Efficacy,metabolic characteristics,safety and immunogenicity of AK-HER2 compared with reference trastuzumab in patients with metastatic HER2-positive breast cancer:a multicenter,randomized,double-blind phase Ⅲ equivalence trial / 中国癌症杂志

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.

Analysis of the metabolites of isoacteoside in rat urine by UHPLC-LTQ-Orbitrap / 国际中医中药杂志

Objective:To analyze the metabolites of isoacteoside in rat's urine after oral administration by UHPLC-LTQ-Orbitrap and then summarize its metabolic pathways.Methods:The rats were randomly divided into treatment and control groups. Isoacteoside dissolved in saline was orally administered to the rats in the treatment group witht a single dose of 100 mg/kg. At the same time, saline was orally administered to the control group with the same volume. The urine samples were collected for 12 h and then purified. Sample analyses were performed on a Thermo Scientific BOS Hypersil C18 column (2.1 mm × 150 mm, 2.4 μm), the mobile phase consisted of water containing 0.1% formic acid-acetonitrile in a gradient program, the flow rate was set at 0.3 ml/min and the column was maintained at 30 ℃. The urine samples of the treatment group and control groups were detected with negative ion mode.Results:The metabolites were identified according to their protonated molecular ions and fragment ions and by comparing the mass data with that of reference standards and the published data. In total, 8 metabolites of isoacteoside were detected and identified in the urine samples of treatment group and the major metabolic pathway of isoacteoside included glucuronide conjugation, dehydroxylation, hydrolyzation, methyl conjugation and sulphate conjugation.Conclusions:UHPLC-LTQ-Orbitrap could be used to analyze the main metabolites and metabolic pathways of isophylloside in rats, which can provide references for further studies on pharmacodynamics and pharmacological mechanisms.

The research progress on the role of ATF3 in the malignant tumor / 中国医师杂志

Activating transcription factor 3 (ATF3) is a protein produced by the cells in the ischemic reperfusion injury,neuronal or liver damage,skin damage,viral oncogene expression or DNA damage.Recent studies have found that ATF3 plays an important role in the occurrence and development of human malignant tumors.

Efficacy observation of transcranial direct current stimulation for improving the attention in patients with infarction in basal ganglia region / 中国脑血管病杂志

Objective To investigate the efficacy observation of transcranial direct current stimulation (tDCS)for improving the attention in patients with infarction in basal ganglia area. Methods Sixty consecutive patients with basal ganglia infarction admitted to the Department of Rehabilitation Medicine,the First Affiliated Hospital of Nanchang University from May 2015 to May 2016 were enrolled. They were randomly divided into either a control group or a test group according to the random number table (n = 30 in each group). The patients in both groups received routine rehabilitation training,and those in the test group received tDCS therapy synchronously,and the control group received the sham tDCS stimulation. The evaluations and analyses were conducted with the Montreal cognitive assessment (MoCA),d2 test of attention,and event-related potential-P300 (ERP-P300),respectively in all patients before intervention and 4 weeks after intervention,and they were compared between the groups. Results There was no significant difference before intervention between the two groups (all P > 0. 05). Compared with before intervention,the ERP-P300 latencies were reduced,the amplitudes were increased after intervention in the patients of the test group and the control group (all P 2. 4;the control group:17. 2 ±2. 5 vs. 15. 6 ±2. 3),attention dimension scores (the test group:4. 6 ± 1. 2 vs. 2. 4 ± 1. 6;the control group:3. 6 ± 1. 5 vs. 2. 5 ± 1. 5),and the total completion of d2 attention test task, total scores,and concentration degree scores (the test group:295 ± 31 vs. 250 ± 45,279 ± 38 vs. 223 ± 52, 97 ± 22 vs. 75 ± 25;the control group:276 ± 33 vs. 247 ± 45,257 ± 39 vs. 211 ± 56,84 ± 23 vs. 71 ± 24) were all increased (all P < 0. 05),and all the indexes of the test group were better than those of the control group (all P < 0. 05). Conclusion tDCS contributes to the improvement of the attention in patients with infarction in the internal capsule-basal ganglia region.

Expression of chemokine receptor CCR7 and VEGF-C is associated with prognosis of breast carcinoma / 中国病理生理杂志

AIM: To explore the protein levels of chemokine receptor 7 (CCR7) and vascular endothelial growth factor ( VEGF)-C in breast carcinoma , and to investigate the effects of CCR 7 and VEGF-C on prognosis of breast carcinoma.METHODS:The protein expression levels of CCR 7 and VEGF-C in the breast carcinoma tissues and normal breast tissues were detected by the method of immunohistochemistry .At the same time, the relationship between clinico-pathologic characteristics and the protein expression of CCR 7 and VEGF-C in the breast carcinoma tissues was analyzed . The relationship between the protein expression of CCR 7 and VEGF-C and survival time of the breast cancer patients was estimated by Kaplan-Meier method.RESULTS:The positive expression rates of CCR 7 and VEGF-C in the breast carcino-ma tissues were significantly higher than those in the normal breast tissues (P<0.01).A positive correlation was observed between the protein expression of CCR7 and the protein expression of VEGF-C in the breast carcinoma tissues (r=0.613, P<0.01).The protein expression of CCR7 and VEGF-C was correlated with lymph node metastasis and TNM stage (P<0.05), but both were not related to patients ’ age, primary tumor size, estrogen receptor and progesterone receptor .The survival time of the patients with CCR 7 and VEGF-C positive expression was significantly shorter than that of the patients without the expression (P<0.05).CONCLUSION:The positive expression of CCR7 and VEGF-C proteins is associated with the prognosis of breast cancer , and combined detection of CCR 7 and VEGF-C protein expression levels may be helpful to judge the prognosis of breast cancer .

Application of cluster management in patients with massive cerebral in-farction / 中国现代医生

Objective To study the application of cluster management in patients with massive cerebral infarction. Methods 200 cases of massive cerebral infarction patients in our hospital were randomly divided into two groups, 100 cases in the experimental group, reduced lip breathing, effective cough, regular turning knock back, inhalation,bronchoscopy were applied; 100 cases in the control group, conventional measures of respiratory care were applied. 3 days, 7 days, 14 days expectoration ability, 7 days, 14 days atelectasis, pulmonary infection,the cases of respiratory failure of patients were observed. Results The independent expectoration capacity in the experimental group was better than the control group, atelectasis, pulmonary infection and respiratory failure of patients in the experimental group were significantly less than the control group. Conclusion Cluster management can improve patients'autonomy massive cerebral infarction expectoration capacity,reduce atelectasis,pulmonary infection,respiratory failure.

Clinicopathologic features and prognosis of primary bone anaplastic large cell lymphoma / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the clinicopathologic features, differential diagnosis and prognosis of primary bone anaplastic large cell lymphoma(ALCL).</p><p><b>METHODS</b>Twelve patients diagnosed with primary bone ALCL were retrospectively reviewed. The clinicopathologic features, immunohistochemic findings and results of in situ hybridization for EB virus were analyzed.</p><p><b>RESULTS</b>Of the 12 patients, the male-to-female was 7: 5 with a median age of 17.5 years (range from 9 to 64 years). Bone pain was the presenting symptom in all patients. Radiographic examination demonstrated solitary osteolytic lesion in 8 patients and multiple lesions in the rest 4 patients. Spine (7 cases) was the most common site to be involved, followed by ilium (5 cases), sacrum (2 cases), humerus (1 case) and collarbone (1 case). Ten patients were available with the follow-up data including 5 ALK-positive and 5 ALK-negative patients, and the follow-up time was 2 to 47 months. Interestingly, the 3 dead patients were ALK-negative whereas 5 of 7 ALK-positive patients achieved remission.</p><p><b>CONCLUSIONS</b>Primary bone ALCL is a rare type of non-Hodgkin lymphoma and it more frequently involves the axial skeleton. Boys and young males are more commonly affected. Patients usually present at an early stage and have a relatively favorable prognosis. Expression of ALK protein may be associated with a favorable prognosis in primary bone ALCL.</p>

Expression of COX-2 and VEGF in non-hodgkin lymphoma and its clinical significance / 中国医师杂志

Objectiye To explore the expression of COX-2 and VEGF and its clinical significance in non-Hodgkin lymphoma (NHL). Methods The expression of COX-2 and VEGF were detected by immunohistochemistry in 42 cases of NHL and 20 cases of lymph node with benign pathological change. Results The positive rate of COX-2 and VEGF was 45.24% and 73.81% in NHL respectively. The expression rate of VEGF was positively correlated with that of COX-2 in tissues of NHL ( x2 = 4. 63, P ＜ 0. 05).The expression of COX-2 was related to clinical stage and histopathologic grade of NHL ( x2 = 5.43, P ＜0. 05), but it had no association with gender, age, B symptoms, and IPI. The expression of VEGF was significantly related with aggression, B symptoms and IPI ( x2 =8. 979, 8. 893,6. 434, P ＜0. 05), but it had no association with age, gender and clinical stages. Conclusion COX-2 and VEGF may be involved in NHL tumorgenesis, and COX-2 may accelerate angiogenesis by increasing VEGF expression. Specific COX-2 inhibitors may be a novel therapeutic approach for NHL.

Targeting Prnp in bovine fibroblasts by promoter-trap strategy / 生物工程学报

Promoter-trap strategy for enriching targeted colonies has been usually used to elevate the gene targeting efficiency in somatic cells. Knocking out Prnp in animals by gene targeting can render them resistant to Prion diseases. We constructed a bovine Prnp promoter-less targeting vector BoPrPneo, then transfected the linearized vector into the bovine fetal fibroblasts BFF through electroporation. After selecting in cell culture medium with 250 microg/mL G418, we obtained 99 drug-resistant cell colonies, 4 of them were positive for targeted events after PCR screening, and the targeted colonies were further confirmed by sequencing and Southern blotting. This suggests that one allele of Prnp has been successfully knocked out in bovine fetal fibroblasts. This research supplies a simple, safe and effective method to targeting bovine Prnp.

Changes of myocardial membrane gene expression of natrium pump isoforms in rat with myocardial ischemia reperfusion injury / 中国临床药理学与治疗学

AIM: Changes of endoxin level, ATPase activities, intramitochondrial Ca2+ concentration, and gene expression of Na+-K+-ATPase isoforms in myocardium of rats with MIR and effect of verapamil were observed, in order to investigate mechanism of endoxin mediating intracellular calcium overload of myocytes. METHODS: Twenty four male Sprauge Dawley rats were randomized into 3 groups. Sham operation group: silk suture was threaded the left anterior descending coronary artery without ligature; MIR group (MIR): left anterior descending coronary artery was subjected to 30 min ligation followed by 45 min reperfusion; verapamil group: MIR model was given 5 mg/kg verapamil. Verapamil was injected via femoral vein 5 min before reperfusion. Left ventricle myocardium samples were processed immediately after reperfusion in order to measure the activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase, endoxin level, and intramitochondrial Ca2+ concentration. The levels of ?1, ?2, ?3 and ?1 isoforms of Na+-K+-ATPase were measured by immunohistochemical assay. RESULTS: After MIR, the level of endoxin in myocardium was substantially increased; the activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase in myocardial membrane were significantly decreased while the concentration of intramitochondrial Ca2+ was increased; the levels of the ?1, ?2, ?3 and ?1 isoforms of Na+-K+-ATPase were reduced markedly. Verapamil had only effect on reducing the concentration of intramitochondrial Ca2+. CONCLUSION: MIR increases endoxin secretion. The latter may depress the activity of Na+-K+-ATPase by changing the gene expression of ?1, ?2, ?3 and ?1 isoforms of Na+-K+-ATPase in myocardial membrane, inducing intramitochondrial Ca2+ overload.

Endoxin antagonist up-regulates gene expression of sodium pump isoforms in rats with myocardial ischemia reperfusion injury / 中国病理生理杂志

AIM: To observe the effect of endoxin antagonist,anti-digoxin antiserum,on endoxin level,ATPase activities,intramitochondrial total calcium concentration and gene expression of sodium pump isoforms in myocardium of rats with myocardial ischemia reperfusion(MIR).METHODS: Fifty-six male Sprauge Dawley rats were randomly divided into 7 groups.Sham operation group: silk suture threading the left anterior descending coronary artery without ligature;MIR group: left anterior descending coronary artery was subjected to 30 min ligation followed by 45 min reperfusion;normal saline group: MIR model was given 5 mL/kg normal saline;verapamil group: MIR model was given 5 mg/kg verapamil;low dose antidigoxin antiserum group: MIR model was given 8.6 mg/kg antidigoxin antiserum;middle dose antidigoxin antiserum group: MIR model was given 17.3 mg/kg antidigoxin antiserum;high dose antidigoxin antiserum group: MIR model was given 34.5 mg/kg antidigoxin antiserum.All drugs were injected into vessel via femoral vein within 5 min before reperfusion,respectively.After reperfusion,left ventricle myocardium samples were processed immediately in order to measure the activity of Na+-K+-ATPase and Ca2+-Mg2+-ATPase,endoxin level,intramitochondrial total calcium concentration and the experssion of ?1,?2,?3 and ?1 isoforms of sodium pump on mRNA and protein levels by RT-PCR and Western blotting and immunohistochemical assay,respectively.RESULTS: After MIR,the level of endoxin in myocardium was obviously increased.The activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase in myocardial membrane were significantly decreased while intramitochondrial total calcium concentration increased.The gene expression of the ?1,?2,?3 and ?1 isoforms of sodium pump at both mRNA and protein levels were reduced markedly.Only the effect of verapamil on reducing intramitochondrial total calcium concentration was observed.Antidigoxin antiserum significantly reduced the level of endoxin in myocardium,restored the activities of Na+-K+-ATPase and Ca2+-Mg2+-ATPase,reduced intramitochondrial total calcium concentration,and up-regulated the expression of ?1,?2,?3 and ?1 isoforms of sodium pump at both mRNA and protein levels.CONCLUSION: MIR results in increase of endoxin secretion.The latter depresses the activity of Na+-K+-ATPase by down-regulating the gene expression of ?1,?2,?3 and ?1 isoforms of sodium pump in myocardial membrane,and also induces intramitochondrial calcium overload,thereby mediates MIR injury.

RELATION OF NONENZYMATIC GLYCOSYLATION OF ERYTHROCYTE MEMBRANE PROTEINS TO CHRONIC DIABETIC COMPLICATIONS / 中华内分泌代谢杂志

0. 20) after D test of normality. The normal range of GEMP was 63. 11-72. 94 ?mol fructose/L (P= 95%). When clinical cardiovasculopathy, nephropathy, retinopathy,peripheral neuropathy and auditus reduction in the aged were compared between two groups of diabetic patients, one with normal and another with abnormal values of GEMP, the clinical indices, excepting cardiovasculopathy, were significantly different between the groups.