Publications by authors named "Qing Cheng"

180 Publications

System-wide identification and prioritization of enzyme substrates by thermal analysis.

Nat Commun 2021 02 26;12(1):1296. Epub 2021 Feb 26.

Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.

Despite the immense importance of enzyme-substrate reactions, there is a lack of general and unbiased tools for identifying and prioritizing substrate proteins that are modified by the enzyme on the structural level. Here we describe a high-throughput unbiased proteomics method called System-wide Identification and prioritization of Enzyme Substrates by Thermal Analysis (SIESTA). The approach assumes that the enzymatic post-translational modification of substrate proteins is likely to change their thermal stability. In our proof-of-concept studies, SIESTA successfully identifies several known and novel substrate candidates for selenoprotein thioredoxin reductase 1, protein kinase B (AKT1) and poly-(ADP-ribose) polymerase-10 systems. Wider application of SIESTA can enhance our understanding of the role of enzymes in homeostasis and disease, opening opportunities to investigate the effect of post-translational modifications on signal transduction and facilitate drug discovery.
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http://dx.doi.org/10.1038/s41467-021-21540-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910609PMC
February 2021

MR-LDP: a two-sample Mendelian randomization for GWAS summary statistics accounting for linkage disequilibrium and horizontal pleiotropy.

NAR Genom Bioinform 2020 Jun 4;2(2):lqaa028. Epub 2020 May 4.

Centre for Quantitative Medicine, Health Services & Systems Research, Duke-NUS Medical School, Singapore 169857, Singapore.

The proliferation of genome-wide association studies (GWAS) has prompted the use of two-sample Mendelian randomization (MR) with genetic variants as instrumental variables (IVs) for drawing reliable causal relationships between health risk factors and disease outcomes. However, the unique features of GWAS demand that MR methods account for both linkage disequilibrium (LD) and ubiquitously existing horizontal pleiotropy among complex traits, which is the phenomenon wherein a variant affects the outcome through mechanisms other than exclusively through the exposure. Therefore, statistical methods that fail to consider LD and horizontal pleiotropy can lead to biased estimates and false-positive causal relationships. To overcome these limitations, we proposed a probabilistic model for MR analysis in identifying the causal effects between risk factors and disease outcomes using GWAS summary statistics in the presence of LD and to properly account for horizontal pleiotropy among genetic variants (MR-LDP) and develop a computationally efficient algorithm to make the causal inference. We then conducted comprehensive simulation studies to demonstrate the advantages of MR-LDP over the existing methods. Moreover, we used two real exposure-outcome pairs to validate the results from MR-LDP compared with alternative methods, showing that our method is more efficient in using all-instrumental variants in LD. By further applying MR-LDP to lipid traits and body mass index (BMI) as risk factors for complex diseases, we identified multiple pairs of significant causal relationships, including a protective effect of high-density lipoprotein cholesterol on peripheral vascular disease and a positive causal effect of BMI on hemorrhoids.
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http://dx.doi.org/10.1093/nargab/lqaa028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671398PMC
June 2020

Qualitative Differences in Protection of PTP1B Activity by the Reductive Trx1 or TRP14 Enzyme Systems upon Oxidative Challenges with Polysulfides or HO Together with Bicarbonate.

Antioxidants (Basel) 2021 Jan 14;10(1). Epub 2021 Jan 14.

Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.

Protein tyrosine phosphatases (PTPs) can be regulated by several redox-dependent mechanisms and control growth factor-activated receptor tyrosine kinase phosphorylation cascades. Reversible oxidation of PTPs is counteracted by reductive enzymes, including thioredoxin (Trx) and Trx-related protein of 14 kDa (TRP14), keeping PTPs in their reduced active states. Different modes of oxidative inactivation of PTPs concomitant with assessment of activating reduction have been little studied in direct comparative analyses. Determining PTP1B activities, we here compared the potency of inactivation by bicarbonate-assisted oxidation using HO with that of polysulfide-mediated inactivation. Inactivation of pure PTP1B was about three times more efficient with polysulfides as compared to the combination of bicarbonate and HO. Bicarbonate alone had no effect on PTP1B, neither with nor without a combination with polysulfides, thus strengthening the notion that bicarbonate-assisted HO-mediated inactivation of PTP1B involves formation of peroxymonocarbonate. Furthermore, PTP1B was potently protected from polysulfide-mediated inactivation by either TRP14 or Trx1, in contrast to the inactivation by bicarbonate and HO. Comparing reductive activation of polysulfide-inactivated PTP1B with that of bicarbonate- and HO-treated enzyme, we found Trx1 to be more potent in reactivation than TRP14. Altogether we conclude that inactivation of PTP1B by polysulfides displays striking qualitative differences compared to that by HO together with bicarbonate, also with regard to maintenance of PTP1B activity by either Trx1 or TRP14.
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http://dx.doi.org/10.3390/antiox10010111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828775PMC
January 2021

Systematic construction and validation of an epithelial-mesenchymal transition risk model to predict prognosis of lung adenocarcinoma.

Aging (Albany NY) 2020 12 3;13(1):794-812. Epub 2020 Dec 3.

Department of Critical Care Medicine, First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China.

Epithelial-mesenchymal transition (EMT) has been shown to be linked to a poor prognosis, particularly in patients with non-small-cell lung cancer. Nevertheless, little is known regarding the existence of EMT-related gene signatures and their prognostic values in lung adenocarcinoma (LUAD). In the current study, we systematically profiled the mRNA expression data of patients with LUAD in The Cancer Genome Atlas and Gene Expression Omnibus databases using a total of 1,184 EMT-related genes. The prognostic values of the EMT-related genes used to develop risk score models for overall survival were determined using LASSO and Cox regression analyses. A prognostic signature that consisted of nine unique EMT-related genes was generated using a training set. A nomogram, incorporating this EMT-related gene signature and clinical features of patients with LUAD, was constructed for potential clinical use. Calibration plots, decision-making curves, and receiver operating characteristic curve analysis showed that this model had a good ability to predict the survival of patients with LUAD. The EMT-associated gene signature and prognostic nomogram established in this study were reliable in predicting the survival of patients with LUAD. Thus, we first identified a novel EMT-related gene signature and developed a nomogram for predicting the prognosis of patients with LUAD.
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http://dx.doi.org/10.18632/aging.202186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835007PMC
December 2020

Heterogeneity and effectiveness analysis of COVID-19 prevention and control in major cities in China through time-varying reproduction number estimation.

Sci Rep 2020 12 15;10(1):21953. Epub 2020 Dec 15.

College of Systems Engineering, National University of Defense Technology, Changsha, 410073, People's Republic of China.

Beginning on December 31, 2019, the large-scale novel coronavirus disease 2019 (COVID-19) emerged in China. Tracking and analysing the heterogeneity and effectiveness of cities' prevention and control of the COVID-19 epidemic is essential to design and adjust epidemic prevention and control measures. The number of newly confirmed cases in 25 of China's most-affected cities for the COVID-19 epidemic from January 11 to February 10 was collected. The heterogeneity and effectiveness of these 25 cities' prevention and control measures for COVID-19 were analysed by using an estimated time-varying reproduction number method and a serial correlation method. The results showed that the effective reproduction number (R) in 25 cities showed a downward trend overall, but there was a significant difference in the R change trends among cities, indicating that there was heterogeneity in the spread and control of COVID-19 in cities. Moreover, the COVID-19 control in 21 of 25 cities was effective, and the risk of infection decreased because their R had dropped below 1 by February 10, 2020. In contrast, the cities of Wuhan, Tianmen, Ezhou and Enshi still had difficulty effectively controlling the COVID-19 epidemic in a short period of time because their R was greater than 1.
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http://dx.doi.org/10.1038/s41598-020-79063-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738538PMC
December 2020

Different doses of ovalbumin exposure on dendritic cells determine their genetic/epigenetic regulation and T cell differentiation.

Aging (Albany NY) 2020 11 24;12(24):25432-25451. Epub 2020 Nov 24.

Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

It has been reported that allergen dosage can impact the differentiation of dendritic cells (DCs)-mediated T cells. However, the mechanisms of such dose-dependent differentiation are poorly understood. In this study, bone marrow-derived immature DCs stimulated with Ovalbumin (OVA) of different concentrations (0, 10, 100, 1000, 10000μg/ml, respectively). DCs were then co-cultured with naïve T cells. RNA-sequencing detection and DNA methylation of DCs were performed. We show that when DCs were stimulated with low-dose (10μg/ml), 77 genes were up-regulated and 87 genes down-regulated. Most activated genes were related to ribosome synthesis and ion channel inhibition. At the medium-dose (100μg/ml), 339 genes were up-regulated and 168 genes down-regulated. Most activated genes involved cytokine synthesis and regulation of immune responses. At high-dose (10000μg/ml), 2497 genes were up-regulated and 1156 genes down-regulated. TNF signaling pathway, NF-kappa B signaling pathway, antigen processing and presentation signaling pathway were mostly up-regulated. The related co-stimulators, co-inhibitory molecules, inhibitory cytokines, negative regulating enzymes were highly expressed. The monocarbate, coenzyme, fatty acid, glucolipid, starch, sucrose and other metabolism-related signaling pathways were down-regulated. The profiles of DNA methylation and RNA synthesis of DCs varied with different doses of OVA, which serves to induce T cells to differentiate in various directions.
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http://dx.doi.org/10.18632/aging.104145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803576PMC
November 2020

Expression profile and diagnostic value of circRNAs in peripheral blood from patients with systemic lupus erythematosus.

Mol Med Rep 2021 Jan 10;23(1). Epub 2020 Nov 10.

Department of Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.

Circular RNAs (circRNAs) have gained attention due to their performance in disease diagnosis. However, the characteristics of circRNAs in peripheral blood from patients with systemic lupus erythematosus (SLE) remain unknown. Therefore, the aim of the present study was to determine the expression profile and diagnostic potential of circRNAs in peripheral blood from patients with SLE. The global circRNA expression in the peripheral blood of patients with SLE and healthy controls (HCs) was detected using a circRNA microarray. Then, the expression levels of three upregulated circRNAs were selected for further validation by reverse transcription‑quantitative PCR (RT‑qPCR) in a training set. Moreover, the diagnostic value of these circRNAs was assessed by constructing a receiver operating characteristic curve, and then verified in a blind testing set. In total, 1,566 circRNAs were identified to be dysregulated between patients with SLE and HCs (≥2 fold change, P<0.05). Furthermore, the RT‑qPCR results were consistent with the microarray data, in that all three selected circRNAs, hsa_circ_0082688, hsa_circ_0082689 and hsa_circ_0008675, were significantly upregulated in patients with SLE (P<0.05). Results from the training set demonstrated that the combination of hsa_circ_0082688‑hsa_circ_0082689 may provide the most beneficial diagnostic potential. Moreover, the blind test results indicated that the combination model of hsa_circ_0082688‑hsa_circ_0082689 could effectively discriminate between patients with SLE from patients with rheumatoid arthritis and HCs, with a sensitivity of 91.30%, a specificity of 78.57% and an accuracy of 82.28%. Moreover, the combination model of hsa_circ_0082688‑hsa_circ_0082689 + anti‑dsDNA could more effectively discriminated the SLE group from the control groups, with a sensitivity of 95.65%, a specificity of 100.00% and an accuracy of 98.73%. In addition, correlation analysis results suggested that all three circRNAs in patients with SLE did not correlate with the SLE disease activity index. In conclusion, the expression levels of hsa_circ_0082688‑hsa_circ_0082689 may serve as potential biomarkers for SLE diagnosis.
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http://dx.doi.org/10.3892/mmr.2020.11639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673322PMC
January 2021

Identification of Chromosomal Abnormalities in Early Pregnancy Loss Using a High-Throughput Ligation-Dependent Probe Amplification-Based Assay.

J Mol Diagn 2021 Jan 15;23(1):38-45. Epub 2020 Oct 15.

Department of Prenatal Diagnosis, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China. Electronic address:

Embryonic chromosomal abnormalities are the major cause of miscarriage. An accurate, rapid, and cheap method of chromosome analysis in miscarriage is warranted in clinical practice. Thus, a high-throughput ligation-dependent probe amplification (HLPA)-based method of detecting aneuploidies and copy number variations in miscarriage was developed. A total of 1060 cases of miscarriage were assessed. Each specimen was subjected to quantitative fluorescence (QF)-PCR/HLPA and chromosomal microarray analysis (CMA) in parallel. All 1060 samples were successfully analyzed using both methods; of these samples, 1.7% (18/1060) were identified as having significant maternal cell contamination. Among the remaining 1042 cases without significant maternal cell contamination, QF-PCR/HLPA reached a diagnostic yield of 59.6% (621/1042), which is comparable to the yield of 60.3% (628/1042) with CMA. Compared with CMA results, the sensitivity and specificity of QF-PCR/HLPA in the identification of total pathogenic chromosomal abnormalities were 98.9% and 100%, respectively. Furthermore, the overall prevalence of chromosomal abnormalities in cases of spontaneous abortion was not significantly different from that in cases of recurrent miscarriage (61.3% versus 58.5%). In summary, QF-PCR/HLPA rapidly and accurately identified chromosomal abnormalities at a comparable performance and lower cost as compared with CMA. Combining simplicity and accuracy with cost-effectiveness, QF-PCR/HLPA may serve as a promising approach to routine genetic testing in miscarriage in clinical practice.
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http://dx.doi.org/10.1016/j.jmoldx.2020.10.002DOI Listing
January 2021

Distinct expression profiles of peptides in placentae from preeclampsia and normal pregnancies.

Sci Rep 2020 10 16;10(1):17558. Epub 2020 Oct 16.

Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, 210004, Jiangsu, China.

This study sought to identify potential bioactive peptides from the placenta that are involved in preeclampsia (PE) to obtain information about the prediction, diagnosis and treatment of PE. The liquid chromatography/mass spectrometry was used to perform a comparative analysis of placental peptides in normal and PE pregnancies. Gene ontology (GO), pathway analysis and ingenuity pathway analysis (IPA) were used to evaluate the underlying biological function of the differential peptides based on their protein precursors. Transwell assays and qPCR were used to study the effect of the identified bioactive peptides on the function of HTR-8/SVneo cells. A total of 392 upregulated peptides and 420 downregulated peptides were identified (absolute fold change ≥ 2 and adjusted P value < 0.05). The GO analysis, pathway analysis, and IPA revealed that these differentially expressed peptides play a role in PE. In addition, the up-regulated peptide "DQSATALHFLGRVANPLSTA" derived from Angiotensinogen exhibited effect on the invasiveness of HTR-8/SVneo cells. The current preliminary research not only provides a new research direction for studying the pathogenesis of PE, but also brings new insights for the prediction, diagnosis and treatment of PE.
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http://dx.doi.org/10.1038/s41598-020-74840-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567870PMC
October 2020

The dual beneficial effects of vermiremediation: Reducing soil bioavailability of cadmium (Cd) and improving soil fertility by earthworm (Eisenia fetida) modified by seasonality.

Sci Total Environ 2021 Feb 1;755(Pt 2):142631. Epub 2020 Oct 1.

College of Resources and Environment, Southwest University, Chongqing, 400715, People's Republic of China. Electronic address:

This study aimed to assess earthworm's capability of reducing the bioavailability of cadmium (Cd) in soil and increasing soil fertility with the modification of seasonal variations of ambient temperatures on the efficacy of vermiremediation. Earthworms were exposed in soil fortified with 0, 5, 10, and 20 mg Cd kg, for 7, 14 and 21 days in winter and spring. The bioavailability of Cd in soil, which is represented in the form of diethylenetriaminepentaacetic acid-extractable fraction (DTPA-Cd), were significantly reduced, ranging from 7.9 to 18.3% in winter and 8.8 to 20.8% in spring. Meanwhile, we found earthworm activities could significantly improve the soil fertility as the results of increasing the availability of nitrogen, phosphorous, and potassium in soil, a prominent advantage of vermiremediation in heavy metal-contaminated soil. Although seasonality could increase Cd toxicity in earthworms, higher ambient temperature in spring season also promoted the reduction of Cd bioavailability and the increase of soil fertility, due to significant increase of microbial populations. In conclusion, we reported the dual beneficial effects of vermiremediation in reducing bioavailability of Cd in soil and simultaneously improving soil fertility in which both outcomes were modified by seasonality.
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http://dx.doi.org/10.1016/j.scitotenv.2020.142631DOI Listing
February 2021

A tissue-specific collaborative mixed model for jointly analyzing multiple tissues in transcriptome-wide association studies.

Nucleic Acids Res 2020 11;48(19):e109

Centre for Quantitative Medicine, Health Services & Systems Research, Duke-NUS Medical School, Singapore.

Transcriptome-wide association studies (TWASs) integrate expression quantitative trait loci (eQTLs) studies with genome-wide association studies (GWASs) to prioritize candidate target genes for complex traits. Several statistical methods have been recently proposed to improve the performance of TWASs in gene prioritization by integrating the expression regulatory information imputed from multiple tissues, and made significant achievements in improving the ability to detect gene-trait associations. Unfortunately, most existing multi-tissue methods focus on prioritization of candidate genes, and cannot directly infer the specific functional effects of candidate genes across different tissues. Here, we propose a tissue-specific collaborative mixed model (TisCoMM) for TWASs, leveraging the co-regulation of genetic variations across different tissues explicitly via a unified probabilistic model. TisCoMM not only performs hypothesis testing to prioritize gene-trait associations, but also detects the tissue-specific role of candidate target genes in complex traits. To make full use of widely available GWASs summary statistics, we extend TisCoMM to use summary-level data, namely, TisCoMM-S2. Using extensive simulation studies, we show that type I error is controlled at the nominal level, the statistical power of identifying associated genes is greatly improved, and the false-positive rate (FPR) for non-causal tissues is well controlled at decent levels. We further illustrate the benefits of our methods in applications to summary-level GWASs data of 33 complex traits. Notably, apart from better identifying potential trait-associated genes, we can elucidate the tissue-specific role of candidate target genes. The follow-up pathway analysis from tissue-specific genes for asthma shows that the immune system plays an essential function for asthma development in both thyroid and lung tissues.
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http://dx.doi.org/10.1093/nar/gkaa767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641735PMC
November 2020

ROS1-fusion protein induces PD-L1 expression via MEK-ERK activation in non-small cell lung cancer.

Oncoimmunology 2020 05 6;9(1):1758003. Epub 2020 May 6.

Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

Introduction: Despite some of the oncogenic driver mutations that have been associated with increased expression of programmed death-ligand 1 (PD-L1), the correlation between PD-L1 expression and ROS1 fusion in NSCLC cells, especially for those with Crizotinib resistance has not been fully addressed.

Materials And Methods: The expression of PD-L1 in 30 primary NSCLC tumors with/without ROS1-fusion protein was evaluated by immunohistochemical (IHC) analysis. To assess the correlation between ROS1 fusion and PD-L1 expression, we down-regulated ROS1 with RNA interference or specific inhibitor (Crizotinib) in ROS1-fusion positive NSCLC cell line HCC78; or up-regulate ROS1-fusion gene in an immortalized human bronchial epithelial cell line (HBE). Mouse xenograft models were also used to determine the effect of ROS1 expression on PD-L1 expression . Crizotinib-resistant cell line was generated for measuring the association between Crizotinib resistance and PD-L1 expression.

Results: ROS1-rearrangement in primary NSCLC tumor was significantly associated with up-regulated PD-L1 expression. PD-L1 expression was significantly up-regulated in bronchial epithelial cells after forced expression of ROS1 fusion and was eliminated when HCC78 xenograft mouse models were treated with Crizotinib. We found PD-L1 expression was modulated by MEK-ERK pathway signaling in both parental and Crizotinib-resistant NSCLC cells with ROS1 fusion.

Conclusions: The correlation between ROS1-fusion and PD-L1 overexpression suggested that PD-L1/PD-1 blockade could be the second-line treatment option for the Crizotinib-resistant NSCLC with rearrangement.
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http://dx.doi.org/10.1080/2162402X.2020.1758003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458663PMC
May 2020

Decreased expression of TNFRSF12A in thyroid gland cancer predicts poor prognosis: A study based on TCGA data.

Medicine (Baltimore) 2020 Aug;99(34):e21882

Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei.

Thyroid cancer (TC) is the most well-known endocrine neoplasia as well as a common malignant tumor in the head and neck. Our study was designed to assess the prognostic meaningful of TNFRSF12A expression in TC dependent on data acquired from TCGA and so as to increase further knowledge into the biological pathways involved in TC pathogenesis related TNFRSF12A.Information on gene expression and comparing clinical data were identified and downloaded from TCGA. Gene set enrichment analysis (GSEA) created an arranged list of all genes indicated by their connection with TNFRSF12A expression.Our study cohort included 370 (73.1%) female and 136 (26.9%) male patients. The scatter plot and paired plot showed the difference of TNFRSF12A expression between normal and tumor samples (P < .01). The univariate analysis suggested that TNFRSF12A-low associated essentially with age (HR: 1.15; 95%CI: 1.08-1.22; P < .01), stage (HR: 2.79; 95%CI: 1.43-5.46; I vs IV; P = .003) and tumor stage (HR: 2.39; 95%CI: 1.08-5.30; P = .031). The GSEA results show that type II diabetes mellitus, pantothenate and CoA biosynthesis, adipocytokine signaling pathway, PPAR signaling pathway, mTOR signaling pathway, insulin signaling pathway, are enriched in TNFRSF12A low expression phenotype.TNFRSF12A expression may be a potential useful prognostic molecular biomarker of bad survival in thyroid cancer, in addition, PPAR signaling pathway, insulin signaling pathway, mTOR signaling pathway may be the key pathway controlled by TNFRSF12A in thyroid cancer. Further experimental ought to be performed to demonstrate the biologic effect of TNFRSF12A.
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http://dx.doi.org/10.1097/MD.0000000000021882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447363PMC
August 2020

Diagnosis and treatment of emergency surgeries in otorhinolaryngology, head and neck surgery during the covid-19 outbreak: A single center experience.

World J Otorhinolaryngol Head Neck Surg 2020 Nov 19;6:S16-S21. Epub 2020 May 19.

Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

The 2019 Novel Coronavirus (2019-nCoV, SARS-CoV-2) infection has already been assigned as a Class B infectious disease requiring Class A management strategy according to "the Law on the Prevention and Control of Infectious Diseases of the People's Republic of China" and become a global pandemic. The incidence of emergencies in otorhinolaryngology, head and neck surgery such as foreign bodies in the esophagus and the respiratory tract, epistaxis, laryngeal obstruction with dyspnea, and head and neck trauma are relatively high. Emergency surgeries are required as some of these diseases progress rapidly and probably be life-threatening. In this article, we drafted the recommendations for diagnosis and treatment of emergency surgeries in otorhinolaryngology, head and neck surgery in the epidemic area of novel coronavirus pneumonia based on "Novel Coronavirus Pneumonia Diagnosis and Treatment Plan (Provisional; 7th Edition Revisions)"and WHO guidelines, combined with the experience of emergency surgeries in the Department of Otorhinolaryngology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, which is at the center outbreak area of the SARS-CoV-2 pneumonia (COVID-19) in China, to improve the success rate of treatment for otorhinolaryngology, head and neck surgery emergency surgeries and to reduce the SARS-CoV-2 infection rate in the perioperative period.
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http://dx.doi.org/10.1016/j.wjorl.2020.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236689PMC
November 2020

[Safety comparison of omalizumab and glucocorticoid in rush allergen immunotherapy].

Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2020 Jul;34(7):610-614

Department of Otolaryngology Head and Neck Surgery,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,430022,China.

To observe the safety of omalizumab and glucocorticoid in the dose-increasing phase of rush allergen immunotherapy(RIT). The clinical data of 88 patients with allergic rhinitis treated with RIT were retrospectively studied, including gender, age, pre-treatment total VAS score, blood EOS%, serum total IgE, local and systemic adverse reactions. Of all patients, fifty-seven were treated with omalizumab combined with RIT(experimental group) and thirty-one were treated with hormone/antiallergic drugs combined with RIT(control group). The safety of the two groups was compared in the dose-increasing phase. There was no grade Ⅰ systemic adverse reactions during the whole process in the experimental group, while Grade Ⅱ systemic adverse reactions were 4 cases(7.1%) during the period of hospitalization, 2 cases(3.6%) after the first injection after discharge, zero(0) after the second injection after discharge. No local pruritus and induration were observed. During the period of hospitalization, the first and second injection after discharge, control group had grade Ⅰ level systemic adverse reactions were 1 case(3.4%), 2 cases(6.9%), 1 case(3.4%) at different time point, respectively. Grade Ⅱ systemic adverse reactions were 5 cases(17.2%), 1 case(3.4%), zero(0) at different time point, respectively. Local injection site itching was observed in 8 patients(5 cases were mild and 3 cases were moderate) and 4 cases(13.8%) had induration during hospitalization. Omalizumab combined with RIT not only shortens the duration of dose-increasing phase of specific immunotherapy, but also increases the safety of the dose-increasing phase during hospitalization, the first and second injection after discharge and improves patient compliance.
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http://dx.doi.org/10.13201/j.issn.2096-7993.2020.07.008DOI Listing
July 2020

Identification and targeting of selective vulnerability rendered by tamoxifen resistance.

Breast Cancer Res 2020 07 29;22(1):80. Epub 2020 Jul 29.

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 65, Stockholm, Sweden.

Background: The estrogen receptor (ER)-positive breast cancer represents over 80% of all breast cancer cases. Even though adjuvant hormone therapy with tamoxifen (TMX) is saving lives of patients with ER-positive breast cancer, the acquired resistance to TMX anti-estrogen therapy is the main hurdle for successful TMX therapy. Here we address the mechanism for TMX resistance and explore the ways to eradicate TMX-resistant breast cancer in both in vitro and ex vivo experiments.

Experimental Design: To identify compounds able to overcome TMX resistance, we used short-term and long-term viability assays in cancer cells in vitro and in patient samples in 3D ex vivo, analysis of gene expression profiles and cell line pharmacology database, shRNA screen, CRISPR-Cas9 genome editing, real-time PCR, immunofluorescent analysis, western blot, measurement of oxidative stress using flow cytometry, and thioredoxin reductase 1 enzymatic activity.

Results: Here, for the first time, we provide an ample evidence that a high level of the detoxifying enzyme SULT1A1 confers resistance to TMX therapy in both in vitro and ex vivo models and correlates with TMX resistance in metastatic samples in relapsed patients. Based on the data from different approaches, we identified three anticancer compounds, RITA (Reactivation of p53 and Induction of Tumor cell Apoptosis), aminoflavone (AF), and oncrasin-1 (ONC-1), whose tumor cell inhibition activity is dependent on SULT1A1. We discovered thioredoxin reductase 1 (TrxR1, encoded by TXNRD1) as a target of bio-activated RITA, AF, and ONC-1. SULT1A1 depletion prevented the inhibition of TrxR1, induction of oxidative stress, DNA damage signaling, and apoptosis triggered by the compounds. Notably, RITA efficiently suppressed TMX-unresponsive patient-derived breast cancer cells ex vivo.

Conclusion: We have identified a mechanism of resistance to TMX via hyperactivated SULT1A1, which renders selective vulnerability to anticancer compounds RITA, AF, and ONC-1, and provide a rationale for a new combination therapy to overcome TMX resistance in breast cancer patients. Our novel findings may provide a strategy to circumvent TMX resistance and suggest that this approach could be developed further for the benefit of relapsed breast cancer patients.
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http://dx.doi.org/10.1186/s13058-020-01315-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388523PMC
July 2020

Diabetes increases the mortality of patients with COVID-19: a meta-analysis.

Acta Diabetol 2021 Feb 24;58(2):139-144. Epub 2020 Jun 24.

Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Aims: Nowadays, the ongoing pandemic of COVID-19 caused by the novel coronavirus Syndrome-Coronavirus-2 (SARS-CoV-2) is an emerging, rapidly evolving situation. Complications such as hypertension, diabetes, COPD, cardiovascular disease, and cerebrovascular disease are major risk factors for patients with COVID-19.

Methods: No meta-analysis has explored if or not diabetes related to mortality of patients with COVID-19. Therefore, this meta-analysis first aims to explore the possible clinical mortality between diabetes and COVID-19, analyze if diabetes patients infected with SARS-CoV-2 are exposed to the worst clinical prognostic risk, and to evaluate the reliability of the evidence.

Results: Our results showed a close relationship between diabetes and mortality of COVID-19, with a pooled OR of 1.75 (95% CI 1.31-2.36; P = 0.0002). The pooled data were calculated with the fixed effects model (FEM) as no heterogeneity appeared in the studies. Sensitivity analysis showed that after omitting any single study or converting a random effect model to FEM, the main results still held.

Conclusions: Our meta-analysis showed that diabetes increases the mortality of patients with COVID-19. These results indicated the disturbance of blood glucose in the COVID-19 patients. More importantly, this meta-analysis grades the reliability of evidence for further basic and clinical research into the diabetes dysfunction in COVID-19 patients.
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http://dx.doi.org/10.1007/s00592-020-01546-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311595PMC
February 2021

An age-independent gene signature for monitoring acute rejection in kidney transplantation.

Theranostics 2020 25;10(15):6977-6986. Epub 2020 May 25.

Department of Surgery, Duke University Medical Center, Durham, United States.

Acute rejection (AR) remains a significant problem that negatively impacts long-term renal allograft survival. Numerous therapies are used to prevent AR that differ by center and recipient age. This variability confounds diagnostic methods. : To develop an age-independent gene signature for AR effective across a broad array of immunosuppressive regimens, we compiled kidney transplant biopsy (n=1091) and peripheral blood (n=392) gene expression profiles from 12 independent public datasets. After removing genes differentially expressed in pediatric and adult patients, we compared gene expression profiles from biopsy and peripheral blood samples of patients with AR to those who were stable (STA), using Mann-Whitney U Tests with validation in independent testing datasets. We confirmed this signature in pediatric and adult patients (42 AR and 47 STA) from our institutional biorepository. : We identified a novel age-independent gene network that identified AR from both kidney and blood samples. We developed a 90-probe set signature targeting 76 genes that differentiated AR from STA and found an 8 gene subset (DIP2C, ENOSF1, FBXO21, KCTD6, PDXDC1, REXO2, HLA-E, and RAB31) that was associated with AR. : We used publicly available datasets to create a gene signature of AR that identified AR irrespective of immunosuppression regimen or recipient age. This study highlights a novel model to screen and validate biomarkers across multiple treatment regimens.
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http://dx.doi.org/10.7150/thno.42110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295062PMC
May 2020

DNA Methylation-based Diagnostic and Prognostic Biomarkers for Glioblastoma.

Cell Transplant 2020 Jan-Dec;29:963689720933241

Department of Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Jiangxi, China.

Glioblastomas are the most common primary central nervous system malignancy tumor in adults. Glioblastoma patients have poor prognosis, with an average survival period of approximately 14 mo after diagnosis. To date, there are a limited number of effective treatment methods for glioblastoma, and its molecular mechanisms remain elusive. In this article, we analyzed the key biomarkers and pathways in glioblastoma patients based on gene expression and DNA methylation datasets. The 60 hypomethylated/upregulated genes and 110 hypermethylated/downregulated genes were identified in GSE50923, GSE50161, and GSE116520 microarrays. Functional enrichment analyses indicated that these methylated-differentially expressed genes were primarily involved in collagen fibril organization, chemical synaptic transmission, extracellular matrix-receptor interaction, and GABAergic synapse. The hub genes were screened from a protein-protein interaction network; in selected genes, increased NMB mRNA level was associated with favorable overall survival, while elevated CHI3L1, POSTN, S100A4, LOX, S100A11, IGFBP2, SLC12A5, VSNL1, and RGS4 mRNA levels were associated with poor overall survival in glioblastoma patients. Additionally, CHI3L1, S100A4, LOX, and S100A11 expressions were negatively correlated with their corresponding methylation status. Furthermore, the receiver-operator characteristic curve analysis indicated that CHI3L1, S100A4, LOX, and S100A11 can also serve as highly specific and sensitive diagnostic biomarkers for glioblastoma patients. Collectively, our study revealed the possible methylated-differentially expressed genes and associated pathways in glioblastoma and identified four DNA methylation-based biomarkers of glioblastoma. These results may provide insight on diagnostic and prognostic biomarkers, and therapeutic targets in glioblastoma.
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http://dx.doi.org/10.1177/0963689720933241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563836PMC
June 2020

Data Mining Identifies Six Proteins that Can Act as Prognostic Markers for Head and Neck Squamous Cell Carcinoma.

Cell Transplant 2020 Jan-Dec;29:963689720929308

Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Head and neck squamous cell carcinoma (HNSCC) is a malignant tumor of the upper aerodigestive tract affecting the oral cavity, lips, paranasal sinuses, larynx, and nasopharynx. Proteogenomics combines proteomics and genomics and employs mass spectrometry and high-throughput sequencing technologies to identify novel peptides. The aim of this study was to identify potential protein biomarkers for clinical treatment of HNSCC. To achieve this, we utilized two sets of data, one on proteins from The Cancer Proteome Atlas (TCPA) and the other on gene expression from The Cancer Genome Atlas (TCGA) database, to evaluate dysfunctional proteogenomics microenvironment. Univariate Cox regression analysis was performed to examine the relationship between protein signatures and prognosis. A total of 19 proteins were significantly associated with overall survival (OS) of patients, of which E2F transcription factor 1 (E2F1; HR = 4.557, 95% CI = 1.810 to 11.469) and enhancer of zeste homolog 2 (EZH2; HR = 0.430, 95% CI = 0.187 to 0.984) were the most differentially expressed between patients with longer and shorter OS, respectively. Furthermore, multivariate Cox regression analysis on six proteins (ERALPHA, HER3, BRAF, P27, RAPTOR, and E2F1) was performed to build the prognostic model. The receiver operating characteristic curves were used to determine whether the expression pattern of survival-related proteins could provide an early prediction of the occurrence of HNSCC. Herein, we found an AUC of 0.720. Based on an online database, we identified novel protein markers for the prognosis of HNSCC. The findings of the present study may provide new insights into the development of new and reliable tools for precise cancer intervention.
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http://dx.doi.org/10.1177/0963689720929308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563932PMC
May 2020

The Antimicrobial Peptide LL-37 Promotes Migration and Odonto/Osteogenic Differentiation of Stem Cells from the Apical Papilla through the Akt/Wnt/β-catenin Signaling Pathway.

J Endod 2020 Jul 7;46(7):964-972. Epub 2020 May 7.

Department of Endodontics, Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address:

Introduction: The antimicrobial peptide LL-37, in addition to its broad spectrum of antibacterial function, can promote odontogenesis and osteogenesis. Stem cells from the apical papilla (SCAPs) are essential for the formation of dentin/bonelike tissues. However, little information on these cells is available in regenerative endodontics. This study aimed to evaluate the effects of LL-37 on the proliferation, migration, and differentiation of SCAPs.

Methods: SCAPs were isolated, cultured, and characterized. Cell viability was analyzed by Cell Counting Kit-8 assays (Dojindo, Kumamoto, Japan). Cell migration was investigated by transwell assays. Dentin sialophosphoprotein, dentin matrix protein 1, runt-related transcription factor 2, and osterix were assessed by quantitative polymerase chain reaction and Western blots. Alkaline phosphatase (ALP) activity and ALP staining were assessed to determine the in vitro potential for osteogenic differentiation. The involvement of the Akt/Wnt/β-catenin signaling pathway was also studied.

Results: In the 2.5-μg/mL LL-37 -treated group, cell proliferation and migration were up-regulated. Quantitative polymerase chain reaction and Western blot assays both revealed that LL-37 at 2.5 μg/mL up-regulated odonto/osteogenic markers (dentin sialophosphoprotein, dentin matrix protein 1, runt-related transcription factor 2, and osterix). LL-37 at 2.5 μg/mL significantly promoted ALP activity and increased the staining in SCAPs. In addition, the p-Akt and p-glycogen synthase kinase-3β levels were increased in LL-37-treated SCAPs. The migratory and odonto/osteogenic differentiation capacities of SCAPs were inhibited after treatment with inhibitors LY294002 and XAV-939.

Conclusions: Our study showed that LL-37 at 2.5 μg/mL promoted the migration and odonto/osteogenic differentiation of SCAPs by activating the Akt/Wnt/β-catenin signaling pathway.
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http://dx.doi.org/10.1016/j.joen.2020.03.013DOI Listing
July 2020

Media Exposure, Disaster Experience, and Risk Perception of Rural Households in Earthquake-Stricken Areas: Evidence from Rural China.

Int J Environ Res Public Health 2020 05 6;17(9). Epub 2020 May 6.

College of Management of Sichuan Agricultural University, Chengdu 611130, China.

For effective communication and management of disaster risks, it is important to explore how media exposure and disaster experience related to earthquake events affect residents' prospect ranks of disaster risk perceptions. Using survey data from 327 households located in the Wenchuan and Lushan earthquake regions in China, the ordinary least square method was used to explore the associations among media exposure, severity of disaster experience, and residents' perception of prospect ranks of the possibility and severity of disasters. The results showed the following. (1) Rural households relied predominately on television broadcasts from traditional media, and on mobile phones and internet content from new media to obtain disaster information. From the residents surveyed, 90% believed that a disaster experience was serious, 82% considered that another major earthquake would seriously affect their lives and property, while approximately 40% of the residents did not believe there would be another major earthquake in the next 10 years. (2) Media exposure was negatively correlated with the perceived prospect ranks of the probability and severity of disasters, with traditional media exposure significantly negatively correlated with the perceived prospect ranks of the severity of disasters and new media exposure significantly negatively correlated with the perceived prospect ranks of the probability of disasters. Severity experience was significantly and positively correlated with the perceived prospect ranks of the probability and severity of disasters. (3) New media exposure moderated the relationship between residents' disaster experience and their perception of prospect ranks of the severity of disasters. This study can help deepen our understanding of disaster risk communication and better guide the practice of disaster risk management.
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http://dx.doi.org/10.3390/ijerph17093246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246616PMC
May 2020

Distinct expression and prognostic value of members of SMAD family in non-small cell lung cancer.

Medicine (Baltimore) 2020 03;99(10):e19451

Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China.

Non-small cell lung cancer (NSCLC) is the major cause of cancer mortality worldwide. Though multidisciplinary therapies have been widely used for NSCLC, its overall prognosis remains very poor, presumably owing to lack of effective prognostic biomarkers. SMAD, a well-known transcription factor, plays an essential role in carcinogenesis. Aberrant expression of SMAD have been found in various cancers, and may be regarded as prognostic indicator for some malignancies. However, the expression and prognostic role of SMAD family member, especially at the mRNA level, remain elusive in NSCLC. In the present study, we report the distinct expression and prognostic value of individual SMAD in patients with NSCLC by analyzing several online databases including ONCOMINE, Gene Expression Profiling Interactive Analysis, Human Protein Atlas database, Kaplan-Meier plotter, cBioPortal, and Database for Annotation, Visualization and Integrated Discovery. The mRNA levels of SMAD6/7/9 in NSCLC were significantly down-regulated in NSCLC, and aberrant SMAD2/3/4/5/6/7/9 mRNA levels were all correlated with the prognosis of NSCLC. Collectively, SMAD2/3/4/5/6/7/9 may server as prognostic biomarkers and potential targets for NSCLC, and thus facilitate the customized treatment strategies for NSCLC patients.
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http://dx.doi.org/10.1097/MD.0000000000019451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220383PMC
March 2020

In vitro testicular organogenesis from human fetal gonads produces fertilization-competent spermatids.

Cell Res 2020 03 21;30(3):244-255. Epub 2020 Feb 21.

State Key Laboratory of Reproductive Medicine, Department of Histology and Embryology, Nanjing Medical University, 211166, Nanjing, Jiangsu, China.

Unlike most organs that mature during the fetal period, the male reproductive system reaches maturity only at puberty with the commencement of spermatogenesis. Robust modelling of human testicular organogenesis in vitro would facilitate research into mechanisms of and factors affecting human spermatogenic failure and male fertility preservation in prepubertal tumor patients. Here, we report successful recapitulation of human testicular organogenesis in vitro from fetal gonadal ridge. Our model displayed the formation of mature seminiferous epithelium and self-renewing spermatogonia. Remarkably, in vitro-derived haploid spermatids have undergone meiotic recombination, and showed increased genetic diversity as indicated by genetic analysis. Moreover, these spermatids were able to fertilize oocytes and support subsequent blastocyst formation. The in vitro testicular organogenesis system described here will play an important role in elucidating the regulation of human testis development and maintaining male fertility in prepubertal cancer patients.
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http://dx.doi.org/10.1038/s41422-020-0283-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054335PMC
March 2020

Direct Observation of Methylmercury and Auranofin Binding to Selenocysteine in Thioredoxin Reductase.

Inorg Chem 2020 Mar 12;59(5):2711-2718. Epub 2020 Feb 12.

Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm SE-171 77, Sweden.

Selenoenzymes, containing a selenocysteine (Sec) residue, fulfill important roles in biology. The mammalian thioredoxin reductase selenoenzymes are key regulators of antioxidant defense and redox signaling and are inhibited by methylmercury species and by the gold-containing drug auranofin. It has been proposed that such inhibition is mediated by metal binding to Sec in the enzyme. However, direct structural observations of these classes of inhibitors binding to selenoenzymes have been few to date. Here we therefore have used extended X-ray absorption fine structure as a direct structural probe to investigate binding to the selenium site in recombinant rat thioredoxin reductase 1 (TrxR1). The results demonstrate for the first time the direct and complete binding of the metal atom of the inhibitors to the selenium atom in TrxR1 for both methylmercury and auranofin, indicating that TrxR1 inhibition indeed can be attributed to such direct metal-selenium binding.
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http://dx.doi.org/10.1021/acs.inorgchem.9b03072DOI Listing
March 2020

Multiplex immunohistochemistry/immunofluorescence (mIHC/IF) for PD-L1 testing in triple-negative breast cancer: a translational assay compared with conventional IHC.

J Clin Pathol 2020 Sep 22;73(9):557-562. Epub 2020 Jan 22.

Division of Pathology, Singapore General Hospital, Singapore

Background: Programmed death-ligand 1 (PD-L1) monoclonal antibody therapy has recently gained approval for treating metastatic triple-negative breast cancer (TNBC) -, in particular in the PD-L1 patient subgroup of the recent IMpassion130 trial. The SP142 PD-L1 antibody clone was used as a predictive assay in this trial, but this clone was found to be an outlier in previous harmonisation studies in lung cancer.

Aims: To address the comparability of PD-L1 clones in TNBC, we evaluated the concordance between conventional immunohistochemistry (IHC) and multiplex immunohistochemistry/immunofluorescence (mIHC/IF) that allowed simultaneous quantification of three different PD-L1 antibodies (22C3, SP142 and SP263).

Methods: Our cohort comprised 25 TNBC cases, 12 non-small-cell lung carcinomas and 8 other cancers. EpCAM labelling was used to distinguish tumour cells from immune cells.

Results: Moderate-to-strong correlations in PD-L1 positivity were found between results obtained through mIHC/IF and IHC. Individual concordance rates in the study ranged from 67% to 100%, with Spearman's rank correlation coefficient values up to 0.88.

Conclusions: mIHC/IF represents a promising tool in the era of cancer immunotherapy, as it can simultaneously detect and quantify PD-L1 labelling with multiple antibody clones, and allow accurate evaluation of tumour and immune cells. Clinicians and pathologists require this information to predict patient response to anti-PD-1/PD-L1 therapy. The adoption of this assay may represent a significant advance in the management of therapeutically challenging cancers. Further analysis and assay harmonisation are essential for translation to a routine diagnostic setting.
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http://dx.doi.org/10.1136/jclinpath-2019-206252DOI Listing
September 2020

Overexpression of Long Noncoding RNA Uc.187 Induces Preeclampsia-Like Symptoms in Pregnancy Rats.

Am J Hypertens 2020 04;33(5):439-451

Nanjing Maternity and Child Health Care Hospital, Women's Hospital of Nanjing Medical University, Nanjing, China.

Background: As a serious pregnancy-specific condition, preeclampsia (PE) is a serious pregnancy-specific condition characterized by insufficient trophoblastic invasion and shallow placental implantation. Long noncoding RNA uc.187, which is transcribed from an ultra-conserved region is highly expressed in the placental tissue of patients with PE, is associated with abnormal trophoblast invasion. Therefore, we aimed to further characterize the relationship between uc.187 and PE through in vitro experimental studies to find new targets to treat PE.

Methods: In this study, we constructed PE rat models induced by lipopolysaccharide, experimented with overexpressing uc.187 and performed experiments using HTR-8/SVneo cells.

Results: We found uc.187 was elevated in the placenta of PE rats. By injecting pregnant rats with a lentivirus containing the lncRNA uc.187, we successfully triggered maternal hypertension along with a series of symptoms similar to PE in humans. In vitro experiments demonstrated that high levels of uc.187 lead to decreased trophoblast invasion. In addition, our results revealed that uc.187 had high expression in PE and fetal growth restricted cells, but low expression in placental site trophoblastic tumors compared with the control groups. Results of western blot and cell immunofluorescence indicated that the aberrant biological behavior of HTR-8/SVneo cells were related to the distribution of β-catenin in the cytoplasm and nucleus.

Conclusions: Taken together, our study revealed that uc.187 was negatively correlated to trophoblastic cell invasion, and overexpression of uc.187 could induce PE-like symptoms in a pregnant rat model by affecting the distribution of β-catenin in the cytoplasm and nucleus.
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http://dx.doi.org/10.1093/ajh/hpaa011DOI Listing
April 2020

Characterization of Lead Compounds Targeting the Selenoprotein Thioredoxin Glutathione Reductase for Treatment of Schistosomiasis.

ACS Infect Dis 2020 03 24;6(3):393-405. Epub 2020 Jan 24.

Department of Microbial Pathogens and Immunity, Rush University Medical Center, Chicago, Illinois 60612, United States.

Schistosomiasis is a widespread human parasitic disease currently affecting over 200 million people. Chemotherapy for schistosomiasis relies exclusively on praziquantel. Although significant advances have been made in recent years to reduce the incidence and intensity of schistosome infections, these gains will be at risk should drug-resistant parasites evolve. Thioredoxin glutathione reductase (TGR) is a selenoprotein of the parasite essential for the survival of schistosomes in the mammalian host. Several high-throughput screening campaigns have identified inhibitors of TGR. Follow up analyses of select active compounds form the basis of the present study. We identified eight compounds effective against worms. Compounds - are active against all major species and development stages. The ability of these compounds to target immature worms is especially critical because praziquantel is poorly active against this stage. Compounds -, , and displayed schistosomicidal activity even after only 1 h incubation with the worms. Compounds - meet or exceed standards set by the World Health Organization for leads for schistosomiasis therapy activity. The mechanism of TGR inhibition was studied further with wild-type and mutant TGR proteins. Compounds - were found to induce an nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in TGR, leading to the production of superoxide and hydrogen peroxide. Collectively, this effort has identified several active compound series that may serve as the basis for the development of new schistosomicidal compounds.
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http://dx.doi.org/10.1021/acsinfecdis.9b00354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072008PMC
March 2020

Phenotypic, genetic, and molecular function of msc-2, a genic male sterile mutant in pepper (Capsicum annuum L.).

Theor Appl Genet 2020 Mar 20;133(3):843-855. Epub 2019 Dec 20.

Beijing Key Laboratory of Growth and Developmental Regulation for Protected Vegetable Crops, Department of Vegetable Science, College of Horticulture, China Agricultural University, Beijing, 100193, China.

Key Message: Bulked segregant analysis and fine mapping delimited the pepper genic male sterile (msc-2) locus into a 336 kb region on chromosome 5. A strong candidate gene, Capana05g000766, a homolog of AtMS1, was indentified in this region. Genic male sterility (msc-2) is used to produce hybrid seeds in Northern China. However, no co-segregated markers have been reported or candidate genes controlling this trait have been cloned. Here, bulked segregant analysis and genotyping of an F population and a 18Q5431AB line were employed to fine map msc-2, which was delimited to a 336 kb region. In this region, Capana05g000766 was a homolog of AtMS1, which encodes a plant homeodomain finger involved in tapetum development. A "T" deletion in the Capana05g000766 locus leads to a premature stop codon, which may cause a loss-of-function mutation. Real-time PCR analysis revealed that Capana05g000766 was an anther-specific gene and down-regulation of the gene resulted in male sterility. Therefore, Capana05g000766 was identified as the strongest candidate gene for the msc-2 locus. Allelism tests showed that msc-1 and msc-2 were nonallelic, and bimolecular fluorescence complementation analysis indicated that the two genes did not interact directly with each other at the protein level. As msc-1 and msc-2 are homologs of AtDYT1 and AtMS1 in Arabidopsis, they may play similar roles in tapetum development in genic male sterile peppers, and Msc-1 might be up stream of Msc-2 in the regulation of other genes involved in tapetum development.
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http://dx.doi.org/10.1007/s00122-019-03510-1DOI Listing
March 2020

A compartmental approach to isosteviol's disposition in Sprague-Dawley rats.

Naunyn Schmiedebergs Arch Pharmacol 2020 06 9;393(6):1003-1011. Epub 2019 Dec 9.

Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, China.

Isosteviol has been reported to reverse hypertrophy and related inflammatory responses in in vitro models representative of cardiac muscle cells. The disposition of isosteviol is, however, characterized by secondary peaks and long plasma residence time despite reports of a relatively short half-life in liver fractions. The present study describes a compartmental approach to modelling the secondary peaks characteristic of isosteviol's concentration-time data in Sprague-Dawley rats. Oral (4 mg/kg) and intravenous (4 mg/kg) doses of isosteviol were administered to male and female Sprague-Dawley rats. Plasma samples collected between 0 and 72 h, and total bile secreted in 24 h, were analysed for isosteviol content with LC-MS/MS techniques. The disposition of isosteviol was, thereafter, described with a structural model that accounted for the sampling, liver and biliary secretion compartments, with a gap-time characterizing the accumulation and subsequent emptying of isosteviol for re-absorption. The half-life of isosteviol following oral dosing was about 103% greater in female rats than in the male, and the model-derived area under the concentration-time curve (AUC) in 72 h was about 756% greater in female animals than in males. Following the administration of intravenous doses of isosteviol, half-life and AUC in 24 h were about 332% and 595%, respectively, higher in female rats than in males. Isosteviol equivalent secreted into bile over 24 h accounted for about 94% of orally administered dose in male rats, and about 59% of oral dose in females. These findings show a differential systemic removal of isosteviol in Sprague-Dawley rats, likely explainable by gender-related differences in the glucuronidation-capacity of isosteviol.
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http://dx.doi.org/10.1007/s00210-019-01757-5DOI Listing
June 2020