Publications by authors named "Yuxi Wang"

189 Publications

Combination Foretinib and Anti-PD-1 Antibody Immunotherapy for Colorectal Carcinoma.

Front Cell Dev Biol 2021 8;9:689727. Epub 2021 Jul 8.

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

Immune checkpoint inhibitors have achieved unprecedented success in cancer immunotherapy. However, the overall response rate to immune checkpoint inhibitor therapy for many cancers is only between 20 and 40%, and even less for colorectal cancer (CRC) patients. Thus, there is an urgent need to develop an efficient immunotherapeutic strategy for CRC. Here, we developed a novel CRC combination therapy consisting of a multiple receptor tyrosine kinase inhibitor (Foretinib) and anti-PD-1 antibody. The combination therapy significantly inhibited tumor growth in mice, led to improved tumor regression without relapse (83% for CT26 tumors and 50% for MC38 tumors) and prolonged overall survival. Mechanistically, Foretinib caused increased levels of PD-L1 via activating the JAK2-STAT1 pathway, which could improve the effectiveness of the immune checkpoint inhibitor. Moreover, the combination therapy remodeled the tumor microenvironment and enhanced anti-tumor immunity by further increasing the infiltration and improving the function of T cells, decreasing the percentage of tumor-associated macrophages (TAMs) and inhibiting their polarization toward the M2 phenotype. Furthermore, the combination therapy inhibited the metastasis of CT26-Luc tumors to the lung in BALB/c mouse by reducing proportions of regulatory T-cells, TAMs and M2 phenotype TAMs in their lungs. This study suggests that a novel combination therapy utilizing both Foretinib and anti-PD-1 antibody could be an effective combination strategy for CRC immunotherapy.
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http://dx.doi.org/10.3389/fcell.2021.689727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298272PMC
July 2021

The probiotic L. casei Zhang slows the progression of acute and chronic kidney disease.

Cell Metab 2021 Jul 8. Epub 2021 Jul 8.

Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, China. Electronic address:

The relationship between gut microbial dysbiosis and acute or chronic kidney disease (CKD) is still unclear. Here, we show that oral administration of the probiotic Lactobacillus casei Zhang (L. casei Zhang) corrected bilateral renal ischemia-reperfusion (I/R)-induced gut microbial dysbiosis, alleviated kidney injury, and delayed its progression to CKD in mice. L. casei Zhang elevated the levels of short-chain fatty acids (SCFAs) and nicotinamide in the serum and kidney, resulting in reduced renal inflammation and damage to renal tubular epithelial cells. We also performed a 1-year phase 1 placebo-controlled study of oral L. casei Zhang use (Chinese clinical trial registry, ChiCTR-INR-17013952), which was well tolerated and slowed the decline of kidney function in individuals with stage 3-5 CKD. These results show that oral administration of L. casei Zhang, by altering SCFAs and nicotinamide metabolism, is a potential therapy to mitigate kidney injury and slow the progression of renal decline.
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http://dx.doi.org/10.1016/j.cmet.2021.06.014DOI Listing
July 2021

Electrocoagulation treatment of shale gas drilling wastewater: Performance and statistical optimization.

Sci Total Environ 2021 Jun 17;794:148436. Epub 2021 Jun 17.

CNPC Research Institute of Safety and Environmental Technology, Beijing 102206, China; State Key Laboratory of Petroleum Pollution Control, Beijing 102206, China.

Shale gas drilling wastewater is a challenging waste stream generated in gas industries. It is a mixture of different organic and inorganic compounds. Treatment of this complex wastewater relies on a suitable technology for the removal of small suspended particles and dissolved elements. This study employed electrocoagulation (EC) as an efficient method for shale gas drilling wastewater pretreatment. The optimum operating conditions for turbidity, TOC, and Ca removal were determined using a response surface methodology (RSM). The chloride (Cl) removal and residual iron of effluent in the EC process were also tested and evaluated. Based on the analysis of variance (ANOVA), the coefficient of determination (R) was calculated and found to be above 0.86 for all the responses. The maximum removal efficiencies were found to be around 98.3%, 78.5%, and 56.5% for turbidity, TOC, and Ca removal under the optimum conditions, respectively. In order to treat drilling wastewater by EC process both efficiently and economically, the following operating parameters are recommended: 318 A/m for current density, 20 min for reaction time and 4.4 for initial pH. A total operation cost of 0.80 US$/m was estimated under these conditions.
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http://dx.doi.org/10.1016/j.scitotenv.2021.148436DOI Listing
June 2021

Investigation on the Sampling Frequency and Channel Number for Force Myography Based Hand Gesture Recognition.

Sensors (Basel) 2021 Jun 3;21(11). Epub 2021 Jun 3.

College of Communication Engineering, Hangzhou Dianzi University, Hangzhou 310018, China.

Force myography (FMG) is a method that uses pressure sensors to measure muscle contraction indirectly. Compared with the conventional approach utilizing myoelectric signals in hand gesture recognition, it is a valuable substitute. To achieve the aim of gesture recognition at minimum cost, it is necessary to study the minimum sampling frequency and the minimal number of channels. For purpose of investigating the effect of sampling frequency and the number of channels on the accuracy of gesture recognition, a hardware system that has 16 channels has been designed for capturing forearm FMG signals with a maximum sampling frequency of 1 kHz. Using this acquisition equipment, a force myography database containing 10 subjects' data has been created. In this paper, gesture accuracies under different sampling frequencies and channel's number are obtained. Under 1 kHz sampling rate and 16 channels, four of five tested classifiers reach an accuracy up to about 99%. Other experimental results indicate that: (1) the sampling frequency of the FMG signal can be as low as 5 Hz for the recognition of static movements; (2) the reduction of channel number has a large impact on the accuracy, and the suggested channel number for gesture recognition is eight; and (3) the distribution of the sensors on the forearm would affect the recognition accuracy, and it is possible to improve the accuracy via optimizing the sensor position.
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http://dx.doi.org/10.3390/s21113872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200028PMC
June 2021

Enhancement of Patchoulol Production in Multiple Engineering Strategies.

J Agric Food Chem 2021 Jul 1;69(27):7572-7580. Epub 2021 Jul 1.

The Key Laboratory of Industrial Biotechnology of Ministry of Education, School of Biotechnology, Jiangnan University, 1800 Lihu Avenue, Wuxi 214122, People's Republic of China.

As a natural sesquiterpene compound with numerous biological activities, patchoulol has extensive applications in the cosmetic industry and potential usage in pharmaceuticals. Although several patchoulol-producing microbial strains have been constructed, the low productivity still hampers large-scale fermentation. possesses the ease of genetic manipulation and simple nutritional requirements and does not comprise competing pathways for the farnesyl diphosphate (FPP) precursor, showing its potential for patchoulol biosynthesis. Here, combinatorial strategies were applied to produce patchoulol in . The initial strain was constructed, and it produced 14 mg/L patchoulol after fermentation optimization. Patchoulol synthase (PTS) was engineered by semirational design, resulting in improved substrate binding affinity and a patchoulol titer of 40.3 mg/L; the patchoulol titer reached 66.2 mg/L after fusing of PTS with FPP synthase. To further improve the patchoulol production, the genome of an efficient chassis strain was engineered by deleting the competitive routes for acetate, lactate, ethanol, and succinate synthesis and cumulatively enhancing the expression of efflux transporters, which improved patchoulol production to 338.6 mg/L. When tested in a bioreactor, the patchoulol titer and productivity were further improved to 970.1 mg/L and 199 mg/L/d, respectively, and were among the highest levels reported using mineral salt medium.
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http://dx.doi.org/10.1021/acs.jafc.1c02399DOI Listing
July 2021

C3 ester side chain plays a pivotal role in the antitumor activity of Maytansinoids.

Biochem Biophys Res Commun 2021 Aug 15;566:197-203. Epub 2021 Jun 15.

State Key Laboratory of Biotherapy and Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, PR China. Electronic address:

Maytansinoids, the chemical derivatives of Maytansine, are commonly used as potent cytotoxic payloads in antibody-drug conjugates (ADC). Structure-activity-relationship studies had identified the C3 ester side chain as a critical element for antitumor activity of maytansinoids. The maytansinoids bearing the methyl group at C3 position with D configuration were about 100 to 400-fold less cytotoxic than their corresponding L-epimers toward various cell lines. The detailed mechanism of how chirality affects the anticancer activity remains elusive. In this study, we determined the high-resolution crystal structure of tubulin in complex with maytansinol, L-DM1-SMe and D-DM1-SMe. And we found the carbonyl oxygen atom of the ester moiety and the tail thiomethyl group at C3 side chain of L-DM1-SMe form strong intramolecular interaction with the hydroxyl at position 9 and the benzene ring, respectively, fixing the bioactive conformation and enhancing the binding affinity. Additionally, ligand-based and structure-based virtually screening methods were used to screen the commercially macrocyclic compounds library, and 15 macrocyclic structures were picketed out as putatively new maytansine-site inhibitors. Our study provides a possible strategy for the rational discovery of next-generation maytansine site inhibitors.
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http://dx.doi.org/10.1016/j.bbrc.2021.05.071DOI Listing
August 2021

Separated parabiont reveals the fate and lifespan of peripheral-derived immune cells in normal and ischaemia-induced injured kidneys.

Open Biol 2021 Jun 9;11(6):200340. Epub 2021 Jun 9.

Division of Nephrology, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei 430030, People's Republic of China.

Immune cell infiltration plays a key role in acute kidney injury (AKI) to chronic kidney disease (CKD) progression. T lymphocytes, neutrophils, monocytes/macrophages and other immune cells regulate inflammation, tissue remodelling and repair. To determine the kinetics of accumulation of various immune cell populations, we established an animal model combining parabiosis and separation surgery to explore the fate and lifespan of peripheral leucocytes that migrate to the kidney. We found that peripheral T lymphocytes could survive for a long time (more than 14 days), whereas peripheral neutrophils survived for a short time in both healthy and ischaemia-induced damaged kidneys. Nearly half of the peripheral-derived macrophages disappeared after 14 days in normal kidneys, while their existing time in the inflammatory kidneys was prolonged. A fraction of F4/80 macrophages were renewed from the circulating monocyte pool. In addition, we found that after renal ischaemia reperfusion, neutrophils increased significantly in the early phase, and T lymphocytes mainly accumulated in the late stage, whereas macrophages infiltrated throughout AKI-CKD progression and were sustained longer in injured as opposed to normal kidneys. In conclusion, peripheral-derived macrophages, T lymphocytes and neutrophils exhibit different lifespans in the kidney, which may play different roles during AKI-CKD progression.
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http://dx.doi.org/10.1098/rsob.200340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187026PMC
June 2021

Recent Progress on Tubulin Inhibitors with Dual Targeting Capabilities for Cancer Therapy.

J Med Chem 2021 Jun 8;64(12):7963-7990. Epub 2021 Jun 8.

State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, Innovation Center of Nursing Research, National Clinical Research Center for Geriatrics, West China Hospital, and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, Sichuan, China.

Microtubules play a crucial role in multiple cellular functions including mitosis, cell signaling, and organelle trafficking, which makes the microtubule an important target for cancer therapy. Despite the great successes of microtubule-targeting agents in the clinic, the development of drug resistance and dose-limiting toxicity restrict their clinical efficacy. In recent years, multitarget therapy has been considered an effective strategy to achieve higher therapeutic efficacy, in particular dual-target drugs. In terms of the synergetic effect of tubulin and other antitumor agents such as receptor tyrosine kinases inhibitors, histone deacetylases inhibitors, DNA-damaging agents, and topoisomerase inhibitors in combination therapy, designing dual-target tubulin inhibitors is regarded as a promising approach to overcome these limitations and improve therapeutic efficacy. In this Perspective, we discussed rational target combinations, design strategies, structure-activity relationships, and future directions of dual-target tubulin inhibitors.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00100DOI Listing
June 2021

Metabolic reprogramming of terminally exhausted CD8 T cells by IL-10 enhances anti-tumor immunity.

Nat Immunol 2021 06 24;22(6):746-756. Epub 2021 May 24.

Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

T cell exhaustion presents one of the major hurdles to cancer immunotherapy. Among exhausted CD8 tumor-infiltrating lymphocytes, the terminally exhausted subset contributes directly to tumor cell killing owing to its cytotoxic effector function. However, this subset does not respond to immune checkpoint blockades and is difficult to be reinvigorated with restored proliferative capacity. Here, we show that a half-life-extended interleukin-10-Fc fusion protein directly and potently enhanced expansion and effector function of terminally exhausted CD8 tumor-infiltrating lymphocytes by promoting oxidative phosphorylation, a process that was independent of the progenitor exhausted T cells. Interleukin-10-Fc was a safe and highly efficient metabolic intervention that synergized with adoptive T cell transfer immunotherapy, leading to eradication of established solid tumors and durable cures in the majority of treated mice. These findings show that metabolic reprogramming by upregulating mitochondrial pyruvate carrier-dependent oxidative phosphorylation can revitalize terminally exhausted T cells and enhance the response to cancer immunotherapy.
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http://dx.doi.org/10.1038/s41590-021-00940-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610876PMC
June 2021

Discovery of Novel and Potent -Methyl-d-aspartate Receptor Positive Allosteric Modulators with Antidepressant-like Activity in Rodent Models.

J Med Chem 2021 05 3;64(9):5551-5576. Epub 2021 May 3.

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.

-Methyl-d-aspartate receptors (NMDARs) are glutamate-gated Na and Ca-permeable ion channels involved in excitatory synaptic transmission and synaptic plasticity. NMDAR hypofunction has long been implicated in the pathophysiology including major depressive disorders (MDDs). Herein, we report a series of furan-2-carboxamide analogues as novel NMDAR-positive allosteric modulators (PAMs). Through structure-based virtual screen and electrophysiological tests, FS2921 was identified as a novel NMDAR PAM with potential antidepressant effects. Further structure-activity relationship studies led to the discovery of novel analogues with increased potentiation. Compound caused a significant increase in NMDAR excitability and impressive activity in the forced swimming test. Moreover, compound showed no significant inhibition of hERG or cell viability and possessed a favorable PK/PD profile. Our study presented a series of novel NMDAR PAMs and provided potential opportunities for discovering of new antidepressants.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02018DOI Listing
May 2021

Direct Imaging of Integrated Circuits in CPU with 60 nm Super-Resolution Optical Microscope.

Nano Lett 2021 05 27;21(9):3887-3893. Epub 2021 Apr 27.

Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.

Far-field super-resolution optical microscopies have achieved incredible success in life science for visualization of vital nanostructures organized in single cells. However, such resolution power has been much less extended to material science for inspection of human-made ultrafine nanostructures, simply because the current super-resolution optical microscopies modalities are rarely applicable to nonfluorescent samples or unlabeled systems. Here, we report an antiphase demodulation pump-probe (DPP) super-resolution microscope for direct optical inspection of integrated circuits (ICs) with a lateral resolution down to 60 nm. Because of the strong pump-probe (PP) signal from copper, we performed label-free super-resolution imaging of multilayered copper interconnects on a small central processing unit (CPU) chip. The label-free super-resolution DPP optical microscopy opens possibilities for easy, fast, and large-scale electronic inspection in the whole pipeline chain for designing and manufacturing ICs.
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http://dx.doi.org/10.1021/acs.nanolett.1c00403DOI Listing
May 2021

Eradication of large established tumors by drug-loaded bacterial particles via a neutrophil-mediated mechanism.

J Control Release 2021 06 17;334:52-63. Epub 2021 Apr 17.

State Key Laboratory of Biotherapy and Cancer center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu 610041, China; Experimental and Research Animal Institute, Sichuan University, Chengdu 610041, China. Electronic address:

The treatment of large established tumors remains a significant challenge and is generally hampered by poor drug penetration and intrinsic drug resistance of tumor cells in the central tumor region. In the present study, we developed bacterial particles (BactPs) to deliver chemotherapeutics into the tumor mass by hijacking neutrophils as natural cell-based carriers. BactPs loaded with doxorubicin, 5-fluorosuracil, or paclitaxel induced significantly greater tumor regression than unconjugated drugs. This effect was mediated by the ability of BactPs to incorporate chemotherapeutics and serve as vascular disrupting agents that trigger innate host responses and recruit phagocytic neutrophils. Vascular disruption resulted in extensive cell death in the central areas of the tumor mass. Recruited neutrophils acted as natural cellular carriers to deliver engulfed BactPs, which ensured drug delivery into the tumor mass and cytotoxic effects in areas that are normally inaccessible to traditional chemotherapy. Thus, BactPs eradicate large established tumors by functioning as vascular disrupters and natural drug carriers for neutrophil-mediated chemotherapy.
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http://dx.doi.org/10.1016/j.jconrel.2021.04.015DOI Listing
June 2021

Electroconvulsive therapy in a catatonic patient with subdural hematoma.

Psychiatry Clin Neurosci 2021 Apr 13. Epub 2021 Apr 13.

Department of Psychiatry, Sengkang General Hospital, Singapore Health Services, Singapore.

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http://dx.doi.org/10.1111/pcn.13218DOI Listing
April 2021

Discovery of Novel Benzimidazole and Indazole Analogues as Tubulin Polymerization Inhibitors with Potent Anticancer Activities.

J Med Chem 2021 04 31;64(8):4498-4515. Epub 2021 Mar 31.

School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.

Novel indazole and benzimidazole analogues were designed and synthesized as tubulin inhibitors with potent antiproliferative activities. Among them, compound exhibited the strongest inhibitory effects on the growth of cancer cells with an average IC value of 50 nM, slightly better than colchicine. exhibited nearly equal potency against both, a paclitaxel-resistant cancer cell line (A2780/T, IC = 9.7 nM) and the corresponding parental cell line (A2780S, IC = 6.2 nM), thus effectively overcoming paclitaxel resistance . The crystal structure of in complex with tubulin was solved to 2.45 Å resolution by X-ray crystallography, and its direct binding was confirmed to the colchicine site. Furthermore, displayed significant antitumor efficacy in a melanoma tumor model with tumor growth inhibition rates of 78.70% (15 mg/kg) and 84.32% (30 mg/kg). Collectively, this work shows that is a promising lead compound deserving further investigation as a potential anticancer agent.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01837DOI Listing
April 2021

Structure-based development of three- and four-antibody cocktails against SARS-CoV-2 via multiple mechanisms.

Cell Res 2021 05 29;31(5):597-600. Epub 2021 Mar 29.

CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.

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http://dx.doi.org/10.1038/s41422-021-00497-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005859PMC
May 2021

Illicium verum and Eucommia ulmoides leaf extracts promote nutrient availability and antioxidant capacity in piglets by upregulating duodenal and jejunal Nrf2/TNF-α.

J Anim Physiol Anim Nutr (Berl) 2021 Mar 26. Epub 2021 Mar 26.

Department of Animal Sciences and Technology, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian City, Shandong Province, China.

The effect of Illicium verum extracts (IVE) or Eucommia ulmoides leaf extracts (ELE) on nutrient availability, duodenal and jejunal antioxidant ability of Duroc ×Landrace × Yorkshire (DLY) and Chinese native Licha-black (LCB) piglets was investigated. Ninety-six piglets (48 DLY and 48 LCB respectively) without significant difference in body weight (11.22 ± 0.32 kg) were used in a 2 × 4 factorial design. Animals were randomly allocated to four treatments, and each had four replicates with three DLY and three LCB piglets. Treatments were basal diet (CON) and basal diet with 500 mg/kg IVE, 250 mg/kg ELE and 50 mg/kg chlortetracycline (CHL) respectively. Animals were placed individually for 7-days adaptation following 42-days test. Results showed the significant interaction (p < 0.05) between dietary treatments and pig species in activity of total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px), content of malondialdehyde (MDA), and α-tumour necrosis factor (TNF-α), nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2/TNF-α at mRNA and protein level in duodenum and jejunum of DLY and LCB piglets. The IVE and ELE increased (p < 0.05) activity of GSH-Px and T-SOD, and the Nrf2/TNF-α at mRNA and protein level, however, the decreased (p < 0.05) MDA content, and TNF-α at mRNA and protein level in duodenum and jejunum were observed. The CHL decreased (p < 0.05) activity of GSH-Px and T-SOD, TNF-α and Nrf2 at mRNA and protein level in duodenum, but increased (p < 0.05) MDA content and Nrf2/TNF-α in jejunum. DLY piglets had higher (p < 0.05) nutrient digestibility (organic matter, crude protein and gross energy), availability (biological value and net protein utilization), MDA content, and TNF-α at mRNA and protein level in jejunum, and had lower (p < 0.05) activity of GSH-Px and T-SOD, and Nrf2 and Nrf2/TNF-α at mRNA and protein level in duodenum and jejunum than LCB. In conclusion, the 500 mg/kg IVE and 250 mg/kg ELE improved the nutrient availability, and the improvement of antioxidant capacity is realized by activating the Nrf2/TNF-α of duodenum and jejunum. The CHL had adverse effects on antioxidant ability of DLY and LCB piglets. The results showed that the nutrient digestion and absorption capacity of DLY were stronger than that of LCB piglets, but the antioxidant capacity was lower than that of LCB piglets. Therefore, the IVE and ELE are recommended as a new potential alternative to antibiotics in piglets' diets.
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http://dx.doi.org/10.1111/jpn.13534DOI Listing
March 2021

Chromosome 8 gain is associated with high-grade transformation in MPNST.

JCI Insight 2021 Mar 22;6(6). Epub 2021 Mar 22.

Department of Internal Medicine, Division of Oncology, Washington University in St. Louis, St. Louis, Missouri, USA.

One of the most common malignancies affecting adults with Neurofibromatosis type 1 (NF1) is the malignant peripheral nerve sheath tumor (MPNST), an aggressive and often fatal sarcoma that commonly arises from benign plexiform neurofibromas. Despite advances in our understanding of MPNST pathobiology, there are few effective therapeutic options, and no investigational agents have proven successful in clinical trials. To further understand the genomic heterogeneity of MPNST, and to generate a preclinical platform that encompasses this heterogeneity, we developed a collection of NF1-MPNST patient-derived xenografts (PDX). These PDX were compared with the primary tumors from which they were derived using copy number analysis, whole exome sequencing, and RNA sequencing. We identified chromosome 8 gain as a recurrent genomic event in MPNST and validated its occurrence by FISH in the PDX and parental tumors, in a validation cohort, and by single-cell sequencing in the PDX. Finally, we show that chromosome 8 gain is associated with inferior overall survival in soft-tissue sarcomas. These data suggest that chromosome 8 gain is a critical event in MPNST pathogenesis and may account for the aggressive nature and poor outcomes in this sarcoma subtype.
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http://dx.doi.org/10.1172/jci.insight.146351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026192PMC
March 2021

A Rationale for Drug Design Provided by Co-Crystal Structure of IC261 in Complex with Tubulin.

Molecules 2021 Feb 10;26(4). Epub 2021 Feb 10.

Department of Clinical Research Management, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.

Microtubules composed of α/β tubulin heterodimers are an essential part of the cytoskeleton of eukaryotic cells and are widely regarded as targets for cancer chemotherapy. IC261, which is discovered as an ATP-competitive inhibitor of serine/threonine-specific casein kinase 1 (CK1), has shown its inhibitory activity on microtubule polymerization in recent studies. However, the structural information of the interaction between tubulin and IC261 is still unclear. Here, we provided a high-resolution (2.85 Å) crystal structure of tubulin and IC261 complex, revealed the intermolecular interaction between tubulin and IC261, and analyzed the structure-activity relationship (SAR). Subsequently, the structure of tubulin-IC261 complex was compared with tubulin-colchicine complex to further elucidate the novelty of IC261. Furthermore, eight optimal candidate compounds of new IC261-based microtubule inhibitors were obtained through molecular docking studies. In conclusion, the co-crystal structure of tubulin-IC261 complex paves a way for the design and development of microtubule inhibitor drugs.
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http://dx.doi.org/10.3390/molecules26040946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916759PMC
February 2021

Detection of SARS-CoV-2 and Its Mutated Variants via CRISPR-Cas13-Based Transcription Amplification.

Anal Chem 2021 02 29;93(7):3393-3402. Epub 2021 Jan 29.

Department of Respiratory and Critical Care Medicine, West China Medical School/West China Hospital, Sichuan University, Chengdu 610041, China.

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global health emergency, and its gene mutation and evolution further posed uncertainty of epidemic risk. Herein, we reported a light-up CRISPR-Cas13 transcription amplification method, which enables the detection of SARS-CoV-2 and its mutated variants. Sequence specificity was ensured by both the ligation process and Cas13a/crRNA recognition, allowing us to identify viral RNA mutation. Light-up RNA aptamer allows sensitive output of amplification signals via target-activated ribonuclease activity of CRISPR-Cas13a. The RNA virus assay has been designed to detect coronavirus, SARS-CoV-2, Middle East respiratory syndrome (MERS), and SARS, as well as the influenza viruses such as, H1N1, H7N9, and H9N2. It was accommodated to sense as low as 82 copies of SARS-CoV-2. Particularly, it allowed us to strictly discriminate key mutation of the SARS-CoV-2 variant, D614G, which may induce higher epidemic and pathogenetic risk. The proposed RNA virus assays are promising for point-of-care monitoring of SARS-CoV-2 and its risking variants.
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http://dx.doi.org/10.1021/acs.analchem.0c04303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860141PMC
February 2021

Self-inhibition effect of metal incorporation in nanoscaled semiconductors.

Proc Natl Acad Sci U S A 2021 Jan;118(4)

National Laboratory of Solid State Microstructures, College of Engineering and Applied Sciences, Nanjing University, Nanjing 210093, People's Republic of China;

There has been a persistent effort to understand and control the incorporation of metal impurities in semiconductors at nanoscale, as it is important for semiconductor processing from growth, doping to making contact. Previously, the injection of metal atoms into nanoscaled semiconductor, with concentrations orders of magnitude higher than the equilibrium solid solubility, has been reported, which is often deemed to be detrimental. Here our theoretical exploration reveals that this colossal injection is because gold or aluminum atoms tend to substitute Si atoms and thus are not mobile in the lattice of Si. In contrast, the interstitial atoms in the Si lattice such as manganese (Mn) are expected to quickly diffuse out conveniently. Experimentally, we confirm the self-inhibition effect of Mn incorporation in nanoscaled silicon, as no metal atoms can be found in the body of silicon (below 10 atoms per cm) by careful three-dimensional atomic mappings using highly focused ultraviolet-laser-assisted atom-probe tomography. As a result of self-inhibition effect of metal incorporation, the corresponding field-effect devices demonstrate superior transport properties. This finding of self-inhibition effect provides a missing piece for understanding the metal incorporation in semiconductor at nanoscale, which is critical not only for growing nanoscale building blocks, but also for designing and processing metal-semiconductor structures and fine-tuning their properties at nanoscale.
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http://dx.doi.org/10.1073/pnas.2010642118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848686PMC
January 2021

Contributing Factors Affecting the Severity of Metro Escalator Injuries in the Guangzhou Metro, China.

Int J Environ Res Public Health 2021 01 14;18(2). Epub 2021 Jan 14.

Key Laboratory of Road and Traffic Engineering of the State Ministry of Education, College of Transportation Engineering, Tongji University, Shanghai 201804, China.

Urban rail transit has become one of the indispensable modes of public transportation in large cities. Escalators are ubiquitous in metro stations, as passengers typically use escalators when entering or leaving a metro station. Thus, escalators have become an accident-prone location. To develop suitable prevention strategies, it is necessary to understand the risk factors that affect the severity of escalator accidents. This study analyzed 967 escalator passenger accidents that occurred in the Guangzhou Metro from 2013 to 2015. The Haddon matrix was used to evaluate the interaction of humans, escalators, and environmental factors before, during, and after accidents. Then, the contributing factors associated with the severity levels were determined based on chi-square tests. Passengers aged 66 years and older are more vulnerable to serious injuries ( < 0.001), and previous health conditions are significantly related to the severity of the passenger's injuries ( = 0.002). The weather conditions (rainy days) are also significantly related to the severity of escalator accident injuries ( = 0.039), and injured people with head injuries are at greater risk of being severely injured ( < 0.001). The analysis results of these risk factors can provide theoretical support for the metro operators to develop reasonable and effective preventive measures to reduce the escalator risk.
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http://dx.doi.org/10.3390/ijerph18020651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828651PMC
January 2021

Severe glomerular C3 deposition indicates severe renal lesions and a poor prognosis in patients with immunoglobulin A nephropathy.

Histopathology 2021 May 13;78(6):882-895. Epub 2021 Mar 13.

Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Aims: Glomerular complement 3 (C3) deposition is often observed in renal biopsies of patients with IgA nephropathy (IgAN); however, the relationship between the intensity of C3 deposition and the long-term prognosis of IgAN has rarely been reported. In this retrospective study, we aimed to evaluate the prognostic value of glomerular C3 deposition for IgAN progression.

Methods And Results: From June 2009 to June 2010, a total of 136 adult patients with IgAN were enrolled in the study. According to the intensity of glomerular C3 deposition, patients were divided into a glomerular C3 group (34 patients) and a glomerular C3 group (102 patients). The levels of clinical parameters, glomerular immune complexes, histopathological features, and serum cytokines of the two groups were compared. On the basis of an average of 105 months of follow-up, the predictive value of glomerular C3 deposition for IgAN progression was also investigated. Patients in the C3 group had more severe glomerular IgA, IgG, IgM, and complement factor H deposition, a higher percentage of mesangial hypercellularity (M1), and higher levels of segmental glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis (T2), and crescents (C2) than those in the C3 group. Renal biopsies in the C3 group showed higher densities of interstitial inflammatory cells and higher levels of serum interferon-γ than those in the C3 group. Multivariate Cox regression analysis revealed that a higher intensity of glomerular C3 deposition remained as an independent predictor of serum creatinine doubling and end-stage renal disease.

Conclusions: A high intensity of glomerular C3 deposition is associated with the severity of renal lesions, and predicts long-term poor renal survival for IgAN patients.
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http://dx.doi.org/10.1111/his.14318DOI Listing
May 2021

Folate-mediated one-carbon metabolism: a targeting strategy in cancer therapy.

Drug Discov Today 2021 Mar 11;26(3):817-825. Epub 2020 Dec 11.

State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, China; The Research Units of West China, Chinese Academy of Medical Sciences, China. Electronic address:

Folate-mediated one-carbon metabolism (FOCM) supports vital events for the growth and survival of proliferating cells. Nucleotide synthesis and DNA methylation are the biochemical bases of cancers that are highly dependent on FOCM. Recent studies revealed that FOCM is connected with redox homeostasis and epigenetics in cancer. Furthermore, folate-metabolizing enzymes, such as serine hydroxymethyltransferase 2 (SHMT2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), are associated with the development of cancers, including breast cancer, highlighting their potential application in tumor-targeted therapy. Therefore, targeting metabolizing enzymes, especially SHMT2 and MTHFD2, provides a novel strategy for cancer treatment. In this review, we outline current understanding of the functions of SHMT2 and MTHFD2, discussing their expression, potential functions, and regulatory mechanism in cancers. Furthermore, we discuss examples of inhibitors of SHMT2 and MTHFD2.
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http://dx.doi.org/10.1016/j.drudis.2020.12.006DOI Listing
March 2021

Fuzzy Evaluation of Crowd Safety Based on Pedestrians' Number and Distribution Entropy.

Entropy (Basel) 2020 Jul 30;22(8). Epub 2020 Jul 30.

School of Communication Engineering, Hangzhou Dianzi University, Hangzhou 310000, China.

Crowd video monitoring and analysis is a hot topic in computer vision and public management. The pre-evaluation of crowd safety is beneficial to the prediction of crowd status to avoid the occurrence of catastrophic events. This paper proposes a method to evaluate crowd safety based on fuzzy inference. Pedestrian's number and distribution uniformity are considered in a fuzzy inference system as two kinds of attributes of a crowd. Firstly, the pedestrian's number is estimated by the number of foreground pixels. Then, the distribution uniformity of a crowd is calculated using distribution entropy by dividing the monitoring scene into several small areas. Furthermore, through the fuzzy operation, the fuzzy system is constructed by using two input variables (pedestrian's number and distribution entropy) and one output variable (crowd safety status). Finally, inference rules between the crowd safety state and the pedestrian's number and distribution uniformity are constructed to obtain the pre-evaluation of the safety state of the crowd. Three video sequences extracted from different scenes are used in the experiment. Experimental results show that the proposed method can be used to evaluate the safety status of the crowd in a monitoring scene.
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http://dx.doi.org/10.3390/e22080832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517432PMC
July 2020

High-resolution X-ray structure of three microtubule-stabilizing agents in complex with tubulin provide a rationale for drug design.

Biochem Biophys Res Commun 2021 01 30;534:330-336. Epub 2020 Nov 30.

Cancer Center, West China Hospital, Sichuan University, And Collaborative Innovation Center of Biotherapy, Chengdu, 610041, People's Republic of China; Precision Medicine Research Center, Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China. Electronic address:

Microtubule is a key component of cytoskeleton and has been considered as an important target for the treatment of cancer. In particular, the tubulin taxane-site inhibitors such as taxol analogs and epothilones have achieved great success in clinical trials. However, the structural basis of many taxane-site inhibitors is still lacking in exploring their mechanism of action. We here reported crystal complex structures for three taxane-site inhibitors, Ixabepilone, Epothilone B, and Epothilone D, which were determined to 2.4 Å, 2.4 Å, and 2.85 Å, respectively. The crystal structures revealed that these taxane-site inhibitors possess similar binding modes to that of Epothilone A at the taxane site, e.g. making critical hydrogen-bonding interactions with multiple residues on the M-loop, which facilitating the tubulin polymerization. Furthermore, we summarized the binding modes of almost all taxane-site inhibitors and identified novel taxane-site ligands with simpler chemical structures through virtual screening. On this basis, new derivatives with higher binding affinity to tubulin were designed and developed, which can form additional hydrogen bond interactions with tubulin. Overall, this work determined the mechanism of action of epothilones and provided a structural basis to design reasonably novel taxane-site inhibitors with simpler structure and improved pharmacokinetic properties.
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http://dx.doi.org/10.1016/j.bbrc.2020.11.082DOI Listing
January 2021

Structure-based development of human antibody cocktails against SARS-CoV-2.

Cell Res 2021 01 1;31(1):101-103. Epub 2020 Dec 1.

CAS Key Laboratory of Infection and Immunity, National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.

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http://dx.doi.org/10.1038/s41422-020-00446-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705432PMC
January 2021

Effects of Dietary Zearalenone Exposure on the Growth Performance, Small Intestine Disaccharidase, and Antioxidant Activities of Weaned Gilts.

Animals (Basel) 2020 Nov 19;10(11). Epub 2020 Nov 19.

Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Department of Animal Sciences and Technology, Shandong Agricultural University, No. 61 Daizong Street, Tai'an 271018, China.

Zearalenone (ZEA) is a secondary metabolite with estrogenic effects produced by fungi and mainly occurs as a contaminant of grains such as corn and wheat. ZEA, to which weaned gilts are extremely sensitive, is the main toxin detected in corn-soybean meal diets. Our aim was to examine the effects of ZEA on the growth performance, intestinal disaccharidase activity, and anti-stress capacity of weaned gilts. Twenty 42-day-old healthy Duroc × Landrace × Large White weaned gilts (12.84 ± 0.26 kg) were randomly divided into control and treatment (diet containing 1.04 mg/kg ZEA) groups. The experiment included a 7-day pre-trial period followed by a 35-day test period, all gilts were euthanized and small intestinal samples were collected and subjected to immunohistochemical and western blot analyses. The results revealed that inclusion of 1.04 mg/kg ZEA in the diet significantly reduced the activities of lactase, sucrase, and maltase in the duodenum, jejunum, and ileum of gilts. Similarly, the activities of superoxide dismutase and glutathione peroxidase in the duodenum, jejunum, and ileum, and activities of catalase in the jejunum and ileum were reduced ( < 0.05). Conversely, the content of malondialdehyde in the duodenum, jejunum, and ileum, and the integrated optical density (IOD), IOD in single villi, and the mRNA and protein expression of heat shock protein 70 (Hsp70) were significantly increased ( < 0.05). The results of immunohistochemical analyses revealed that the positive reaction of Hsp70 in the duodenum, jejunum, and ileum of weaned gilts was enhanced in the ZEA treatment, compared with the control. The findings of this study indicate the inclusion of ZEA (1.04 mg/kg) in the diet of gilts reduced the activity of disaccharidase enzymes and induced oxidative stress in the small intestine, thereby indicating that ZEA would have the effect of reducing nutrient absorption in these animals.
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http://dx.doi.org/10.3390/ani10112157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699518PMC
November 2020

The high-resolution X-ray structure of vinca-domain inhibitors of microtubules provides a rational approach for drug design.

FEBS Lett 2021 01 10;595(2):195-205. Epub 2021 Jan 10.

Cancer Center, West China Hospital, Sichuan University, Chengdu, China.

Tubulin vinca-domain ligands can inhibit microtubule polymerization, causing cell death in mitosis, and their potential against multiple cancer types has been demonstrated. However, due to drug resistance and toxicities, development of novel vinca-domain ligands is still needed. In this study, we determined the high-resolution crystal structures of vinorelbine, YXD, and Phomopsin A in complex with tubulin at 2.5 Å. Additionally, we recapitulated all previously published high-resolution crystal structures of the vinca binding site to reveal critical residues and the molecular mechanism of vinca-domain ligands interacting with tubulin. Furthermore, we designed putatively novel triazolopyrimidine derivatives by introducing secondary amine groups to establish salt-bridge and H-bond interactions with Asp179 and Asn329 . Our studies provided the structural basis for designing novel tubulin vinca-domain ligands.
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http://dx.doi.org/10.1002/1873-3468.14003DOI Listing
January 2021

Exogenous bone marrow derived-putative endothelial progenitor cells attenuate ischemia reperfusion-induced vascular injury and renal fibrosis in mice dependent on pericytes.

Theranostics 2020 25;10(26):12144-12157. Epub 2020 Oct 25.

Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, Hubei, 430030, China.

Capillaries are composed of endothelial cells and the surrounding mural cells, pericytes. Microvascular repair after injury involves not only the proliferation of endothelial cells but also pericyte-based vessel stabilization. Exogenous bone marrow derived-putative endothelial progenitor cells (b-pEPCs) have the potential for vascular repair; however, their effect on vascular structure stabilization and pericyte-related pathobiological outcomes in the injured kidney has not been fully examined. We applied ischemia-reperfusion (IR) to induce renal vascular injury and renal fibrosis in mice. Platelet-derived growth factor receptor β (PDGFR-β)-DTR-positive mice were generated to deplete pericytes, and exogenous b-pEPCs and the PDGFR-β ligand, PDGF chain B (PDGF-BB), were employed to explore the relationship among b-pEPCs, pericytes, vascular repair, and early renal fibrosis. Administration of b-pEPCs reduced IR-induced pericyte-endothelial detachment, pericyte proliferation, and myofibroblast transition via a paracrine mode, which preserved not only vascular stabilization but also ameliorated IR-initiated renal fibrosis. PDGF-BB upregulated the expression of PDGFR-β, exacerbated vascular abnormality, and pericyte-myofibroblast transition, which were ameliorated by b-pEPCs administration. The exogenous b-pEPCs and their culture medium (CM) induced vascular injury protection, and renal fibrosis was blocked by selective deletion of pericytes. Exogenous b-pEPCs directly protect against IR-induced vascular injury and prevent renal fibrosis by inhibiting the activation of PDGFR-β-positive pericytes.
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http://dx.doi.org/10.7150/thno.48562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667688PMC
June 2021

Multi-Domain Image-to-Image Translation via a Unified Circular Framework.

IEEE Trans Image Process 2021 4;30:670-684. Epub 2020 Dec 4.

The image-to-image translation aims to learn the corresponding information between the source and target domains. Several state-of-the-art works have made significant progress based on generative adversarial networks (GANs). However, most existing one-to-one translation methods ignore the correlations among different domain pairs. We argue that there is common information among different domain pairs and it is vital to multiple domain pairs translation. In this paper, we propose a unified circular framework for multiple domain pairs translation, leveraging a shared knowledge module across numerous domains. One selected translation pair can benefit from the complementary information from other pairs, and the sharing knowledge is conducive to mutual learning between domains. Moreover, absolute consistency loss is proposed and applied in the corresponding feature maps to ensure intra-domain consistency. Furthermore, our model can be trained in an end-to-end manner. Extensive experiments demonstrate the effectiveness of our approach on several complex translation scenarios, such as Thermal IR switching, weather changing, and semantic transfer tasks.
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http://dx.doi.org/10.1109/TIP.2020.3037528DOI Listing
December 2020
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