Publications by authors named "Yuquan Wei"

573 Publications

Black TiO Films with Photothermal-Assisted Photocatalytic Activity Prepared by Reactive Sputtering.

Materials (Basel) 2021 May 12;14(10). Epub 2021 May 12.

State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, 1295 Dingxi Road, Shanghai 200050, China.

Titanium oxide is widely applied as a photocatalyst. However, its low efficiency and narrow light absorption range are two main disadvantages that severely impede its practical application. In this work, black TiO films with different chemical compositions were fabricated by tuning target voltage and controlling O flow during reactive DC magnetron sputtering. The optimized TiO films with mixed phases (TiO, TiO, TiO, and TiO) exhibited fantastic photothermal and photocatalytic activity by combining high light-absorptive TiO and TiO phases with the photocatalytic TiO phase. The sample prepared with oxygen flow at 5.6 ± 0.2 sccm and target voltage near 400 V exhibited excellent optical absorbance of 89.29% under visible light, which could improve surface temperature to 114 °C under sunlight. This film could degrade Rhodamine-B up to 74% after 150 min of UV irradiation. In a word, this work provides a guideline for fabricating black TiO films with photothermal-assisted photocatalytic activity by reactive DC magnetron sputtering, which could avoid the usage of hydrogen and is convenient for quantity preparation.
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http://dx.doi.org/10.3390/ma14102508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151715PMC
May 2021

Role of lysosomes in physiological activities, diseases, and therapy.

J Hematol Oncol 2021 May 14;14(1):79. Epub 2021 May 14.

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China.

Long known as digestive organelles, lysosomes have now emerged as multifaceted centers responsible for degradation, nutrient sensing, and immunity. Growing evidence also implicates role of lysosome-related mechanisms in pathologic process. In this review, we discuss physiological function of lysosomes and, more importantly, how the homeostasis of lysosomes is disrupted in several diseases, including atherosclerosis, neurodegenerative diseases, autoimmune disorders, pancreatitis, lysosomal storage disorders, and malignant tumors. In atherosclerosis and Gaucher disease, dysfunction of lysosomes changes cytokine secretion from macrophages, partially through inflammasome activation. In neurodegenerative diseases, defect autophagy facilitates accumulation of toxic protein and dysfunctional organelles leading to neuron death. Lysosomal dysfunction has been demonstrated in pathology of pancreatitis. Abnormal autophagy activation or inhibition has been revealed in autoimmune disorders. In tumor microenvironment, malignant phenotypes, including tumorigenesis, growth regulation, invasion, drug resistance, and radiotherapy resistance, of tumor cells and behaviors of tumor-associated macrophages, fibroblasts, dendritic cells, and T cells are also mediated by lysosomes. Based on these findings, a series of therapeutic methods targeting lysosomal proteins and processes have been developed from bench to bedside. In a word, present researches corroborate lysosomes to be pivotal organelles for understanding pathology of atherosclerosis, neurodegenerative diseases, autoimmune disorders, pancreatitis, and lysosomal storage disorders, and malignant tumors and developing novel therapeutic strategies.
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http://dx.doi.org/10.1186/s13045-021-01087-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120021PMC
May 2021

Controllable Design and Preparation of Hollow Carbon-Based Nanotubes for Asymmetric Supercapacitors and Capacitive Deionization.

ACS Appl Mater Interfaces 2021 May 28;13(18):21217-21230. Epub 2021 Apr 28.

School of Environment and State Key Joint Laboratory of Environment Simulation and Pollution Control, School of Environment, Tsinghua University, Beijing 100084, PR China.

Carbon-based materials are important desirable materials in areas such as supercapacitors and capacitive deionization. However, traditional commercial materials are heterogeneous and prone to agglomeration in nanoscale and have structural limitation of electrochemical and desalination performance due to poor transport channels and low capacitance of prepared electrodes. Here, we introduce the facile strategy for controllable preparation of two types of hollow carbon-based nanotubes (HCTs) with amorphous mesoporous structures, which are synthesized by employing a MnO linear template method and calcination of polymer precursors. The porous N-doped HCT (NHCT) shows a specific capacitance of 412.6 F g (1 A g), with 77.3% rate capability (20 A g). The fabricated asymmetric MnO//NHCT supercapacitor displays the energy density of 55.8 Wh kg at a power density of 803.9 W kg. Furthermore, two typical MnO//HCT and MnO//NHCT devices both show the selective desalination performance of sulfate, and the MnO//NHCT device possesses a high deionization value of 11.37 mg g (500 mg L NaSO). These fabricated hollow carbon-based architectures with functional characteristics promise potential applications in energy and environmental related fields.
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http://dx.doi.org/10.1021/acsami.1c01137DOI Listing
May 2021

ZNF37A promotes tumor metastasis through transcriptional control of THSD4/TGF-β axis in colorectal cancer.

Oncogene 2021 May 19;40(19):3394-3407. Epub 2021 Apr 19.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China.

Poorly differentiated colorectal cancer (CRC) is characterized by aggressive invasion and stromal fibroblast activation, which results in rapid progression and poor therapeutic consequences. However, the regulatory mechanism involved remains unclear. Here, we showed that ZNF37A, a member of KRAB-ZFP family, was upregulated in poorly differentiated CRCs and associated with tumor metastasis. ZNF37A enhanced the metastatic potential of multiple CRC cell lines and promoted distant metastasis in an orthotopic CRC model. Further investigation attributed the ZNF37A-exacerbated metastasis to increased extracellular TGF-β and the consequent activation of cancer-associated fibroblasts (CAFs) in tumor microenvironment (TME). Mechanistically, ZNF37A formed a complex with KAP1 and bound to the promoter of THSD4, a TME modulator, to suppress its transcription, which is required for ZNF37A-mediated TGF-β activation and CRC metastasis. Collectively, our study indicates that ZNF37A promotes TGF-β signaling in CRC cells and activates CAFs by transcriptionally repressing THSD4 to drive CRC metastasis, implicating ZNF37A as a potential biomarker for CRC differentiation and progression.
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http://dx.doi.org/10.1038/s41388-021-01713-9DOI Listing
May 2021

Two types nitrogen source supply adjusted interaction patterns of bacterial community to affect humifaction process of rice straw composting.

Bioresour Technol 2021 Jul 7;332:125129. Epub 2021 Apr 7.

College of Life Science, Northeast Agricultural University, Harbin 150030, China. Electronic address:

This study investigated effects of high-nitrogen source (urea) (R_UR) and protein-like nitrogen source (chicken manure) (R_CM) on humification process during lignocellulose biomass composting. It demonstrated that decreasing ratio of crude fiber (CF), polysaccharide (PS) and amino acids (AAs) in R_CM (29.75%, 53.93% and 73.73%, respectively) was higher than that in R_UR (14.73%, 28.74% and 51.92%, respectively). Humic substance (HS) concentration increased by 7.51% and 73.05% during R_UR and R_CM composting, respectively. The lower total links, more independent modularization and higher proportion of positive correlations between functional bacteria and organic components was observed with R_CM network than R_UR, indicating that protein-like nitrogen source supply may alleviate competition within bacterial community. Moreover, chicken manure supply favorably selects greater special functional bacterial taxa (Pusillimonas, Pedomicrobium, Romboustia and other 24 genus) related to AAs and stimulates the collaborative division of bacterial community. This is significance for strengthening effective transformation of organic components.
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http://dx.doi.org/10.1016/j.biortech.2021.125129DOI Listing
July 2021

Targeting CXCR2 inhibits the progression of lung cancer and promotes therapeutic effect of cisplatin.

Mol Cancer 2021 04 4;20(1):62. Epub 2021 Apr 4.

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, People's Republic of China.

Background: Drug-resistance and severe side effects of chemotherapeutic agents result in unsatisfied survival of patients with lung cancer. CXCLs/CXCR2 axis plays an important role in progression of cancer including lung cancer. However, the specific anti-cancer mechanism of targeting CXCR2 remains unclear.

Methods: Immunohistochemical analysis of CXCR2 was performed on the microarray of tumor tissues of clinical lung adenocarcinoma and lung squamous cell carcinoma patients. CCK8 test, TUNEL immunofluorescence staining, PI-Annexin V staining, β-galactosidase staining, and Western blot were used to verify the role of CXCR2 in vitro. Animal models of tail vein and subcutaneous injection were applied to investigate the therapeutic role of targeting CXCR2. Flow cytometry, qRT-PCR, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry analysis were performed for further mechanistic investigation.

Results: The expression of CXCR2 was elevated in both human lung cancer stroma and tumor cells, which was associated with patients' prognosis. Inhibition of CXCR2 promoted apoptosis, senescence, epithelial-to-mesenchymal transition (EMT), and anti-proliferation of lung cancer cells. In vivo study showed that tumor-associated neutrophils (TANs) were significantly infiltrate into tumor tissues of mouse model, with up-regulated CXCLs/CXCR2 signaling and suppressive molecules, including Arg-1 and TGF-β. SB225002, a selective inhibitor of CXCR2 showed promising therapeutic effect, and significantly reduced infiltration of neutrophils and enhanced anti-tumor T cell activity via promoting CD8 T cell activation. Meanwhile, blockade of CXCR2 could enhance therapeutic effect of cisplatin via regulation of neutrophils infiltration.

Conclusions: Our finds verify the therapeutic effects of targeting CXCR2 in lung cancer and uncover the potential mechanism for the increased sensitivity to chemotherapeutic agents by antagonists of CXCR2.
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http://dx.doi.org/10.1186/s12943-021-01355-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019513PMC
April 2021

Large-scale molecular epidemiological analysis of AAV in a cancer patient population.

Oncogene 2021 Apr 29;40(17):3060-3071. Epub 2021 Mar 29.

Horae Gene Therapy Center, University of Massachusetts, Medical School, Worcester, MA, USA.

Recombinant adeno-associated viruses (rAAVs) are well-established vectors for delivering therapeutic genes. However, previous reports have suggested that wild-type AAV is linked to hepatocellular carcinoma, raising concern with the safety of rAAVs. In addition, a recent long-term follow-up study in canines, which received rAAVs for factor VIII gene therapy, demonstrated vector integration into the genome of liver cells, reviving the uncertainty between AAV and cancer. To further explore this relationship, we performed large-scale molecular epidemiology of AAV in resected tumor samples and non-lesion tissues collected from 413 patients, reflecting nine carcinoma types: breast carcinoma, rectal cancer, pancreas carcinoma, brain tumor, hepatoid adenocarcinoma, hepatocellular carcinoma, gastric carcinoma, lung squamous, and adenocarcinoma. We found that over 80% of patients were AAV-positive among all nine types of carcinoma examined. Importantly, the AAV sequences detected in patient-matched tumor and adjacent non-lesion tissues showed no significant difference in incidence, abundance, and variation. In addition, no specific AAV sequences predominated in tumor samples. Our data shows that AAV genomes are equally abundant in tumors and adjacent normal tissues, but lack clonality. The finding critically adds to the epidemiological profile of AAV in humans, and provides insights that may assist rAAV-based clinical studies and gene therapy strategies.
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http://dx.doi.org/10.1038/s41388-021-01725-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087635PMC
April 2021

Diversity of the reaction mechanisms of SAM-dependent enzymes.

Acta Pharm Sin B 2021 Mar 26;11(3):632-650. Epub 2020 Aug 26.

State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.

-adenosylmethionine (SAM) is ubiquitous in living organisms and is of great significance in metabolism as a cofactor of various enzymes. Methyltransferases (MTases), a major group of SAM-dependent enzymes, catalyze methyl transfer from SAM to C, O, N, and S atoms in small-molecule secondary metabolites and macromolecules, including proteins and nucleic acids. MTases have long been a hot topic in biomedical research because of their crucial role in epigenetic regulation of macromolecules and biosynthesis of natural products with prolific pharmacological moieties. However, another group of SAM-dependent enzymes, sharing similar core domains with MTases, can catalyze nonmethylation reactions and have multiple functions. Herein, we mainly describe the nonmethylation reactions of SAM-dependent enzymes in biosynthesis. First, we compare the structural and mechanistic similarities and distinctions between SAM-dependent MTases and the non-methylating SAM-dependent enzymes. Second, we summarize the reactions catalyzed by these enzymes and explore the mechanisms. Finally, we discuss the structural conservation and catalytical diversity of class I-like non-methylating SAM-dependent enzymes and propose a possibility in enzymes evolution, suggesting future perspectives for enzyme-mediated chemistry and biotechnology, which will help the development of new methods for drug synthesis.
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http://dx.doi.org/10.1016/j.apsb.2020.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982431PMC
March 2021

Rheb mediates neuronal-activity-induced mitochondrial energetics through mTORC1-independent PDH activation.

Dev Cell 2021 Mar 15;56(6):811-825.e6. Epub 2021 Mar 15.

Department of Biology, School of Life Sciences, Brain Research Center, Southern University of Science and Technology, Shenzhen Key Laboratory of Gene Regulation and Systems Biology, Shenzhen 518055, People's Republic of China. Electronic address:

Neuronal activity increases energy consumption and requires balanced production to maintain neuronal function. How activity is coupled to energy production remains incompletely understood. Here, we report that Rheb regulates mitochondrial tricarboxylic acid cycle flux of acetyl-CoA by activating pyruvate dehydrogenase (PDH) to increase ATP production. Rheb is induced by synaptic activity and lactate and dynamically trafficked to the mitochondrial matrix through its interaction with Tom20. Mitochondria-localized Rheb protein is required for activity-induced PDH activation and ATP production. Cell-type-specific gain- and loss-of-function genetic models for Rheb reveal reciprocal changes in PDH phosphorylation/activity, acetyl-CoA, and ATP that are not evident with genetic or pharmacological manipulations of mTORC1. Mechanistically, Rheb physically associates with PDH phosphatase (PDP), enhancing its activity and association with the catalytic E1α-subunit of PDH to reduce PDH phosphorylation and increase its activity. Findings identify Rheb as a nodal point that balances neuronal activity and neuroenergetics via Rheb-PDH axis.
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http://dx.doi.org/10.1016/j.devcel.2021.02.022DOI Listing
March 2021

Inhibition of FGF-FGFR and VEGF-VEGFR signalling in cancer treatment.

Cell Prolif 2021 Apr 2;54(4):e13009. Epub 2021 Mar 2.

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.

The sites of targeted therapy are limited and need to be expanded. The FGF-FGFR signalling plays pivotal roles in the oncogenic process, and FGF/FGFR inhibitors are a promising method to treat FGFR-altered tumours. The VEGF-VEGFR signalling is the most crucial pathway to induce angiogenesis, and inhibiting this cascade has already got success in treating tumours. While both their efficacy and antitumour spectrum are limited, combining FGF/FGFR inhibitors with VEGF/VEGFR inhibitors are an excellent way to optimize the curative effect and expand the antitumour range because their combination can target both tumour cells and the tumour microenvironment. In addition, biomarkers need to be developed to predict the efficacy, and combination with immune checkpoint inhibitors is a promising direction in the future. The article will discuss the FGF-FGFR signalling pathway, the VEGF-VEGFR signalling pathway, the rationale of combining these two signalling pathways and recent small-molecule FGFR/VEGFR inhibitors based on clinical trials.
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http://dx.doi.org/10.1111/cpr.13009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016646PMC
April 2021

Insight into the mechanisms of insoluble phosphate transformation driven by the interactions of compound microbes during composting.

Environ Sci Pollut Res Int 2021 Feb 25. Epub 2021 Feb 25.

College of Resources and Environmental Sciences, China Agricultural University, Beijing, 100193, China.

Phosphate-solubilizing (PS) microbes are important to improve phosphorus availability and transformation of insoluble phosphate, e.g., rock phosphate (RP). The use of phosphate solubilizing bacteria (PSB) as inoculants have been proposed as an alternative to increase phosphate availability in RP and composting fertilizers. In this study, the effect of compound PSB coinoculation and single-strain inoculation on the transformation of insoluble phosphate were compared in a liquid medium incubation and RP-enriched composting. The goal of this study was to understand the possible mechanisms of insoluble phosphate transformation driven by the interactions of compound PS microbes during composting. The correlations between organic acids production, P-solubilization capacity and bacterial community with PSB inoculation were investigated in the RP-enriched composting by redundancy analysis (RDA) and structural equation models (SEM). Results showed that both single-strain and compound PSB inoculants had a high P-solubilization capacity in medium, but the proportion of Olsen P to total P in composts with inoculating compound PS microbes was 7% higher than that with single strain. PS inoculants could secrete different organic acids and lactic was the most abundant. However, RDA and SEM suggested that oxalic might play an important role on PS activity, inducing RP solubilization by changing pH during composting. Interaction between compound microbes could intensify the acidolysis process for insoluble P transformation compared to the single strain. Our findings help to understand the roles of complex microbial inoculants and regulate P availability of insoluble phosphate for the agricultural purposes.
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http://dx.doi.org/10.1007/s11356-021-13113-3DOI Listing
February 2021

Genomic evolution and diverse models of systemic metastases in colorectal cancer.

Gut 2021 Feb 25. Epub 2021 Feb 25.

Department of Gastrointestinal Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

Objective: The systemic spread of colorectal cancer (CRC) is dominated by the portal system and exhibits diverse patterns of metastasis without systematical genomic investigation. Here, we evaluated the genomic evolution of CRC with multiorgan metastases using multiregion sequencing.

Design: Whole-exome sequencing was performed on multiple regions (n=74) of matched primary tumour, adjacent non-cancerous mucosa, liver metastasis and lung metastasis from six patients with CRC. Phylogenetic reconstruction and evolutionary analyses were used to investigate the metastatic seeding pattern and clonal origin. Recurrent driver gene mutations were analysed across patients and validated in two independent cohorts. Metastatic assays were performed to examine the effect of the novel driver gene on the malignant behaviour of CRC cells.

Results: Based on the migration patterns and clonal origins, three models were revealed (sequential, branch-off and diaspora), which not only supported the anatomic assumption that CRC cells spread to lung after clonally expanding in the liver, but also illustrated the direct seeding of extrahepatic metastases from primary tumours independently. Unlike other cancer types, polyphyletic seeding occurs in CRC, which may result in late metastases with intermetastatic driver gene heterogeneity. In cases with rapid dissemination, we found recurrent trunk loss-of-function mutations in , which is enriched in metastatic CRC and associated with poor overall survival. CRISPR/Cas9-mediated knockout of enhances the metastatic potential of CRC cells.

Conclusion: Our results provide genomic evidence for metastatic evolution and indicate that biopsy/sequencing of metastases may be considered for patients with CRC with multiorgan or late postoperative metastasis.
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http://dx.doi.org/10.1136/gutjnl-2020-323703DOI Listing
February 2021

mRNA vaccine: a potential therapeutic strategy.

Mol Cancer 2021 02 16;20(1):33. Epub 2021 Feb 16.

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, PR China.

mRNA vaccines have tremendous potential to fight against cancer and viral diseases due to superiorities in safety, efficacy and industrial production. In recent decades, we have witnessed the development of different kinds of mRNAs by sequence optimization to overcome the disadvantage of excessive mRNA immunogenicity, instability and inefficiency. Based on the immunological study, mRNA vaccines are coupled with immunologic adjuvant and various delivery strategies. Except for sequence optimization, the assistance of mRNA-delivering strategies is another method to stabilize mRNAs and improve their efficacy. The understanding of increasing the antigen reactiveness gains insight into mRNA-induced innate immunity and adaptive immunity without antibody-dependent enhancement activity. Therefore, to address the problem, scientists further exploited carrier-based mRNA vaccines (lipid-based delivery, polymer-based delivery, peptide-based delivery, virus-like replicon particle and cationic nanoemulsion), naked mRNA vaccines and dendritic cells-based mRNA vaccines. The article will discuss the molecular biology of mRNA vaccines and underlying anti-virus and anti-tumor mechanisms, with an introduction of their immunological phenomena, delivery strategies, their importance on Corona Virus Disease 2019 (COVID-19) and related clinical trials against cancer and viral diseases. Finally, we will discuss the challenge of mRNA vaccines against bacterial and parasitic diseases.
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http://dx.doi.org/10.1186/s12943-021-01311-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884263PMC
February 2021

Genomic monitoring of SARS-CoV-2 uncovers an Nsp1 deletion variant that modulates type I interferon response.

Cell Host Microbe 2021 03 29;29(3):489-502.e8. Epub 2021 Jan 29.

Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China; Department of Laboratory Medicine and Department of Pediatric Infectious Diseases, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu 610041, China.

The SARS-CoV-2 virus, the causative agent of COVID-19, is undergoing constant mutation. Here, we utilized an integrative approach combining epidemiology, virus genome sequencing, clinical phenotyping, and experimental validation to locate mutations of clinical importance. We identified 35 recurrent variants, some of which are associated with clinical phenotypes related to severity. One variant, containing a deletion in the Nsp1-coding region (Δ500-532), was found in more than 20% of our sequenced samples and associates with higher RT-PCR cycle thresholds and lower serum IFN-β levels of infected patients. Deletion variants in this locus were found in 37 countries worldwide, and viruses isolated from clinical samples or engineered by reverse genetics with related deletions in Nsp1 also induce lower IFN-β responses in infected Calu-3 cells. Taken together, our virologic surveillance characterizes recurrent genetic diversity and identified mutations in Nsp1 of biological and clinical importance, which collectively may aid molecular diagnostics and drug design.
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http://dx.doi.org/10.1016/j.chom.2021.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846228PMC
March 2021

Personalized neoantigen pulsed dendritic cell vaccine for advanced lung cancer.

Signal Transduct Target Ther 2021 Jan 20;6(1):26. Epub 2021 Jan 20.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China.

Neoantigens are considered to be ultimate target of tumor immunotherapy due to their high tumor specificity and immunogenicity. Dendritic cell (DCs) vaccines based on neoantigens have exciting effects in treatment of some malignant tumors and are a promising therapeutic modality. Lung cancer is a lethal disease with the highest morbidity and mortality rate in the world. Despite the rapid development of targeted therapy and immune checkpoint inhibitors for lung cancer in recent years, their efficacy is still unsatisfactory overall. Therefore, there is an urgent unmet clinical need for lung cancer treatment. Here, we attempted to treat lung cancer using a personalized neoantigen peptide-pulsed autologous DC vaccine and conducted a single-arm, 2 medical centers, pilot study initiated by the investigator (ChiCTR-ONC-16009100, NCT02956551). The patients enrolled were patients with heavily treated metastatic lung cancer. Candidate neoantigens were derived from whole-exome sequencing and RNA sequencing of fresh biopsy tissues as well as bioinformatics analysis. A total of 12 patients were enrolled in this study. A total of 85 vaccine treatments were administered with a median value of 5 doses/person (range: 3-14 doses/person). In total, 12-30 peptide-based neoantigens were selected for each patient. All treatment-related adverse events were grade 1-2 and there were no delays in dosing due to toxic effects. The objective effectiveness rate was 25%; the disease control rate was 75%; the median progression-free survival was 5.5 months and the median overall survival was 7.9 months. This study provides new evidence for neoantigen vaccine therapy and new therapeutic opportunities for lung cancer treatment.
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http://dx.doi.org/10.1038/s41392-020-00448-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817684PMC
January 2021

Publisher Correction: A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity.

Nature 2021 Feb;590(7844):E23

Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.

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http://dx.doi.org/10.1038/s41586-020-03108-4DOI Listing
February 2021

Treatment of Colon Cancer by Degradable rrPPC Nano-Conjugates Delivered STAT3 siRNA.

Int J Nanomedicine 2020 7;15:9875-9890. Epub 2020 Dec 7.

Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, People's Republic of China.

Background: Drugs that work based on the mechanism of RNA interference have shown strong potential in cancer gene therapy. Although significant progress has been made in small interfering RNA (siRNA) design and manufacturing, ideal delivery system remains a limitation for the development of siRNA-based drugs. Particularly, it is necessary to focus on parameters including delivery efficiency, stability, and safety when developing siRNA formulations for cancer therapy.

Methods: In this work, a novel degradable siRNA delivery system cRGD-R9-PEG-PEI-Cholesterol (rrPPC) was synthesized based on low molecular weight polyethyleneimine (PEI). Functional groups including cholesterol, cell penetrating peptides (CPPs), and poly(ethylene oxide) were introduced to PEI backbone to attain enhanced transfection efficiency and biocompatibility.

Results: The synthesized rrPPC was dispersed as nanoparticles in water with an average size of 195 nm and 41.9 mV in potential. rrPPC nanoparticles could efficiently deliver siRNA into C26 clone cancer cells and trigger caveolae-mediated pathway during transmembrane transportation. By loading the signal transducer and activator of transcription 3 (STAT3) targeting siRNA, rrPPC/STAT3 siRNA (rrPPC/siSTAT3) complex demonstrated strong anti-cancer effects in multiple colon cancer models following local delivery. In addition, intravenous (IV) injection of rrPPC/siSTAT3 complex efficiently suppressed lung metastasis tumor progression with ideal in vivo safety.

Conclusion: Our results provide evidence that rrPPC nanoparticles constitute a potential candidate vector for siRNA-based colon cancer gene therapy.
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http://dx.doi.org/10.2147/IJN.S277845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732178PMC
December 2020

Publisher Correction: Heat stress activates YAP/TAZ to induce the heat shock transcriptome.

Nat Cell Biol 2021 Feb;23(2):209

Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.

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http://dx.doi.org/10.1038/s41556-020-00623-4DOI Listing
February 2021

Targeting Myeloid-Derived Suppressor Cells for Premetastatic Niche Disruption After Tumor Resection.

Ann Surg Oncol 2021 Jul 30;28(7):4030-4048. Epub 2020 Nov 30.

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.

Surgical resection is a common therapeutic option for primary solid tumors. However, high cancer recurrence and metastatic rates after resection are the main cause of cancer related mortalities. This implies the existence of a "fertile soil" following surgery that facilitates colonization by circulating cancer cells. Myeloid-derived suppressor cells (MDSCs) are essential for premetastatic niche formation, and may persist in distant organs for up to 2 weeks after surgery. These postsurgical persistent lung MDSCs exhibit stronger immunosuppression compared with presurgical MDSCs, suggesting that surgery enhances MDSC function. Surgical stress and trauma trigger the secretion of systemic inflammatory cytokines, which enhance MDSC mobilization and proliferation. Additionally, damage associated molecular patterns (DAMPs) directly activate MDSCs through pattern recognition receptor-mediated signals. Surgery also increases vascular permeability, induces an increase in lysyl oxidase and extracellular matrix remodeling in lungs, that enhances MDSC mobilization. Postsurgical therapies that inhibit the induction of premetastatic niches by MDSCs promote the long-term survival of patients. Cyclooxygenase-2 inhibitors and β-blockade, or their combination, may minimize the impact of surgical stress on MDSCs. Anti-DAMPs and associated inflammatory signaling inhibitors also are potential therapies. Existing therapies under tumor-bearing conditions, such as MDSCs depletion with low-dose chemotherapy or tyrosine kinase inhibitors, MDSCs differentiation using all-trans retinoic acid, and STAT3 inhibition merit clinical evaluation during the perioperative period. In addition, combining low-dose epigenetic drugs with chemokine receptors, reversing immunosuppression through the Enhanced Recovery After Surgery protocol, repairing vascular leakage, or inhibiting extracellular matrix remodeling also may enhance the long-term survival of curative resection patients.
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http://dx.doi.org/10.1245/s10434-020-09371-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703739PMC
July 2021

History of petroleum disturbance triggering the depth-resolved assembly process of microbial communities in the vadose zone.

J Hazard Mater 2021 01 22;402:124060. Epub 2020 Sep 22.

School of Environment & State Key Joint Laboratory of Environment Simulation and Pollution Control, Tsinghua University, Beijing 100084, China; Research Institute for Environmental Innovation (Suzhou), Tsinghua, Suzhou 215163, China. Electronic address:

Biogeochemical gradient forms in vadose zone, yet little is known about the assembly processes of microbial communities in this zone under petroleum disturbance. This study collected vadose zone soils at three sites with 0, 5, and 30 years of petroleum contamination to unravel the vertical microbial community successions and their assembly mechanisms. The results showed that petroleum hydrocarbons exhibited higher concentrations at the long-term contaminated site, showing negative impacts on some soil properties, retarding in the surface soils and decreasing along soil depth. Cultivable fraction of heterotrophic bacteria and microbial α-diversity decreased along depth in vadose zones with short-term/no contamination history, but exhibited an opposite trend with long-term contamination history. Petroleum contamination intensified the vertical heterogeneity of microbial communities based on the contamination time. Microbial co-occurrence network revealed the lowest species co-occurrence pattern at the long-term contaminated site. The distance-decay patterns and null model analysis together suggested distinct assembly mechanisms at three sites, where dispersal limitation (42-45%) was higher and variable and homogenizing selections were lower (37-38%) in vadose zones under petroleum disturbance than those in the uncontaminated vadose zone. Our findings help to better understand the subsurface biogeochemical cycles and bioremediation of petroleum-contaminated vadose zones.
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http://dx.doi.org/10.1016/j.jhazmat.2020.124060DOI Listing
January 2021

Heat stress activates YAP/TAZ to induce the heat shock transcriptome.

Nat Cell Biol 2020 12 16;22(12):1447-1459. Epub 2020 Nov 16.

Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.

The Hippo pathway plays critical roles in cell growth, differentiation, organ development and tissue homeostasis, whereas its dysregulation can lead to tumorigenesis. YAP and TAZ are transcription co-activators and represent the main downstream effectors of the Hippo pathway. Here, we show that heat stress induces a strong and rapid YAP dephosphorylation and activation. The effect of heat shock on YAP is dominant to other signals known to modulate the Hippo pathway. Heat shock inhibits LATS kinase by promoting HSP90-dependent LATS interaction with and inactivation by protein phosphatase 5. Heat shock also induces LATS ubiquitination and degradation. YAP and TAZ are crucial for cellular heat shock responses, including the heat shock transcriptome and cell viability. This study uncovers previously unknown mechanisms of Hippo regulation by heat shock, as well as physiological functions of YAP, in the heat stress response. Our observations also reveal a potential combinational therapy involving hyperthermia and targeting of the Hippo pathway.
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http://dx.doi.org/10.1038/s41556-020-00602-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757600PMC
December 2020

Corrigendum to "Anti-TNF-α monoclonal antibody reverses psoriasis through dual inhibition of inflammation and angiogenesis" [Int. Immunopharmacol. 28(1) (2015) 731-743].

Int Immunopharmacol 2020 Nov 23;88:107019. Epub 2020 Sep 23.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, People's Republic of China. Electronic address:

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http://dx.doi.org/10.1016/j.intimp.2020.107019DOI Listing
November 2020

Coronavirus in human diseases: Mechanisms and advances in clinical treatment.

MedComm (Beijing) 2020 Oct 1. Epub 2020 Oct 1.

Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer Center National Clinical Research Center for Geriatrics West China Hospital Sichuan University Chengdu China.

Coronaviruses (CoVs), a subfamily of coronavirinae, are a panel of single-stranded RNA virus. Human coronavirus (HCoV) strains (HCoV-229E, HCoV-OC43, HCoV-HKU1, HCoV-NL63) usually cause mild upper respiratory diseases and are believed to be harmless. However, other HCoVs, associated with severe acute respiratory syndrome, Middle East respiratory syndrome, and COVID-19, have been identified as important pathogens due to their potent infectivity and lethality worldwide. Moreover, currently, no effective antiviral drugs treatments are available so far. In this review, we summarize the biological characters of HCoVs, their association with human diseases, and current therapeutic options for the three severe HCoVs. We also highlight the discussion about novel treatment strategies for HCoVs infections.
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http://dx.doi.org/10.1002/mco2.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646666PMC
October 2020

The role of lysosome in regulated necrosis.

Acta Pharm Sin B 2020 Oct 13;10(10):1880-1903. Epub 2020 Jul 13.

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China.

Lysosome is a ubiquitous acidic organelle fundamental for the turnover of unwanted cellular molecules, particles, and organelles. Currently, the pivotal role of lysosome in regulating cell death is drawing great attention. Over the past decades, we largely focused on how lysosome influences apoptosis and autophagic cell death. However, extensive studies showed that lysosome is also prerequisite for the execution of regulated necrosis (RN). Different types of RN have been uncovered, among which, necroptosis, ferroptosis, and pyroptosis are under the most intensive investigation. It becomes a hot topic nowadays to target RN as a therapeutic intervention, since it is important in many patho/physiological settings and contributing to numerous diseases. It is promising to target lysosome to control the occurrence of RN thus altering the outcomes of diseases. Therefore, we aim to give an introduction about the common factors influencing lysosomal stability and then summarize the current knowledge on the role of lysosome in the execution of RN, especially in that of necroptosis, ferroptosis, and pyroptosis.
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http://dx.doi.org/10.1016/j.apsb.2020.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606114PMC
October 2020

Structural and Functional Insights into an Archaeal Lipid Synthase.

Cell Rep 2020 10;33(3):108294

Division of Respiratory and Critical Care Medicine, Respiratory Infection and Intervention Laboratory of Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China. Electronic address:

The UbiA superfamily of intramembrane prenyltransferases catalyzes an isoprenyl transfer reaction in the biosynthesis of lipophilic compounds involved in cellular physiological processes. Digeranylgeranylglyceryl phosphate (DGGGP) synthase (DGGGPase) generates unique membrane core lipids for the formation of the ether bond between the glycerol moiety and the alkyl chains in archaea and has been confirmed to be a member of the UbiA superfamily. Here, the crystal structure is reported to exhibit nine transmembrane helices along with a large lateral opening covered by a cytosolic cap domain and a unique substrate-binding central cavity. Notably, the lipid-bound states of this enzyme demonstrate that the putative substrate-binding pocket is occupied by the lipidic molecules used for crystallization, indicating the binding mode of hydrophobic substrates. Collectively, these structural and functional studies provide not only an understanding of lipid biosynthesis by substrate-specific lipid-modifying enzymes but also insights into the mechanisms of lipid membrane remodeling and adaptation.
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http://dx.doi.org/10.1016/j.celrep.2020.108294DOI Listing
October 2020

Structure of the human gonadotropin-releasing hormone receptor GnRH1R reveals an unusual ligand binding mode.

Nat Commun 2020 10 20;11(1):5287. Epub 2020 Oct 20.

Division of Nephrology and Kidney Research Institute, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.

Gonadotrophin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone, is the main regulator of the reproductive system, acting on gonadotropic cells by binding to the GnRH1 receptor (GnRH1R). The GnRH-GnRH1R system is a promising therapeutic target for maintaining reproductive function; to date, a number of ligands targeting GnRH1R for disease treatment are available on the market. Here, we report the crystal structure of GnRH1R bound to the small-molecule drug elagolix at 2.8 Å resolution. The structure reveals an interesting N-terminus that could co-occupy the enlarged orthosteric binding site together with elagolix. The unusual ligand binding mode was further investigated by structural analyses, functional assays and molecular docking studies. On the other hand, because of the unique characteristic of lacking a cytoplasmic C-terminal helix, GnRH1R exhibits different microswitch structural features from other class A GPCRs. In summary, this study provides insight into the ligand binding mode of GnRH1R and offers an atomic framework for rational drug design.
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http://dx.doi.org/10.1038/s41467-020-19109-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576152PMC
October 2020

Induction of neutrophil extracellular traps during tissue injury: Involvement of STING and Toll-like receptor 9 pathways.

Cell Prolif 2020 Oct;53(10):e12775

Lab of Aging Research and Nanotoxicology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan, China.

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http://dx.doi.org/10.1111/cpr.12775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574867PMC
October 2020

Composting with biochar or woody peat addition reduces phosphorus bioavailability.

Sci Total Environ 2021 Apr 8;764:142841. Epub 2020 Oct 8.

Beijing Key Laboratory of Farmland Soil Pollution Prevention and Remediation, College of Resource and Environmental Sciences, China Agricultural University, Beijing 100193, China. Electronic address:

Biochar and woody peat have been recognized as an additive to reduce carbon and nitrogen loss during composting. Yet little is known about their influences on the transformation of phosphorus (P) fractions in composting. This study investigated the quantitative and qualitative changes in different P forms during composting with adding biochar or woody peat using sequential extraction and P K-edge X-ray absorption near-edge structure (XANES). The results showed that compost products from the treatment with adding woody peat had a higher HA/FA (the ratio of humic acid to fulvic acid) compared to biochar treatment and the control, suggesting that the addition of woody peat might benefit the humification process of composting. Sequential extraction and XANES illustrated that adding biochar or woody peat limited the P availability. Biochar increased the proportion of Pi and woody peat decreased the conversion from Po to Pi compared to the control. Structural equation modeling and redundancy analysis suggested that biochar improved the refractory P based on the indirect effects of NH-N by regulating microbial community, while woody peat was beneficial for Po accumulation by affecting humic acid. Taken together, this research provides basis for regulating the nutrient level of carbon, nitrogen, and phosphorus in composts and reducing environmental risks.
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http://dx.doi.org/10.1016/j.scitotenv.2020.142841DOI Listing
April 2021

The molecular mechanisms of MLKL-dependent and MLKL-independent necrosis.

J Mol Cell Biol 2021 Apr;13(1):3-14

Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China.

Necrosis, a type of unwanted and passive cell demise, usually occurs under the excessive external stress and is considered to be unregulated. However, under some special conditions such as caspase inhibition, necrosis is regulable in a well-orchestrated way. The term 'regulated necrosis' has been proposed to describe such programed necrosis. Recently, several forms of necrosis, including necroptosis, pyroptosis, ferroptosis, parthanatos, oxytosis, NETosis, and Na+/K+-ATPase-mediated necrosis, have been identified, and some crucial regulators governing regulated necrosis have also been discovered. Mixed lineage kinase domain-like pseudokinase (MLKL), a core regulator in necroptosis, acts as an executioner in response to ligands of death receptor family. Its activation requires the receptor-interacting protein kinases, RIP1 and RIP3. However, MLKL is only involved in necroptosis, i.e. MLKL is dispensable for necrosis. Therefore, this review is aimed at summarizing the molecular mechanisms of MLKL-dependent and MLKL-independent necrosis.
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http://dx.doi.org/10.1093/jmcb/mjaa055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035999PMC
April 2021