products obtained by domestic enterprises in 2020 is the main driving force of development of oncology drug clinical trials in China.

Objective:To explore the latest progress of oncology drug clinical trials in China under COVID-19, as well as to provide decision-making evidence for related stakeholders. Research progress of oncology drug trials and approved cancer drugs in China in 2020 were systematically summarized and compared with 2019.Methods:Information Disclosure Platform for Drug Clinical Studies and China Food and Drug Administration Query System for Domestic and Imported Drug were searched for registered clinical trials and approved oncology drugs, respectively. The trial scope, stage, drug type, effect and mechanism of domestic and global pharmaceutical enterprises were compared between 2019 and 2020.Results:A total of 722 cancer drug trials registered in China in 2020, with an annual growth rate of 52.3%, accounting for 28.3% of all registered trials. Among them, 603 (83.5%) trials were initiated by domestic pharmaceutical enterprises, and 105 (14.5%) were international multicenter trials, phase I trials accounted for 44.5%. For all those trials, there were 458 cancer drug varieties, with an annual growth rate of 36.7%, and 361 (85.8%) were developed by domestic enterprises. Most of the investigational products were therapeutic innovative drugs (77.1%), major in tumor treatment (92.8%). In terms of mechanism, targeted drugs were the most popular, accounting for 76.6%, and programmed cell death-1 (PD-1) and epithelial growth factor receptor (EGFR) were the most common targets. In addition, there were 19 anticancer drugs from 17 companies approved in China in 2019, with 10 drugs from domestic companies. Lung cancer and breast cancer are the most common indications for both registered trials and marketed drugs. No statistically significant differences were found between 2020 and 2019 in terms of the distribution of trial sponsor, scope and stage, as well as the distribution of drug type, effect and mechanism ( P>0.05). Conclusions:During the Covid-19 epidemic period, clinical trials of oncology drugs in China progress smoothly and maintain a high growth rate. Series of innovative products obtained by domestic enterprises in 2020 is the main driving force of development of oncology drug clinical trials in China.