Publications by authors named "Yongxiang Zhao"

151 Publications

Yolk-Shell Nanocapsule Catalysts as Nanoreactors with Various Shell Structures and Their Diffusion Effect on the CO Reforming of Methane.

ACS Appl Mater Interfaces 2021 Jul 30;13(27):31699-31709. Epub 2021 Jun 30.

Engineering Research Center of the Ministry of Education for Fine Chemicals, Shanxi University, Taiyuan 030006, P. R. China.

Well-geometric-confined yolk-shell catalysts can act as nanoreactors that are of benefit for the antisintering of metals and resistance to coke formation in high-temperature reactions such as the CO reforming of methane. Notwithstanding the credible advances of core/yolk-shell catalysts, the enlarged shell diffusion effects that occur under high space velocity can deactivate the catalysts and hence pose a hurdle for the potential application of these types of catalysts. Here, we demonstrated the importance of the shell thickness and porosity of small-sized [email protected] nanoreactor catalysts, which can vary the diffusional paths/rates of the diffusants that directly affect the catalytic activity. The nanoreactor with an ∼4.5 nm shell thickness and rich pores performed the best in tolerating the shell diffusion effects, and importantly, no catalytic deactivation was observed. We further proposed a shell diffusion effect scheme by modifying the Weisz-Prater and blocker model and found that the "gas wall/hard blocker" formed on the openings of the shell pores can cause reversible/irreversible interruption of the shell mass transfer and thus temporarily/permanently deactivate the nanoreactor catalysts. This work highlights the shell diffusion effects, apart from the metal sintering and coke formation, as an important factor that are ascribed to the deactivation of a nanoreactor catalyst.
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http://dx.doi.org/10.1021/acsami.1c06847DOI Listing
July 2021

Application of Molecular Nanoprobes in the Analysis of Differentially Expressed Genes and Prognostic Models of Primary Hepatocellular Carcinoma.

J Biomed Nanotechnol 2021 Jun;17(6):1020-1033

National Center for International Research of Biotargeting Theranostics, Guangxi Key Laboratory of Biotargeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Biotargeting Theranostics, Guangxi Medical University, Nanning, 530021, China.

Analyzing hub genes related to tumorigenesis based on biological big data has recently become a hotspot in biomedicine. Nanoprobes, nanobodies and theranostic molecules targeting hub genes delivered by nanocarriers have been widely applied in tumor theranostics. Hepatocellular carcinoma (HCC) is one of the most common cancers, with a poor prognosis and high mortality. Identifying hub genes according to the gene expression levels and constructing prognostic signatures related to the onset and outcome of HCC will be of great significance. In this study, the expression profiles of HCC and normal tissue were obtained from the GEO database and analyzed by GEO₂R to identify DEGs. GO terms and KEGG pathways were enriched in DAVID software. The STRING database was consulted to find protein-protein interactions between proteins encoded by the DEGs, which were visualized by Cytoscape. Then, overall survival associated with the hub genes was calculated by the Kaplan-Meier plotter online tool, and verification of the results was carried out on TCGA samples and their corresponding clinical information. A total of 603 DEGs were obtained, of which 479 were upregulated and 124 were downregulated. PPI networks including 603 DEGs and 18 clusters were constructed, of which 7 clusters with MCODE score ≥3 and nodes ≥5 were selected. The 5 genes with the highest degrees of connectivity were identified as hub genes, and a prognostic model was constructed. The expression and prognostic potential of this model was validated on TCGA clinical data. In conclusion, a five-gene signature (TOP2A, PCNA, AURKA, CDC20, CCNB2) overexpressed inHCC was identified, and a prognostic model was constructed. This gene signature may act as a prognostic model for HCC and provide potential targets of nanotechnology.
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http://dx.doi.org/10.1166/jbn.2021.3098DOI Listing
June 2021

Extensively sparse C labeling to simplify solid-state NMR C spectra of membrane proteins.

J Biomol NMR 2021 Jul 20;75(6-7):245-254. Epub 2021 Jun 20.

National Center for Magnetic Resonance in Wuhan, Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan, 430071, People's Republic of China.

Solid-state Nuclear Magnetic Resonance (ssNMR) is an emerging technique to investigate the structures and dynamics of membrane proteins in an artificial or native membrane environment. However, the structural studies of proteins by ssNMR are usually prolonged or impeded by signal assignments, especially the assignments of signals for collection of distance restraints, because of serious overlapping of signals in 2D C-C spectra. Sparse labeling of C spins is an effective approach to simplify the C spectra and facilitate the extractions of distance restraints. Here, we propose a new reverse labeling combination of six types of amino acid residues (Ile, Leu, Phe, Trp, Tyr and Lys), and show a clean reverse labeling effect on a model membrane protein E. coli aquaporin Z (AqpZ). We further combine this reverse labeling combination and alternate C-C labeling, and demonstrate an enhanced dilution effect in C-C spectra. In addition, the influences of reverse labeling on the labeling of the other types of residues are quantitatively analyzed in the two strategies (1, reverse labeling and 2, reverse labeling combining alternate C-C labeling). The signal intensities of some other types of residues in 2D C-C spectra are observed to be 20-50% weaker because of the unwanted reverse labeling. The extensively sparse C labeling proposed in this study is expected to be useful in the collection of distance restraints using 2D C-C spectra of membrane proteins.
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http://dx.doi.org/10.1007/s10858-021-00372-yDOI Listing
July 2021

The Impact of TRPV1 on Cancer Pathogenesis and Therapy: A Systematic Review.

Int J Biol Sci 2021 11;17(8):2034-2049. Epub 2021 May 11.

Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University International Cancer Center, Department of Cell Biology and Genetics, School of Medicine, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518055, China.

The transient receptor potential cation channel subfamily V member 1 (TRPV1) is a transmembrane protein that can be activated by various physical and chemical stimuli and is associated with pain transduction. In recent years, TRPV1 was discovered to play essential roles in cancer tumorigenesis and development, as TRPV1 expression levels are altered in numerous cancer cell types. Several investigations have discovered direct associations between TRPV1 and cancer cell proliferation, cell death, and metastasis. Furthermore, about two dozen TRPV1 agonists/antagonists are under clinical trial, as TRPV1 is a potential drug target for treating various diseases. Hence, more researchers are focusing on the effects of TRPV1 agonists or antagonists on cancer tumorigenesis and development. However, both agonists and antagonists may reveal anti-cancer effects, and the effect may function via or be independent of TRPV1. In this review, we provide an overview of the impact of TRPV1 on cancer cell proliferation, cell death, and metastasis, as well as on cancer therapy and the tumor microenvironment, and consider the implications of using TRPV1 agonists and antagonists for future research and potential therapeutic approaches.
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http://dx.doi.org/10.7150/ijbs.59918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193258PMC
May 2021

Identification of SARS-CoV-2-against aptamer with high neutralization activity by blocking the RBD domain of spike protein 1.

Signal Transduct Target Ther 2021 06 10;6(1):227. Epub 2021 Jun 10.

School of Life Science; Advanced Research Institute of Multidisciplinary Science; Institute of Engineering Medicine; Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, Beijing, China.

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http://dx.doi.org/10.1038/s41392-021-00649-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190169PMC
June 2021

Co-infection analysis of bacterial and viral respiratory pathogens from clinically healthy swine in Eastern China.

Vet Med Sci 2021 May 25. Epub 2021 May 25.

Institute of Veterinary Medicine, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Jiangsu Academy of Agricultural Sciences, Nanjing, China.

Porcine respiratory disease complex (PRDC) is one of the most challenging health concerns for pig production worldwide. The aim of the present study was to determine the prevalence of pathogens associated with PRDC, including porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2) and bacterial agents, such as Streptococcus suis, Haemophilus parasuis and Actinobacillus pleuropneumoniae, in clinically healthy pigs in Eastern China. Molecular detection revealed positive single-pathogen detection rates of 59.9%, 27.2%, 52.3%, 33.2% and 0.4% for PCV2, PRRSV, S. suis, H. parasuis and A. pleuropneumoniae, respectively. Co-infection with more than one pathogen was frequently detected in these samples, with PCV2/S. suis, H. parasuis and PCV2/H. parasuis mixed infection rates of 35.4%, 33.2% and 21.6%, respectively, and PCV2/S. suis/H. parasuis and PRRSV/PCV2/S. suis co-infection rates of 21.6% and 6.2%, respectively. These results suggest that mixed infections are prevalent among PRDC cases in swine, which may pose a greater threat to the health of herds compared with single-pathogen infections.
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http://dx.doi.org/10.1002/vms3.533DOI Listing
May 2021

Human endoglin-CD3 bispecific T cell engager antibody induces anti-tumor effect .

Theranostics 2021 19;11(13):6393-6406. Epub 2021 Apr 19.

Department of Oncology, The First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, China.

Endoglin, also known as CD105, is a homo-dimeric membrane glycoprotein required for angiogenesis and serves as a marker for cancer vasculature. In this study, we constructed a bispecific T-cell engager (BiTE) antibody that targets human endoglin and CD3 (hEND-CD3/BiTE). We examined BiTE binding to endoglin-expressing cells and its effects on the cytolytic activity of T cells and cancer development. The effects of hEND-CD3/BiTE, including binding to target cells, T-cell activation, proliferation, and cytotoxicity, were examined in endoglin-expressing 293T cells, human umbilical vascular endothelial cells, tumor-derived endothelial cells, and CD3 T cells. An xenograft tumor model was established using A549 human lung cancer cells. The therapeutic efficacy of hEND-CD3/BiTE was assessed by monitoring tumor growth, angiogenesis, and mouse survival. hEND-CD3/BiTE specifically bound to endoglin-expressing cells and CD3 T cells and stimulated T-cell activation, proliferation, and Th1 cytokine secretion, and promoted T-cell-mediated cytolysis of endoglin-expressing cells. The hEND-CD3/BiTE caused minimal toxicity to major organs, reduced tumor neoangiogenesis, inhibited tumor growth, and significantly improved mouse survival. Our study demonstrated the therapeutic potential of hEND-CD3/BiTE and provided a novel approach to clinical cancer treatment.
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http://dx.doi.org/10.7150/thno.53121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120215PMC
April 2021

Fluid and White Matter Suppression Imaging and Voxel-Based Morphometric Analysis in Conventional Magnetic Resonance Imaging-Negative Epilepsy.

Front Neurol 2021 29;12:651592. Epub 2021 Apr 29.

Beijing Institute of Functional Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China.

Delineation of subtle lesions in magnetic resonance imaging (MRI)-negative patients is of great importance in preoperative epilepsy evaluation. The aim of our study was to explore the diagnostic value of the novel fluid and white matter suppression (FLAWS) sequence in comparison with a voxel-based MRI postprocessing morphometric analysis program (MAP) in a consecutive cohort of non-lesional patients. Surgical candidates with a negative finding on an official neuroradiology report were enrolled. High-resolution FLAWS image and MAP maps generated based on high-resolution three-dimensional (3D) T1 image were visually inspected for each patient. The findings of FLAWS or MAP-positive (FLAWS/MAP+) regions were compared with the surgical resection cavity in correlation with surgical outcome and pathology. Forty-five patients were enrolled; the pathological examination revealed focal cortical dysplasia (FCD) in 32 patients and other findings in 13 patients. The positive rate, sensitivity, and specificity were 48.9%, 0.43, and 0.87, respectively, for FLAWS and 64.4%, 0.57, and 0.8, respectively, for MAP. Concordance between surgical resection and FLAWS+ or MAP+ regions was significantly associated with a seizure-free outcome (FLAWS: = 0.002; MAP: = 0.0003). A positive finding in FLAWS and MAP together with abnormalities in the same gyrus (FLAWS-MAP gyral+) was detected in 31.1% of patients. FLAWS+ only and MAP+ only were found in 7 (15.5%) and 14 (31.1%) patients, respectively. FLAWS showed a promising value for identifying subtle epileptogenic lesions and can be used as a complement to current MAP in patients with MRI-negative epilepsy.
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http://dx.doi.org/10.3389/fneur.2021.651592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116947PMC
April 2021

Advances in the Study of Antitumour Immunotherapy for Newcastle Disease Virus.

Int J Med Sci 2021 30;18(11):2294-2302. Epub 2021 Mar 30.

National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, Guangxi, China.

This article reviews the preclinical research, clinical application and development of Newcastle disease virus (NDV) in the field of cancer therapy. Based on the distinctive antitumour properties of NDV and its positive interaction with the patient's immune system, this biologic could be considered a major breakthrough in cancer treatment. On one hand, NDV infection creates an inflammatory environment in the tumour microenvironment, which can directly activate NK cells, monocytes, macrophages and dendritic cells and promote the recruitment of immune cells. On the other hand, NDV can induce the upregulation of immune checkpoint molecules, which may break immune tolerance and immune checkpoint blockade resistance. In fact, clinical data have shown that NDV combined with immune checkpoint blockade can effectively enhance the antitumour response, leading to the regression of local tumours and distant tumours when injected, and this effect is further enhanced by targeted manipulation and modification of the NDV genome. At present, recombinant NDV and recombinant NDV combined with immune checkpoint blockers have entered different stages of clinical trials. Based on these studies, further research on NDV is warranted.
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http://dx.doi.org/10.7150/ijms.59185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100649PMC
March 2021

Spectral editing of alanine, serine, and threonine in uniformly labeled proteins based on frequency-selective homonuclear recoupling in solid-state NMR.

J Biomol NMR 2021 May 22;75(4-5):193-202. Epub 2021 Apr 22.

State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Innovation Academy for Precision Measurement Science and Technology, National Center for Magnetic Resonance in Wuhan, Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, 430071, P. R. China.

Spectral editing is crucial to simplify the crowded solid-state NMR spectra of proteins. New techniques are introduced to edit C-C correlations of uniformly labeled proteins under moderate magic-angle spinning (MAS), based on our recent frequency-selective homonuclear recoupling sequences [Zhang et al., J. Phys. Chem. Lett. 2020, 11, 8077-8083]. The signals of alanine, serine, or threonine residues are selected out by selective Cα-Cβ double-quantum filtering (DQF). The Cα-Cβ correlations of alanine residues are selectively established with efficiency up to ~ 1.8 times that by dipolar-assisted rotational resonance (DARR). The techniques are shown in 2D/3D NCCX experiments and applied to the uniformly C, N labeled Aquaporin Z (AqpZ) membrane protein, demonstrating their potential to simplify spectral analyses in biological solid-state NMR.
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http://dx.doi.org/10.1007/s10858-021-00367-9DOI Listing
May 2021

Exploring the Relationship between Gray and White Matter in Healthy Adults: A Hybrid Research of Cortical Reconstruction and Tractography.

Biomed Res Int 2021 11;2021:6628506. Epub 2021 Mar 11.

Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.

The gray matter (GM) and white matter (WM) are structurally and functionally related in the human brain. Among the numerous neuroimaging studies, yet only a few have investigated these two structures in the same sample. So, there is limited and inconsistent information about how they are correlated in the brain of healthy adults. In this study, we combined cortical reconstruction with diffusion spectrum imaging (DSI) tractography to investigate the relationship between cortical morphology and microstructural properties of major WM tracts in 163 healthy young adults. The results showed that cortical thickness (CTh) was positively correlated with the coherent tract-wise fractional anisotropy (FA) value, and the correlation was stronger in the dorsal areas than in the ventral areas. For other diffusion parameters, CTh was positively correlated with axial diffusivity (AD) of coherent fibers in the frontal areas and negatively correlated with radial diffusivity (RD) of coherent fibers in the dorsal areas. These findings suggest that the correlation between GM and WM is inhomogeneity and could be interpreted with different mechanisms in different brain regions. We hope our research could provide new insights into the studies of diseases in which the GM and WM are both affected.
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http://dx.doi.org/10.1155/2021/6628506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979294PMC
May 2021

Exploiting the acquired vulnerability of cisplatin-resistant tumors with a hypoxia-amplifying DNA repair-inhibiting (HYDRI) nanomedicine.

Sci Adv 2021 Mar 26;7(13). Epub 2021 Mar 26.

Laboratory of Controllable Nanopharmaceuticals, Chinese Academy of Sciences (CAS) Center for Excellence in Nanoscience and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, P. R. China.

Various cancers treated with cisplatin almost invariably develop drug resistance that is frequently caused by substantial DNA repair. We searched for acquired vulnerabilities of cisplatin-resistant cancers to identify undiscovered therapy. We herein found that cisplatin resistance of cancer cells comes at a fitness cost of increased intracellular hypoxia. Then, we conceived an inspired strategy to combat the tumor drug resistance by exploiting the increased intracellular hypoxia that occurs as the cells develop drug resistance. Here, we constructed a hypoxia-amplifying DNA repair-inhibiting liposomal nanomedicine (denoted as HYDRI NM), which is formulated from a platinum(IV) prodrug as a building block and payloads of glucose oxidase (GOx) and hypoxia-activatable tirapazamine (TPZ). In studies on clinically relevant models, including patient-derived organoids and patient-derived xenograft tumors, the HYDRI NM is able to effectively suppress the growth of cisplatin-resistant tumors. Thus, this study provides clinical proof of concept for the therapy identified here.
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http://dx.doi.org/10.1126/sciadv.abc5267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997498PMC
March 2021

Oncolytic adenovirus: A tool for reversing the tumor microenvironment and promoting cancer treatment (Review).

Oncol Rep 2021 04 24;45(4). Epub 2021 Mar 24.

National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China.

Immunogene therapy can enhance the antitumor immune effect by introducing genes encoding co‑stimulation molecules, cytokines, chemokines and tumor‑associated antigens into treatment cells or human cells through genetic engineering techniques. Oncolytic viruses can specifically target tumor cells and replicate indefinitely until they kill tumor cells. If combined with immunogene therapy, oncolytic viruses can play a more powerful antitumor role. The high pressure, hypoxia and acidity in the tumor microenvironment (TME) provide suitable conditions for tumor cells to survive. To maximize the potency of oncolytic viruses, various methods are being developed to promote the reversal of the TME, thereby maximizing transmission of replication and immunogenicity. The aim of the present review was to discuss the basic mechanisms underlying the effects of oncolytic adenoviruses on the TME, and suggest how to combine the modification of the adenovirus with the TME to further combat malignant tumors.
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http://dx.doi.org/10.3892/or.2021.8000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934214PMC
April 2021

Current strategies of virotherapy in clinical trials for cancer treatment.

J Med Virol 2021 Aug 23;93(8):4668-4692. Epub 2021 Apr 23.

National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, China.

As a novel immune-active agent for cancer treatment, viruses have the ability of infecting and replicating in tumor cells. The safety and efficacy of viruses has been tested and confirmed in preclinical and clinical trials. In the last decade, virotherapy has been adopted as a monotherapy or combined therapy with immunotherapy, chemotherapy, or radiotherapy, showing promising outcomes against cancer. In this review, the current strategies of viruses used in clinical trials are classified and described. Besides this, the challenge and future prospects of virotherapy in the management for cancer patients are discussed in this review.
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http://dx.doi.org/10.1002/jmv.26947DOI Listing
August 2021

Antigen-Presenting Hybrid Colloidal Crystal Clusters for Promoting T cells Expansion.

Small 2021 04 12;17(14):e2006955. Epub 2021 Mar 12.

Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China.

T cell based-immunotherapy has been a powerful strategy to eradicate tumor cells in clinical trials. Effectively expanding the therapeutic T cells for clinical demand is still a challenge. Here, artificial antigen-presenting scaffolds are created for T cell ex vivo expansion. The antigen-presenting hybrid colloidal crystal clusters (HCCCs) with multiple stimuli are generated by internal encapsulation with prosurvival cytokines and surface decoration with activating antibodies to CD3ε and CD28, respectively. With the large loading capacity endowed by their abundant nanoporous structures, the antigen-presenting HCCCs can constantly release prosurvival cytokine IL-2. It is found that following the direct and multiple stimulations, the antigen-presenting HCCCs can effectively promote the expansion of T cells, which exhibits robust antitumor activity in vitro. Thus, the antigen-presenting HCCCs provide a novel expansion platform for clinical manufacturing of T cells.
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http://dx.doi.org/10.1002/smll.202006955DOI Listing
April 2021

The predictive effect of the platelet-to-lymphocyte ratio (PLR) and the neutrophil-to-lymphocyte ratio (NLR) on the risk of death in patients with severe fever with thrombocytopenia syndrome (SFTS): a multi-center study in China.

Ann Transl Med 2021 Feb;9(3):208

Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University. Beijing, China.

Background: Severe fever with thrombocytopenia syndrome is caused by infection with the severe fever with thrombocytopenia syndrome virus.

Methods: Between April 2011 and December 2019, data on consecutive patients who were diagnosed with severe fever with thrombocytopenia syndrome were prospectively collected from five medical centers in China. The score of the death risk model was correlated with the platelet-to-lymphocyte ratio and the neutrophil-to-lymphocyte ratio. Multivariable Cox analyses were used to identify the independent factors associated with mortality.

Results: During the study period, 763 patients were diagnosed with severe fever with thrombocytopenia syndrome; 415 of these patients were enrolled in our study. We found that the neutrophil-to-lymphocyte ratio of the group that died was significantly higher on admission (P=0.007) than that of the group that survived, and the neutrophil-to-lymphocyte ratio showed a positive correlation with the score of the death risk model. Multivariate Cox regression suggested that a neutrophil-to-lymphocyte ratio greater than 5.4 was an independent risk factor for survival time (HR=6.767, P=0.011). Platelet-to-lymphocyte ratio did not show a special role in this study.

Conclusions: A neutrophil-to-lymphocyte ratio greater than 5.4 can increase the risk of death and decrease the survival time of patients. In summary, the neutrophil-to-lymphocyte ratio provides a supplementary means for effectively managing severe fever with thrombocytopenia syndrome (SFTS).
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http://dx.doi.org/10.21037/atm-20-4736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940944PMC
February 2021

Core Role of Hydrophobic Core of Polymeric Nanomicelle in Endosomal Escape of siRNA.

Nano Lett 2021 04 17;21(8):3680-3689. Epub 2021 Feb 17.

School of Life Science, Advanced Research Institute of Multidisciplinary Science, Institute of Engineering Medicine, Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, Beijing 100081, China.

Efficient endosomal escape is the most essential but challenging issue for siRNA drug development. Herein, a series of quaternary ammonium-based amphiphilic triblock polymers harnessing an elaborately tailored pH-sensitive hydrophobic core were synthesized and screened. Upon incubating in an endosomal pH environment (pH 6.5-6.8), mPEG-P(DPA--DMAEMA)-PT (PDDT, the optimized polymer) nanomicelles (PDDT-Ms) and PDDT-Ms/siRNA polyplexes rapidly disassembled, leading to promoted cytosolic release of internalized siRNA and enhanced silencing activity evident from comprehensive analysis of the colocalization and gene silencing using a lysosomotropic agent (chloroquine) and an endosomal trafficking inhibitor (bafilomycin A1). In addition, PDDT-Ms/siPLK1 dramatically repressed tumor growth in both HepG2-xenograft and highly malignant patient-derived xenograft models. PDDT-Ms-armed siPD-L1 efficiently blocked the interaction of PD-L1 and PD-1 and restored immunological surveillance in CT-26-xenograft murine model. PDDT-Ms/siRNA exhibited ideal safety profiles in these assays. This study provides guidelines for rational design and optimization of block polymers for efficient endosomal escape of internalized siRNA and cancer therapy.
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http://dx.doi.org/10.1021/acs.nanolett.0c04468DOI Listing
April 2021

Modification of oncolytic adenovirus and its application in cancer therapy.

Discov Med 2020 Nov-Dec;30(161):129-144

National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, China.

Oncolytic virus refers to a type of virus that can replicate in tumor cells and eventually lyse them. Oncolytic adenoviruses are widely used because of their acceptable safety, but they are also limited in their clinical applications due to their own limitations. Therefore, the adenovirus is modified in multiple ways to improve the safety of the treatment, enhance the impact of oncolysis, and reduce the effect of neutralizing antibodies on the virus. The combined application of oncolytic adenovirus and other drugs plays a synergistic role in the treatment of tumors.
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February 2021

Multishell Nanoparticles with "Linkage Mechanism" for Thermal Responsive Photodynamic and Gas Synergistic Therapy.

Adv Healthc Mater 2021 05 15;10(10):e2002038. Epub 2021 Feb 15.

Key Laboratory of Flexible Electronics (KLOFE) and Institute of Advanced Materials (IAM), School of Physical and Mathematical Sciences, Nanjing Tech University (NanjingTech), Nanjing, 211800, China.

The strategies of combining photodynamic therapy (PDT) with other therapeutics are considered to be the most suitable methods in improving the antitumor therapeutic efficiency. Herein, a "Linkage Mechanism" strategy based on thermal controllable multishell nanoparticles ([email protected] -l-Arg (l-arginine)@PCM (phase-change material)-Ce6 (chiorin e6)) is proposed for combing PDT and NO-based gas therapy. Upon 1060 nm laser irradiation, the PCMs will melt under the photothermal effect induced by CuS and the loaded Ce6 and l-Arg can accurately release from the nanoparticles. Under further 660 nm laser irradiation, the released Ce6 will produce plenty of singlet oxygen ( O ) for PDT, while the generated O can oxidize l-Arg to release NO for the synergy of PDT and gas therapy. The "Linkage Mechanism" can achieve precise release of the payloads under the control of photothermal effect at tumor site, and the chain reaction of PDT and gas therapy overcomes the problem of premature release of gas during transportation. Benefiting from the guidance of fluorescence imaging and second near infrared photoacoustic imaging by Ce6 and CuS, both in vitro and in vivo experiments present effective antitumor efficiencies. The nanoparticles provide new ideas for controllable release of drugs and the synergistic effect of multiple treatments, possessing great application prospects.
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http://dx.doi.org/10.1002/adhm.202002038DOI Listing
May 2021

Development and application of reverse genetic technology for the influenza virus.

Virus Genes 2021 Apr 2;57(2):151-163. Epub 2021 Feb 2.

National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning, 530021, Guangxi, China.

Influenza virus is a common virus in people's daily lives, and it has certain infectivity in humans and animals. Influenza viruses have the characteristics of a high mutation rate and wide distribution. Reverse genetic technology is primarily used to modify viruses at the DNA level through targeted modification of the virus cDNA. Genetically modified influenza viruses have a unique advantage when researching the transmission and pathogenicity of influenza. With the continuous development of oncolytic viruses in recent years, studies have found that influenza viruses also have certain oncolytic activity. Influenza viruses can specifically recognize tumor cells; activate cytotoxic T cells, NK cells, dendritic cells, etc.; and stimulate the body to produce an immune response, thereby killing tumor cells. This article will review the development and application of influenza virus reverse genetic technology.
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http://dx.doi.org/10.1007/s11262-020-01822-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851324PMC
April 2021

Metformin loaded porous particles with bio-microenvironment responsiveness for promoting tumor immunotherapy.

Biomater Sci 2021 Mar 21;9(6):2082-2089. Epub 2021 Jan 21.

Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China.

PD1/PD-L1 antibody blockade-based immunotherapy has been widely recognized in the field of cancer treatment; however, only a small number of cancer patients have been shown to respond well due to the PD1/PD-L1 antibody hydrolysis induced substandard immunotherapeutic efficacy and the low immunogenicity and immunosuppressive tumor microenvironment of the patients. Here, we present a novel tumor microenvironment (TME) responsive particle delivery system with a metformin-loaded chitosan (CS) inverse opal core and a manganese dioxide (MnO) shell (denoted as [email protected] particles) for inhibiting the PD-1/PD-L1 signaling pathway and promoting tumor immunotherapy. Benefiting from the interconnected porous structure of the inverse opal, metformin can be easily extensively loaded into the CS particles. With the coating of the TME responsive MnO shells, the particle delivery system was imparted with an intelligent "trigger" to prevent premature leaking of the drug until it reaches the tumor tissue. We have demonstrated that [email protected] particles were able to promote the apoptosis of tumor cells through immunotherapeutic means both in vivo and in vitro. Specifically, the viability of tumor cells in the drug carrier-treated group was nearly 20% less than in the untreated group. In addition, the CS particles could serve as scaffolds for the regeneration of normal tissues and promote post-surgical wound healing due to their biocompatibility and antibacterial ability. These results make [email protected] particles an excellent delivery system in tumor immunotherapy and post-surgical wound healing applications.
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http://dx.doi.org/10.1039/d0bm01931cDOI Listing
March 2021

Biodegradable Charge-Transfer Complexes for Glutathione Depletion Induced Ferroptosis and NIR-II Photoacoustic Imaging Guided Cancer Photothermal Therapy.

Angew Chem Int Ed Engl 2021 04 4;60(15):8157-8163. Epub 2021 Mar 4.

Institute of Advanced Materials and Flexible Electronics (IAMFE), School of Chemistry and Materials Science, Nanjing University of Information Science & Technology, Nanjing, 210044, China.

Suffering from the laborious synthesis and undesirable tumor microenvironment response, the exploitation of novel NIR-II absorbing organic photothermal agents is of importance to promote phototherapeutic efficacy. Herein, two kinds of charge-transfer complex nanoparticles (TMB-F4TCNQ and TMB-TCNQ) are prepared by supramolecular assembly. Because of the larger energy gap between donor and acceptor, TMB-F4TCNQ presents higher charge-transfer degree (72 %) than that of TMB-TCNQ (48 %) in nanoaggregates. Therefore, TMB-F4TCNQ exhibits stronger NIR-II absorption ability with a mass extinction coefficient of 15.4 Lg  cm at 1300 nm and excellent photothermal effect. Impressively, the specific cysteine response can make the TMB-F4TCNQ effectively inhibit the intracellular biosynthesis of GSH, leading to redox dsyhomeostasis and ROS-mediated ferroptosis. TMB-F4TCNQ can serve as a contrast agent for NIR-II photoacoustic imaging to guide precise and efficient photothermal therapy in vivo.
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http://dx.doi.org/10.1002/anie.202014852DOI Listing
April 2021

Antitumor Activity of Lipid-DNA Aptamer Modified T Lymphocytes in Carcinoma.

J Biomed Nanotechnol 2020 Jul;16(7):1110-1118

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with no current effective therapeutics. One of the main reasons for the low efficacy of PDAC immunotherapy is the limited CD8 T cell infiltration, without neo antigen present in PDAC. Aptamers represent single-stranded oligonucleotides which bind to specific targets with high specificity. We developed DNA conjugates and prepared diacyl phospholipid-aptamer XQ-2d which has potential for the targeted therapy and diagnosis of PDAC. In this study, flow cytometry and fluorescence microscopy were employed to assess whether the Lipo-XQ-2d probe could anchor on activated T cells to constitute ligands specifically recognizing PDAC PL45 cells. Flow cytometry was employed to determine cytotoxicity in activated T cells. Results showed that the Lipo-XQ-2d probe could be inserted into T cells, and was specifically bound to both T cells and PL45 cells. In addition, the Lipo-XQ-2d probe redirected T cells to kill PL45 cells and was not toxic to cells. In conclusion, lipid-DNA-aptamer-modified T-lymphocytes might effectively kill PDAC , supporting the clinical application of T cell adoptive immunotherapy.
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http://dx.doi.org/10.1166/jbn.2020.2954DOI Listing
July 2020

Development of a Novel Double Antibody Sandwich Quantitative Enzyme-Linked Immunosorbent Assay for Detection of Porcine Epidemic Diarrhea Virus Antigen.

Front Vet Sci 2020 26;7:540248. Epub 2020 Oct 26.

Key Laboratory of Veterinary Biological Engineering and Technology Ministry of Agriculture, Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China.

Porcine epidemic diarrhea virus (PEDV) causes acute diarrhea and dehydration in sucking piglets with a high mortality rate. Here, we developed a double antibody sandwich quantitative enzyme-linked immunosorbent assay (DAS-qELISA) for detection of PEDV using a specific monoclonal antibody against PEDV N protein and anti-PEDV rabbit serum. Using DAS-qELISA, the detection limit of recombinant PEDV N protein and virus titer were approximately 1 μg/L and 10 TCID/ml, respectively. A total of 90 intestinal and 237 fecal samples were then screened for the presence of PEDV using DAS-qELISA and reverse transcriptase PCR (RT-PCR). DAS-qELISA had a high specificity of 98.1% and sensitivity of 93.5%. The accuracy rate between DAS-qELISA and RT-PCR was 95.7%. More importantly, the viral antigen concentrations remained unchanged before and after one inactivated vaccine preparation by using the DAS-qELISA. These results suggest DAS-qELISA could be used for antigen detection of inactivated vaccine samples and clinical samples. It is a novel method for diagnosing diseases and evaluation of the PEDV vaccine.
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http://dx.doi.org/10.3389/fvets.2020.540248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649156PMC
October 2020

Near-Infrared Light Irradiation Induced Mild Hyperthermia Enhances Glutathione Depletion and DNA Interstrand Cross-Link Formation for Efficient Chemotherapy.

ACS Nano 2020 11 21;14(11):14831-14845. Epub 2020 Oct 21.

Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.

DNA alkylating agents generally kill tumor cells by covalently binding with DNA to form interstrand or intrastrand cross-links. However, in the case of cisplatin, only a few DNA adducts (<1%) are highly toxic irreparable interstrand cross-links. Furthermore, cisplatin is rapidly detoxified by high levels of intracellular thiols such as glutathione (GSH). Since the discovery of its mechanism of action, people have been looking for ways to directly and efficiently remove intracellular GSH and increase interstrand cross-links to improve drug efficacy and overcome resistance, but there has been little breakthrough. Herein, we hypothesized that the anticancer efficiency of cisplatin can be enhanced through iodo-thiol click chemistry mediated GSH depletion and increased formation of DNA interstrand cross-links mild hyperthermia triggered by near-infrared (NIR) light. This was achieved by preparing an amphiphilic polymer with platinum(IV) (Pt(IV)) prodrugs and pendant iodine atoms (iodides). The polymer was further used to encapsulate IR780 and assembled into Pt-I-IR780 nanoparticles. Induction of mild hyperthermia (43 °C) at the tumor site by NIR light irradiation had three effects: (1) it accelerated the GSH-mediated reduction of Pt(IV) in the polymer main chain to platinum(II) (Pt(II)); (2) it boosted the iodo-thiol substitution click reaction between GSH and iodide, thereby attenuating the GSH-mediated detoxification of cisplatin; (3) it increased the proportion of highly toxic and irreparable Pt-DNA interstrand cross-links. Therefore, we find that mild hyperthermia induced NIR irradiation can enhance the killing of cancer cells and reduce the tumor burden, thus delivering efficient chemotherapy.
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http://dx.doi.org/10.1021/acsnano.0c03781DOI Listing
November 2020

Porcine reproductive and respiratory syndrome virus Nsp4 cleaves ZAP to antagonize its antiviral activity.

Vet Microbiol 2020 Nov 29;250:108863. Epub 2020 Sep 29.

Key Laboratory of Animal Diseases Diagnostic and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China. Electronic address:

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically important pathogens impacting the global swine industry. PRRSV has been recognized to modulate the host immune response through a number of mechanisms. In our previous study, we found that over-expression of ZAP, a zinc finger antiviral protein of host, could suppress PRRSV replication, but how PRRSV escape the restriction of ZAP under natural conditions was still unknown. In this study, We found PRRSV infection significantly down-regulate the endogenous ZAP protein expression in Marc-145 cells. And PRRSV nonstructural protein 4 (Nsp4), a 3C-like serine proteinase, was screened to be responsible for ZAP reduction. Nsp4 could cleave ZAP, depending on its protease activity. The anti-PRRSV activity of ZAP was antagonized by Nsp4 in Marc-145 cells. In addition, we identified a unique amino acid, serine 180 of Nsp4 was required for efficient degradation of ZAP, and the mutation at residue 180 could decrease the ability of recombinant PRRSV to degrade ZAP. Those findings reveal a manner of PRRSV Nsp4 antagonizing the antiviral activity of ZAP, and shed light on a new strategy evolved by PRRSV to escape the host defense.
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http://dx.doi.org/10.1016/j.vetmic.2020.108863DOI Listing
November 2020

Advances of aptamer-based clinical applications for the diagnosis and therapy of cancer.

Discov Med 2020 May-Jun;29(158):169-180

National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning 530021, Guangxi, China.

Aptamers are short single-stranded oligonucleotides that have attracted considerable attention due to their favorable biological characteristics. Aptamers can specifically target and bind to proteins or tumor cells, achieving tumor diagnosis and therapy in vitro and in vivo. Following an introduction of methodologies of producing aptamers and the recent advances of aptamers being applied to clinical samples or xenograft tumors, tumor diagnosis using aptamers will be reviewed, including fluorescence imaging, radionuclide-based imaging, MRI, histochemical imaging, and multimodality imaging. Preclinical applications in tumor therapy in vivo will also be discussed, covering different kinds of treatment mechanisms, including aptamer therapeutics, chemotherapy, gene therapy, immunotherapy, and combination therapy. Safety and efficacy of tumor-targeting therapeutics via aptamers, as well as the current challenges and future perspectives about aptamers' clinical applications, will be summarized.
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October 2020

Production of aptamers by cell-SELEX and their applications in cancer biomarker identification.

Discov Med 2020 May-Jun;29(158):159-167

National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, Nanning 530021, Guangxi, China.

Cancer is a major cause of disease-related deaths worldwide, and early diagnosis involving detecting biomarkers of tumors can improve the cure rate and prognosis of patients. Biomarkers are signature proteins that can distinguish diseased cells from healthy cells, facilitating the diagnosis and treatment of diseases, especially cancer. Aptamers are single-stranded oligonucleotides that can recognize target proteins with high affinity and specificity. The development of biomarkers identified by aptamers has experienced extensive progress in current applications. The combinatorial strategy of cell-SELEX technology and proteomics analysis makes targeted protein identification more cost-effective and efficient and improves the success rate of discovery of multiple biomarkers simultaneously. In this methodology, biomarkers are identified via a series of operations such as screening of aptamers, separation, extraction, and analysis of target proteins, which has brought about the discovery of a number of new biomarkers of cancer. This review summarizes the current strategies, challenges, and potential applications for biomarker discovery using aptamers engendered by cell-SELEX.
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October 2020

Nitazoxanide and JIB-04 have broad-spectrum antiviral activity and inhibit SARS-CoV-2 replication in cell culture and coronavirus pathogenesis in a pig model.

bioRxiv 2020 Sep 25. Epub 2020 Sep 25.

Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.

Pathogenic coronaviruses represent a major threat to global public health. Here, using a recombinant reporter virus-based compound screening approach, we identified several small-molecule inhibitors that potently block the replication of the newly emerged severe acute respiratory syndrome virus 2 (SARS-CoV-2). Two compounds, nitazoxanide and JIB-04 inhibited SARS-CoV-2 replication in Vero E6 cells with an EC of 4.90 μM and 0.69 μM, respectively, with specificity indices of greater than 150. Both inhibitors had antiviral activity in multiple cell types against some DNA and RNA viruses, including porcine transmissible gastroenteritis virus. In an porcine model of coronavirus infection, administration of JIB-04 reduced virus infection and associated tissue pathology, which resulted in improved body weight gain and survival. These results highlight the potential utility of nitazoxanide and JIB-04 as antiviral agents against SARS-CoV-2 and other viral pathogens.
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http://dx.doi.org/10.1101/2020.09.24.312165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523209PMC
September 2020