Publications by authors named "Yong Zeng"

652 Publications

Using Deep Learning in a Monocentric Study to Characterize Maternal Immune Environment for Predicting Pregnancy Outcomes in the Recurrent Reproductive Failure Patients.

Front Immunol 2021 1;12:642167. Epub 2021 Apr 1.

Department of Pediatric and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

Recurrent reproductive failure (RRF), such as recurrent pregnancy loss and repeated implantation failure, is characterized by complex etiologies and particularly associated with diverse maternal factors. It is currently believed that RRF is closely associated with the maternal environment, which is, in turn, affected by complex immune factors. Without the use of automated tools, it is often difficult to assess the interaction and synergistic effects of the various immune factors on the pregnancy outcome. As a result, the application of Artificial Intelligence (A.I.) has been explored in the field of assisted reproductive technology (ART). In this study, we reviewed studies on the use of A.I. to develop prediction models for pregnancy outcomes of patients who underwent ART treatment. A limited amount of models based on genetic markers or common indices have been established for prediction of pregnancy outcome of patients with RRF. In this study, we applied A.I. to analyze the medical information of patients with RRF, including immune indicators. The entire clinical samples set (561 samples) was divided into two sets: 90% of the set was used for training and 10% for testing. Different data panels were established to predict pregnancy outcomes at four different gestational nodes, including biochemical pregnancy, clinical pregnancy, ongoing pregnancy, and live birth, respectively. The prediction models of pregnancy outcomes were established using sparse coding, based on six data panels: basic patient characteristics, hormone levels, autoantibodies, peripheral immunology, endometrial immunology, and embryo parameters. The six data panels covered 64 variables. In terms of biochemical pregnancy prediction, the area under curve (AUC) using the endometrial immunology panel was the largest (AUC = 0.766, accuracy: 73.0%). The AUC using the autoantibodies panel was the largest in predicting clinical pregnancy (AUC = 0.688, accuracy: 78.4%), ongoing pregnancy (AUC = 0.802, accuracy: 75.0%), and live birth (AUC = 0.909, accuracy: 89.7%). Combining the data panels did not significantly enhance the effect on prediction of all the four pregnancy outcomes. These results give us a new insight on reproductive immunology and establish the basis for assisting clinicians to plan more precise and personalized diagnosis and treatment for patients with RRF.
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http://dx.doi.org/10.3389/fimmu.2021.642167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047052PMC
April 2021

LncRNA SNHG8 Serves as an Oncogene in Breast Cancer Through miR-634/ZBTB20 Axis.

Cancer Manag Res 2021 7;13:3017-3028. Epub 2021 Apr 7.

Key Laboratory of Prevention and treatment of cardiovascular and cerebrovascular diseases of Ministry of Education, Jiangxi Provincial Clinical Research Center for Vascular Anomalies, Basic Medical School, Gannan Medical University, Ganzhou, Jiangxi, 341000, People's Republic of China.

Background: Small nucleolus RNA Host Gene 8 (SNHG8) belongs to a subgroup with long non-coding RNAs. LncRNA SNHG8 presents up-regulated in miscellaneous cancers, like gastric cancer, liver cancer, and esophageal squamous cell cancer. Nevertheless, the expression pattern and the pathological function of lncRNA SNHG8 in breast cancer remain obscure.

Methods: We examined the expression levels of lncRNA SNHG8 in the tissue samples and cell lines from breast cancer via RT-qPCR in the present study. The functions of lncRNA SNHG8 on the progression of breast cancer cell were examined by CCK-8, EdU, Transwell chamber assays, and flow cytometry analyses. The expression of proteins was assessed using Western blot assay.

Results: We found that proliferation, migration, and invasion of breast cancer cells were significantly inhibited due to knockdown of lncRNA SNHG8, while inducing apoptosis of these cells. Mechanistically, SNHG8 functioned as an inhibitor of miR-634 in tumor tissues.

Conclusion: LncRNA SNHG8 sponged the miR-634 to increase the expression level of ZBTB20, thus further aggravating the malignancy of breast cancer. Hence, the lncRNA SNHG8-miR-634-ZBTB20 axis may be a promising therapeutic target to treat breast cancers.
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http://dx.doi.org/10.2147/CMAR.S270128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039051PMC
April 2021

Hepatic fibroblast growth factor 21 is involved in mediating functions of liraglutide in mice with dietary challenge.

Hepatology 2021 Apr 13. Epub 2021 Apr 13.

Div. of Advanced Diagnostics, Toronto General Hospital Research Institute, University Health Network, Canada.

Background And Aims: Several studies have shown that expression of hepatic fibroblast growth factor 21 (FGF21) can be stimulated by GLP-1-based diabetes drugs. As GLP-1 receptor (GLP-1R) is unlikely expressed in hepatocytes, we aimed to compare such stimulation in mice and in mouse-hepatocytes; determine the involvement of GLP-1R, and clarify whether FGF21 mediates certain functions of the GLP-1R agonist liraglutide.

Approaches And Results: Liver FGF21 expression was assessed in mice with daily liraglutide injection for 3 days, or in mouse primary hepatocytes (MPH) with direct liraglutide treatment. Effects of liraglutide on metabolic improvement and FGF21 expression were then assessed in high fat diet (HFD)-fed mice, in comparison with the DPP-4 inhibitor sitagliptin. Animal studies were also performed in Glp1r mice and hepatic FGF21 knockout (lFgf21-KO) mice. In wild-type mice with RNA-seq and qRT-PCR, we observed liraglutide-stimulated hepatic Fgf21 expression, and the lack of Glp1r expression in mouse liver. In MPH, liraglutide did not stimulate Fgf21. In HFD-induced obese mice, liraglutide or sitagliptin treatment reduced plasma triglyceride levels, while their effect on reducing body-weight gain was different. Importantly, increased hepatic FGF21 expression was observed in liraglutide-treated but not sitagliptin-treated mice. In HFD-fed Glp1r mice, liraglutide showed no beneficial effects and could not stimulate Fgf21 expression. In lFgf21-KO mice on dietary challenge, body-weight gain attenuation and lipid homeostatic effects of liraglutide was lost or significantly reduced.

Conclusions: We suggest that liraglutide-stimulated hepatic Fgf21 expression may require GLP-1R expressed in extra-hepatic organs. Importantly, we revealed that hepatic FGF21 is required for liraglutide to lower body weight and improve hepatic lipid homeostasis. These observations advanced our mechanistic understanding on function of GLP-1-based drugs in nonalcoholic fatty liver disease (NAFLD).
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http://dx.doi.org/10.1002/hep.31856DOI Listing
April 2021

Pan-ERBB kinase inhibition augments CDK4/6 inhibitor efficacy in oesophageal squamous cell carcinoma.

Gut 2021 Mar 31. Epub 2021 Mar 31.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

Objective: Oesophageal squamous cell carcinoma (OSCC), like other squamous carcinomas, harbour highly recurrent cell cycle pathway alterations, especially hyperactivation of the CCND1/CDK4/6 axis, raising the potential for use of existing CDK4/6 inhibitors in these cancers. Although CDK4/6 inhibition has shown striking success when combined with endocrine therapy in oestrogen receptor positive breast cancer, CDK4/6 inhibitor palbociclib monotherapy has not revealed evidence of efficacy to date in OSCC clinical studies. Herein, we sought to elucidate the identification of key dependencies in OSCC as a foundation for the selection of targets whose blockade could be combined with CDK4/6 inhibition.

Design: We combined large-scale genomic dependency and pharmaceutical screening datasets with preclinical cell line models, to identified potential combination therapies in squamous cell cancer.

Results: We identified sensitivity to inhibitors to the ERBB family of receptor kinases, results clearly extending beyond the previously described minority of tumours with EGFR amplification/dependence, specifically finding a subset of OSCCs with dual dependence on ERBB3 and ERBB2. Subsequently. we demonstrated marked efficacy of combined pan-ERBB and CDK4/6 inhibition in vitro and in vivo. Furthermore, we demonstrated that squamous lineage transcription factor KLF5 facilitated activation of ERBBs in OSCC.

Conclusion: These results provide clear rationale for development of combined ERBB and CDK4/6 inhibition in these cancers and raises the potential for KLF5 expression as a candidate biomarker to guide the use of these agents. These data suggested that by combining existing Food and Drug Administration (FDA)-approved agents, we have the capacity to improve therapy for OSCC and other squamous cancer.
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http://dx.doi.org/10.1136/gutjnl-2020-323276DOI Listing
March 2021

NKG2D as a Cell Surface Marker on γδ-T Cells for Predicting Pregnancy Outcomes in Patients With Unexplained Repeated Implantation Failure.

Front Immunol 2021 10;12:631077. Epub 2021 Mar 10.

Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.

Maternal immune tolerance to semi-allogeneic fetus is essential for a successful implantation and pregnancy. Growing evidence indicated that low cytotoxic activity of γδ-T cells, which is mediated by activation and inhibitory receptors, is important for establishment of maternal immune tolerant microenvironment. However, the correlation between receptors on peripheral blood γδ-T cells, such as NKG2D, CD158a, and CD158b, and pregnancy outcome in patients with unexplained repeated implantation failure (uRIF) remains unclear. In this study, the association between the expression level of these receptors and pregnancy outcome in patients with uRIF was investigated. Thirty-eight women with uRIF were enrolled and divided into two groups: successful group and failed group, according to the pregnancy outcome on different gestational periods. The percentage of NKG2D γδ-T cells in lymphocytes was significantly higher in uRIF patients who had failed clinical pregnancy in subsequent cycle, compared with those who had successful clinical pregnancy. However, there were no differences about the frequencies of CD158a and CD158b γδ-T cells between the successful and failed groups. The receiver operating characteristic curve exhibited that the optimal cut-off value of NKG2D γδ-T cells was 3.24%, with 92.3% sensitivity and 66.7% specificity in predicting clinical pregnancy failure in uRIF patients. The patients with uRIF were further divided into two groups, group 1 (NKG2D γδ-T cells <3.24%) and group 2 (NKG2D γδ-T cells ≥3.24%), based on the cut-off value. The live birth rate of patients in the group 1 and group 2 were 61.5 and 28.0%, respectively. Kaplan-Meier survival curve further suggested that the frequency of NKG2D γδ-T cells in lymphocytes negatively correlated with live birth rate in patients with uRIF. In conclusion, our study demonstrated that the frequency of peripheral blood NKG2D γδ-T cells among lymphocytes is a potential predictor for pregnancy outcome in uRIF patients.
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http://dx.doi.org/10.3389/fimmu.2021.631077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988228PMC
March 2021

TagBiFC technique allows long-term single-molecule tracking of protein-protein interactions in living cells.

Commun Biol 2021 Mar 19;4(1):378. Epub 2021 Mar 19.

State Key Laboratory of Membrane Biology, Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China.

Protein-protein interactions (PPIs) are critical for cellular activity regulation. Visualization of PPIs using bimolecular fluorescence complementation (BiFC) techniques helps to understand how PPIs implement their functions. However, current BiFC is based on fluorescent proteins and the brightness and photostability are suboptimal for single molecule tracking experiments, resulting in either low spatiotemporal resolution or incapability of tracking for extended time course. Here, we developed the TagBiFC technique based on split HaloTag, a self-labeling tag that could conjugate an organic dye molecule and thus offered better brightness and photostability than fluorescent proteins for PPI visualization inside living cells. Through screening and optimization, we demonstrated that the reconstituted HaloTag exhibited higher localization precision and longer tracking length than previous methods. Using TagBiFC, we reveal that the dynamic interactions of transcription factor dimers with chromatin DNA are distinct and closely related to their dimeric states, indicating a general regulatory mechanism for these kinds of transcription factors. In addition, we also demonstrated the advantageous applications of TagBiFC in single nucleosome imaging, light-burden imaging of single mRNA, low background imaging of cellular structures. We believe these superior properties of our TagBiFC system will have broad applications in the studies of single molecule imaging inside living cells.
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http://dx.doi.org/10.1038/s42003-021-01896-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979928PMC
March 2021

CRISPRi screens reveal a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer.

Nat Commun 2021 03 19;12(1):1781. Epub 2021 Mar 19.

Princess Margaret Cancer Center/University Health Network, Toronto, ON, Canada.

Prostate cancer (PCa) risk-associated SNPs are enriched in noncoding cis-regulatory elements (rCREs), yet their modi operandi and clinical impact remain elusive. Here, we perform CRISPRi screens of 260 rCREs in PCa cell lines. We find that rCREs harboring high risk SNPs are more essential for cell proliferation and H3K27ac occupancy is a strong indicator of essentiality. We also show that cell-line-specific essential rCREs are enriched in the 8q24.21 region, with the rs11986220-containing rCRE regulating MYC and PVT1 expression, cell proliferation and tumorigenesis in a cell-line-specific manner, depending on DNA methylation-orchestrated occupancy of a CTCF binding site in between this rCRE and the MYC promoter. We demonstrate that CTCF deposition at this site as measured by DNA methylation level is highly variable in prostate specimens, and observe the MYC eQTL in the 8q24.21 locus in individuals with low CTCF binding. Together our findings highlight a causal mechanism synergistically driven by a risk SNP and DNA methylation-mediated 3D genome architecture, advocating for the integration of genetics and epigenetics in assessing risks conferred by genetic predispositions.
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http://dx.doi.org/10.1038/s41467-021-21867-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979745PMC
March 2021

Assessment of the anti-inflammatory effects of three rhubarb anthraquinones in LPS-Stimulated RAW264.7 macrophages using a pharmacodynamic model and evaluation of the structure-activity relationships.

J Ethnopharmacol 2021 Jun 17;273:114027. Epub 2021 Mar 17.

Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, China. Electronic address:

Ethnopharmacological Relevance: Rhubarb (Rhei Radix et Rhizoma) is a traditional Chinese medicine, has been used as a strong astringent in China to treat inflammation-related diseases, such as acute pancreatitis, acute cholecystitis, appendicitis and so on. Rhein, emodin and aloe-emodin are the important active anthraquinone in rhubarb, and are considered to be the main ingredients contributing to anti-inflammatory.

Aim Of The Study: Rhein, emodin and aloe-emodin, anthraquinones with the same parent structure that are found in rhubarb, have beneficial anti-inflammatory effects in vitro and in vivo. Anthraquinone derivatives also have important clinical roles. However, their pharmacodynamic differences and the structure-activity relationships associated with their anti-inflammatory properties have not been systematically explored. The present study was designed to quantify the effects of three rhubarb anthraquinones on inflammation and to explore the structure-activity relationships of these compounds.

Materials And Methods: In this study, we detected NF-κB phosphorylation, iNOS protein expression, and IL-6 and NO production in LPS-stimulated RAW264.7 cells and then calculated median effect equations and built a dynamic pharmacodynamic model to quantitatively evaluate the efficacy of these three anthraquinones. Additionally, to determine the structure-activity relationships, we investigated the physicochemical properties and molecular electrostatic potentials of the drug molecules.

Results: We found that rhein, emodin, and aloe-emodin exerted at least dual-target (NF-κB, iNOS) inhibition of LPS-induced inflammatory responses. Compared with rhein and emodin, aloe-emodin had a stronger anti-inflammatory effect, and its inhibition of iNOS protein expression was approximately twice that of NF-κB phosphorylation. In addition, aloe-emodin had the strongest hydrophobic effect among the three anthraquinones.

Conclusions: Overall, we concluded that the receptor binding the rhubarb anthraquinones had a hydrophobic pocket. Anthraquinone molecules with stronger hydrophobic effects had higher affinity for the receptor, resulting in greater anti-inflammatory activity. These results suggest that the addition of a hydrophobic group is a potential method for structural modification to design anti-inflammatory anthraquinone derivatives with enhanced potency.
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http://dx.doi.org/10.1016/j.jep.2021.114027DOI Listing
June 2021

Stabilizing a laser frequency by the Pound-Drever-Hall technique with an acousto-optic modulator.

Appl Opt 2021 Feb;60(5):1159-1163

We develop and demonstrate a method of optical phase modulation in the Pound-Drever-Hall (PDH) technique. The phase modulation in this paper is realized by an acousto-optic modulator (AOM) operating in the Bragg diffraction regime. In this process, a light beam separated from a laser (780 nm) is sent through the AOM twice and coupled to a high finesse Fabry-Perot cavity. Then, the light power coupling into the cavity is stabilized by modulating the optical amplitude with this AOM. The coupling light power is stabilized to a level of 10. In the meantime, the PDH error signal is obtained by modulating the optical phase with the same AOM. After the error signal is fed back to the laser current, the laser linewidth is suppressed to approximately 907.91 Hz. This method of phase modulation is simple and convenient, and we believe it can be widely used in modulation transfer spectroscopy and frequency-modulation sideband spectroscopy.
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http://dx.doi.org/10.1364/AO.415011DOI Listing
February 2021

Advances in Analytical Technologies for Extracellular Vesicles.

Anal Chem 2021 03 26;93(11):4739-4774. Epub 2021 Feb 26.

Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States.

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http://dx.doi.org/10.1021/acs.analchem.1c00693DOI Listing
March 2021

Low molecular weight-PAHs induced inflammation in A549 cells by activating PI3K/AKT and NF-κB signaling pathways.

Toxicol Res (Camb) 2021 Jan 25;10(1):150-157. Epub 2021 Jan 25.

Department of Toxicology, School of Public Health, Lanzhou University, No. 199 Donggang West Road, Lanzhou 730000, Gansu, China.

Our previous study has demonstrated that two low molecular weight-polycyclic aromatic hydrocarbons (LMW-PAHs), phenanthrene (Phe) and fluorene (Flu), alone and as a mixture could induce oxidative damage and inflammation in A549 cells. However, the associated mechanisms have not been well discussed. The aim of this study was to further investigate the roles of PI3K/AKT and NF-κB signaling pathways in the inflammatory effects in A549 cells induced by Phe, Flu and their mixture. The results indicated that Phe, Flu and their mixture significantly activated PI3K/AKT and NF-κB signaling pathways by increasing the phosphorylation levels of PI3K, AKT, IκBα and NF-κB p65. In addition, pro-inflammatory cytokine expressions of TNF-α and IL-6 induced by the binary mixture of Phe and Flu were all alleviated by co-treatment with PI3K/AKT and NF-κB specific inhibitors (LY294002 and BAY11-7082). The results suggested that PI3K/AKT and NF-κB signaling pathways played an important role in LMW-PAHs induced inflammation in A549 cells.
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http://dx.doi.org/10.1093/toxres/tfaa105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885328PMC
January 2021

Distinct functions of transforming growth factor-β signaling in c-MYC driven hepatocellular carcinoma initiation and progression.

Cell Death Dis 2021 Feb 19;12(2):200. Epub 2021 Feb 19.

Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.

Dysregulation of transforming growth factor-beta (TGFβ) signaling has been implicated in liver carcinogenesis with both tumor promoting and inhibiting activities. Activation of the c-MYC protooncogene is another critical genetic event in hepatocellular carcinoma (HCC). However, the precise functional crosstalk between c-MYC and TGFβ signaling pathways remains unclear. In the present investigation, we investigated the expression of TGFβ signaling in c-MYC amplified human HCC samples as well as the mechanisms whereby TGFβ modulates c-Myc driven hepatocarcinogenesis during initiation and progression. We found that several TGFβ target genes are overexpressed in human HCCs with c-MYC amplification. In vivo, activation of TGFβ1 impaired c-Myc murine HCC initiation, whereas inhibition of TGFβ pathway accelerated this process. In contrast, overexpression of TGFβ1 enhanced c-Myc HCC progression by promoting tumor cell metastasis. Mechanistically, activation of TGFβ promoted tumor microenvironment reprogramming rather than inducing epithelial-to-mesenchymal transition during HCC progression. Moreover, we identified PMEPA1 as a potential TGFβ1 target. Altogether, our data underline the divergent roles of TGFβ signaling during c-MYC induced HCC initiation and progression.
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http://dx.doi.org/10.1038/s41419-021-03488-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895828PMC
February 2021

Evaluation of endometrial immune status of polycystic ovary syndrome.

J Reprod Immunol 2021 04 2;144:103282. Epub 2021 Feb 2.

Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, China. Electronic address:

Polycystic ovary syndrome (PCOS) is described as a low-grade chronic inflammatory state. However, there are limited studies on the specific endometrial immune status of PCOS patients. Whether this endometrial immune cell pattern is intrinsic to PCOS or the consequence of PCOS-associated obesity is a subject of debate. This study retrospectively included one hundred women diagnosed with PCOS and ninety-five normal fertile controls, which further divided into four groups (normoweight PCOS; overweight PCOS; normoweight control; overweight control) based on body mass index. The percentages of endometrial CD68 macrophages (1.97 % vs. 1.17 %; P < 0.001), CD163 M2 macrophages (2.30 % vs. 1.83 %; P = 0.001), CD1a iDCs (0.044 % vs. 0.029 %; P = 0.002), CD83 mDCs (1.72 % vs. 1.07 %; P < 0.001) and CD8 T cells (2.82 % vs. 1.95 %; P < 0.001) were significantly higher in normoweight PCOS women than normoweight controls. The percentage of CD68 macrophages (2.09 % vs. 1.15 %; P < 0.001) was significantly higher in overweight PCOS women compared with overweight controls. In multivariant linear regression analysis, participants' PCOS status was the main predictors of endometrial CD68 macrophages, CD163 M2 macrophages, CD1a iDCs, CD83 mDCs and CD8 T cells in the whole study population. Additionally, in PCOS group, positive correlations were found between endometrial CD56 NK, CD163 M2 macrophages and QUICKI, indicating there was an association between endometrial immune cells and insulin resistance in PCOS women. Our study suggests that women with PCOS have altered endometrial immune cells, which may reflect a state of chronic low grade inflammation. The chronic inflammation, independent of obesity, may help understand the pathophysiologic mechanisms of intrinsic PCOS.
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http://dx.doi.org/10.1016/j.jri.2021.103282DOI Listing
April 2021

Immune function in X-linked retinoschisis subjects in an AAV8-RS1 phase I/IIa gene therapy trial.

Mol Ther 2021 Feb 15. Epub 2021 Feb 15.

National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA; Department of Ophthalmology, University of California Davis, Davis, CA 95817, USA. Electronic address:

This study explored systemic immune changes in 11 subjects with X-linked retinoschisis (XLRS) in a phase I/IIa adeno-associated virus 8 (AAV8)-RS1 gene therapy trial (ClinicalTrials.gov: NCT02317887). Immune cell proportions and serum analytes were compared to 12 healthy male controls. At pre-dosing baseline the mean CD4/CD8 ratio of XLRS subjects was elevated. CD11c myeloid dendritic cells (DCs) and the serum epidermal growth factor (EGF) level were decreased, while CD123 plasmacytoid DCs and serum interferon (IFN)-γ and tumor necrosis factor (TNF)-α were increased, indicating that the XLRS baseline immune status differs from that of controls. XLRS samples 14 days after AAV8-RS1 administration were compared with the XLRS baseline. Frequency of CD11bCD11c DCc was decreased in 8 of 11 XLRS subjects across all vector doses (1e9-3e11 vector genomes [vg]/eye). CD8human leukocyte antigen-DR isotype (HLA-DR) cytotoxic T cells and CD68CD80 macrophages were upregulated in 10 of 11 XLRS subjects, along with increased serum granzyme B in 8 of 11 XLRS subjects and elevated IFN-γ in 9 of 11 XLRS subjects. The six XLRS subjects with ocular inflammation after vector application gave a modestly positive correlation of inflammation score to their respective baseline CD4/CD8 ratios. This exploratory study indicates that XLRS subjects may exhibit a proinflammatory, baseline immune phenotype, and that intravitreal dosing with AAV8-RS1 leads to systemic immune activation with an increase of activated lymphocytes, macrophages, and proinflammatory cytokines.
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http://dx.doi.org/10.1016/j.ymthe.2021.02.013DOI Listing
February 2021

Questions about data: Importance of serum amyloid A level in patients with multiple sclerosis.

J Neuroimmunol 2021 Apr 3;353:577516. Epub 2021 Feb 3.

Department of Orthopaedics, Chengdu Second People's Hospital, Chengdu, Sichuan, China. Electronic address:

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http://dx.doi.org/10.1016/j.jneuroim.2021.577516DOI Listing
April 2021

Impact of Implementing CYP2C19 Genotype-Guided Antiplatelet Therapy on P2Y Inhibitor Selection and Clinical Outcomes in Acute Coronary Syndrome Patients After Percutaneous Coronary Intervention: A Real-World Study in China.

Front Pharmacol 2020 20;11:582929. Epub 2021 Jan 20.

Department of Pharmacy, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.

CYP2C19 loss-of-function (LOF) alleles reduce the effectiveness of clopidogrel in patients undergoing percutaneous coronary intervention for acute coronary syndrome. However, the clinical impact of implementing CYP2C19 gene-guided pharmacotherapy is unclear, especially among the Chinese population. The purpose of this study was to evaluate P2Y12 receptor inhibitor selection and clinical outcomes upon implementation of CYP2C19 genotype-guided pharmacotherapy in current clinical practice. This was a single-center observational cohort study. Adult percutaneous coronary intervention patients who received CYP2C19 genetic testing (*2, *3, *17 alleles) were included. Ticagrelor was recommended for patients with a LOF allele. Factors related to P2Y12 inhibitor selection were determined by logistic regression. The primary endpoint was major cardiac or cerebrovascular adverse events (MACCE) within 12 months. MACCE and clinically significant bleeding events (BARC ≥2) in the LOF-clopidogrel group, non-LOF-clopidogrel group, and non-LOF-ticagrelor group were compared with those in the LOF-ticagrelor group. The inverse probability of treatment weighting (IPTW) was adjusted in a Cox regression analysis to eliminate confounding factors. Among 1,361 patients, 826 (60.7%) had a LOF allele. Patients with a LOF allele were more likely to be prescribed ticagrelor (multivariate-adjusted OR 1.349; 95% CI 1.040 to 1.751; = 0.024). The MACCE rate was higher in the LOF-clopidogrel group than in the LOF-ticagrelor group (7.8 vs. 4.0%; log-rank = 0.029; IPTW-adjusted HR 2.138; 95% CI 1.300-3.515). Compared with the LOF-ticagrelor group, the non-LOF-clopidogrel group showed no significant difference in MACCE rate (5.8 vs. 4.0%; log-rank = 0.272; IPTW-adjusted HR 1.531; 95% CI 0.864-2.714). Among the patients treated with ticagrelor, there was no significant difference in the MACCE rate between the LOF group and non-LOF group (4.3 vs. 4.0%; log-rank = 0.846; IPTW-adjusted HR 1.184; 95% CI 0.582-2.410). There was no significant difference in the incidence of clinically significant bleeding events among the four groups. This study confirms that efficiently returned CYP2C19 genotype results did partially guide cardiologists to prescribe ticagrelor for patients with a LOF allele, and that clopidogrel had a higher risk of MACCE than ticagrelor in these patients, which provides support for the implementation of CYP2C19 gene-guided antiplatelet therapy in clinical practice.
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http://dx.doi.org/10.3389/fphar.2020.582929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854467PMC
January 2021

Granzyme B-expressing γδ-T and NK cells as a predictor of clinical pregnancy failure in patients with unexplained repeated implantation failure.

J Reprod Immunol 2021 04 28;144:103269. Epub 2020 Dec 28.

Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility Center, Shenzhen Zhongshan Urology Hospital, Shenzhen, Guangdong, 518045, PR China. Electronic address:

The limited cytotoxicity of immune cells facilitates a successful establishment of pregnancy. However, the association between cytotoxic granules and unexplained repeated implantation failure (uRIF) remains unkown. Twenty-one fertile controls and 54 patients with uRIF were included in this study. The pregnancy outcomes were monitored at different gestational periods. The peripheral blood lymphocytes were detected using specific monoclonal antibodies by flow cytometry. The percentage of perforin (Pfr), granzyme B (GrB), or granulysin (Gnly) lymphocytes was not significantly different among fertile controls, uRIF patients with successful pregnancy outcomes, and uRIF patients with pregnancy failure. The percentage of GrB γδ-T cells in lymphocytes was markedly higher in uRIF patients with implantation failure and clinical pregnancy failure than that in uRIF patients with a corresponding successful pregnancy outcome. A four-tier risk model showed that the risk of suffering clinical pregnancy failure in uRIF patients among high risk tier (83.3 %), normal risk tier (65.0 %) and low risk tier (39.1 %) was elevated by 2-4 fold compared with uRIF patients among lowest risk tier (20.0 %). In addition, the percentage of GrB NK cells in lymphocytes tended to decrease in uRIF patients with pregnancy failure. The AUC of the combined indicator with GrB γδ-T cells and GrB NK cells was increased than that of GrB γδ-T cells and GrB NK cells for predicting clinical pregnancy failure. In conclusion, the frequency of GrB-expressing γδ-T and NK cells in peripheral blood could serve as a predictor of clinical pregnancy failure in patients with uRIF.
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http://dx.doi.org/10.1016/j.jri.2020.103269DOI Listing
April 2021

High grade trophectoderm is associated with monozygotic twinning in frozen-thawed single blastocyst transfer.

Arch Gynecol Obstet 2021 Feb 3. Epub 2021 Feb 3.

Shenzhen Key Laboratory of Reproductive Immunology for Peri-Implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Shenzhen Zhongshan Urology Hospital, Shenzhen, Guangdong, 518045, People's Republic of China.

Background: The aim of this study was to explore specific factors that predispose to monozygotic twinning (MZT) at the blastocyst stage.

Methods: This was a retrospective observational study of a cohort of 2863 pregnancies after single blastocyst transfer (SBT) between January 2011 and June 2019 in our hospital. MZT pregnancy was identified as the number of fetuses exceeded the number of gestational sacs (GSs) by transvaginal ultrasound at 6-7 gestational weeks. The incidences of MZT regarding the maternal age at oocyte retrieval, paternal age, ovarian stimulation protocol, fertilization method, endometrium preparation protocol, vitrified day, and the Gardner grading of the blastocyst were calculated. The serum estrogen (E), progesterone (P) levels, endometrium thickness and serum hCG levels on day 11 after embryo transfer (ET) were compared between the MZT and singleton pregnancies. Statistical analyses were used appropriately.

Results: Fifty-one MZT pregnancies (1.78%) were identified. The only significant differences observed between MZT and singleton pregnancies were the proportion of TE grade (P = 0.022) and the hCG levels on day 11 after ET (P = 0.003). Multivariate logistic regression revealed that trophectoderm (TE) grade was an independent factor affecting MZT, the adjusted odds ratios (aORs) of grade A and B TE were 5.46 [95% confidential interval (CI) 1.48-20.16, P = 0.011) and 3.96 (95% CI 1.17-13.40, P = 0.027) compared to grade C respectively. There were no significant associations between the parental age, fertilization method, ovarian stimulation protocol, endometrium preparation protocol, vitrified day, expansion stage, inner cell mass (ICM) grade and MZT.

Conclusions: TE grade is associated with MZT at the blastocyst stage, potentially mediated via increased secretion of hCG from more well developed TE. Increased hCG secretion in turn may prolong the implantation window to support the embryo splitting.
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http://dx.doi.org/10.1007/s00404-020-05928-1DOI Listing
February 2021

Expert Consensus on Clinical Practice of Burn Units in Shanghai during the COVID-19 Epidemic.

J Burn Care Res 2021 Jan 23. Epub 2021 Jan 23.

Department of Burn Surgery, Changhai Hospital, Navy Military Medical University, Shanghai, China.

In response to coronavirus disease (COVID-19), the Shanghai Burn Clinical Quality Control Center organized experts to formulate and implement a set of rapid, simple, and effective prevention and control measures, and there have not been any cases of healthcare professionals or inpatients in burn units suspected or confirmed with COVID-19. This article elaborates on the specific measures in burn units in response to the epidemic, including the implementation of standardized procedures, remote consultations, strengthened follow-up, exchange of experience, and popular science, among others. We share experience from Shanghai to benefit related disciplines in other countries and regions.
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http://dx.doi.org/10.1093/jbcr/irab010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928907PMC
January 2021

EEG signals respond differently to idea generation, idea evolution and evaluation in a loosely controlled creativity experiment.

Sci Rep 2021 Jan 22;11(1):2119. Epub 2021 Jan 22.

Concordia Institute for Information Systems Engineering, Gina Cody School of Engineering and Computer Science, Concordia University, Montreal, QC, Canada.

Many neurocognitive studies endeavor to understand neural mechanisms of basic creative activities in strictly controlled experiments. However, little evidence is available regarding the neural mechanisms of interactions between basic activities underlying creativity in such experiments. Moreover, strictly controlled experiments might limit flexibility/freedom needed for creative exploration. Thus, this study investigated the whole-brain neuronal networks' interactions between three modes of thinking: idea generation, idea evolution, and evaluation in a loosely controlled creativity experiment. The loosely controlled creativity experiment will provide a degree of flexibility/freedom for participants to incubate creative ideas through extending response time from a few seconds to 3 min. In the experiment, participants accomplished a modified figural Torrance Test of Creative Thinking (TTCT-F) while their EEG signals were recorded. During idea generation, a participant was instructed to complete a sketch that was immediately triggered by a sketch stimulus at first sight. During idea evolution, a participant was instructed to complete a sketch that is radically distinctive from what was immediately triggered by the sketch stimulus. During the evaluation, a participant was instructed to evaluate difficulties of thinking and drawing during idea generation and evolution. It is expected that participants would use their experience to intuitively complete a sketch during idea generation while they could use more divergent and imaginative thinking to complete a possible creative sketch during idea evolution. Such an experimental design is named as a loosely controlled creativity experiment, which offers an approach to studying creativity in an ecologically valid manner. The validity of the loosely controlled creativity experiment could be verified through comparing its findings on phenomena that have been effectively studied by validated experimental research. It was found from our experiment that alpha power decreased significantly from rest to the three modes of thinking. These findings are consistent with that from visual creativity research based on event-related (de)synchronization (ERD/ERS) and task-related power changes (TRP). Specifically, in the lower alpha band (8-10 Hz), the decreases of alpha power were significantly lower over almost the entire scalp during idea evolution compared to the other modes of thinking. This finding indicated that idea evolution requires less general attention demands than the other two modes of thinking since the lower alpha ERD has been reported as being more likely to reflect general task demands such as attentional processes. In the upper alpha band (10-12 Hz), the decreases of alpha power were significantly higher over central sites during the evaluation compared to idea evolution. This finding indicated that evaluation involves more task-specific demands since the upper alpha ERD has been found as being more likely to reflect task-specific demands such as memory and intelligence, as was defined in the literature. In addition, new findings were obtained since the loosely controlled creativity experiment could activate multiple brain networks to accomplish the tasks involving the three modes of thinking. EEG microstate analysis was used to structure the unstructured EEG data to detect the activation of multiple brain networks. Combined EEG-fMRI and EEG source localization studies have indicated that EEG microstate classes are closely associated with the resting-state network as identified using fMRI. It was found that the default mode network was more active during idea evolution compared to the other two modes of thinking, while the cognitive control network was more active during the evaluation compared to the other two modes of thinking. This finding indicated that idea evolution might be more associated with unconscious and internal directed attention processes. Taken together, the loosely controlled creativity experiment with the support of EEG microstate analysis appears to offer an effective approach to investigating the real-world complex creativity activity.
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http://dx.doi.org/10.1038/s41598-021-81655-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822831PMC
January 2021

Single-cell RNA Sequencing Deciphers Immune Landscape of Human Recurrent Miscarriage.

Genomics Proteomics Bioinformatics 2021 Jan 19. Epub 2021 Jan 19.

Department of Paediatric and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China. Electronic address:

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http://dx.doi.org/10.1016/j.gpb.2020.12.005DOI Listing
January 2021

Association between endometrial indoleamine 2,3-dioxygenase expression level and pregnancy outcomes in women undergoing first in vitro fertilization treatment.

BMC Pregnancy Childbirth 2021 Jan 7;21(1):33. Epub 2021 Jan 7.

Shenzhen Key Laboratory of Reproductive Immunology for Peri-implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Fertility Center, Shenzhen Zhongshan Urology Hospital, No.1001 Fuqiang Road Futian District, 518045, Shenzhen, China.

Background: Indoleamine 2,3-dioxygenase (IDO) has been reported to play a key role in placental development during normal pregnancy. However, the question of whether endometrial IDO expression affects in vitro fertilization (IVF) pregnancy outcomes remains unclear. The current study was undertaken to investigate whether there was any association between endometrial IDO immunohistochemical staining and IVF treatment outcome.

Methods: This retrospective study was designed to compare pregnancy outcomes among women with different endometrial IDO expression levels under their first IVF treatment. A total of 140 women undergoing their IVF treatment were selected from January 2017 to December 2017. Endometrial samples were collected during mid-luteal phase before IVF cycle. The endometrial IDO expression levels were analyzed by immunohistochemistry, and compared between women who were pregnant or not. A logistic regression analysis was performed to determine the impact of endometrial IDO staining on live birth.

Results: No significant differences in the endometrial IDO immunohistochemical staining were found between women who had clinical pregnancy and those who failed (P>0.05). However, the endometrial IDO staining was significantly higher among women who had live birth compared with those who had no live birth (P=0.031). Additionally, after adjusting for differences in maternal age, BMI and duration of gonadotropin stimulation, women with higher IDO expression level had an increased live birth rate (adjusted odds ratio [aOR] 2.863, 95% confidence interval [CI] 1.180-6.947).

Conclusions: Higher endometrial IDO expression level during mid-luteal phase is associated with an increased live birth rate in women undergoing their first IVF treatment.
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http://dx.doi.org/10.1186/s12884-020-03511-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792114PMC
January 2021

The low cytotoxic activity of peripheral blood NK cells may relate to unexplained recurrent miscarriage.

Am J Reprod Immunol 2021 Jan 7:e13388. Epub 2021 Jan 7.

Department of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

Problem: Unexplained recurrent miscarriage (uRM) is defined as two or more spontaneous abortions prior to 20 weeks of gestation with unknown etiology. Peripheral blood natural killer (pNK) cells contact with the villus and exert important role in normal pregnancy. However, it is still controversial about the association between pNK cytotoxicity and uRM, and the underlying mechanism remains unknown so far.

Method Of Study: In this study, we aim to compare the percentage, immunophenotype, and function of pNK cells between patients with uRM and fertile controls. The peripheral blood was collected from 49 patients with uRM and 11 fertile women in their middle luteal phase of the menstrual cycle. pNK cells were co-cultured with K562 cells at different cell ratios to measure the cytotoxicity. The percentage of CD3 CD56 , CD3 CD56 , and CD3 CD56 pNK was analyzed by flow cytometry and quantified to evaluate the expression of cytotoxic granules (granzyme B, granulysin, and perforin), and the cell surface receptors related to pNK cell cytotoxicity (NKG2D, NKp30, NKp46, CD158a, and CD158b) were also detected.

Results: The general linear model analysis showed that pNK cell cytotoxicity in patients with uRM was significantly lower than that in fertile controls. In addition, the ratios of NKG2D/CD158a, NKp30/CD158a, and NKp46/CD158a in CD3 CD56 pNK subsets were significantly lower in uRM group than that in fertile control. The logistical regression analysis showed that the reduced NKp30/CD158a, NKp46/CD158a ratios in CD3 CD56 pNK subsets were significantly associated with uRM.

Conclusion: Our results suggested that a low pNK cytotoxicity, which is mediated by inhibitory signals, might be associated with uRM.
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http://dx.doi.org/10.1111/aji.13388DOI Listing
January 2021

Circular RNA circDLC1 inhibits MMP1-mediated liver cancer progression via interaction with HuR.

Theranostics 2021 1;11(3):1396-1411. Epub 2021 Jan 1.

Department of Liver Surgery & Liver Transplantation, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.

circular RNAs (circRNAs) have been demonstrated to play a crucial role in cancer progression. KIAA1429, a key component of the m6A methyltransferase complex, has recently been reported to promote hepatocellular carcinoma (HCC) progression by regulating the m6A methylation. The aim of present study is to investigate the role of circular RNAs in KIAA1429-mediated HCC progression. RNA sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (m6A-seq) were utilized to identify KIAA1429-regulated circRNAs. The effects of circDLC1 on proliferation and metastasis of hepatoma cells were examined and . RT-qPCR was used to measure the expression of circDLC1 in HCC tissues and hepatoma cells. RNA FISH, RIP assays and biotin-labeled RNA pull-down were used to investigate the downstream effector of circDLC1. The downstream targets of circDLC1 were identified using RNA-seq. Our data demonstrated that circDLC1 was downregulated in HCC tissues and closely relevant to favorable prognosis. Overexpression of circDLC1 inhibited the proliferation and motility of hepatoma cells and while silencing of circDLC1 played the opposite role. Mechanistic investigations revealed that circDLC1 could bind to RNA-binding protein HuR, which subsequently reduced the interaction between HuR and MMP1 mRNAs, and thus inhibited the expression of MMP1, ultimately contributing to inhibition of HCC progression. Our work suggests that circDLC1, a downstream target of KIAA1429, is a promising prognostic marker for HCC patients, and the circDLC1-HuR-MMP1 axis may serve as a potential therapeutic target for HCC treatment.
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http://dx.doi.org/10.7150/thno.53227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738888PMC
January 2021

KLF4 down-regulation resulting from TLR4 promotion of ERK1/2 phosphorylation underpins inflammatory response in sepsis.

J Cell Mol Med 2021 Feb 27;25(4):2013-2024. Epub 2020 Dec 27.

Emergency Department, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Sepsis is a systemic inflammatory response to invading pathogens, leading to high mortality rates in intensive care units worldwide. Krüppel-like factor 4 (KLF4) is an important anti-inflammatory transcription factor. In this study, we investigate the anti-inflammatory role of KLF4 in caecal ligation and puncture (CLP)-induced septic mice and lipopolysaccharide (LPS)-induced RAW264.7 cells and its potential mechanism. We found that KLF4 was down-regulated in CLP-induced septic mice and in LPS-induced RAW264.7 cells, and that its overexpression led to increased survival rates of septic mice along with inhibited inflammatory response in vivo and in vitro. ITGA2B was up-regulated in the setting of sepsis and was inhibited by KLF4 overexpression. ITGA2B knock-down mimicked the effects of KLF4 overexpression on septic mice and LPS-induced RAW264.7 cells. TLR4 promoted the phosphorylation of ERK1/2 and then up-regulated the ubiquitination and the degradation of KLF4, thereby elevating the expression of ITGA2B. Moreover, TLR4 knock-down or treatment with PD98059 (a MEK inhibitor) inhibited inflammatory response in the setting of sepsis in vivo and in vitro. Furthermore, this effect of PD98059 treatment was lost upon KLF4 knock-down. Collectively, these results explain the down-regulation of KLF4 in sepsis, namely via TLR4 promotion of ERK1/2 phosphorylation, and identify ITGA2B as the downstream gene of KLF4, thus highlighting the anti-inflammatory role of KLF4 in sepsis.
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http://dx.doi.org/10.1111/jcmm.16082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882990PMC
February 2021

Overexpression of SMAD7 activates the YAP/NOTCH cascade and promotes liver carcinogenesis in mice and humans.

Hepatology 2020 Dec 24. Epub 2020 Dec 24.

Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California, USA.

Background & Aims: Mothers against decapentaplegic homolog 7 (SMAD7) is an antagonist of the transforming growth factor β (TGF-β) signaling. In the present investigation, we sought to determine the relevance of SMAD7 in liver carcinogenesis using in vitro and in vivo approaches.

Approach & Results: We found that SMAD7 is upregulated in a subset of human hepatocellular carcinoma (HCC) samples with poor prognosis. Gene set enrichment analysis (GSEA) revealed that SMAD7 expression correlates with activated YAP/NOTCH pathway and cholangiocellular signature genes in HCCs. These findings were substantiated in human HCC cell lines. In vivo, overexpression of Smad7 alone was unable to initiate HCC development, but it significantly accelerated c-Myc/MCL1 induced mouse HCC formation. Consistent with human HCC data, c-Myc/MCL1/Smad7 liver tumors exhibited an increased cholangiocellular gene expression along with Yap/Notch activation and epithelial-mesenchymal transition (EMT). Intriguingly, blocking of the Notch signaling did not affect c-Myc/MCL1/Smad7-induced hepatocarcinogenesis while preventing cholangiocellular signature expression and EMT, whereas ablation of Yap abolished c-Myc/MCL1/Smad7-driven HCC formation. In mice overexpressing a myristoylated/activated form of AKT, co-expression of SMAD7 accelerated carcinogenesis and switched the phenotype from HCC to intrahepatic cholangiocarcinoma (iCCA) lesions. In human iCCA, SMAD7 expression was robustly upregulated, especially in the most aggressive tumors and directly correlated with the levels of YAP/NOTCH targets as well as cholangiocellular and EMT markers.

Conclusions: The present data indicate that SMAD7 contributes to liver carcinogenesis by activating the YAP/NOTCH signaling cascade and by inducing a cholangiocellular and EMT signature.
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http://dx.doi.org/10.1002/hep.31692DOI Listing
December 2020

Association between matrix metalloproteinase-1 (MMP-1) protein level and the risk of rheumatoid arthritis and osteoarthritis: a meta-analysis.

Braz J Med Biol Res 2020 9;54(2):e10366. Epub 2020 Dec 9.

Department of Orthopedics, Affiliated Renhe Hospital of China Three Gorges University, Yichang, Hubei, China.

Recent publications have investigated the potential role of the protein level of matrix metalloproteinase-1 (MMP-1) in the susceptibility to rheumatoid arthritis (RA) and osteoarthritis (OA). However, no unanimous conclusion was obtained. Therefore, we carried out a meta-analysis to explore the association between MMP-1 expression and these two clinical disorders. After database searching and screening, we enrolled a total of eighteen articles for the pooled analysis. We observed a significant association between RA cases and controls in the whole population [SMD (standard mean difference)=1.01, P=0.017]. There were similar positive results in the subgroup analysis of "population-based control" (SMD=1.50, P=0.032) and "synovial fluid" (SMD=1.32, P=0.049). In addition, we observed an increased risk in OA cases, compared with controls, in the overall analysis (SMD=0.47, P=0.004) and subsequent subgroup analysis of "knee OA" (SMD=0.86, P<0.001), "Asian/China" (SMD=0.76, P=0.003), "cartilage-Asian/China" (SMD=1.21, P<0.001), and "synovial fluid-Asian/China" (SMD=0.73, P=0.004). In summary, a high protein level of MMP-1 in synovial fluid may be associated with the susceptibility to RA, and the high MMP-1 level in the cartilage tissue or synovial fluid may be related to the pathogenesis of knee OA in the Chinese population. This should be confirmed by larger sample sizes.
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http://dx.doi.org/10.1590/1414-431X202010366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727110PMC
February 2021

Keratin 17 Suppresses Cell Proliferation and Epithelial-Mesenchymal Transition in Pancreatic Cancer.

Front Med (Lausanne) 2020 26;7:572494. Epub 2020 Nov 26.

Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Keratin 17 (K17), a member of type I acidic epithelial keratin family, has been reported to be upregulated in many malignant tumors and to be involved in promoting the development of tumors. However, the precise role of K17 in progression of pancreatic cancer is still unknown. In this study, we found that K17 expression was highly expressed in pancreatic cancer tissues and cell lines and that upregulated expression was associated with the pathological grade and poor prognosis. K17 expression served as an independent predictor of pancreatic cancer survival. Meanwhile, we showed that knocking down K17 induced pancreatic cancer cell proliferation, colony formation and tumor growth in xenografts in mice. However, K17 upregulation inhibited pancreatic cancer cell proliferation and colony formation. Further mechanistic study revealed that K17 knockdown promoted cell cycle progression by upregulating CyclinD1 expression and repressed cell apoptosis. However, K17 upregulation suppressed cell cycle progression by decreasing CyclinD1 expression, and induced apoptosis by increasing the levels of cleaved Caspase3. In addition, K17 knockdown promoted pancreatic cancer cell migration and invasion, but K17 upregulation suppressed cell migration and invasion. Moreover, knocking down K17 promoted epithelial-mesenchymal transition (EMT) in pancreatic cancer cell by inhibiting E-cadherin expression and inducing Vimentin expression, and the effects of K17 upregulation were opposite to that of K17downregulation. Taken together, our findings suggest that K17 functions as a potential tumor suppressor, even though it is upregulated in pancreatic cancer.
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http://dx.doi.org/10.3389/fmed.2020.572494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726264PMC
November 2020

Species and tissue specific analysis based on quantitative proteomics from allotetraploid and the parents.

J Proteomics 2021 02 10;232:104073. Epub 2020 Dec 10.

State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Science, Hunan Normal University, Changsha, 410081, Hunan, China. Electronic address:

Allotetraploids play central roles in the field of polyploid breeding of freshwater fishes. The molecular basis underlying distant hybridization and individual differences between allotetraploids and their parents is largely unknown. In this study, we performed quantitative proteomics profiling in gonad and liver tissues between allotetraploid and its parents Red Crucian Carp (♀) and Common Carp (♂) respectively. Thousands of proteins were identified and quantified. Species and tissue specific analysis revealed that a large number of causal proteins are specifically regulated in gonad or liver tissue in allotetraploid and its parents respectively. Subsequently, integrative bioinformatics analyses including functional enrichment, pathway and network analyses were conducted. The results suggested a series of gonad and liver specifically regulated proteins such as LSM3, LSM7, PABPC1B and ALDH3A1, EHHADHB, ACAT2 play crucial roles in reproduction-related and metabolism-related pathways including "DNA replication", "Spliceosome" and "Metabolic pathways", "Biosynthesis of antibiotics". Meanwhile, species specifically regulated proteins such as FMR1, MAO are involved in "RNA transport", "Glycine, serine and threonine metabolism". Herein, we established the first comprehensive proteomics knowledgebase for particular freshwater fishes. It may shed light on the molecular mechanisms underlying polyploidy breeding and individual differences and serve as an indispensable reference for further studies. SIGNIFICANCE: The molecular basis underlying distant hybridization and individual differences between allotetraploid and their parents Red Crucian Carp and Common Carp is largely unknown. Quantitative proteomics profiling integrated with multiple bioinformatics analysis revealed that a large number of causal proteins are specifically expressed in gonad or liver tissue in allotetraploid and its parents. Herein, we established the first comprehensive proteomics knowledgebase for particular freshwater fishes. It may shed light on the molecular mechanisms underlying polyploidy breeding and individual differences and serve as an indispensable reference for further associated studies.
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http://dx.doi.org/10.1016/j.jprot.2020.104073DOI Listing
February 2021

CRISPR screen identifies genes that sensitize AML cells to double negative T cell therapy.

Blood 2020 Dec 3. Epub 2020 Dec 3.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada., Canada.

Acute myeloid leukemia (AML) remains a devastating disease in need of new therapies to improve patient survival. Targeted, adoptive T cell therapies have achieved impressive clinical outcomes in some B-cell leukemias and lymphomas but not in AML. Double negative T cells (DNTs) effectively kill blast cells from the majority of AML patients and are now being tested in clinical trials. However, AML blasts obtained from ~30% of patients show resistance to DNT cell-mediated cytotoxicity; the markers or mechanisms underlying this resistance have not been elucidated. Here, we used a targeted CRISPR/Cas9 screen to identify genes that confer susceptibility of AML cells to DNT cell therapy. Inactivation of the SAGA deubiquitinating complex components sensitized AML cells to DNT-mediated cytotoxicity. In contrast, CD64 inactivation resulted in resistance to DNT-mediated cytotoxicity. Importantly, the level of CD64 expression strongly correlated with the sensitivity of AML cells to DNT cell treatment. Furthermore, the ectopic expression of CD64 overcame AML resistance to DNTs both in vitro and in vivo. Altogether, our data demonstrate the utility of CRISPR/Cas9 screens to uncover mechanisms underlying the sensitivity to DNT cell therapy and suggest CD64 as a predictive marker for response in AML patients.
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http://dx.doi.org/10.1182/blood.2019004108DOI Listing
December 2020