Safety and immunogenicity of a recombinant COVID-19 vaccine (Sf9 cells) in healthy population aged 18 years or older: two single-center, randomised, double-blind, placebo-controlled, phase 1 and phase 2 trials.

COVID-19 vaccines from multiple manufacturers are needed to cope with the problem of insufficient supply. We did two single-center, randomised, double-blind, placebo-controlled phase 1 and phase 2 trials to assess the safety, tolerability and immunogenicity of a recombinant COVID-19 vaccine (Sf9 cells) in healthy population aged 18 years or older in China. Eligible participants were enrolled, the ratio of candidate vaccine and placebo within each dose group was 3:1 (phase 1) or 5:1 (phase 2). From August 28, 2020, 168 participants were sequentially enrolled and randomly assigned to receive the low dose vaccine, high dose vaccine or placebo with the schedule of 0, 28 days or 0, 14, 28 days in phase 1 trial. From November 18, 2020, 960 participants were randomly assigned to receive the low dose vaccine, high dose vaccine or placebo with the schedule of 0, 21 days or 0, 14, 28 days in phase 2 trial. The most common solicited injection site adverse reaction within 7 days in both trials was pain. The most common solicited systematic adverse reactions within 7 days were fatigue, cough, sore throat, fever and headache. ELISA antibodies and neutralising antibodies increased at 14 days, and peaked at 28 days (phase 1) or 30 days (phase 2) after the last dose vaccination. The GMTs of neutralising antibody against live SARS-CoV-2 at 28 days or 30 days after the last dose vaccination were highest in the adult high dose group (0, 14, 28 days), with 102.9 (95% CI 61.9-171.2) and 102.6 (95% CI 75.2-140.1) in phase 1 and phase 2 trials, respectively. Specific T-cell response peaked at 14 days after the last dose vaccination in phase 1 trial. This vaccine is safe, and induced significant immune responses after three doses of vaccination.

Immunogenicity noninferiority study of 2 doses and 3 doses of an Escherichia coli-produced HPV bivalent vaccine in girls vs. 3 doses in young women.

A new HPV-16/18 bivalent vaccine expressed by the Escherichia coli has been proven to be efficacious in adult women. A randomized, immunogenicity noninferiority study of this candidate vaccine was conducted in December 2015 in China. Girls aged 9-14 years were randomized to receive 2 doses at months 0 and 6 (n=301) or 3 doses at months 0, 1 and 6 (n=304). Girls aged 15-17 years (n=149) and women aged 18-26 years (n=225) received 3 doses. The objectives included noninferiority analysis of the IgG geometric mean concentration (GMC) ratio (95% CI, lower bound>0.5) to HPV-16 and HPV-18 at month 7 in girls compared with women. In the per-protocol set, the GMC ratio of IgG was noninferior for girls aged 9-17 years receiving 3 doses compared with women (1.76 (95% CI, 1.56, 1.99) for HPV-16 and 1.93 (95% CI, 1.69, 2.21) for HPV-18) and noninferior for girls aged 9-14 years receiving 2 doses compared with women (1.45 (95% CI, 1.25, 1.62) for HPV-16 and 1.17 (95% CI, 1.02, 1.33) for HPV-18). Noninferiority was also demonstrated for neutralizing antibodies. The immunogenicity of the HPV vaccine in girls receiving 3 or 2 doses was noninferior compared with that in young adult women.

LPS Induces Occludin Dysregulation in Cerebral Microvascular Endothelial Cells via MAPK Signaling and Augmenting MMP-2 Levels.

Disrupted blood-brain barrier (BBB) integrity contributes to cerebral edema during central nervous system infection. The current study explored the mechanism of lipopolysaccharide- (LPS-) induced dysregulation of tight junction (TJ) proteins. Human cerebral microvascular endothelial cells (hCMEC/D3) were exposed to LPS, SB203580 (p38MAPK inhibitor), or SP600125 (JNK inhibitor), and cell vitality was determined by MTT assay. The proteins expressions of p38MAPK, JNK, and TJs (occludin and zonula occludens- (ZO-) 1) were determined by western blot. The mRNA levels of TJ components and MMP-2 were measured with quantitative real-time polymerase chain reaction (qRT-PCR), and MMP-2 protein levels were determined by enzyme-linked immunosorbent assay (ELISA). LPS, SB203580, and SP600125 under respective concentrations of 10, 7.69, or 0.22 µg/mL had no effects on cell vitality. Treatment with LPS decreased mRNA and protein levels of occludin and ZO-1 and enhanced p38MAPK and JNK phosphorylation and MMP-2 expression. These effects were attenuated by pretreatment with SB203580 or SP600125, but not in ZO-1 expression. Both doxycycline hyclate (a total MMP inhibitor) and SB-3CT (a specific MMP-2 inhibitor) partially attenuated the LPS-induced downregulation of occludin. These data suggest that MMP-2 overexpression and p38MAPK/JNK pathways are involved in the LPS-mediated alterations of occludin in hCMEC/D3; however, ZO-1 levels are not influenced by p38MAPK/JNK.

Features and variations of a radial artery approach in southern Chinese populations and their clinical significance in percutaneous coronary intervention.

BACKGROUND: More and more percutaneous coronary intervention were done from radial artery approach. But the great limitation of radial artery approach and main failure cause of transradial coronary intervention is smaller size and more variations of a radial artery approach. The aim of the study is to explore the features and variations of a radial artery approach in southern Chinese populations and their clinical significance in percutaneous coronary intervention. METHODS: A total of 1400 patients who underwent scheduled first time transradial coronary angiography between July 2007 and September 2010 were enrolled. Radial arteriography was performed in all patients to detect the anatomical variations of this vessel. All patients' radial and ulnar artery inner diameters were measured using a computer assisted quantification method. A detailed patient history was recorded. Multivariate Logistic regression analysis was performed to evaluate the predictive value of variables (including age, gender, ethnicity, height, weight, body mass index, smoking, diabetes, hypertension and dyslipidemia) in arterial tortuosities and variations of this vessel. RESULTS: In southern Chinese populations, there were no significant differences in the diameters of the forearm arteries: the mean radial artery inner diameter was (3.04 ± 0.43) mm in ethnic Han Chinese and (3.05 ± 0.42) mm in ethnic Zhuang Chinese, P > 0.05), the mean ulnar artery inner diameter was (3.03 ± 0.38) mm in Han Chinese and (3.05 ± 0.36) mm in Zhuang Chinese, P > 0.05). It was estimated that the inner diameter of the radial artery was not smaller than a 6F Cordis sheath in 86.1% of male patients and in 57.0% of female patients, and not smaller than a 7F Cordis sheath in 59.3% of male patients and 24.9% of female patients. The factors found to positively affect the size of the radial artery were sex (bj = 0.309, P < 0.01), weight (bj = 0.103, P < 0.01), and diabetes mellitus (bj = -0.088, P < 0.01) was found to negatively affect radial artery size. Arterial tortuosities occurred in 12.1% of patients and arterial variations in 4.1%. The incidence of tortuosities and variations included radial artery tortuosity (3.6%), high origin of radial artery (1.7%), radial artery loop (0.6%), double radial artery (0.1%), brachial artery tortuosity (0.4%), double brachial artery (0.1%), subclavian artery tortuosity (5.4%), small subclavian artery (0.4%), right retro-esophageal subclavian artery (0.6%), brachiocephalic trunk tortuosity (2.8%), small brachiocephalic artery (0.1%), and brachiocephalic artery anomaly (0.4%). For people in Guangxi province, tortuosities of the subclavian artery and radial artery are the most common among the vascular tortuosities of the radial artery approach. The overall rate of transradial procedural success was 96.1%. Procedural failure was more common in patients with anomalous radial artery approach than in patients with normal radial artery approach (22.8% vs. 1.8%, P = 0.000). According to multivariate Logistic regression analysis, age (OR = 2.695, 95%CI 2.232 - 3.253, P = 0.000), female gender (OR = 5.127, 95%CI 3.000 - 8.762, P = 0.000), height (OR = 0.612, 95%CI 0.465 - 0.807, P = 0.000), body mass index (OR = 2.377, 95%CI 1.834 - 3.082, P = 0.000), hypertension (OR = 1.668, 95%CI 1.132 - 2.458, P = 0.010), hyperlipidemia (OR = 1.273, 95%CI 1.425 - 2.049, P = 0.034) and smoking (OR = 5.750, 95%CI 3.636 - 9.093, P = 0.000), were independently associated with arterial tortuosities of the radial artery approach. Female gender was independently associated with arterial variations of the radial artery approach (OR = 3.613, 95%CI 3.208 - 7.826, P = 0.000). CONCLUSIONS: The diameters of the radial and ulnar arteries between the Han people and the Zhuang people in southern Chinese populations are similar. In a transradial operation, the most southern Chinese populations, the use of a 6F sheath and guiding catheter is safe, and using a 7F sheath and guiding catheter is feasible in some selected patients. Radial arterial tortuosities and variations in southern Chinese populations are relatively common and are a significant cause of the failure of transradial coronary procedure. Old age, female gender, short stature, high body mass index, hypertension, hyperlipidemia and smoking, were independently associated with an increased risk of arterial tortuosity. In addition, female gender was an independent predictor of arterial variations.

[Cardiomyocyte apoptosis and death receptor pathway in a rat model of coronary microembolization].

OBJECTIVE: To investigate the dynamic changes of cardiomyocyte apoptosis and the role of death receptor apoptotic pathway in a rat model of coronary microembolization (CME). METHODS: Adult rats were randomized to coronary microembolization (CME group, n = 63) or sham-operated group (S group, n = 55). CME model was established by aortic injection of 0.1 ml microspheres (42 microm, 3 x 10(4)/ml) into the left ventricle when the ascending aorta was temporarily clamped.S group received 0.1 ml saline injection and survived rats were randomly examined at 0, 3, 6, 12 and 24 hour post CME (n = 10 each). Heart function was evaluated by echocardiography. Myocardium sample was stained with hematoxylin-eosin and hematoxylin-basic fuchsin-picric acid to detect infarct areas. Cardiomyocyte apoptosis was detected with TUNEL staining. The expression of caspase-3 and caspase-8 was measured by Western blot analysis. RESULTS: Compared with S group, the left ventricular ejection fraction was significantly decreased and left ventricular end-diastolic diameter was significantly increased in CME group (all P < 0.05) except 0 hour CME group. The infarct sizes were similar in 3 hour, 6 hour, 12 hour, and 24 hour CME groups (P > 0.05). The apoptosis index (AI) in CME group were significantly higher at each time point compared to S group (P < 0.05) except 0 hour CME group and peaked at 6 hours. Apoptotic cardiomyocytes were found mainly in the myocardial microinfarcted area and border zones. The relative expression of caspase-3 and caspase-8 in CME group were both significantly increased at 3 hours and peaked at 6 hour post CME (P < 0.05). CONCLUSION: Cardiomyocytes apoptosis was significantly increased after coronary microembolization via activating death receptor apoptotic pathway in this coronary microembolization model.

[Short- and long-term therapeutic effects of combination therapy with perindopril and irbesartan in a rat model of dilated cardiomyopathy].

OBJECTIVE: To evaluate the short-term, and long-term therapeutic effects of combination therapy with perindopril and irbesartan in a rat model of dilated cardiomyopathy (DCM). METHODS: Sprague-Dawley rats were administered adriamycin intraperitoneally to develop DCM. Grouping of rats: Group A contained normal rats, and Group B contained DCM rats. Both Group A and B were not given drug treatment. Group C and D contained DCM rats, however, Group C was administered perindopril 2mg/(kg x d) while Group D was administered perindopril 1mg/(kg x d) and irbesartan 25mg/(kg x d). Brain natriuretic peptide (BNP) was determined by enzyme linked immunosorbent assay; plasma potassium and creatinine were measured; the pathological lesions of cardiac muscle tissues were evaluated after HE staining; and the survival time of each rat during the intervention was recorded. RESULTS: After the three-week intervention, the plasma concentrations of BNP in Group D were lower than those in Group C (P<0.05). In each group, plasma concentrations of potassium and creatinine showed no significant differences between pre-intervention and post-intervention (P>0.05); pathological lesions of cardiac muscle tissues in both Group C and D were attenuated compared with those in Group B (P<0.01), but pathological lesions of cardiac muscle tissues showed no significant differences between Group C and Group D (P>0.05). Log-rank test showed that the life span of Group C was shorter than that of Group D (P<0.05); Cox regression analysis showed that both combination therapy and monotherapy with perindopril could prolong the survival time, but the effect of combination therapy was more obvious. CONCLUSION: Combination therapy with perindopril and irbesartan in a rat model of DCM can more effectively improve the cardiac function and long-term prognosis than those monotherapy with perindopril. Both these two treatment plans can attenuate the pathological lesions of cardiac muscle tissues, without elevating the concentrations of plasma potassium and creatinine.

[Effect of mesenchymal stem cells transplantation on heart function after acute myocardial infarction].

OBJECTIVE: To investigate whether mesenchymal stem cells (MSCs) transplantation after acute myocardial infarction (AMI) can improve heart function and decrease infarct size in rabbits and their correlation. METHODS: Twenty-four rabbits were randomly divided into AMI group and MSCs group, each n=12. Exogenous MSCs labeled with bromodeoxyuridine (BrdU) were injected into the border and central area of the ischemic myocardium. Heart function was assessed with echocardiography before transplantation of MSCs and in 6th week after the transplantation. Surviving MSCs in infarcted myocardium were identified by immunohistochemistry. Infarct size was measured histologically. Correlation of heart function and infarct size were analysed. RESULTS: Immunohistochemical stain revealed that BrdU-positive cells were seen in the infarcted myocardium in MSCs group but not in AMI group. Transplantation of MSCs was associated with a significant diminution of left ventricular end-diastolic dimension (LVEDD), and left ventricular end-systolic dimension (LVESD, both P<0.05), and left ventricular ejection fraction (LVEF) and fractional shortening (DeltaFS%)increased (both P<0.05) as compared with AMI group. Infarct size as measured histologically was significant smaller in MSCs group than AMI group (P<0.05). There were negative correlations between LVEF and infarct size in two groups (both P<0.01). CONCLUSION: Exogenous MSCs transplantation can improve heart function by decreasing infarct size and therefore it might be beneficial in the treatment of AMI.

Solution-phase reductive cyclization of 2-quinoxalinol analogs: systematic study of parallel synthesis.

1,5-Difluoro-2,4-dinitrobenzene starting material was treated via primary and/or secondary substitution with a variety of amino acids or amines and the aromatic m-dinitro groups were then reductively cyclized provide the 2-quinoxalinol analogs. The conditions for 1,5-dialkylamino-2,4-dinitrobenzene reduction have been systematically studied and optimized in solution. Three effective methods are described for the high-throughout generation of 2-quinoxalinol analogs.

Parallel approach for solution-phase synthesis of 2-quinoxalinol analogues and their inhibition of LPS-induced TNF-alpha release on mouse macrophages in vitro.

A parallel solution-phase synthesis of 2-quinoxalinol analogues is described. The key step-simultaneous reductions of m-Ar(NO2)2 to m-Ar(NH2)2 was investigated extensively. We obtained preliminary pharmacological activity of those analogues for the inhibition of LPS-induced TNF-alpha release on mouse macrophage in vitro. Two compounds revealed inhibitory activity, with IC50 values of 0.40 microM (7-amino-6-[(3-methoxypropyl)amino]-3-methyl-2-quinoxalinol) and 2.2 microM (7-amino-6-[(3-butoxypropyl)amino]-3-methyl-2-quinoxalinol), respectively.