Safety and efficacy of fruquintinib-based therapy in patients with advanced or metastatic sarcoma.

BACKGROUND: The purpose of this study was to evaluate the efficacy and safety of fruquintinib-based therapy as a salvage therapy for patients with advanced or metastatic sarcoma, including soft tissue sarcoma (STS) and bone sarcoma. METHODS: Patients with advanced or metastatic sarcoma were divided into two groups. One group received fruquintinib monotherapy, while the other received fruquintinib combined therapy. Safety and efficacy of fruquintinib-based therapy were recorded and reviewed retrospectively, including progression-free survival (PFS), overall response rate (ORR), and adverse events (AEs). RESULTS: Between August 2021 and December 2022, 38 sarcoma patients were retrospectively included. A total of 14 patients received fruquintinib alone (including 6 STS and 8 bone sarcoma), while 24 were treated with fruquintinib combined therapy (including 2 STS and 22 bone sarcoma). The median follow-up was 10.2 months (95% CI, 6.4-11.5). For the entire population, the median PFS was 8.0 months (95% CI, 5.5-13.0). The ORR was 13.1%, while the disease control rate (DCR) was 86.8%. The univariate analysis showed that radiotherapy history (HR, 4.56; 95% CI, 1.70-12.24; p = 0.003), bone sarcoma (HR, 0.34; 95% CI, 0.14-0.87; p = 0.024), and treatment method of fruquintinib (HR, 0.36; 95% CI, 0.15-0.85; p = 0.021) were significantly associated with PFS. The multivariate analysis showed that patients without radiotherapy history were associated with a better PFS (HR, 3.71; 95% CI: 1.31-10.55; p = 0.014) than patients with radiotherapy history. Patients in combination group reported pneumothorax (8.3%), leukopenia (33.3%), thrombocytopenia (12.5%), diarrhea (4.2%), and anemia (4.2%) as the most frequent grade 3 or higher treatment-emergent AEs (TEAEs), while there was no severe TEAEs occurred in the monotherapy group. CONCLUSIONS: Fruquintinib-based therapy displayed an optimal tumor control and an acceptable safety profile in patients with advanced or metastatic sarcoma.

Alterations in Serum Lipids and Lipoproteins Induced by Neoadjuvant Chemotherapy in Patients with Osteosarcoma around the Knee Joint: A Retrospective Analysis.

OBJECTIVE: To investigate the serum lipid profiles of patients with localized osteosarcoma around the knee joint before and after neoadjuvant chemotherapy. METHODS: After retrospectively screening the data of 742 patients between January 2007 and July 2020, 50 patients aged 13 to 39 years with Enneking stage II disease were included in the study. Serum lipid levels, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), lipoprotein-α [Lp(a)], and apolipoprotein A1, B, and E (ApoA1, ApoB, and ApoE), and clinicopathological characteristics were collected before and after neoadjuvant chemotherapy. RESULTS: The mean levels of TC, TG, and ApoB were significantly increased following neoadjuvant chemotherapy (16%, 38%, and 20%, respectively, vs. pretreatment values; P<0.01). The mean levels of LDL-C and ApoE were also 19% and 16% higher, respectively (P<0.05). No correlation was found between the pretreatment lipid profile and the histologic response to chemotherapy. An increase in Lp(a) was strongly correlated with the Ki-67 index (R=0.31, P=0.023). Moreover, a trend toward longer disease-free survival (DFS) was observed in patients with decreased TG and increased LDL-C following chemotherapy, although this difference was not statistically significant (P=0.23 and P=0.24, respectively). CONCLUSION: Significant elevations in serum lipids were observed after neoadjuvant chemotherapy in patients with localized osteosarcoma. There was no prognostic significance of pretreatment serum lipid levels on histologic response to neoadjuvant chemotherapy. The scale of increase in serum Lp(a) might have a potential prognostic role in osteosarcoma. Patients with increased LDL-C or reduced TG after chemotherapy seem to exhibit a trend toward favorable DFS.

Development and validation of a nomogram for predicting in-hospital survival rates of patients with COVID-19.

Objective: Our aim was to develop and validate a nomogram for predicting the in-hospital 14-day (14 d) and 28-day (28 d) survival rates of patients with coronavirus disease 2019 (COVID-19). Methods: Clinical data of patients with COVID-19 admitted to the Renmin Hospital of Wuhan University from December 2022 to February 2023 and the north campus of Shanghai Ninth People's Hospital from April 2022 to June 2022 were collected. A total of 408 patients from Renmin Hospital of Wuhan University were selected as the training cohort, and 151 patients from Shanghai Ninth People's Hospital were selected as the verification cohort. Independent variables were screened using Cox regression analysis, and a nomogram was constructed using R software. The prediction accuracy of the nomogram was evaluated using the receiver operating characteristic (ROC) curve, C-index, and calibration curve. Decision curve analysis was used to evaluate the clinical application value of the model. The nomogram was externally validated using a validation cohort. Result: In total, 559 patients with severe/critical COVID-19 were included in this study, of whom 179 (32.02 %) died. Multivariate Cox regression analysis showed that age >80 years [hazard ratio (HR) = 1.539, 95 % confidence interval (CI): 1.027-2.306, P = 0.037], history of diabetes (HR = 1.741, 95 % CI: 1.253-2.420, P = 0.001), high APACHE II score (HR = 1.083, 95 % CI: 1.042-1.126, P < 0.001), sepsis (HR = 2.387, 95 % CI: 1.707-3.338, P < 0.001), high neutrophil-to-lymphocyte ratio (NLR) (HR = 1.010, 95 % CI: 1.003-1.017, P = 0.007), and high D-dimer level (HR = 1.005, 95 % CI: 1.001-1.009, P = 0.028) were independent risk factors for 14 d and 28 d survival rates, whereas COVID-19 vaccination (HR = 0.625, 95 % CI: 0.440-0.886, P = 0.008) was a protective factor affecting prognosis. ROC curve analysis showed that the area under the curve (AUC) of the 14 d and 28 d hospital survival rates in the training cohort was 0.765 (95 % CI: 0.641-0.923) and 0.814 (95 % CI: 0.702-0.938), respectively, and the AUC of the 14 d and 28 d hospital survival rates in the verification cohort was 0.898 (95 % CI: 0.765-0.962) and 0.875 (95 % CI: 0.741-0.945), respectively. The calibration curves of 14 d and 28 d hospital survival showed that the predicted probability of the model agreed well with the actual probability. Decision curve analysis (DCA) showed that the nomogram has high clinical application value. Conclusion: In-hospital survival rates of patients with COVID-19 were predicted using a nomogram, which will help clinicians in make appropriate clinical decisions.

Mechanism insight into the N-C polar bond and Pd-Co heterojunction for improved hydrogen evolution activity.

Constructing platinum-like materials with excellent catalytic activity and low cost has great significance for hydrogen evolution reaction (HER) during electrolysis of water. Herein, palladium nanoparticles (NPs) deposition on the surface of Co NPs using nitrogen-doped carbon (NC) as substrate, denoted as N-ZIFC/CoPd-30, are manufactured and served as HER electrocatalysts. Characterization results and density functional theory calculations validate that Pd-Co heterojunctions with NC acting as "electron donators" promote the Pd species transiting to the electron-rich state based on an efficient electron transfer mechanism, namely the N-C polar bonds induced strong metal-support interaction effect. The electron-rich Pd sites are beneficial to HER. Satisfactorily, N-ZIFC/CoPd-30 have only low overpotentials of 16, 162, and 13 mV@-10 mA cm-2 with the small Tafel slopes of 98 mV/decade, 126 mV/decade, and 72 mV/decade in pH of 13, 7, and 0, respectively. The success in fabricating N-ZIFC/CoPd opens a promising path to constructing other platinum-like electrocatalysts with high HER activity.

Effect of rmEGF combined with ELF-EMF on promoting wound healing in rats.

BACKGROUND: The process of wound healing is complex, and expediting it remains a challenge. The advantages of extremely low frequency electric and magnetic fields (ELF-EMF) are its non-invasive treatment, promotes healing and promotes myogenesis of C2C12 cells. Epidermal growth factor (EGF) is known to play a vital role in promoting wound healing, so a combination of ELF-EMF and EGF can have far-reaching significance. OBJECTIVE: To study the effect of recombinant murine epidermal growth factor (rmEGF) combined with ELF-EMF on wound healing. METHODS: Thirty-six rats were randomly divided into three groups: normal control group, EGF group, and ELF-EMF+EGF group, and a 20 mm × 20 mm dorsal wound was made. The wound healing rate of rats was calculated on the 3rd, 7th, 11th and 15th day. HE staining was used to observe the micro-morphological changes during the wound healing process. RESULTS: The wound healing rate of EGF+ELF-EMF group was better than other groups. On the 15th day of wound healing, the wounds of each group were completely healed. On the 3rd, 7th, 11th and 15th day of HE staining, the early inflammatory cell infiltration, the arrangement of fibroblasts and the number of new capillaries in the wounds of EGF+ELF-EMF group were better than those of the other groups. CONCLUSIONS: rmEGF combined with ELF-EMF significantly promotes wound healing in SD rats.

Enhancing singlet oxygen production of dioxygen activation on the carbon-supported rare-earth oxide nanocluster and rare-earth single atom catalyst to remove antibiotics.

Singlet oxygen (1O2) is extensively employed in the fields of chemical, biomedical and environmental. However, it is still a challenge to produce high- concentration 1O2 by dioxygen activation. Herein, a system of carbon-supported rare-earth oxide nanocluster and single atom catalysts (named as RE2O3/RE-C, RE=La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Sc and Y) with similar morphology, structure, and physicochemical characteristic are constructed to activate dissolved oxygen (DO) to enhance 1O2 production. The catalytic activity trends and mechanisms are revealed experimentally and are also proven by theoretical analyses and calculations. The 1O2 generation activity trend is Gd2O3/Gd-C>Er2O3/Er-C>Sm2O3/Sm-C>pristine carbon (C). More than 95.0% of common antibiotics (ciprofloxacin, ofloxacin, norfloxacin and carbamazepine) can be removed in 60 min by Gd2O3/Gd-C. Density functional theory calculations indicate that Gd2O3 nanoclusters and Gd single atoms exhibit the moderate adsorption energy of ·O2- to enhance 1O2 production. This study offers a universal strategy to enhance 1O2 production in dioxygen activation for future application and reveals the natural essence of basic mechanisms of 1O2 production via rare-earth oxide nanoclusters and rare-earth single atoms.

Mechanism insight into double S-scheme heterojunctions and atomic vacancies with tunable band structures for notably enhanced light-driven enrofloxacin decomposition.

Building narrow band gap semiconductors and fast separation of photogenerated electron-hole (e--h+) structures are of great significance for photocatalytic process. In this contribution, the CeO2-x/C3-yN4/Ce(CO3)(OH) double S-scheme heterojunctions with atomic vacancies tunable band gap (2.54 eV) have been designed and fabricated as a boost photocatalyst for enrofloxacin (ENR) photodegradation. Compared with the control samples, the experimental results indicate that the typical sample (CeO2-x/C3-yN4/Ce(CO3)(OH)-2) achieves the highest ENR photodegradation efficiency (93.6 %) in 240 min under a pH of 6, and the possible photodegradation pathways are also proposed. The superior performance is ascribed to the CeO2-x/C3-yN4/Ce(CO3)(OH) double S-scheme heterojunctions for selective recombination of photogenerated electrons with weak-reduction ability in conduction band (CB) of CeO2-x, C3-yN4 and the photogenerated holes with weak-oxidation nature in valance band (VB) of C3-yN4, Ce(CO3)(OH), which increase the retention rate of photogenerated electrons in CB of Ce(CO3)(OH) and photogenerated holes in VB of CeO2-x to degrade ENR. This is the first systematic study of CeO2-x/C3-yN4/Ce(CO3)(OH) double S-scheme heterojunctions for ENR photodegradation.

Research Progress on the Effects of Support and Support Modification on the FTO Reaction Performance of Fe-Based Catalysts.

In recent years, the non-petroleum production of light olefins has been the research focus of Fischer-Tropsch olefin synthesis (FTO). Iron-based catalysts have attracted much attention because of their low price, high catalytic activity, and wide temperature range. In this paper, traditional modification, hydrophobic modification, and amphiphobic modification of the catalyst are summarized and analyzed. It was found that traditional modification (changing the pore size and surface pH of the catalyst) will reduce the dispersion of Fe, change the active center of the catalyst, and improve the selectivity of light olefins (for example, SiO2: 32%). However, compared with functional methods, these traditional methods lead to poor stability and high carbon dioxide selectivity (for example, SiO2: 34%). Hydrophobic modification can inhibit the adsorption and retention of water molecules on the catalyst and reduce the local water pressure near the iron species in the nuclear layer, thus inhibiting the further formation of CO2 (for example, SiO2: 5%) of the WGSR. Amphiphobic modification can not only inhibit the WGSR, but also reduce the steric hindrance of the catalyst, increase the diffusion rate of olefins, and inhibit the reabsorption of olefins. Follow-up research should focus on these issues.

A pilot study of multi-antigen stimulated cell therapy-I plus camrelizumab and apatinib in patients with advanced bone and soft-tissue sarcomas.

BACKGROUND: Cell-based  immunotherapy shows the therapeutic potential in sarcomas, in addition to angiogenesis-targeted tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI). Multi-antigen stimulated cell therapy-I (MASCT-I) technology is a sequential immune cell therapy for cancer, which composes of multiple antigen-loaded dendritic cell (DC) vaccines followed by the adoptive transfer of anti-tumor effector T-cells. METHODS: In this phase 1 study, we assessed MASCT-I plus camrelizumab (an ICI against PD-1) and apatinib (a highly selective TKI targeting VEGFR2) in patients with unresectable recurrent or metastatic bone and soft-tissue sarcoma after at least one line of prior systemic therapy. One MASCT-I course consisted of 3 DC subcutaneous injections, followed by 3 active T cell infusions administered 18-27 days after each DC injection. In schedule-I group, 3 DC injections were administered with a 28-day interval in all courses; in schedule-II group, 3 DC injections were administered with a 7-day interval in the first course and with a 28-day interval thereafter. All patients received intravenous camrelizumab 200 mg every 3 weeks and oral apatinib 250 mg daily. RESULTS: From October 30, 2019, to August 12, 2021, 19 patients were enrolled and randomly assigned to schedule-I group (n = 9) and schedule-II group (n = 10). Of the 19 patients, 11 (57.9%) experienced grade 3 or 4 treatment-related adverse events. No treatment-related deaths occurred. Patients in schedule-II group showed similar objective response rate (ORR) with those in schedule-I group (30.0% versus 33.3%) but had higher disease control rate (DCR; 90.0% versus 44.4%) and longer median progression-free survival (PFS; 7.7 versus 4.0 months). For the 13 patients with soft-tissue sarcomas, the ORR was 30.8%, DCR was 76.9%, and median PFS was 12.9 months; for the 6 patients with osteosarcomas, the ORR was 33.3%, the DCR was 50.0%, and median PFS was 5.7 months. CONCLUSIONS: Overall, MASCT-I plus camrelizumab and apatinib was safe and showed encouraging efficacy in advanced bone and soft-tissue sarcoma, and schedule-II administration method was recommended. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04074564.

Bcl-2 Antagonist Obatoclax Reactivates Latent HIV-1 via the NF-κB Pathway and Induces Latent Reservoir Cell Apoptosis in Latently Infected Cells.

The implementation of combined antiretroviral therapy (cART) has rendered HIV-1 infection clinically manageable and efficiently improves the quality of life for patients with AIDS. However, the persistence of a latent HIV-1 reservoir is a major obstacle to achieving a cure for AIDS. A "shock and kill" strategy aims to reactivate latent HIV and then kill it by the immune system or cART drugs. To date, none of the LRA candidates has yet demonstrated effectiveness in achieving a promising functional cure. Interestingly, the phosphorylation and activation of antiapoptotic Bcl-2 protein induce resistance to apoptosis during HIV-1 infection and the reactivation of HIV-1 latency in central memory CD4+ T cells from HIV-1-positive patients. Therefore, a Bcl-2 antagonist might be an effective LRA candidate for HIV-1 cure. In this study, we reported that a pan-Bcl-2 antagonist obatoclax induces HIV-1 reactivation in latently infected cell lines in vitro and in PBMCs/CD4+ T cells of HIV-infected individuals ex vivo. Obatoclax promotes HIV-1 transcriptional initiation and elongation by regulating the NF-κB pathway. Obatoclax activates caspase 8 and does not induce the phosphorylation of the antiapoptotic protein Bcl-2 in latent HIV-1 infected cell lines. More importantly, it preferentially induces apoptosis in latently infected cells. In addition, obatoclax exhibited potent anti-HIV-1 activity on target cells. The abilities to reactivate latent HIV-1 reservoirs, inhibit HIV-1 infection, and induce HIV-1 latent cell apoptosis make obatoclax worth investigating for development as an ideal LRA for use in the "shock and kill" approach.

Preparation of Yb-Sb co-doped Ti/SnO2 electrode for electrocatalytic degradation of sulfamethoxazole (SMX).

To efficiently break down residual sulfonamide antibiotics in environmental water, Yb-Sb co-doped Ti/SnO2 electrodes were fabricated using a solvothermal method. The effect of different amounts of Yb doping on the properties of the electrodes was studied. When the atom ratio of Sn: Yb is 100 : 7.5 in the preparation, the as-obtained coral-like electrodes (denoted as Yb 7.5%) possessed the smallest diameter of spherical particles on the surfaces, to result in the denser surface, highest electrocatalytic activity and smallest resistance of the electrode. As anode for electrocatalytic degradation of sulfamethoxazole, the Yb 7.5% electrode showed a degradation rate of 92% in 90 min, which was much higher than that of Yb 0% electrode (62.7% degradation rate). The electrocatalytic degradation of sulfamethoxazole was investigated with varying current densities and initial concentrations. Results indicated that the degradation process followed pseudo-first-order kinetics, and the degradation rate constants for Yb 7.5% and Yb 0% electrodes were 0.0278 min-1 and 0.0114 min-1, respectively. Furthermore, the service life of Ti/SnO2 electrodes was significantly improved after Yb doping, as demonstrated by accelerated life testing. Yb 7.5% exhibited a service life that was 2.7 times longer than that of Yb 0%. This work offers a new approach to construct Yb-Sb co-doped Ti/SnO2 electrodes with excellent electrooxidation activity and high stability for the electrochemical oxidation degradation of sulfamethoxazole.

Development and Validation of a Nomograph Model for Post-Operative Central Nervous System Infection after Craniocerebral Surgery.

PURPOSE: A nomograph model of predicting the risk of post-operative central nervous system infection (PCNSI) after craniocerebral surgery was established and validated. METHODS: The clinical medical records of patients after cranial surgery in Renmin Hospital of Wuhan University from January 2020 to September 2022 were collected, of whom 998 patients admitted to Shouyi Hospital District were used as the training set and 866 patients admitted to Guanggu Hospital District were used as the validation set. Lasso regression was applied to screen the independent variables in the training set, and the model was externally validated in the validation set. RESULTS: A total of 1864 patients after craniocerebral surgery were included in this study, of whom 219 (11.75%) had PCNSI. Multivariate logistic regression analysis showed that age > 70 years, a previous history of diabetes, emergency operation, an operation time ≥ 4 h, insertion of a lumbar cistern drainage tube ≥ 72 h, insertion of an intracranial drainage tube ≥ 72 h, intraoperative blood loss ≥ 400 mL, complicated with shock, postoperative albumin ≤ 30 g/L, and an ICU length of stay ≥ 3 days were independent risk factors for PCNSI. The area under the curve (AUC) of the training set was 0.816 (95% confidence interval (95%CI), 0.773-0.859, and the AUC of the validation set was 0.760 (95%CI, 0.715-0.805). The calibration curves of the training set and the validation set showed p-values of 0.439 and 0.561, respectively, with the Hosmer-Lemeshow test. The analysis of the clinical decision curve showed that the nomograph model had high clinical application value. CONCLUSION: The nomograph model constructed in this study to predict the risk of PCNSI after craniocerebral surgery has a good predictive ability.

Dopamine modified natural glucomannan as a highly efficient inhibitor for mild steel: Experimental and theoretical methods.

In this work, Glucomannan was modified with dopamine to synthesize a new polysaccharide Schiff base (GAD). After confirmation of GAD by NMR and FT-IR spectroscopic methods, it was introduced as a sustainable corrosion inhibitor with excellent anti-corrosion action for mild steel in 0.5 M hydrochloric acid (HCl) solution. Employing electrochemical test, morphology measurement, and theoretical analysis, the anticorrosion performance of GAD on mild steel in 0.5 M HCl solution is determined. Maximum efficiency of GAD for suppressing the corrosion rate of mild steel at 0.12 g L-1 reaches 99.0 %. After immersion in HCl solution for 24 h, the results from scanning electron microscopy indicate that GAD is firmly attached to the mild steel surface by making a protective layer. According to the X-ray photoelectron spectroscopy (XPS), FeN bonds existed on the steel surface indicate the presence of chemisorption between GAD and Fe to form stable complexes attracted to the active position on the mild steel. The effects of Schiff base groups on the corrosion inhibition efficiencies were also investigated. Moreover, the inhibition mechanism of GAD was further illustrated by the free Gibbs energy, quantum chemical calculation and molecular dynamics simulation.

Activation of the IL-17/TRAF6/NF-κB pathway is implicated in Aß-induced neurotoxicity.

BACKGROUND: Neuroinflammation plays a critical role in Amyloid-ß (Aß) pathophysiology. The cytokine, interleukin-17A (IL-17) is involved in the learning and memory process in the central nervous system and its level was reported to be increased in Alzheimer's disease (AD) brain, while the effect of IL-17 on the course of Aß has not been well defined. METHODS: Here, we used APP/PS1 mice to detect the IL-17 expression level. Primary hippocampal neurons were treated with IL-17, and immunofluorescence was used to investigate whether IL-17 induced neuron damage. At the same time, male C57BL/6 mice were injected with Aß42 to mimic the Aß model. Then IL-17 neutralizing antibody (IL-17Ab) was used to inject into the lateral ventricle, and the Open field test, Novel Objective Recognition test, Fear condition test were used to detect cognitive function. LTP was used to assess synaptic plasticity, molecular biology technology was used to assess the IL-17/TRAF6/NF-κB pathway, and ELISA was used to detect inflammatory factors. RESULTS: Altogether, we here found that IL-17 was increased in APP/PS1 mice, and it induced neural damage by the administration to primary hippocampal neurons. Interestingly, Using Aß42 mice, the results showed that the level of IL-17 was increased in Aß42 model mice, and IL-17Ab could ameliorate Aß-induced neurotoxicity and cognitive decline in C57BL/6 mice by downregulation the TRAF6/NF-κB pathway. CONCLUSION: These findings highlight the pathogenic role of IL-17 in Aß induced-synaptic dysfunction and cognitive deficits. Inhibition of IL-17 could ameliorate Aß-induced neurotoxicity and cognitive decline in C57BL/6 mice by downregulation of the TRAF6/NF-κB pathway, which provides new clues for the mechanism of Aß-induced cognitive impairments, and a basis for therapeutic intervention.

In-depth characterization of protein N-glycosylation for a COVID-19 variant-design vaccine spike protein.

COVID-19 is caused by SARS-CoV-2 infection and remains one of the biggest pandemics around the world since 2019. Vaccination has proved to be an effective way of preventing SARS-CoV-2 infection and alleviating the hospitalization burden. Among different forms of COVID-19 vaccine design, the spike protein of SARS-CoV-2 virus is widely used as a candidate vaccine antigen. As a surface protein on the virus envelop, the spike was reported to be heavily N-glycosylated and glycosylation had a great impact on its immunogenicity and efficacy. Besides, N-glycosylation might vary greatly on different expression systems and sequence variant designs. Therefore, comprehensive analysis of spike N-glycosylation is of great significance for better vaccine understanding and quality control. In this study, full characterization of N-glycosylation was performed for a Chinese Hamster Ovary (CHO) cell expressed variant-designed spike protein. The spike protein featured the latest six-proline substitution design together with the incorporation of a combination of mutation sites. Trypsin and Glu-C digestion coupled with PNGase F strategies were adopted, and effective LC-MS/MS methods were applied to analyze samples. As a result, a total of 19 N-glycosites were identified in the recombinant pike protein at intact N-glycopeptide level. Quantitative analysis of released glycan by LC-MS/MS was also performed, and 31 high-abundance N-glycans were identified. Sequencing analysis of glycan was further provided to assist glycan structure confirmation. Moreover, all of the analyses were performed on three consecutive manufactured batches and the glycosylation results on both glycosite and glycans showed good batch-to-batch consistency. Thus, the reported analytical strategy and N-glycosylation information may well facilitate studies on SARS-CoV-2 spike protein analysis and quality studies.

First-in-Maintenance Therapy for Localized High-Grade Osteosarcoma: An Open-Label Phase I/II Trial of the Anti-PD-L1 Antibody ZKAB001.

PURPOSE: We investigated the safety and preliminary efficacy of anti-PD-L1 antibody (ZKAB001) as maintenance therapy for localized patients with high-grade osteosarcoma to reduce the risk of recurrence and metastasis. PATIENTS AND METHODS: This open-label Phase I/II study was divided into dose-escalation Phase I and expansion Phase II. Phase I used a 3+3 design with ZKAB001 at three escalating doses ranging: 5, 10, 15 mg/kg every 2 weeks in 9 patients with localized high-grade osteosarcoma and Phase II tested 10 mg/kg in 12 patients for up to 24 cycles. Primary endpoints were safety and tolerability assessed using CTCAE4.0.3. RESULTS: Between October 2018 and 2019, 21 eligible patients were enrolled and accepted ZKAB001 treatment: 9 in the dose-escalation phase, and 12 in expansion phase. Six patients with disease progression withdrew from this study and follow-up is ongoing. The MTD was not defined in Phase I. All doses had a manageable safety profile. The recommended dose in Phase II was set at 10 mg/kg. Most frequent immune-related adverse events were thyroiditis (76.2%) and dermatitis (42.9%). Only 1 (4.8%) of 21 patients had a Grade 3 skin rash. The median 3-year event-free survival (EFS) and overall survival (OS) were not established; however, 24-month EFS was 71.4% (95% confidence interval, 47.2-86.0) and 2-year OS was 100%. Preliminary efficacy data showed EFS benefits in patients with PD-L1 positive or an MSI-H sub-population. CONCLUSIONS: Switching to maintenance using ZKAB001 showed an acceptable safety profile and provided preliminary evidence of clinical activity in localized patients with osteosarcoma.

A potent, broadly protective vaccine against SARS-CoV-2 variants of concern.

Since the first outbreak in December 2019, SARS-CoV-2 has been constantly evolving and five variants have been classified as Variant of Concern (VOC) by the World Health Organization (WHO). These VOCs were found to enhance transmission and/or decrease neutralization capabilities of monoclonal antibodies and vaccine-induced antibodies. Here, we successfully designed and produced a recombinant COVID-19 vaccine in CHO cells at a high yield. The vaccine antigen contains four hot spot substitutions, K417N, E484K, N501Y and D614G, based on a prefusion-stabilized spike trimer of SARS-CoV-2 (S-6P) and formulated with an Alum/CpG 7909 dual adjuvant system. Results of immunogenicity studies showed that the variant vaccine elicited robust cross-neutralizing antibody responses against SARS-CoV-2 prototype (Wuhan) strain and all 5 VOCs. It further, stimulated a TH1 (T Helper type 1) cytokine profile and substantial CD4+ T cell responses in BALB/c mice and rhesus macaques were recorded. Protective efficacy of the vaccine candidate was evaluated in hamster and rhesus macaque models of SARS-CoV-2. In Golden Syrian hamsters challenged with Beta or Delta strains, the vaccine candidate reduced the viral loads in nasal turbinates and lung tissues, accompanied by significant weight gain and relieved inflammation in the lungs. In rhesus macaque challenged with prototype SARS-CoV-2, the vaccine candidate decreased viral shedding in throat, anal, blood swabs over time, reduced viral loads of bronchus and lung tissue, and effectively relieved the lung pathological inflammatory response. Together, our data demonstrated the broadly neutralizing activity and efficacy of the variant vaccine against both prototype and current VOCs of SARS-CoV-2, justifying further clinical development.

Identification of phytochemicals in Qingfei Paidu decoction for the treatment of coronavirus disease 2019 by targeting the virus-host interactome.

Qingfei Paidu decoction (QFPDD) has been clinically proven to be effective in the treatment of coronavirus disease 2019 (COVID-19). However, the bioactive components and therapeutic mechanisms remain unclear. This study aimed to explore the effective components and underlying mechanisms of QFPDD in the treatment of COVID-19 by targeting the virus-host interactome and verifying the antiviral activities of its active components in vitro. Key active components and targets were identified by analysing the topological features of a compound-target-pathway-disease regulatory network of QFPDD for the treatment of COVID-19. The antiviral activity of the active components was determined by a live virus infection assay, and possible mechanisms were analysed by pseudotyped virus infection and molecular docking assays. The inhibitory effects of the components tested on the virus-induced release of IL-6, IL-1ß and CXCL-10 were detected by ELISA. Three components of QFPDD, oroxylin A, hesperetin and scutellarin, exhibited potent antiviral activities against live SARS-CoV-2 virus and HCoV-OC43 virus with IC50 values ranging from 18.68 to 63.27 µM. Oroxylin A inhibited the entry of SARS-CoV-2 pseudovirus into target cells and inhibited SARS-CoV-2 S protein-mediated cell-cell fusion by binding with the ACE2 receptor. The active components of QFPDD obviously inhibited the IL-6, IL-1ß and CXCL-10 release induced by the SARS-CoV-2 S protein. This study supports the clinical application of QFPDD and provides an effective analysis method for the in-depth study of the mechanisms of traditional Chinese medicine (TCM) in the prevention and treatment of COVID-19.

Construction and Validation of Mortality Risk Nomograph Model for Severe/Critical Patients with COVID-19.

Objective: A nomograph model of mortality risk for patients with coronavirus disease 2019 (COVID-19) was established and validated. Methods: We collected the clinical medical records of patients with severe/critical COVID-19 admitted to the eastern campus of Renmin Hospital of Wuhan University from January 2020 to May 2020 and to the north campus of Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, from April 2022 to June 2022. We assigned 254 patients to the former group, which served as the training set, and 113 patients were assigned to the latter group, which served as the validation set. The least absolute shrinkage and selection operator (LASSO) and multivariable logistic regression were used to select the variables and build the mortality risk prediction model. Results: The nomogram model was constructed with four risk factors for patient mortality following severe/critical COVID-19 (≥3 basic diseases, APACHE II score, urea nitrogen (Urea), and lactic acid (Lac)) and two protective factors (percentage of lymphocyte (L%) and neutrophil-to-platelets ratio (NPR)). The area under the curve (AUC) of the training set was 0.880 (95% confidence interval (95%CI), 0.837~0.923) and the AUC of the validation set was 0.814 (95%CI, 0.705~0.923). The decision curve analysis (DCA) showed that the nomogram model had high clinical value. Conclusion: The nomogram model for predicting the death risk of patients with severe/critical COVID-19 showed good prediction performance, and may be helpful in making appropriate clinical decisions for high-risk patients.