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Aim: This meta-analysis aimed to evaluate the pharmacokinetics, efficacy, safety and immunogenicity of rHuPH20-facilitated subcutaneous (SC) administration of monoclonal antibody compared with intravenous (IV) administration for patients with cancer. Materials & methods: Outcomes included trough concentrations (Ctrough), overall response rate, adverse events, serious adverse events and antidrug antibody positivity rate. Subgroup analysis was also performed. Results: Five studies involving 1575 participants (788/787) were included. All studies met the non-inferiority criterion in Ctrough. No significant differences were observed in overall response rate (p = 0.12), adverse events (p = 0.05), and severe adverse events (p = 0.73) between SC and IV groups. The SC group also had lower immunogenicity than the IV group. Conclusion: rHuPH20-facilitated subcutaneous administration of monoclonal antibody is highly similar to IV administration in terms of pharmacokinetics, efficacy, and safety, but with lower immunogenicity.

Recombinant human HER2 monoclonal antibody for injection (AK-HER2) is a potential biosimilar of trastuzumab (Herceptin®). This phase Ⅰ study aimed to demonstrate the pharmacokinetic (PK) equivalence between AK-HER2 and trastuzumab in healthy volunteers. Besides, safety and immunogenicity were investigated.This was a randomized, double-blind phase Ⅰ trial in 96 healthy adults who received a single intravenous infusion of AK-HER2 or trastuzumab at 6 mg/kg. The primary PK endpoints were area under the serum concentration curve (AUC) from time 0 to the last time point (AUCThe PK profiles of AK-HER2 and trastuzumab displayed high similarity. The geometric mean ratios (90% confidence intervals) of primary PK endpoints were within 80%-125%. The C AK-HER2 was demonstrated to have highly similar PK to trastuzumab in healthy Chinese adults. Both drugs showed comparable safety and immunogenicity using dexamethasone as premedication to prevent IRRs..

This study was conducted to compare the similarity of the pharmacokinetics (PKs), safety, and immunogenicity of GB222, a potential bevacizumab biosimilar, to that of reference bevacizumab in Chinese healthy males.This was a randomized, double-blind, single-dose, parallel-group clinical trial performed in 84 Chinese healthy males, who were randomly assigned to receive a single infusion dose of 1 mg/kg GB222 or bevacizumab with an 84-days follow-up. The primary endpoint was the area under the plasma concentration-time curve (AUC) from zero to the last quantifiable concentration at time t (AUCThe PK profiles of GB222 and bevacizumab were comparable. The 90% CIs of GM ratio of GB222 to bevacizumab for AUCGB222 was found to be comparable to bevacizumab in terms of PKs, safety, and immunogenicity for Chinese healthy males.ChiCTR-IIR-17,011,143.

IntroductionPsoriasis is a life-long, immune-mediated disease that greatly reduces the quality of life of patients. Plaque psoriasis is the most common form of psoriasis. Treatment options for plaque psoriasis with good tolerance and sufficient response remain profoundly limited. Based on mechanistic findings that suggest the key pathogenic role of interleukin (IL)-17 in plaque psoriasis, we hypothesise that GR1501, a new monoclonal antibody (IL-17A targeted), will be an efficacious treatment for plaque psoriasis. This phase I/II trial aims to evaluate the safety, tolerability, pharmacokinetics, immunogenicity and preliminary efficacy of GR1501.Methods and analysisA multicentre, randomised, double-blind, phase I/II dose escalation and expansion trial will be conducted at four hospitals in China. In total, 226 patients with plaque psoriasis will be enrolled in the study, with 46 cases in the dose-escalation stage and 180 cases randomised to GR1501 or the placebo in a 3:1 ratio in the expansion cohort. The primary outcomes are safety and tolerability; the secondary outcomes include pharmacokinetics, immunogenicity and efficacy.Ethics and disseminationThe study is in accordance with the Declaration of Helsinki, and the ethics approvals of the protocol have been obtained from the ethics committees of all participating centres, including Peking University People’s Hospital, Chinese PLA General Hospital, The First Affiliated Hospital, College of Medicine, Zhejiang University and the Second Xiangya Hospital of Central South University. The findings of the study will be presented in published journals or at scientific conferences or meetings.Trial registration numberChiCTR1800017956.

Summary Immune checkpoint blockade has resulted in durable responses in patients with metastatic melanoma, but only in a fraction of treated patients. For immune checkpoint inhibitors (ICI) to be effective, sufficient infiltration with tumor-reactive T cells is essential. Oncolytic viruses (OV) selectively replicate in and lyse tumor cells and so induce an immunogenic form of cell death, providing at once a source of tumor-associated (neo)antigens and of danger signals that together induce effective T cell immunity and tumor infiltration. Melanoma-associated suppression of dendritic cell (DC) differentiation effectively hampers OV- or immune checkpoint inhibitor (ICI)-induced anti-tumor immunity, due to a consequent inability to prime and attract anti-tumor effector T cells. Here, we set out to study the effect of ORCA-010, a clinical stage oncolytic adenovirus, on DC differentiation and functionality in the context of human melanoma. In melanoma and monocyte co-cultures, employing a panel of five melanoma cell lines with varying origins and oncogenic mutation status, we observed clear suppression of DC development with apparent skewing of monocyte differentiation to a more M2-macrophage-like state. We established the ability of ORCA-010 to productively infect and lyse the melanoma cells. Moreover, although ORCA-010 was unable to restore DC differentiation, it induced activation and an increased co-stimulatory capacity of monocyte-derived antigen-presenting cells. Their subsequent ability to prime effector T cells with a type I cytokine profile was significantly increased in an allogeneic mixed leukocyte reaction. Our findings suggest that ORCA-010 is a valuable immunotherapeutic agent for melanoma.

Background/objective SSS07, a humanized rabbit monoclonal antibody, can selectively block human tumor necrosis factor-α (TNF-α). The objective of this study was to assess the safety, tolerability, and relative immunogenicity of SSS07 after multiple single subcutaneous (SC) doses in healthy volunteers. Methods A total of 71 healthy volunteers were randomized to six sequential ascending-dose groups (5, 15, 30, 50, 75, and 100 mg), and except for the 100 mg group that only had one subject who received a placebo, all of the other groups included two placebo-control subjects. Safety, tolerability, and immunogenicity were assessed by physical examinations, vital signs, electrocardiography (ECG), clinical laboratory tests, and plasma anti-drug antibody (ADA) over 28 days for each group. Their concentrations of TNF-α were also analyzed. Only after safety and tolerance were determined in the lower-dose groups was the next dose group initiated. The dose increments did not exceed 100 mg. Results No serious adverse events or dose-limited toxicity (DLT) were observed, so 100 mg was defined as the maximum tolerated dose (MTD). Overall, 71 AEs and 59 treatment-related adverse events (TRAEs) were reported in 36 (60.0%) and 30 (50.0%) volunteers, respectively, who received SSS07. All AEs and TRAEs were mild or moderate and expected based on previous results with similar types of drugs, without new safety concerns. Except for infections and administration site reactions, the frequency and intensity of the other TRAEs were similar for SSS07 and placebo. No severe acute immune reactions occurred. The lower dose’s immunogenicity was stronger than the higher doses. The highest ADA titer was observed 3 to 6 months after administration. Conclusion SSS07 was generally safe and well tolerated in healthy Chinese volunteers. Higher immunogenicity was observed at low SSS07 concentration levels. The infections and administration site conditions might have been related to the immunogenicity and the degree of inhibition of TNF-α. However, the existence of ADA did not appear to affect the safety of the subjects throughout the follow-up period. These findings could support further investigations of treatments with humanized monoclonal antibodies.

Background: Desloratadine is a drug with a phenotypic polymorphism in metabolism and has been approved for use in many countries to treat allergic diseases. CYP2C8 and UGT2B10 are metabolic enzymes, which may be involved in the metabolism of desloratadine. Objective: This study aimed to demonstrate bioequivalence between the test product (desloratadine tablet) and the reference product AERIUS (5mg), both orally administered. And the role of UGT2B10 and CYP2C8 genotypes in healthy Chinese subjects with different Desloratadine metabolic phenotypes was examined. Methods: It was a randomized, open-label, and four-sequence, single-dose crossover study conducted on 56 healthy Chinese subjects. The pharmacokinetics (PK) and safety of the test and reference Desloratadine products were compared. UGT2B10 and CYP2C8 genotypes were determined by the TaqMan assay using genomic DNA. Multiple linear regression was applied to analyze the correlation between genotypes and the metabolic ratio. Results: The mean serum concentration-time curves of desloratadine and 3-OH-desloratadine were similar between the test product and the reference product. For the PK similarity comparison, the 90% CIs for the geometric mean ratios of Cmax, AUC0-t, and AUC0-∞ of desloratadine and 3-OH-desloratadine of test and reference product were completely within 80-125%. None of all 56 subjects had serious adverse events. Only 2 subjects were poor-metabolizers in 56 healthy subjects. There was no significant correlation between investigated genotypes of CYP2C8 and UGT2B10 and the metabolic ratio. Conclusion: The test desloratadine tablet was bioequivalent to the reference product. No direct relationship between CYP2C8 and UGT2B10 genotypes and desloratadine metabolic ratio was identified.

Background: Preclinical and clinical evidence suggests that mesenchymal stem cells (MSCs) may be beneficial in treating Heart Failure (HF). However, the effects of stem cell therapy in patients with heart failure is an ongoing debate and the safety and efficacy of MSCs therapy are not well-known. We conducted a systematic review of clinical trials that evaluated the safety and efficacy of MSCs for HF. This study aimed to assess the safety and efficacy of MSCs therapy compared to the placebo in heart failure patients. Methods: We searched PubMed, Embase, Cochrane library systematically, with no language restrictions. Randomized Controlled Trials (RCTs) assessing the influence of MSCs treatment function controlled with placebo in heart failure were included in this analysis. We included RCTs with data on safety and efficacy in patients with heart failure after mesenchymal stem cell transplantation. Two investigators independently searched the articles, extracted data, and assessed the quality of the included studies. Pooled data was performed using the fixed-effect model or random-effect model by the use of Review Manager 5.3. The Cochrane risk of bias tool was used to assess the bias of included studies. The primary outcome was safely assessed by death and rehospitalization and the secondary outcome was efficacy, which was assessed by six-minute walk distance and Left Ventricular Ejection Fraction (LVEF), Left Ventricular End-systolic Volume (LVESV), Left Ventricular End-diastolic Volume (LVEDV) and Brain Natriuretic Peptide (BNP). Results: A total of twelve studies were included, involving 823 patients who underwent MSCs or placebo treatment. The overall rate of death showed a trend of reduction of 27% (RR [CI]=0.73 [0.49, 1.09], p=0.12) in the MSCs treatment group. The incidence of rehospitalization was reduced by 47% (RR [CI]=0.53[0.38, 0.75], p=0.0004). The patients in the MSCs treatment group realised an average of 117.01m (MD [95% CI]=117.01m [94.87, 139.14], p Conclusions: Our results suggested that mesenchymal stem cells as a regenerative therapeutic approach for heart failure are safe and effective by virtue of their self-renewal potential, vast differentiation capacity and immune modulating properties. Allogenic MSCs have superior therapeutic effects and intracoronary injection is the optimum delivery approach. In the tissue origin, patients who received treatment with umbilical cord MSCs seem more effective than bone marrow MSCs. As to dosage injected, (1-10)*10^8 cells were of better effect.

Recombinant human HER2 monoclonal antibody for injection (AK-HER2) is a potential biosimilar of trastuzumab (Herceptin®). This phase Ⅰ study aimed to demonstrate the pharmacokinetic (PK) equivalence between AK-HER2 and trastuzumab in healthy volunteers. Besides, safety and immunogenicity were investigated. This was a randomized, double-blind phase Ⅰ trial in 96 healthy adults who received a single intravenous infusion of AK-HER2 or trastuzumab at 6 mg/kg. The primary PK endpoints were area under the serum concentration curve (AUC) from time 0 to the last time point (AUC0-t) and peak concentration in serum (Cmax). The PK bioequivalence was confirmed using the standard equivalence margins of 80%-125%. The PK profiles of AK-HER2 and trastuzumab displayed high similarity. The geometric mean ratios (90% confidence intervals) of primary PK endpoints were within 80%-125%. The C max and AUC 0-t of female subjects in the AK-HER2 group were greater than those of male subjects (P

Vacuumcircuit breaker (VCB) is one of the important elements in the power grid that can control and protect the system. The diagnosis of the vacuum arc images in VCBs is helpful to the study on their breaking performance. But up to now, there are few reports on the macro-particle motion trajectories in the arc. As the macro-particles in the arc are flowing, the particle image velocimetry (PIV) can be grafted into the vacuum arc image processing. In this paper, the power frequency vacuum arc (peak is 6.9kA) was used as the treatment object, geometric characteristics of the vacuum arc shape using digital image processing technology were extracted, and the two dimensional motion trajectory and velocity distribution of the arc macro particles in different arc combustion stages were obtained based on 2D-PIV technology. Three stages were analyzed. In the rapid diffusion stage, the collision of the macro-particles is very intense in the anode region, and they spray along the anode surface. In the stable combustion stage, the velocity of the particles near the anode is small, and there is a smaller shrink. And finally in the extinction stage, their motion trajectories are in a state of rotation, near the anode and cathode are in a state of contraction.

Aims To inform clinical practice by comparing and ranking the lowing blood glucose and weight-loss abilities of 8 glucagon-like peptide-1 receptor agonists (GLP-1RAs) in patients with type 2 diabetes (T2D). Methods We searched PubMed, EMBASE, and CENTRAL from database inception to April 13, 2021. The outcomes were Δ HbA1c, Δ weight, adverse events [AE] withdrawals, and incidence of hypoglycemia. We estimated standardized mean differences [SMD] and summary odds ratios (ORs) using frequentist network meta-analysis with random effects. Results Retrieved trials included 11,126 patients, the overall mean age was 56.7 ± 10.36 years old. In terms of efficacy, all GLP-1RAs were more effective than the placebo except albiglutide-30 mg QW (Δ weight: SMD −0.26 kg [95 %CI: −1.10, 0.59 kg). When it came to safety, oral semaglutide-14mgQD, semaglutide-1mgQW, Liraglutide-1.8mgQD, and Exenatide-2ugBID were associated with an increased risk of AE withdrawals. And GLP-1RAs were associated with a higher incidence of hypoglycemia than placebo except albiglutide-30mgQW and orally administered semaglutide-14mgQD. Conclusion Overall GLP-1RAs were more efficacious than placebo in patients with T2D on efficacy. Unfortunately, differences between GLP1-RAs regarding safety were mostly not significant. We may realize the individualized GLP-1RAs administration based on blood glucose level and obesity degree.

To solve the problem of existing consensus algorithms converging to the same equilibrium point, a new consensus algorithm for unmanned aerial vehicle formation is proposed. By constructing virtual relative position errors, this algorithm's equilibrium point isn't determined by initial states and it can make all members approaching to ideal positions as well as consistent velocity. Based on algebraic graph theory, the topological conditions and parameter conditions required by algorithm convergence are derived. Simulation results verify the validity of this algorithm which is suitable for general design of unmanned aerial vehicle formation system.

An alkaloid (1), an amide (2), three lactones (3, 6 and 7), two coumarins (4–5), eight lignans (8–15), four alcohols (16–19) and three phenols (20–22) are obtained from the EtOAc soluble portion of the MeOH extract of the rhizome of Menispermum dauricum DC. The chemical structures of the compounds are determined by using spectroscopic methods and further supported by comparison with previous literatures. This is the first report that compounds 4–5, 12–17, 19 and 20–21 are obtained from the family Menispermaceae. Compounds 1–2, 6–11 and 22 are isolated for the first time from Menispermum genus. The chemotaxonomic significance of the compounds is also discussed.

Breaking capacity of DC circuit breaker is one of the important technical indicator, breaking performance of operating mechanism restricting its development. DC vacuum circuit breaker based on the principle of force zero-cross in electric power system, short-circuit current can be effectively breaking circuit. Mult- breakers in series with excellent insulating capacity of short vacuum gap improve the ability to withstand voltage insulation. Therefore, short stroke and fast opening of operating mechanisms are need to design and research. Electromagnetic repulsion operating mechanism mainly includes repulsion opening part, permanent magnetic closing part, overtravel spring holding part and capacitor charging and discharging driving part. Through the modeling and simulation of electromagnetic field of electromagnetic repulsion operator, analysis the capacitor discharge current, Multi-function press machine and mechanical characteristic analyzer tester are used to test electromagnetic repulsion operator movement characteristics with stress and displacement. Test measured operating mechanism analysis the movement characteristics in different drive capacitance voltage, analysis movement speed and mechanical bounce in the security and whole clearance between break contact, which test data can satisfy the application of DC circuit breaker with rapid and reliablity.

The current zero period of vacuum arc determines the breaking performance of vacuum circuit breakers, and post-arc current is one of main parameters of current zero period. DC vacuum circuit breaker is one practical solution to solve the bottleneck of DC transmission circuit breaker. It is difficult to measure the post-arc current, when artificial current zero method is used to break the DC short circuit fault, because the current drop rate is very large. In this paper, the experimental circuit is built, and the post-arc current with different commutation parameters is measured by the resistance-transfer method. The results show that the peak value of post-arc current is related to arcing time and the drop rate of current zero period. Either arcing time or current drop rate of current zero period is larger can cause a higher peak value of post-arc current. The experimental waveform also validates the phenomenon that high-energy particles penetrate the sheath at the beginning of sheath development.

High-voltage direct current (HVDC) circuit breaker with rapid fault clearing is an important equipment for protecting DC transmission system. The mechanical vacuum circuit breaker based on artificial current zero (ACZ) is excellent to interrupt the large current. A prototype of mechanical HVDC circuit breaker based on ACZ is simulated by Matlab in this paper. The main circuit breaker and the commutation switch are composed of two vacuum interrupters connected in series. Both of them are operated by electromagnetic repulsion actuators. The commutation process of the circuit breaker is analyzed in detail. Furthermore, a mechanical HVDC circuit breaker module based on ACZ has been tested to interrupt the current, which is provided by a LC circuit. The corresponding waveform of the circuit breaker is obtained and analyzed.

The melanoma tumor environment suppresses the immune reaction, favoring tumor escape from the immune system. This suppressive environment is in part sustained by tumor associated M2-like macrophages. In order to activate the immune system, one approach is macrophage-targeted therapies, that repolarize M2-like macrophages to M1-like macrophages. ORCA-010 is a potency enhanced, replication selective oncolytic adenovirus, with strong anti-tumor activity. As a model of macrophage polarization in the tumor microenvironment, human melanoma cell lines were co-cultured in vitro with CD14+ monocytes. The effects to induce M1-like macrophages by addition of lipopolysaccharide (LPS) and interferon (IFN)-gamma, JAK2 or p38 MAPK inhibitors combined with ORCA-010, was assessed in the co-cultures. Cell phenotypes were characterized by flow cytometry. Our data demonstrate that ORCA-010 significantly reduces M2-like macrophage marker CD163 on CD45+ cells in co-cultures, and increases co-stimulatory M1-like macrophage markers CD80 and CD86 expression on macrophages. CD80 is significantly up-regulated by ORCA-010 with LPS and IFN-gamma. Next, the macrophage polarizing effects of combining ORCA-010 with p38 MAPK and JAK2 inhibitors, known for their favorable myeloid M1 and dendritic cell skewing properties, were assessed in the melanoma co-cultures. The inhibitors JAK2 (AG490) and p38 MAPK (LY2228820) both significantly reduced CD163 levels, however did not induce increased CD80 and CD86 by themselves. Only when combining these with ORCA-010 did we observe a CD86 up-regulation. In a B16.OVA immunocompetent mouse model, ORCA-010 appeared to enhance recruitment of CD8+ T cells to the tumor. Interestingly, combining ORCA-010 with anti-PD-1 resulted in a significant increase of recruitment of CD8+ T cells at the tumor, which could be further enhanced by co-treatment with a p38 inhibitor. Our data suggest that ORCA-010 induces a repolarization of the M2-like macrophages to a favorable M1-like phenotype. This can be further enhanced by the combined administration of ORCA-010 with a TLR4 agonist and IFNγ, or with a JAK2 inhibitor. This work is supported by the European Union Horizon2020 ITN-EID grant 643130 “VIRION”. Citation Format: Ioanna E. Milenova, Rieneke van de Ven, Wenliang Dong, Victor W. van Beusechem, Tanja D. de Gruijl. The in vitro melanoma tumor microenvironment conditions macrophages to an immunosuppressive M2-like phenotype, which is reversible by oncolytic virus ORCA-010 with immune modulators [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4133.

To study the periodontal health status of Hui and Han adults in Ningxia Hui autonomous region, thus to provide scientific basis for the establishment of oral health care policies in this region.2 628 adults in Ningxia Hui autonomous region were investigated in this study according to the criterion issued by World Health Organization on the basic methods of oral health investigation and China oral health third epidemiological survey protocol. The inspection item included gingival bleeding (bleeding on probing, BOP), dental calculus, probing depth (PD) and attachment loss (AL). SPSS 15.0 statistical software was applied to analyze the results.1) The positive rate of BOP sites, detection rate of calculus and PD were peaked in 36-45 and 46-59 years old, but in theor = 60 age group rather lower. The prevalence of periodontitis and the percentage of ALor = 4 mm sites were increased with the adults' age. 2) In addition to the percentage of ALor = 4 mm sites, the differences of the other indicators between the genders were not statistically significant. 3) The positive rate of BOP sites, detection rate of calculus, PD, the prevalence of periodontitis and the percentage of ALor = 4 mm sites were higher for the mountain areas than the plain areas. 4) Hui population's positive rate of BOP sites, detection rate of calculus, PD, the prevalence of periodontitis and the percentage of ALor = 4 mm sites were significantly lower than the Han population in Ningxia.The periodontal health status of adults in Ningxia Hui autonomous region is associated with age, gender, nationality and region.