Publications by authors named "Tao Lu"

630 Publications

Expression and Functional Relevance of ANXA1 in Hypopharyngeal Carcinoma with Lymph Node Metastasis.

Onco Targets Ther 2021 25;14:1387-1399. Epub 2021 Feb 25.

Department of Otolaryngology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.

Purpose: The purpose of this study is to investigate the expression and functional role of Annexin (ANXA1) in lymph node (LN) metastasis of hypopharyngeal carcinoma (HSCC).

Methods: Differentially expressed genes in tissue from HSCC with or without LN metastasis were obtained from a previous RNA sequencing experiment. The presence of LN metastasis is determined by pathological diagnosis after neck dissection. ANXA1 expression was detected by qRT-PCR and Western blotting. Immunohistochemistry was used to detect the expression of ANXA1 in 74 cases of HSCC and normal control tissues. We also evaluated the clinical significance of ANXA1 in HSCC. Differentially expressed genes related to ANXA1 were analyzed using bioinformatic tools, and potential mechanisms of action of ANXA1 were assessed using in vitro experiments. In these in vitro experiments, cell proliferation was detected by CCK8 staining, and colony formation, migration and invasion were assessed using Transwell assays, and apoptosis as well as cell cycle status were quantified by flow cytometry.

Results: ANXA1 was significantly downregulated in HSCC with LN metastasis. The survival rate of patients with low ANXA1 expression was significantly worse than that of patients with high ANXA1 expression (p<0.05). Silencing ANXA1 in cell culture experiments promoted the proliferation, migration and invasion of FaDu cells, inhibited apoptosis, and increased the proportion of cells in S phase. We furthermore found that the mRNA expression of ANXA1 was positively correlated with Yap1 expression (p<0.0001). Our in vitro experiments showed that ANXA1 regulates the expression of Yap1, and over-expression of Yap1 could reverse the effect of ANXA1 silencing on cancer cell progression.

Conclusion: Our findings suggest that ANXA1 is a putative LN metastasis suppressor gene in tumor, which may suppress the LN metastasis of HSCC by regulating the expression of Yap1.
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http://dx.doi.org/10.2147/OTT.S292287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920586PMC
February 2021

Pancreatic metastasis from squamous cell lung cancer: computed tomography and magnetic resonance imaging findings.

J Int Med Res 2021 Feb;49(2):300060521996188

Department of Hepatobiliary surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.

Metastatic lesions of the pancreas are uncommon. The incidence of pancreatic involvement with squamous cell carcinoma is the lowest among the different histological subtypes of lung cancer. We present the clinical data, pathological findings, and imaging features of two cases of pancreatic metastasis from squamous cell lung cancer with a literature review. A 75-year-old man and a 67-year-old man were both diagnosed with metastatic pancreatic tumors from squamous cell lung cancer during a multidisciplinary team discussion. Both patients were misdiagnosed as having a neuroendocrine tumor of the pancreas by imaging examination before surgery. Squamous cell lung cancer metastasis to the pancreas is extremely rare, and the atypical clinical and radiological presentations make it difficult to distinguish metastatic tumors from primary pancreatic tumors.
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http://dx.doi.org/10.1177/0300060521996188DOI Listing
February 2021

Follistatin-like 1 deficiency impairs T cell development to promote lung metastasis of triple negative breast cancer.

Aging (Albany NY) 2021 Feb 26;13. Epub 2021 Feb 26.

Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing, China.

Our study aims to detect the underlying mechanism of the suppressive effect of Follistatin-like 1 (FSTL1) on lung metastasis of triple negative breast cancer (TNBC). We found that FSTL1 had no effect on the proliferation and metastasis of 4T1 cells in , while in the tumor-bearing Fstl1 heterozygous () mice, the number of anti-tumor T lymphocytes in the lung was significantly reduced with the increase in lung metastasis. Impaired development of T cells can cause dysfunction of adaptive immune system, which promotes cancer metastasis. Therefore the effect of FSTL1 on T cell development was further investigated. Lower population of T cells in periphery and decreased proliferation of CD4 CD8 double negative (DN) thymocytes and impairment development of T cells were found in mice. Furthermore, high expression of FSTL1 in medullary thymus epithelial (mTEC) cells and decreased mRNA expression of inducible costimulator on activated T-cell ligand ( in mTEC were detected. Combining other studies that the generation of ICOSL by mTEC cells promotes CD4 single positive (SP) thymocytes to produce IL-2, which promotes T cell development. Our results indicate FSTL1 deficiency in mTEC cells impairs T cell development to promote the lung metastasis of TNBC.
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http://dx.doi.org/10.18632/aging.202579DOI Listing
February 2021

Updating and identifying three novel variants of the gene in Chinese Han patients with psoriasis.

J Genet 2020 ;99

Department of Dermatology, Huashan Hospital, Shanghai Medical College of Fudan University, Shanghai 200040, People's Republic of China.

Psoriasis-2 (PSORS2) is caused by the heterozygous mutation of the caspase recruitment domain 14 () gene on chromosome 17q25. To evaluate the contribution of variants in psoriasis of the Chinese Han population, we performed deep sequencing of the gene in 372 Chinese Han patients with psoriasis. The exonic nucleotide variants were confirmed by Sanger sequencing in the affected individuals and 1114 controls. In 27 patients with psoriasis, we identified 15 variations, including three novel variants: c.381C[G (p.Cys127Trp), c.712A[G (p.Met238Val) and c.2260_2261delinsGG (p.Gln754Gly). These findings could enrich and update the Human Gene Mutation Database of variants for psoriasis.
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January 2020

A case report of duodenal perforation caused by imatinib mesylate during adjuvant treatment of gastric stromal tumor.

Int J Clin Pharmacol Ther 2021 Feb 19. Epub 2021 Feb 19.

Imatinib, a tyrosine kinase inhibitor, is frequently used to treat unresectable or metastatic gastrointestinal stromal tumors. The application of this medication is considered an adjuvant treatment of gastrointestinal stromal tumors. It can reduce the postoperative recurrence of the tumors. During the treatment with imatinib, there can be various gastrointestinal adverse reactions, which are mild and can be alleviated following a reduction in the dose. It is rare that perforation of the digestive tract happens after the employment of this medication. This study reported that imatinib mesylate caused bowel perforation in one patient with gastric stromal tumors after its use for 3 months.
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http://dx.doi.org/10.5414/CP203808DOI Listing
February 2021

Macleaya cordata extract, an antibiotic alternative, does not contribute to antibiotic resistance gene dissemination.

J Hazard Mater 2021 Jan 30;412:125272. Epub 2021 Jan 30.

College of Environment, Zhejiang University of Technology, Hangzhou 310032, PR China. Electronic address:

The abuse of antibiotics and their associated health risks are receiving global attention. The use of antibiotic additives in fodder has been banned in the European Union since 2006 and in China since 2020. Antibiotic alternatives are being developed, but their risks to the soil ecosystem remain poorly understood. Here, we compared the effects of the antibiotic oxytetracycline (OTC10, 10 mg/kg) with those of a Macleaya cordata extract (MCE, 10 and 100 mg/kg), the major antibiotic substitute. All tested concentrations of MCE and OTC10 exerted slight effects on the soil microbiome, but OTC10 and MCE100 could interfere with the structures and functions of the gut microbiome and might thus affect the soil ecological functions of Enchytraeus crypticus. Furthermore, OTC10 exposure inevitably increased the antibiotic resistance gene (ARG) abundance by 213%, whereas MCE did not induce ARG dissemination, which explains why MCE is considered to be associated with a low ecological risk. Our research provides the first demonstration of the risks posed by antibiotic alternatives to soil animals from the perspective of environmental toxicology and explores the potential development of antibiotic alternatives associated with a low ecological risk from a new perspective.
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http://dx.doi.org/10.1016/j.jhazmat.2021.125272DOI Listing
January 2021

Tumour microenvironment-based molecular profiling reveals ideal candidates for high-grade serous ovarian cancer immunotherapy.

Cell Prolif 2021 Jan 31:e12979. Epub 2021 Jan 31.

State Key laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.

Objective: Due to limited immunological profiles of high-grade serous ovarian cancer (HGSOC), we aimed to characterize its molecular features to determine whether a specific subset that can respond to immunotherapy exists.

Materials And Methods: A training cohort of 418 HGSOC samples from TCGA was analysed by consensus non-negative matrix factorization. We correlated the expression patterns with the presence of immune cell infiltrates, immune regulatory molecules and other genomic or epigenetic features. Two independent cohorts containing 482 HGSOCs and in vitro experiments were used for validation.

Results: We identified immune and non-immune groups where the former was enriched in signatures that reflect immune cells, infiltration and PD-1 signalling (all, P < 0.001), and presented with a lower chromosomal aberrations but increased neoantigens, tumour mutation burden, and microsatellite instability (all, P < 0.05); this group was further refined into two microenvironment-based subtypes characterized by either immunoactivation or carcinoma-associated fibroblasts (CAFs) and distinct prognosis. CAFs-immune subtype was enriched for factors that mediate immunosuppression and promote tumour progression, including highly expressed stromal signature, TGF-β signalling, epithelial-mesenchymal transition and tumour-associated M2-polarized macrophages (all, P < 0.001). Robustness of these immune-specific subtypes was verified in validation cohorts, and in vitro experiments indicated that activated-immune subtype may benefit from anti-PD1 antibody therapy (P < 0.05).

Conclusion: Our findings revealed two immune subtypes with different responses to immunotherapy and indicated that some HGSOCs may be susceptible to immunotherapies or combination therapies.
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http://dx.doi.org/10.1111/cpr.12979DOI Listing
January 2021

Association Between Blood Pressure Variability and Short-Term Outcome After Intra-arterial Thrombectomy in Acute Stroke Patients With Large-Vessel Occlusion.

Front Neurol 2020 11;11:604437. Epub 2021 Jan 11.

Neurology and Stroke Center, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, China.

The optimal range of blood pressure variability (BPV) for acute stroke patients with large-vessel occlusion (LVO) remains unclear. This study investigated the association between BPV from admission through the first 24 h after intra-arterial thrombectomy (IAT) and short-term outcome in LVO patients. We retrospectively analyzed 257 consecutive patients with LVO stroke who were treated with IAT. BP values were recorded at 2-h intervals from admission through the first 24 h after IAT. BPV, as reflected by pulse pressure variability (PPV), was determined based on standard deviation (SD), coefficient of variation (CV), successive variation (SV), and the difference between maximum and minimum blood pressure (ΔBP; systolic BP minus diastolic BP). The association between BPV and clinical outcome (Modified Rankin Scale score at 90 days) was analyzed by multivariate logistic regression analysis. Of the 257 included patients, 70 had a good outcome at 3 months. PPV from admission through the first 24 h after IAT was independently associated in a graded manner with poor outcome [multivariable-adjusted odds ratios (95% confidence interval) for the highest of PPV were 43.0 (8.7-212.8) for SD, 40.3 (9.8-165.0) for CV, 55.0 (11.2-271.2) for SV, and 40.1 (8.0-201.9) for ΔBP]. The area under the receiver operating characteristic curve (95% confidence interval) of the PPV parameters were 0.924 (0.882-0.965) for SD, 0.886 (0.835-0.938) for CV, 0.932 (0.891-0.973) for SV, and 0.892 (0.845-0.939) for ΔBP, and the Youden index values were 0.740, 0.633, 0.759, and 0.756, respectively. In summary, BPV from admission through the first 24 h after IAT was independently associated with poor outcome at 3 months in patients with LVO, with greater variability corresponding to a stronger association. Thus, PPV may be a clinically useful predictor of functional prognosis in LVO patients treated with IAT.
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http://dx.doi.org/10.3389/fneur.2020.604437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829217PMC
January 2021

Synergistic effects of glyphosate and multiwall carbon nanotubes on Arabidopsis thaliana physiology and metabolism.

Sci Total Environ 2021 Jan 15;769:145156. Epub 2021 Jan 15.

College of Environment, Zhejiang University of Technology, Hangzhou 310032, China. Electronic address:

Agricultural chemicals have the potential to become pollutants that adversely affect plant growth. Interactions between these compounds are likely, but potential synergies are under-researched. Multiwall carbon nanotubes are increasingly finding novel uses in agriculture, as delivery mechanisms and as slow-release fertilizers. There is potential for nanotubes to interact with other agricultural chemicals in unpredictable ways. To investigate this possibility, we examined interactions with glyphosate, a widely used herbicide that is also attracting increasing concern over its potential for non-target effects. Here we examined potential synergistic effects on hydroponically grown Arabidopsis thaliana. Single treatments did not affect plant growth significantly, or did only mildly. However, combined treatment significantly affected both plant root and shoot growth. High-level content of malondialdehyde and up-regulated of metabolic antioxidant molecules in plant indicated that combined group caused the strong oxidative damage, while the decreased of antioxidant enzyme activities indicated an imbalance between reactive oxygen species (ROS)and the antioxidant defense system due to the continuously generated ROS. Besides, several intermediate metabolites of unsaturated fatty acids synthesis pathways were up-regulated in combined treatment, which clarified that combined group changed membrane components. The increase of intermediate metabolites in combined group also reflected more energy consumption in the repairment of the disrupt of combined treatment. The synergistic effect observed was attributed to the accumulation of glyphosate resulting from permeability and transportability of the carbon nanotubes. Overall, the risk of nanotube-herbicide interaction suggests a caution use of nanotubes in agricultural applications.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145156DOI Listing
January 2021

On-chip tunable microdisk laser fabricated on Er-doped lithium niobate on insulator.

Opt Lett 2021 Jan;46(2):380-383

We demonstrate a C-band wavelength-tunable microlaser with an -doped high quality (∼1.8×10) lithium niobate microdisk resonator. With a 976 nm continuous-wave pump laser, lasing action can be observed at a pump power threshold lower than 400 µW at room temperature. Furthermore, the microdisk laser wavelength can be tuned by varying the pump laser power, showing a tuning efficiency of ∼-17.03/ at low pump power below 13 mW, and 10.58 pm/mW at high pump power above 13 mW.
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http://dx.doi.org/10.1364/OL.410608DOI Listing
January 2021

Analysis of mutations in six Chinese families with autosomal dominant polycystic kidney disease.

Am J Transl Res 2020 15;12(12):8123-8136. Epub 2020 Dec 15.

Shengli Clinical Medical College of Fujian Medical University Fuzhou 350001, China.

Autosomal dominant polycystic kidney disease (ADPKD) is the common hereditary kidney disease, resulting from mutations in polycystic kidney disease 1 () and polycystic kidney disease 2 (). Clinical data and genetic features of six Chinese families including ADPKD patients were analyzed via Next generation sequencing (NGS), Sanger sequencing, and multiplex ligation-dependent probe amplification. In family A, the proband (II5) with polycystic kidney (PK), hypertension, left ventricular hypertrophy, and valvular heart disease exhibited a heterozygous nonsense mutation, c.5086C>T (p.Gln1696Ter), in (NM_001009944). In family B, the proband (II3) with PK, polycystic liver (PL), hypertension, hypertrophy of the left ventricle and septum, valvular heart disease, chronic kidney disease (CKD) stage 5, bilateral renal calculi, and right inguinal hernia exhibited a heterozygous missense mutation, c.6695T>C (p.Phe2232Ser), in . In family C, the proband (III1) with PK, PL, seminal vesicle cyst, hypertension, CKD stage 3, hypertrophy of the left ventricle and septum, and valvular heart disease harbored a heterozygous nonsense mutation, c.662T>G (p.Leu221Ter), in (NM_000297). In family D, the proband (III3) with PK, hypertension, and CKD stage 5 harbored a heterozygous missense mutation, c.8311G>A (p.Glu2771Lys), in . In family E, the proband (II1) with PK, PL, hypertension, and CKD stage 5 exhibited a heterozygous deletion mutation, exon15-22, in . In family F, the proband (II2) with PK, PL, CKD stage 3, hypertension, thickened interventricular septum, and valvular heart disease carried a heterozygous missense mutation, c.1649A>G (p.His550Arg), in . Thus, three novel mutation sites which are responsible for ADPKD were discovered in this study.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791523PMC
December 2020

Exclusive Strain Effect Boosts Overall Water Splitting in PdCu/Ir Core/Shell Nanocrystals.

Angew Chem Int Ed Engl 2021 Jan 12. Epub 2021 Jan 12.

School of Materials Science and Engineering, Peking University, Beijing, 100871, China.

Core/shell nanocatalysts are a class of promising materials, which achieve the enhanced catalytic activities through the synergy between ligand effect and strain effect. However, it has been challenging to disentangle the contributions from the two effects, which hinders the rational design of superior core/shell nanocatalysts. Herein, we report precise synthesis of PdCu/Ir core/shell nanocrystals, which can significantly boost oxygen evolution reaction (OER) via the exclusive strain effect. The heteroepitaxial coating of four Ir atomic layers onto PdCu nanoparticle gives a relatively thick Ir shell eliminating the ligand effect, but creates a compressive strain of ca. 3.60%. The strained PdCu/Ir catalysts can deliver a low OER overpotential and a high mass activity. Density functional theory (DFT) calculations reveal that the compressive strain in Ir shell downshifts the d-band center and weakens the binding of the intermediates, causing the enhanced OER activity. The compressive strain also boosts hydrogen evolution reaction (HER) activity and the strained nanocrystals can be served as excellent catalysts for both anode and cathode in overall water-splitting electrocatalysis.
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http://dx.doi.org/10.1002/anie.202016199DOI Listing
January 2021

Clean version: Electrospun fibrinogen scaffolds from discarded blood for wound healing.

J Biomed Mater Res B Appl Biomater 2021 Jan 5. Epub 2021 Jan 5.

Department of Orthopaedics, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.

Immediate reutilization of discarded blood from surgery has not received much attention, leading to the waste of a large amount of autologous blood. We used a concentration gradient and high-voltage electrospinning technology to immediately prepare a scaffold material with high biological activity but without immunogenicity from autologous waste blood collected during surgery. Here, we fabricated and characterized a 90 mg/mL group, 110 mg/mL group, and 130 mg/mL group of fibrinogen (FBG) scaffolds. Analyses revealed that the FBG scaffolds had good film-forming properties and a clear fiber structure. in vitro cell viability experiments confirmed that the cells showed an increasing trend with increasing FBG concentrations. The cells grew well in the scaffold material and secreted more cell matrix. When human bone mesenchymal stem cells (hBMSCs) were cocultured with the scaffold material, the hBMSCs expressed osteogenic and chondrogenic biomarkers. The cellular scaffold complexes from the 3 groups were implanted in four full-thickness round wounds (Φ12 mm) on the dorsal back of each rat, the 130 mg/mL group showed a 90% reduction in wound size and the data compared to other groups were better at 14 day. These results suggest that electrospinning technology-based FBG scaffold materials derived from autologous waste blood may become an ideal tissue engineering scaffold and can be immediately used for autologous hemostasis, anti-adhesion films, and wound dressing in surgery.
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http://dx.doi.org/10.1002/jbm.b.34777DOI Listing
January 2021

Potential Mechanisms for Traditional Chinese Medicine in Treating Airway Mucus Hypersecretion Associated With Coronavirus Disease 2019.

Front Mol Biosci 2020 14;7:577285. Epub 2020 Dec 14.

School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.

Background: The rapid development of coronavirus disease 2019 (COVID-19) pandemic has become a great threat to global health. Its mortality is associated with inflammation-related airway mucus hypersecretion and dysfunction of expectoration, and the subsequent mucus blockage of the bronchioles at critical stage is attributed to hypoxemia, complications, and even death. Traditional Chinese medicine (TCM) has rich experience in expectorant, including treatment of COVID-19 patients with airway mucus dysfunction, yet little is known about the mechanisms. This study is aiming to explore the potential biological basis of TCM herbal expectorant for treating COVID-19.

Objective: To get core herbs with high used frequency applications in the actions of expectoration by using association rule algorithm and to investigate the multitarget mechanisms of core herbs in expectorant formulae for COVID-19 therapies.

Methods: Forty prescriptions for expectorant were retrieved from TCM Formulae. The ingredient compounds and targets of core herbs were collected from the TCMSP database, Gene-Cards, and NCBI. The protein interaction network (PPI) was constructed by SRING, and the network analysis was done by Cytoscape software. Bioconductor was applied for functional enrichment analysis of targets.

Results: The core herbs of expectorant could regulate core pathways (MAP kinase activity, cytokine receptor binding, G-protein-coupled receptor binding, etc.) via interactions of ingredients (glycyrol, citromitin, etc.) on mucin family to eliminate phlegm.

Conclusion: TCM herbal expectorant could regulate MAPK and cytokine-related pathways, thereby modulating Mucin-family to affect mucus generation and clearance and eventually retarding the deterioration of COVID-19 disease.
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http://dx.doi.org/10.3389/fmolb.2020.577285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768030PMC
December 2020

Phosphorylation of the Regulators, a Complex Facet of NF-κB Signaling in Cancer.

Biomolecules 2020 12 26;11(1). Epub 2020 Dec 26.

Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

The nuclear factor kappa B (NF-κB) is a ubiquitous transcription factor central to inflammation and various malignant diseases in humans. The regulation of NF-κB can be influenced by a myriad of post-translational modifications (PTMs), including phosphorylation, one of the most popular PTM formats in NF-κB signaling. The regulation by phosphorylation modification is not limited to NF-κB subunits, but it also encompasses the diverse regulators of NF-κB signaling. The differential site-specific phosphorylation of NF-κB itself or some NF-κB regulators can result in dysregulated NF-κB signaling, often culminating in events that induce cancer progression and other hyper NF-κB related diseases, such as inflammation, cardiovascular diseases, diabetes, as well as neurodegenerative diseases, etc. In this review, we discuss the regulatory role of phosphorylation in NF-κB signaling and the mechanisms through which they aid cancer progression. Additionally, we highlight some of the known and novel NF-κB regulators that are frequently subjected to phosphorylation. Finally, we provide some future perspectives in terms of drug development to target kinases that regulate NF-κB signaling for cancer therapeutic purposes.
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http://dx.doi.org/10.3390/biom11010015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823564PMC
December 2020

N-Heterocyclic Carbene/Magnesium Cocatalyzed Radical Relay Assembly of Aliphatic Keto Nitriles.

Org Lett 2021 Jan 29;23(2):394-399. Epub 2020 Dec 29.

School of Science, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China.

An unprecedented N-heterocyclic carbene and magnesium cocatalyzed three-component acylcyanoalkylation of alkenes with cycloketone oxime esters and aldehydes is presented. This method displayed good scope generality, providing a transition-metal- and photoredox-free pathway to access various multifunctionalized aliphatic keto nitrile structures under mild reaction conditions. Moreover, this strategy is supposed to follow a radical relay mechanism via a single electron transfer event of a Mg/matched Breslow intermediate/oxime ester electron-donating acceptor (EDA) complex.
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http://dx.doi.org/10.1021/acs.orglett.0c03883DOI Listing
January 2021

Structure-based discovery of 1H-indole-2-carboxamide derivatives as potent ASK1 inhibitors for potential treatment of ulcerative colitis.

Eur J Med Chem 2021 Feb 25;211:113114. Epub 2020 Dec 25.

School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China. Electronic address:

Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase (MAPK) family, is implicated in many human diseases. Here, we describe the structural optimization of hit compound 7 and conduct further structure-activity relationship (SAR) studies that result in the development of compound 19 with a novel indole-2-carboxamide hinge scaffold. Compound 19 displays potent anti-ASK1 kinase activity and stronger inhibitory effect on ASK1 in AP1-HEK293 cells than previously described ASK1 inhibitor GS-4997. Besides improved in vitro activity, compound 19 also exhibits an appropriate in vivo PK profile. In a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis (UC), compound 19 shows significant anti-UC efficacy and markedly attenuates DSS-induced body weight loss, colonic shortening, elevation in disease activity index (DAI) and inflammatory cell infiltration in colon tissues. Mechanistically, compound 19 represses the phosphorylation of ASK1-p38/JNK signaling pathways and suppresses the overexpression of inflammatory cytokines. Together, these findings suggest that ASK1 inhibitors can potentially be used as a therapeutic strategy for UC.
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http://dx.doi.org/10.1016/j.ejmech.2020.113114DOI Listing
February 2021

[Results of EGFR Mutations Detected in Pleural Effusion and Its 
Clinical Significance in 132 Patients with Advanced Non-small Cell Lung Cancer: 
A Retrospective Study in A Single Center].

Zhongguo Fei Ai Za Zhi 2020 Dec;23(12):1059-1065

Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.

Background: The lack of pathological quality control standard in detecting epidermal growth factor receptor (EGFR) gene mutation in malignant pleural effusion leads to confusion in the interpretation of detection results and the clinical use of EGFR-tyrosine kinase inhibitor (TKI). Therefore, it is very important to propose quality control standards and guide the detection of EGFR mutation in pleural effusion. The aim of this study is to retrospectively analyze the results of EGFR gene mutation in pleural effusion sediment section according to strict pathological quality control standards, and the therapeutic effect of EGFR-TKIs guided by this detection results.

Methods: From January 2012 to June 2018, the clinical data of patients with pleural effusion collected from Department of Pathology of Peking Union Medical College Hospital were analyzed retrospectively. Among them, 132 patients with relatively complete clinical data and with EGFR gene mutation detection of paraffin-embedded pleural effusion sediment section according to the established quality control standard were included. According to the results of EGFR gene mutation, it was divided into positive group and negative group, and the efficacy of EGFR-TKIs in different groups was compared.

Results: After the centrifugation of pleural effusion, the sediment was embedded in paraffin, sectioned, and observed under the microscope after HE staining. If the number of tumor cells ≥100, it met the pathological quality control standard, and it could be used for subsequent EGFR gene mutation detection. EGFR gene mutations were detected in 72 (54.5%) of 132 patients. EGFR-TKIs were used in 69 of 72 mutation positive patients. Of 60 EGFR mutation negative patients, only 15 used EGFR-TKIs. In EGFR mutation positive group, the disease control rate (DCR) was 95.8%, and the median progression-free survival (PFS) was 11 months. In EGFR mutation negative group, the DCR was 0%, and the median PFS was 1 month. The DCR and PFS were significantly different between the two groups (P<0.05).

Conclusions: According to the pathological quality control standards, the embedded section of pleural fluid sediment can be used to detect EGFR gene mutation, and the results can be used to guide the clinical use of EGFR-TKIs.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2020.104.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786230PMC
December 2020

Tazarotene/Betamethasone Dipropionate Cream in Patients with Plaque Psoriasis: Results of a Prospective, Multicenter, Observational Study.

Dermatology 2020 Dec 22:1-8. Epub 2020 Dec 22.

Department of Dermatology, Peking University First Hospital, Beijing, China.

Background: Topical agents are still the mainstay for the treatment of mild-to-moderate plaque psoriasis, in which fixed combinations play an important role. Tazarotene/betamethasone dipropionate (Taz/BD) cream is a novel fixed combination approved for treating plaque psoriasis in China, but its efficacy and safety have not been verified in a real-world environment.

Objectives: The primary objective was to investigate the efficacy and safety of Taz/BD cream in treating plaque psoriasis. The secondary objectives were to assess its relapse after discontinuation and the efficacy and safety profiles during retreatment.

Methods: A prospective, multicenter, large-scale observational study was conducted. Adult patients with chronic plaque psoriasis involving <20% of the body surface area were enrolled. Taz/BD cream was applied once daily for 4 weeks. Patients who achieved ≥90% improvement in the Psoriasis Area and Severity Index (PASI) from baseline to week 4 were followed up to investigate relapse after drug withdrawal. Relapsed patients underwent another 4-week treatment.

Results: In total, 2,299 eligible patients were enrolled, and 2,095 patients (91.1%) completed the 4-week study. The mean PASI improvement at week 4 was 53.7%, and the PASI 50/75 response rates were 62.5 and 26.8%, respectively. The mean PASI reduction in plaque induration, desquamation and erythema were 58.3, 61.0 and 40.0%, respectively (p < 0.001). Adverse reactions occurred in 445 patients (20.8%) at week 4. The most frequently reported adverse reactions were local skin irritation, including pruritus (10%), pain (6.7%), erythema (6.1%) and desquamation (1.8%). During the post-treatment period, 47 patients (24.0%) relapsed within 8 weeks after drug discontinuation. Forty-five patients were retreated for another 4 weeks, and the PASI 50/75 response rates were 72.7 and 40.9%, respectively. There were no unexpected safety signals during retreatment.

Conclusion: Taz/BD cream is effective and well tolerated in treating mild-to-moderate plaque psoriasis under near real-world conditions and demonstrates efficacy and safety during retreatment.
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http://dx.doi.org/10.1159/000511891DOI Listing
December 2020

Inducible beige adipocytes improve impaired glucose metabolism in interscapular BAT-removal mice.

Biochim Biophys Acta Mol Cell Biol Lipids 2021 Mar 18;1866(3):158871. Epub 2020 Dec 18.

Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China. Electronic address:

Inducible beige adipocytes are emerging as an interesting issue in obesity and metabolism research. There is a neglected possibility that brown adipocytes are equally activated when external stimuli induce the formation of beige adipocytes. Thus, the question is whether beige adipocytes have the same functions as brown adipocytes when brown adipose tissue (BAT) is lacking. This question has not been well studied. Therefore we determine the beneficial effects of beige adipocytes upon cold challenge or CL316243 treatments in animal models of interscapular BAT (iBAT) ablation by surgical denervation. We found that denervated iBAT were activated by cold exposure and CL316243 treatments. The data show that beige adipocytes partly contribute to the improvement of impaired glucose metabolism resulting from denervated iBAT. Thus, we further used iBAT-removal animal models to abolish iBAT functions completely. We found that beige adipocytes upon cold exposure or CL316243 treatments improved impaired glucose metabolism and enhanced glucose uptake in iBAT-removal mice. The insulin signaling was activated in iBAT-removal mice upon cold exposure. Both the activation of insulin signaling and up-regulation of glucose transporter expression were observed in iBAT-removal mice with CL316243 treatments. The data show that inducible beige adipocytes may have different mechanisms to improve impaired glucose metabolism. Inducible beige adipocytes can also enhance energy expenditure and lipolytic activity of white adipose tissues when iBAT is lacking. We provide direct evidences for the beneficial effect of inducible beige adipocytes in glucose metabolism and energy expenditure in the absence of iBAT in vivo.
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http://dx.doi.org/10.1016/j.bbalip.2020.158871DOI Listing
March 2021

Genetic diagnosis history and osteoarticular phenotype of a non-transfusion secondary hemochromatosis.

World J Clin Cases 2020 Dec;8(23):5962-5975

Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, Fujian Province, China.

Background: It is not easy to identify the cause of various iron overload diseases because the phenotypes overlap. Therefore, it is important to perform genetic testing to determine the genetic background of patients.

Aim: To investigate the genetic background of a patient with hemochromatosis complicated by psoriasis on both lower extremities.

Methods: Ten years ago, a 61-year-old male presented with iron overload, jaundice, hemolytic anemia and microcytic hypochromic anemia. Computed tomography of the left knee joint showed enlargement of the tibial medullary cavity and thinned bone cortices. Magnetic resonance imaging showed hepatic hemochromatosis, extensive abnormal signals from bone marrow cavities and nodular lesions in the lateral medullary cavity of the upper left lateral tibia. Single photon emission computed tomography showed radial dots of abnormal concentration in the upper end of the left tibia and radial symmetry of abnormal concentrations in joints of the extremities. The patient showed several hot spot mutations of the and genes detected by next-generation sequencing, but no responsible gene mutation was found. The thalassemia gene was detected by gap-PCR.

Results: The patient was found to carry the -α and -- deletion mutations of the globin gene. These two mutations are common causes of Southeast Asian α-thalassemia, but rarely cause severe widespread non-transfusion secondary hemochromatosis osteoarthropathy. The simultaneous presence of an auxiliary superposition effect of a rare missense mutation of the gene (NM_001142864, c.C4748T, p.A1583V) was considered. Moreover, several rare mutations of the and genes may be involved in the pathogenesis of psoriasis.

Conclusion: The selection of genetic detection methods for hemochromatosis still needs to be based on an in-depth study of the clinical manifestations of the disease.
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http://dx.doi.org/10.12998/wjcc.v8.i23.5962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723718PMC
December 2020

External therapy of Chinese medicine for postherpetic neuralgia: A protocol for systematic review and meta-analysis.

Medicine (Baltimore) 2020 Dec;99(50):e23270

School of Life Science.

Background: Postherpetic neuralgia (PHN), the most common complication of herpes zoster, brings about a health-care burden at both the individual and societal levels. External therapy of Chinese medicine (ETCM) is an effective treatment of PHN generally available in China, yet there is incomplete evidence to evaluate the efficacy and safety of it.

Methods: This protocol is based on the previous reporting items. We will search 3 English databases (PubMed, EMBASE, and the Cochrane Library) and 3 Chinese databases (CNKI, CBM, and Wan Fang Database) until January 2020. RCTs to evaluate the efficacy and safety of external therapy of Chinese medicine for postherpetic neuralgia will be included. The primary outcome will be assessed by VAS or NRS. We will use the criteria provided by Cochrane Handbook 5.3.0 for quality evaluation and risk assessment, and use the Revman 5.3 software for meta-analysis.

Ethics And Dissemination: Ethical approval is not required for systematic review and meta- analysis. The results of this review will be disseminated in a peer-review journal.

Prospero Registration Number: CRD42020163511.
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http://dx.doi.org/10.1097/MD.0000000000023270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738126PMC
December 2020

Exploration of the Effects of Substrate Stiffness on Biological Responses of Neural Cells and Their Mechanisms.

ACS Omega 2020 Dec 29;5(48):31115-31125. Epub 2020 Nov 29.

School of Life Sciences, Beijing University of Chinese Medicine, Beijing 100102, China.

Substrate stiffness, as a critical mechanical factor, has been proven to be an important regulator of biological responses, cellular functions, and disease occurrence. However, the effects of substrate stiffness on the phenotypes and drug responses of neural cells remain largely unknown. In this study, polydimethylsiloxane (PDMS) substrates with different stiffnesses were employed to establish the mechanical microenvironment of tissues of different organs. We studied the influences of stiffness on neural cell phenotypes, including cell viability, cell cycle, cytoskeleton structures, cell stiffness, and drug responses of neural cells for hormesis and therapeutic efficacy in neurodegenerative disorders (NDD). The results showed that the greater the range of maximum stimulatory responses, the bigger the width of the stimulatory dosage and the higher the range of maximum neuroprotective activities of hormetic chemicals in neural cells grown on the soft substrate commensurable to the stiffness of the brain, indicating that neural cells on a rigid substrate are resistant to hormetic and neuroprotective effects of hormetic chemicals against 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD) model. The sensitivity of neural cells on the soft substrate to drug response was attributed to the increased cell viability rate, cell cycle progression, actin stress fibers, focal adhesion formation, and decreased cell stiffness. The promoting effect of the soft substrate and the enhanced hormetic and neuroprotective effect of hormetic chemicals on soft substrates in PC12 cells were confirmed to be mediated by the upregulated EGFR/PI3K/AKT signaling pathway by RNA-Seq and bioinformatics analysis. This study demonstrates that the biomechanical properties of the neural microenvironment play important roles in cell phenotypes and drug responses of neural cells in vitro and suggests that substrate stiffness should be considered in the anti-NDD drug design and treatment.
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http://dx.doi.org/10.1021/acsomega.0c04279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726759PMC
December 2020

The preferred conformation of the tetrafluoro-1,3-dithietaneisopropylamine complex as revealed by rotational spectroscopy.

Phys Chem Chem Phys 2020 Dec;22(48):28339-28344

School of Chemistry and Chemical Engineering, Chongqing University, Daxuecheng South Rd. 55, Chongqing, 401331, China.

The 1 : 1 intermolecular complex formed between tetrafluoro-1,3-dithietane and isopropylamine has been studied in a supersonic-jet using Fourier transform microwave spectroscopy. Two isomers, in which the isopropylamine monomer adopts the gauche or trans conformation, were experimentally observed. Isomer formed by gauche isopropylamine has a higher population than that formed by trans with a relative ratio of 3 : 2, contrary to the relative stability of the isopropylamine monomer. In both isomers, the two moieties are linked through a dominant SN chalcogen bond and cooperative secondary interactions. Natural bond orbital theory analysis confirms that the SN interaction formed by gauche isopropylamine is 3.4 kJ mol-1 stronger than that formed by the trans conformer. Symmetry-adapted perturbation theory energy decomposition analysis points out that the intermolecular interactions in the complex are dominated by electrostatics and remarkable charge transfer in the complexation.
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http://dx.doi.org/10.1039/d0cp05033dDOI Listing
December 2020

Cyanobacterial blooms contribute to the diversity of antibiotic-resistance genes in aquatic ecosystems.

Commun Biol 2020 Dec 4;3(1):737. Epub 2020 Dec 4.

College of Environment, Zhejiang University of Technology, 310032, Hangzhou, People's Republic of China.

Cyanobacterial blooms are a global ecological problem that directly threatens human health and crop safety. Cyanobacteria have toxic effects on aquatic microorganisms, which could drive the selection for resistance genes. The effect of cyanobacterial blooms on the dispersal and abundance of antibiotic-resistance genes (ARGs) of concern to human health remains poorly known. We herein investigated the effect of cyanobacterial blooms on ARG composition in Lake Taihu, China. The numbers and relative abundances of total ARGs increased obviously during a Planktothrix bloom. More pathogenic microorganisms were present during this bloom than during a Planktothrix bloom or during the non-bloom period. Microcosmic experiments using additional aquatic ecosystems (an urban river and Lake West) found that a coculture of Microcystis aeruginosa and Planktothrix agardhii increased the richness of the bacterial community, because its phycosphere provided a richer microniche for bacterial colonization and growth. Antibiotic-resistance bacteria were naturally in a rich position, successfully increasing the momentum for the emergence and spread of ARGs. These results demonstrate that cyanobacterial blooms are a crucial driver of ARG diffusion and enrichment in freshwater, thus providing a reference for the ecology and evolution of ARGs and ARBs and for better assessing and managing water quality.
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http://dx.doi.org/10.1038/s42003-020-01468-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718256PMC
December 2020

A Progressive Fusion Generative Adversarial Network for Realistic and Consistent Video Super-Resolution.

IEEE Trans Pattern Anal Mach Intell 2020 Dec 3;PP. Epub 2020 Dec 3.

How to effectively fuse temporal information from consecutive frames remains to be a non-trivial problem in video super-resolution (SR), since most existing fusion strategies (direct fusion, slow fusion or 3D convolution) either fail to make full use of temporal information or cost too much calculation. To this end, we propose a novel progressive fusion network for video SR, in which frames are processed in a way of progressive separation and fusion for the thorough utilization of spatio-temporal information. We particularly incorporate multi-scale structure and hybrid convolutions into the network to capture a wide range of dependencies. We further propose a non-local operation to extract long-range spatio-temporal correlations directly, taking place of traditional motion estimation and motion compensation (ME&MC). This design relieves the complicated ME&MC algorithms, but enjoys better performance than various ME&MC schemes. Finally, we improve generative adversarial training for video SR to avoid temporal artifacts such as flickering and ghosting. In particular, we propose a frame variation loss with a single-sequence training method to generate more realistic and temporally consistent videos. Extensive experiments on public datasets show the superiority of our method over state-of-the-art methods in terms of performance and complexity. Our code is available at https://github.com/psychopa4/MSHPFNL.
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http://dx.doi.org/10.1109/TPAMI.2020.3042298DOI Listing
December 2020

The Characteristics of Disulfide-Centered Hydrogen Bonds.

Angew Chem Int Ed Engl 2021 Mar 27;60(11):5838-5842. Epub 2021 Jan 27.

School of Chemistry and Chemical Engineering, Chongqing University, Daxuecheng South Rd. 55, 401331, Chongqing, China.

The disulfide-centered hydrogen bonds in the three different model systems of diethyl disulfide⋅⋅⋅H O/H CO/HCONH clusters were characterized by high-resolution Fourier transform microwave spectroscopy and quantum chemical computations. The global minimum energy structures for each cluster are experimentally observed and are characterized by one of the three different S-S⋅⋅⋅H-C/N/O disulfide-centered hydrogen bonds and two O⋅⋅⋅H-C hydrogen bonds. Non-covalent interaction and natural bond orbital analyses further confirm the experimental observations. The symmetry-adapted perturbation theory (SAPT) analysis reveals that electrostatic is dominant in diethyl disulfide⋅⋅⋅H O/HCONH clusters being consistent with normal hydrogen bonds, whilst dispersion takes over in diethyl disulfide⋅⋅⋅H CO cluster. Our study gives accurate structural parameters for the disulfide bond involved non-covalent clusters providing important benchmarking data for the theoretical evaluation of more complex systems.
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http://dx.doi.org/10.1002/anie.202014364DOI Listing
March 2021

Association between BRCA mutations and endometrial carcinoma: a systematic review with meta-analysis.

Arch Gynecol Obstet 2020 Nov 20. Epub 2020 Nov 20.

Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, People's Republic of China.

Purpose: To first investigate on the association between BRCA mutations and endometrial carcinoma. To first evaluate the contribution of tamoxifen use and risk-reducing bilateral salping-oophenrectomy (BSO) on endometrial carcinoma in BRCA carriers.

Methods: A systematic search of electronic databases including the PubMed and EMBASE was conducted to identify publications exploring the association between BRCA mutations and endometrial carcinoma. Finally, single rate meta-analysis and diagnostic meta-analysis were performed.

Results: 11 retrospective studies and 3 prospective studies were included in the meta-analysis, single rate meta-analysis was performed on retrospective studies and prospective studies respectively. We got that incidence of BRCA mutations in patients with endometrial carcinoma is about 0.035, the incidence of endometrial carcinoma in BRCA carriers is about 0.004. Diagnostic meta-analysis performed on prospective studies found that tamoxifen increased incidence of endometrial carcinoma in BRCA carriers.

Conclusions: The incidence of BRCA mutations in patients with endometrial carcinoma is about 0.035 according to present studies, the incidence of endometrial carcinoma in BRCA carriers is about 0.004. Tamoxifen use is a certain risk factor for subsequent endometrial carcinoma, while history of breast cancer or risk-reducing BSO is not associated with incidence of follow-up endometrial carcinoma. The necessity and rationality of prophylactic hysterectomy for BRCA carriers remained to be discussed.
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http://dx.doi.org/10.1007/s00404-020-05887-7DOI Listing
November 2020

The discovery of quinoline derivatives, as NF-κB inducing kinase (NIK) inhibitors with anti-inflammatory effects in vitro, low toxicities against T cell growth.

Bioorg Med Chem 2021 Jan 7;29:115856. Epub 2020 Nov 7.

School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China. Electronic address:

NIK is a critical regulatory protein of the non-classical NF-kB pathway, and its dysregulated activation has been proved to be one of the pathogenic factors in a variety of autoimmune diseases and inflammatory diseases. Nevertheless, its corresponding development of inhibitors faces many obstacles, including the lack of structure types of known inhibitors, immature activity evaluation methods of compounds in vitro. In this study, a series of quinoline derivatives were obtained through rational design and chemical synthesis. Among them, the representative compounds 17c and 24c have excellent inhibitory activities on LPS-induced macrophage (J774) nitric oxide release and anti-Con A-stimulated primary T cell proliferation. This evaluation method has good universality and overcomes the obstacles mentioned above, which are faced by the current inhibitor research to a certain extent. Besides, the compound's toxicity against the growth of T cells under non-stress conditions was evaluated, for the first time, as an indicator for the investigation to avoid potential safety risks. Pharmacokinetic properties evaluation of the less toxic compound 24c confirmed its good metabolic behavior (especially oral properties, F% = 21.7%), and subsequent development value.
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http://dx.doi.org/10.1016/j.bmc.2020.115856DOI Listing
January 2021

Genomic Profiling Comparison of Germline and Non- Carriers Reveals Amplification as a Risk Factor for Non- Carriers in Patients With Triple-Negative Breast Cancer.

Front Oncol 2020 30;10:583314. Epub 2020 Oct 30.

Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China.

Differences in genomic profiling and immunity-associated parameters between germline and non- carriers in TNBC with high tumor burden remain unexplored. This study aimed to compare the differences and explore potential prognostic predictors and therapeutic targets. The study cohort included 21 consecutive TNBC cases with germline mutations and 54 non- carriers with a tumor size ≥ 2 cm and/or ≥1 affected lymph nodes. Differences in clinicopathological characteristics and genomic profiles were analyzed through next-generation sequencing. Univariate Kaplan-Meier analysis and Cox regression model were applied to survival analysis. Immunohistochemistry was used to confirm the consistency between amplification and cyclin E1 protein overexpression. The cohort included 16 and five patients with germline and mutations, respectively. Patients with germline mutations were diagnosed at a significantly younger age and were more likely to have a family history of breast and/or ovarian cancer. Six non- carriers (11.11%) carried germline mutations in other cancer susceptibility genes, including five mutations in five homologous recombination repair (HRR) pathway genes (9.26%) and one mutation in (1.85%). Somatic mutations in HRR pathway genes were found in 22.22 and 14.29% of the non- and carriers, respectively. missense mutation ( = 0.046) and amplification ( = 0.2) were found only in the non- carriers. The median tumor mutation burden (TMB) was 4.1 Muts/Mb, whereas none of the cases had high microsatellite instability (MSI). status did not affect disease-free survival (DFS, = 0.15) or overall survival (OS, = 0.52). amplification was an independent risk factor for DFS in non- carriers with TNBC (HR 13.07, 95% CI 2.47-69.24, = 0.003). Consistency between amplification and cyclin E1 protein overexpression was confirmed with an AUC of 0.967 for cyclin E1 signal intensity. We found differences in genetic alterations between germline and non- carriers with TNBC and a high tumor burden. TMB and MSI may not be suitable predictors of TNBC for immune checkpoint inhibitors. Notably, amplification is a novel potential prognostic marker and therapeutic target for non- carriers with TNBC. Cyclin E1 may be used instead of to improve clinical applicability.
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http://dx.doi.org/10.3389/fonc.2020.583314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662137PMC
October 2020