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 explore the clinical features and genetic variant in a child with Cerebral creatine deficiency syndrome (CCDS). METHODS: A child who had presented at the Affiliated Children's Hospital of Fudan University on March 5, 2021 was selected as the study subject. Whole exome sequencing (WES) was carried out for the child, and candidate variant was verified by Sanger sequencing. The level of creatine in the brain was determined by magnetic resonance spectroscopy. RESULTS: The patient, a 1-year-and-10-month male, had presented with developmental delay and epilepsy. Both his mother and grandmother had a history of convulsions. MRS showed reduced cerebral creatine in bilateral basal ganglia and thalamus. The child was found to harbor a hemizygous splicing variant of the SLC6A8 gene, namely c.1767+1_1767+2insA, which may lead to protein truncation. The variant was not found in the public databases. Both his mother and grandmother were heterozygous carriers for the same variant. CONCLUSION The hemizygous c.1767+1_1767+2insA variant of the SLC6A8 gene probably underlay the CCDS in this child. Discovery of the novel variant has also expanded the mutational spectrum of the SLC6A8 gene.
Humans ; Male ; Amino Acid Metabolism, Inborn Errors ; Brain ; Creatine/genetics* ; Heterozygote ; Mothers ; Nerve Tissue Proteins ; Plasma Membrane Neurotransmitter Transport Proteins/genetics* ; Infant

Female ; Humans ; Breast Neoplasms/surgery* ; Inflammatory Breast Neoplasms ; Mastectomy ; Medical Oncology

Objective To investigate the effect of IFN-γ on the proliferation and migration of esophageal squamous cell carcinoma cell line Eca9706 and related mechanism. Methods Cells were cultured in vitro and treated with interferon-γ. Cell morphology changes were observed under microscope, cell proliferation ability was detected by CCK-8 experiment, and cell migration ability was detected by cell scratch experiment and Transwell experiment. Real-time PCR method was used to detect the expression efficiency of chemokine CXCL8 (interleukin 8), and the ELISA experiment was used to detect the change of CXCL8 secretion. Results Compared with the blank control group, Eca9706 cells treated with different concentrations of interferon-γ did not change significantly in cell morphology. CCK8 experiment confirmed that the proliferation ability of Eca9706 cells after IFN-γ treatment was significantly reduced (P < 0.01). Cell scratch experiment found that IFN-γ significantly decreased the migration ability of Eca9706 cells (P < 0.01). Transwell experiment showed that after IFN-γ treatment, the migration ability of Eca9706 cells was significantly inhibited (P < 0.01). CXCL8 gene expression level in Eca9706 cells treated with interferon-γ was significantly down-regulated (P < 0.01), and the amount of CXCL8 secretion significantly reduced (P < 0.05). Conclusion Interferon-γ can inhibit the proliferation and migration of esophageal cancer cell line Eca9706, which may be related to its inhibition of the expression and secretion of CXCL8.

The coronavirus disease 2019 (COVID-19) was confirmed by nucleic acid test in 15 juvenile patients aged 4-17 years in Hangzhou Xixi Hospital from January 24 to February 10, 2020. The clinical data and the initial chest high resolution CT (HRCT) findings were retrospectively analyzed.Among 15 cases, 8 patients with a mean age of (6.5±2.3) years (4-11 year) had normal HRCT manifestations (mild disease), while 7 patients with a mean age of (11.9±3.0) years (7-17 years) showed abnormal manifestations (moderate disease). In the 7 moderate cases the CT findings included local thickening of bronchial wall in 2 cases, single lesion in 1 case, bilateral pulmonary lesions in 4 cases. There were total 11 lesions, 6 of which were ground glass and slightly high-density nodules, 5 of which were speckled ground glass and 2 with a little consolidation. There were 10 subpleural lesions, including 7 in the lower lobe of the two lungs, and 1 non-subpleural lesion; the thickened local bronchioles were observed in 3 cases. None of them had hilum and mediastinal lymph node enlargement or pleural effusion.

Objective: To evaluate the non-carcinogenic health risk of heavy metals (As, Cd, Cr, Cu, Mn, Pb and Zn) in residential indoor dust for young children around an e-waste dismantling area in South China. Methods: A village around an e-waste dismantling area in South China was selected as a research site in October 2016. Convenience sampling method was used to select 36 houses in the village and 36 dust samples were collected by vacuum cleaner. The concentrations of heavy metals (Cd, Cr, Cu, Mn, Pb and Zn) in each sample were determined and expressed by the average value. Non-carcinogenic health risk assessment was conducted using the US Environmental Protection Agency (EPA) Health Risk Assessment (HRA) model, the American Toxicology and Disease Registry (ATSDR) Target-organ Toxicity Dose (TTD) approach and the ATSDR Binary Weight-of-Evidence (BINWOE) model. Results: The mean ± SD of concentrations of As, Cd, Cr, Cu, Mn, Pb and Zn were (48.90±33.91), (5.95±3.89), (173.57±580.37), (412.71±1 190.00), (612.82±540.70), (297.41±293.22) and (1 052.81±1 156.48) mg/kg, respectively. The HI value of TTD (2.670) and BINWOE (2.933) were higher than the safety threshold of EPA recommended non-carcinogenic health risk. The HI value of TTD and BINWOE were 1.93 and 2.12 times higher than the HI value of HRA (1.386). Conclusion There was non-carcinogenic health risk of heavy metals (As, Cd, Cr, Cu, Mn, Pb and Zn) via residential indoor dust around the e-waste dismantling area for local children.

OBJECTIVE:To study the effects Weide'an tablet on gastric function and the expressions of epidermal growth fac-tor(EGF)and its receptor(EGFR)in gastric tissue of model rats with stress-induced gastric injury,and investigate its mechanism in the treatment of gastric ulcer. METHODS:Rats were randomly divided into normal group (normal saline),model group (nor-mal saline),positive group (ranitidine hydrochloride,0.015 mg/kg) and Weide'an tablet high-dose,medium-dose,low-dose groups (1.7,0.87,0.43 g/kg),10 in each group. Except for normal group,rats in other groups were given fasting swimming in cold water to induce gastric ulcer model. After modeling,all rats were intragastrically administrated once a day,for 2 weeks. The body mass of rats in 0,7,14 d of administration was recorded. After 12 h of last administration,gastric juice secretion,gastric juice pH,gastric ulcer area and gastric mucosal damage index of rats were detected,and the expressions of EGF and EGFR in gas-tric tissue were detected. RESULTS:Compared with normal group,body mass and gastric juice pH in 7,14 d in model group were declined;gastric juice secretion and gastric ulcer area were increased,gastric mucosal damage index was increased;and the expressions of EGF and EGFR in gastric tissue were enhanced,with statistical significances(P<0.05 or P<0.01). Compared with model group,except that the body mass,gastric juice secretion,gastric juice pH and gastric ulcer area in Weide'an medium-dose group in 7 d,and body mass,gastric juice secretion,gastric juice pH,gastric ulcer area and the expression of EGF in gastric tis-sue in Weide'an low-dose group in 7,14 d were not significantly improved,above indexes were significantly improved in other ad-ministration groups(P<0.05 or P<0.01);and the effect of Weide'an tablet showed a certain dose-effect relationship. CONCLU-SIONS:Weide'an tablet can significantly improve the gastric function of model rats with stress-induced gastric injury;and the mechanism may be related with enhancing the expressions of EGF and EGFR and promoting ulcer healing.

Objective To compare the effect of hollow screw and double suture anchors for the treatment of the intercondylar eminence fractures of tibia.Methods The data of 68 patients with intercondylar eminence fractures of tibia from January 2006 to January 2012 were retrospectively reviewed.33 patients of them received treatment of hollow screw,35 patients received double suture anchors.All patients had X-ray films before operation.After follow-up of 3,6,12 and 36 months,they all were examined by X-ray eminence in an appropriate position.Union time was from 6 to 12 weeks and evaluated by Lysholm system.Results After a follow-up for 24 to 43 months and the average period was 36 months.A total of 68 patients turned up.The outcome of treatment was evaluated on the basis of X-ray and clinical findings in hollow screw group and double suture anchors group.Union and average time was 8 weeks.During the follow-up time,clinical evaluation included the range of motion and knee joint stability was examined and no knee joint instability and abnormal activity were found.During the 3 months and 6 months,there were significant differences between hollow screw group and double suture anchors group (P ＞ 0.05).But during the follow-up from 12 to 24 months,there were significant differences between hollow screw group and double suture anchors group (P＞0.05) according to Lysholm system,clinical evaluation including range of motion and knee pain was examined and knee pain and abnormal activity were found in this two groups.Conclusion Clinical characteristics of patients and individual requirement should be considered comprehensively before an individual treatment choice is made for the treatment of the intercondylar eminence fractures of tibia.

This study is to investigate the inhibitory effect of kaempferol on inflammatory response of lipopolysaccharide(LPS)-stimulated HMC-1 mast cells. The cytotoxicity of kaempferol to HMC-1 mast cells were analyzed by using MTT assay and then the administration concentrations of kaempferol were established. Histamine, IL-6, IL-8, IL-1β and TNF-α were measured using ELISA assay in activated HMC-1 mast cells after incubation with various concentrations of kaempferol (10, 20 and 40 µmol.L-1). Western blot was used to test the protein expression of p-IKKβ, IκBα, p-IκBα and nucleus NF-κB of LPS-induced HMC-1 mast cells after incubation with different concentrations of kaempferol. The optimal concentrations of kaempferol were defined as the range from 5 µmol.L-1 to 40 µmol.L-1. Kaempferol significantly decreased the release of histamine, IL-6, IL-8, IL-1β and TNF-α of activated HMC-1 mast cells (P<0.01). After incubation with kaempferol, the protein expression of p-IKKβ, p-IKBa and nucleus NF-κB (p65) markedly reduced in LPS-stimulated HMC-1 mast cells (P<0.01). Taken together, we concluded that kaempferol markedly inhibit mast cell-mediated inflammatory response. At the same time, kaempferol can inhibit the activation of IKKβ, block the phosphorylation of IκBα, prevent NF-KB entering into the nucleus, and then decrease the release of inflammatory mediators.