A vaccine to protect against COVID-19 is urgently needed. We aimed to assess the safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 (Ad5) vectored COVID-19 vaccine expressing ...the spike glycoprotein of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain.
We did a dose-escalation, single-centre, open-label, non-randomised, phase 1 trial of an Ad5 vectored COVID-19 vaccine in Wuhan, China. Healthy adults aged between 18 and 60 years were sequentially enrolled and allocated to one of three dose groups (5 × 1010, 1 × 1011, and 1·5 × 1011 viral particles) to receive an intramuscular injection of vaccine. The primary outcome was adverse events in the 7 days post-vaccination. Safety was assessed over 28 days post-vaccination. Specific antibodies were measured with ELISA, and the neutralising antibody responses induced by vaccination were detected with SARS-CoV-2 virus neutralisation and pseudovirus neutralisation tests. T-cell responses were assessed by enzyme-linked immunospot and flow-cytometry assays. This study is registered with ClinicalTrials.gov, NCT04313127.
Between March 16 and March 27, 2020, we screened 195 individuals for eligibility. Of them, 108 participants (51% male, 49% female; mean age 36·3 years) were recruited and received the low dose (n=36), middle dose (n=36), or high dose (n=36) of the vaccine. All enrolled participants were included in the analysis. At least one adverse reaction within the first 7 days after the vaccination was reported in 30 (83%) participants in the low dose group, 30 (83%) participants in the middle dose group, and 27 (75%) participants in the high dose group. The most common injection site adverse reaction was pain, which was reported in 58 (54%) vaccine recipients, and the most commonly reported systematic adverse reactions were fever (50 46%), fatigue (47 44%), headache (42 39%), and muscle pain (18 17%. Most adverse reactions that were reported in all dose groups were mild or moderate in severity. No serious adverse event was noted within 28 days post-vaccination. ELISA antibodies and neutralising antibodies increased significantly at day 14, and peaked 28 days post-vaccination. Specific T-cell response peaked at day 14 post-vaccination.
The Ad5 vectored COVID-19 vaccine is tolerable and immunogenic at 28 days post-vaccination. Humoral responses against SARS-CoV-2 peaked at day 28 post-vaccination in healthy adults, and rapid specific T-cell responses were noted from day 14 post-vaccination. Our findings suggest that the Ad5 vectored COVID-19 vaccine warrants further investigation.
National Key R&D Program of China, National Science and Technology Major Project, and CanSino Biologics.
This is the first randomised controlled trial for assessment of the immunogenicity and safety of a candidate non-replicating adenovirus type-5 (Ad5)-vectored COVID-19 vaccine, aiming to determine an ...appropriate dose of the candidate vaccine for an efficacy study.
This randomised, double-blind, placebo-controlled, phase 2 trial of the Ad5-vectored COVID-19 vaccine was done in a single centre in Wuhan, China. Healthy adults aged 18 years or older, who were HIV-negative and previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-free, were eligible to participate and were randomly assigned to receive the vaccine at a dose of 1 × 1011 viral particles per mL or 5 × 1010 viral particles per mL, or placebo. Investigators allocated participants at a ratio of 2:1:1 to receive a single injection intramuscularly in the arm. The randomisation list (block size 4) was generated by an independent statistician. Participants, investigators, and staff undertaking laboratory analyses were masked to group allocation. The primary endpoints for immunogenicity were the geometric mean titres (GMTs) of specific ELISA antibody responses to the receptor binding domain (RBD) and neutralising antibody responses at day 28. The primary endpoint for safety evaluation was the incidence of adverse reactions within 14 days. All recruited participants who received at least one dose were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, NCT04341389.
603 volunteers were recruited and screened for eligibility between April 11 and 16, 2020. 508 eligible participants (50% male; mean age 39·7 years, SD 12·5) consented to participate in the trial and were randomly assigned to receive the vaccine (1 × 1011 viral particles n=253; 5 × 1010 viral particles n=129) or placebo (n=126). In the 1 × 1011 and 5 × 1010 viral particles dose groups, the RBD-specific ELISA antibodies peaked at 656·5 (95% CI 575·2–749·2) and 571·0 (467·6–697·3), with seroconversion rates at 96% (95% CI 93–98) and 97% (92–99), respectively, at day 28. Both doses of the vaccine induced significant neutralising antibody responses to live SARS-CoV-2, with GMTs of 19·5 (95% CI 16·8–22·7) and 18·3 (14·4–23·3) in participants receiving 1 × 1011 and 5 × 1010 viral particles, respectively. Specific interferon γ enzyme-linked immunospot assay responses post vaccination were observed in 227 (90%, 95% CI 85–93) of 253 and 113 (88%, 81–92) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Solicited adverse reactions were reported by 183 (72%) of 253 and 96 (74%) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Severe adverse reactions were reported by 24 (9%) participants in the 1 × 1011 viral particles dose group and one (1%) participant in the 5 × 1010 viral particles dose group. No serious adverse reactions were documented.
The Ad5-vectored COVID-19 vaccine at 5 × 1010 viral particles is safe, and induced significant immune responses in the majority of recipients after a single immunisation.
National Key R&D Programme of China, National Science and Technology Major Project, and CanSino Biologics.
Phytopathogenic fungi cause plant diseases and economic losses in agriculture. To efficiently control plant pathogen infections, a total of 19 spirotryprostatin A derivatives and 26 spirooxindole ...derivatives were designed, synthesized, and tested for their antifungal activity against ten plant pathogens. Additionally, the intermediates of spirooxindole derivatives were investigated, including proposing a mechanism for diastereoselectivity and performing amplification experiments. The bioassay results demonstrated that spirotryprostatin A derivatives possess good and broad-spectrum antifungal activities. Compound
exhibited excellent antifungal activity in vitro, equal to or higher than the positive control ketoconazole, against
,
,
,
,
,
,
and
(MICs: 8-32 µg/mL). Compound
also displayed remarkable antifungal activity against eight other phytopathogenic fungi, including
f. sp.
and
(MICs: 8-32 µg/mL). The preliminary structure-activity relationships (SARs) were further discussed. Moreover, molecular docking studies revealed that spirotryprostatin A derivatives anchored in the binding site of succinate dehydrogenase (SDH). Therefore, these compounds showed potential as natural compound-based chiral fungicides and hold promise as candidates for further enhancements in terms of structure and properties.
Abstract
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.
With the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, the importance of vaccines in epidemic prevention and public health has become even more obvious than ever. However, the ...emergence of multiple severe acute respiratory syndrome coronavirus 2 variants worldwide has raised concerns about the effectiveness of current COVID-19 vaccines. Here, we review the characteristics of COVID-19 vaccine candidates in five platforms and the latest clinical trial results of them. In addition, we further discuss future directions for the research and development of the next generation of COVID-19 vaccines. We also summarize the serious adverse events reported recently after the large-scale vaccination with the current COVID-19 vaccines, including the thromboembolism caused by the AstraZeneca and Johnson & Johnson vaccines.
A new pyridazine carboxyl derivative, 1-(3-carboxyphenyl)-5-methyl-4-oxo-1,4-dihydropyrida zine-3-carboxylic acid (C13H10N2O5, Mr = 274.06, abbreviate as H2(3-PDCA)) has been synthesized by ethyl ...3-aminobenzoate, its structure was determined by 1H NMR, 13C NMR, FT-IR and X-ray single crystal analysis. According to density functional theory, the reaction sites of title molecule were visualized in molecular electrostatic potential maps plot. Meanwhile, two d10 metal coordination polymers had been constructed by title molecule under solvothermal conditions: Cd(H2O)(3-PDCA)·2H2On (SNUT-10) and {Zn3(H2O)10(3-PDCA)2Zn(H2O)2(3-PDCA)2·8H2O}n (SNUT-11). Single crystal X-ray analysis demonstrates that SNUT-10 features a 2D structure with ligands and metal atoms alternated. SNUT-11 exhibits an 2D unusual double layer architecture. In addition, the fluorescence properties of coordination polymers in the solid state were also investigated at room temperature.
To explore the risk factors for breast cancer-related lymphedema (BCRL) and upper extremity dysfunction (UED) in patients with early breast cancer after modern comprehensive treatment and to compare ...the toxicity of different treatment strategies.
From 2017 to 2020, a total of 1369 female patients with pT1-3N0-1M0 breast cancer who underwent adjuvant radiotherapy in our centre were retrospectively reviewed. BCRL and UED were identified by the Norman and QuickDASH questionnaires. The incidence, severity and risk factors for BCRL and UED were evaluated.
After a median follow-up of 25 months, a total of 249 patients developed BCRL; axillary lymph node dissection (ALND), increased number of dissected nodes, right-sided and hypofractionated radiotherapy containing RNI were found to be significant risk factors (all p values < 0.05). The sentinel lymph node biopsy (SLNB)+ regional nodal irradiation (RNI) group had a significantly lower BCRL risk than the ALND + RNI group (10.8% vs. 32.5%, HR = 0.426, p = 0.020), while there was no significant difference between ALND vs. ALND + RNI or SLNB vs. SLNB + RNI. A total of 193 patients developed UED, and ALND (p = 0.02) was the only significant risk factor. The SLNB + RNI group had a significantly decreased risk of UED compared with the ALND + RNI group (7.5% vs. 23.9%, HR = 0.260, p = 0.001), and there was no significant difference between SLNB vs. SLNB + RNI or ALND vs. ALND + RNI.
Aggressive ALND remains the primary risk factor for BCRL and UED while RNI does not. Thus, replacing ALND with tailored radiotherapy would be an effective preventive strategy in early breast cancer patients.
•Our study is one of the first studies focusing on BCRL and UED among Chinese early breast cancer patients.•Aggressive ALND remains the primary risk factor for BCRL and UED.•Our study confirmed the safety of replacing ALND with SLNB + RNI.
Background
The aim of this study is to assess the clinical benefit of postoperative radiotherapy (PORT) in patients with esophageal cancer (EC) who treated with neoadjuvant chemotherapy (NAC) and ...surgery
via
a national population-based database.
Methods
Patients diagnosed with EC between 2004 and 2015 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan–Meier survival analysis was used to compare the overall survival (OS) and cause-specific survival (CSS) difference between PORT
vs
. no-radiotherapy (RT) groups before and after propensity score matching (PSM). After PSM for baseline characteristics, Cox proportional hazard regression was performed to investigate the factors associated with OS.
Results
A total of 321 patients were included in the analysis. Of them, 91 patients (28%) received PORT. In the unmatched population, the no-RT group had improved OS compared with PORT (44
vs
. 25 months, p = 0.002), and CSS was similar in patients undergoing NAC with or without PORT (42
vs
. 71 months, p = 0.17). After PSM for baseline characteristics, the OS benefit of the no-RT group over the PORT group remained significant with a median OS of 46
vs
. 27 months (p = 0.02), and CSS remained comparable between groups (83
vs
. 81 months, p = 0.49). In subgroup analyses, PORT did not improve the OS among patients with adenocarcinoma in the subgroups of cN0, cN1, and cN2–3 (all p > 0.05). In Cox regression, aged ≥71 years old, cT3–4, cN2–3, and receiving PORT were independent predictors of worse OS, whereas cT4 and cN2–3 were independent predictors of worse CSS (all p < 0.05).
Conclusions
The present study demonstrated that no survival benefit could be obtained from the additional use of PORT after NAC and surgery in patients with EC. Well-designed prospective trials are needed to confirm our findings.
Three new metal coordination polymers with different spatial structure, namely {Co2(H2O)6(4-PDCA)22·3H2O}n (SNUT-12), {Cd(H2O)2(4-PDCA)·2H2O}n (SNUT-13) and Zn2(4-PDCA)2n (SNUT-14), where ...H2(4-PDCA) = 1-(4-carboxyphenyl)-5-methyl-4-oxo-1,4-dihydropyridazine-3-carboxylic acid, were synthesized by changing the central ion with the same ligand under solvothermal and hydrothermal conditions, which were further characterized by single crystal X-ray diffraction, powder XRD, FT-IR and TGA. Single crystal X-ray analysis revealed that SNUT-12 exhibits a 1D infinite zigzag chains which were constructed by Cobalt(II) ion and 4-PDCA2− ligand, SNUT-13 features a 2D ladder-like structure. Meanwhile, SNUT-14 displays 2-fold 3D → 3D parallel interpenetrating frameworks. In addition, SNUT-12 exhibited high electrocatalytic oxygen evolution reaction, and SNUT-13, SNUT-14 showed strong fluorescence at room temperature.
The visual stimulus-specific responses in the primary visual cortex (V1) undergo plastic changes after associative learning. During the learning process, neuronal ensembles, defined as groups of ...coactive neurons, are well known to be related to learning and memory. However, it remains unclear what effect learning has on ensembles, and which neuronal subgroups within those ensembles play a key role in associative learning.
We used two-photon calcium imaging in mice to record the activity of V1 neurons before and after fear conditioning associated with a visual cue (blue light). We first defined neuronal ensembles by thresholding their functional connectivity in response to blue (conditioned) or green (control) light. We defined neurons that existed both before and after conditioning as stable neurons. Neurons which were recruited after conditioning were defined as new neurons. The graph theory-based analysis was performed to quantify the changes in connectivity within ensembles after conditioning.
A significant enhancement in the connectivity strength (the average correlation with other neurons) was observed in the blue ensembles after conditioning. We found that stable neurons within the blue ensembles showed a significantly smaller clustering coefficient (the value represented the degree of interconnectedness among a node's neighbors) after conditioning than they were before conditioning. Additionally, new neurons within the blue ensembles had a larger clustering coefficient, similar relative degree (the value represented the number of functional connections between neurons) and connectivity strength compared to stable neurons in the same ensembles.
Overall, our results demonstrated that the plastic changes caused by conditioning occurred in subgroups of neurons in the ensembles. Moreover, new neurons from conditioned ensembles may play a crucial role in memory formation, as they exhibited not only similar connection competence in relative degree and connectivity strength as stable neurons, but also showed a significantly larger clustering coefficient compared to the stable neurons within the same ensembles after conditioning.
PDF
