Publications by authors named "Qianqian Song"

92 Publications

scGCN is a graph convolutional networks algorithm for knowledge transfer in single cell omics.

Nat Commun 2021 06 22;12(1):3826. Epub 2021 Jun 22.

Center for Cancer Genomics and Precision Oncology, Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston Salem, NC, USA.

Single-cell omics is the fastest-growing type of genomics data in the literature and public genomics repositories. Leveraging the growing repository of labeled datasets and transferring labels from existing datasets to newly generated datasets will empower the exploration of single-cell omics data. However, the current label transfer methods have limited performance, largely due to the intrinsic heterogeneity among cell populations and extrinsic differences between datasets. Here, we present a robust graph artificial intelligence model, single-cell Graph Convolutional Network (scGCN), to achieve effective knowledge transfer across disparate datasets. Through benchmarking with other label transfer methods on a total of 30 single cell omics datasets, scGCN consistently demonstrates superior accuracy on leveraging cells from different tissues, platforms, and species, as well as cells profiled at different molecular layers. scGCN is implemented as an integrated workflow as a python software, which is available at https://github.com/QSong-github/scGCN .
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http://dx.doi.org/10.1038/s41467-021-24172-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219725PMC
June 2021

Outcomes of COVID-19 in Patients With Cancer: Report From the National COVID Cohort Collaborative (N3C).

J Clin Oncol 2021 07 4;39(20):2232-2246. Epub 2021 Jun 4.

Wake Forest School of Medicine, Winston-Salem, NC.

Purpose: Variation in risk of adverse clinical outcomes in patients with cancer and COVID-19 has been reported from relatively small cohorts. The NCATS' National COVID Cohort Collaborative (N3C) is a centralized data resource representing the largest multicenter cohort of COVID-19 cases and controls nationwide. We aimed to construct and characterize the cancer cohort within N3C and identify risk factors for all-cause mortality from COVID-19.

Methods: We used 4,382,085 patients from 50 US medical centers to construct a cohort of patients with cancer. We restricted analyses to adults ≥ 18 years old with a COVID-19-positive or COVID-19-negative diagnosis between January 1, 2020, and March 25, 2021. We followed N3C selection of an index encounter per patient for analyses. All analyses were performed in the N3C Data Enclave Palantir platform.

Results: A total of 398,579 adult patients with cancer were identified from the N3C cohort; 63,413 (15.9%) were COVID-19-positive. Most common represented cancers were skin (13.8%), breast (13.7%), prostate (10.6%), hematologic (10.5%), and GI cancers (10%). COVID-19 positivity was significantly associated with increased risk of all-cause mortality (hazard ratio, 1.20; 95% CI, 1.15 to 1.24). Among COVID-19-positive patients, age ≥ 65 years, male gender, Southern or Western US residence, an adjusted Charlson Comorbidity Index score ≥ 4, hematologic malignancy, multitumor sites, and recent cytotoxic therapy were associated with increased risk of all-cause mortality. Patients who received recent immunotherapies or targeted therapies did not have higher risk of overall mortality.

Conclusion: Using N3C, we assembled the largest nationally representative cohort of patients with cancer and COVID-19 to date. We identified demographic and clinical factors associated with increased all-cause mortality in patients with cancer. Full characterization of the cohort will provide further insights into the effects of COVID-19 on cancer outcomes and the ability to continue specific cancer treatments.
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http://dx.doi.org/10.1200/JCO.21.01074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260918PMC
July 2021

Alteration of vaginal microbiota in patients with recurrent miscarriage.

J Obstet Gynaecol 2021 May 21:1-8. Epub 2021 May 21.

Gynaecology and obstetrics, First Affiliated Hospital of Bengbu Medical College, Bengbu City, China.

The aim of this study was to characterise the structure of vaginal microbiota in unexplained recurrent miscarriage (RM). The vaginal bacterial communities of 16 patients with RM and 20 healthy volunteers were sampled. Then, the microbiomes of bacterial profiles of RM patients and healthy volunteers were compared by sequencing the V3-V4 regions of the bacterial 16S ribosomal RNA gene using the Illumina MiSeq platform (Illumina, San Diego, CA). Taxonomic analysis demonstrated that abundance of and were significantly different between the RM and control groups. Furthermore, at the genus level, was the most dominant genus in the two groups. Statistically significant differences were observed in three genera between RM and control groups. In the control group, two bacterial taxa were significantly more abundant ( and ), while only one taxon was overrepresented in the RM group (). These present findings provide experimental evidence supporting vaginal microbiota dysbiosis in women with RM.Impact statement Currently, bacterial vaginosis is thought to be mainly due to the vaginal dysbacteriosis, which can induce unexplained recurrent miscarriage, premature rupture of membranes, low birth weight premature birth, premature birth, chorioamnionitis and series of diseases. The current study demonstrated that and were significantly decreased in RM patients compared to healthy control, while was overrepresented in the RM group. Clinically, women with RM might benefit from vaginal microbiota treatment, adjuvant therapy with Lactobacillus-based live biotherapeutics.
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http://dx.doi.org/10.1080/01443615.2021.1904851DOI Listing
May 2021

Multi-Omics Analysis of Brain Metastasis Outcomes Following Craniotomy.

Front Oncol 2020 6;10:615472. Epub 2021 Apr 6.

Department of Medicine (Hematology & Oncology), Wake Forest School of Medicine, Winston-Salem, NC, United States.

Background: The incidence of brain metastasis continues to increase as therapeutic strategies have improved for a number of solid tumors. The presence of brain metastasis is associated with worse prognosis but it is unclear if distinctive biomarkers can separate patients at risk for CNS related death.

Methods: We executed a single institution retrospective collection of brain metastasis from patients who were diagnosed with lung, breast, and other primary tumors. The brain metastatic samples were sent for RNA sequencing, proteomic and metabolomic analysis of brain metastasis. The primary outcome was distant brain failure after definitive therapies that included craniotomy resection and radiation to surgical bed. Novel prognostic subtypes were discovered using transcriptomic data and sparse non-negative matrix factorization.

Results: We discovered two molecular subtypes showing statistically significant differential prognosis irrespective of tumor subtype. The median survival time of the good and the poor prognostic subtypes were 7.89 and 42.27 months, respectively. Further integrated characterization and analysis of these two distinctive prognostic subtypes using transcriptomic, proteomic, and metabolomic molecular profiles of patients identified key pathways and metabolites. The analysis suggested that immune microenvironment landscape as well as proliferation and migration signaling pathways may be responsible to the observed survival difference.

Conclusion: A multi-omics approach to characterization of brain metastasis provides an opportunity to identify clinically impactful biomarkers and associated prognostic subtypes and generate provocative integrative understanding of disease.
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http://dx.doi.org/10.3389/fonc.2020.615472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056216PMC
April 2021

Identification and Validation of Ubiquitin-Specific Proteases as a Novel Prognostic Signature for Hepatocellular Carcinoma.

Front Oncol 2021 25;11:629327. Epub 2021 Feb 25.

Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China.

Purpose: Ubiquitin-specific proteases (USPs), as a sub-family of deubiquitinating enzymes (DUBs), are responsible for the elimination of ubiquitin-triggered modification. USPs are recently correlated with various malignancies. However, the expression features and clinical significance of USPs have not been systematically investigated in hepatocellular carcinoma (HCC).

Methods: Genomic alterations and expression profiles of USPs were investigated in CbioPortal and The Cancer Genome Atlas (TCGA) Liver hepatocellular carcinoma (LIHC) dataset. Cox regression and least absolute shrinkage and selection operator (LASSO) analyses were conducted to establish a risk signature for HCC prognosis in TCGA LIHC cohort. Subsequently, Kaplan-Meier analysis, receiver operating characteristic (ROC) curves and univariate/multivariate analyses were performed to evaluate the prognostic significance of the risk signature in TCGA LIHC and international cancer genome consortium (ICGC) cohorts. Furthermore, we explored the alterations of the signature genes during hepatocarcinogenesis and HCC progression in GSE89377. In addition, the expression feature of USP39 was further explored in HCC tissues by performing western blotting and immunohistochemistry.

Results: Genomic alterations and overexpression of USPs were observed in HCC tissues. The consensus analysis indicated that the USPs-overexpressed sub-Cluster was correlated with aggressive characteristics and poor prognosis. Cox regression with LASSO algorithm identified a risk signature formed by eight USPs for HCC prognosis. High-risk group stratified by the signature score was correlated with advanced tumor stage and poor survival HCC patients in TCGA LIHC cohort. In addition, the 8-USPs based signature could also robustly predict overall survival of HCC patients in ICGC(LIRI-JP) cohort. Furthermore, gene sets enrichment analysis (GSEA) showed that the high-risk score was associated with tumor-related pathways. According to the observation in GSE89377, USP39 expression was dynamically increased with hepatocarcinogenesis and HCC progression. The overexpression of USP39 was further determined in a local HCC cohort and correlated with poor prognosis. The co-concurrence analysis suggested that USP39 might promote HCC by regulating cell-cycle- and proliferation- related genes.

Conclusion: The current study provided a USPs-based signature, highlighting its robust prognostic significance and targeted value for HCC treatment.
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http://dx.doi.org/10.3389/fonc.2021.629327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949004PMC
February 2021

Review of the relationships among polysaccharides, gut microbiota, and human health.

Food Res Int 2021 02 2;140:109858. Epub 2020 Nov 2.

State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, China. Electronic address:

As a complex ecosystem of the human body, the intestinal flora maintains a dynamic balance with the host and plays an irreplaceable role in life activities such as nutritional metabolism and host immunity. The intestinal flora interacts with polysaccharides, the intestinal flora digests non-digestible polysaccharides, and polysaccharides can be used as an important energy source for intestinal microorganisms. Disturbance of the gut microbiota (GM) leads to the occurrence of diseases, polysaccharides as prebiotics can improve the disease by regulating the composition of GM. In this paper, we reviewed the current knowledge about the relationship between polysaccharides, gut microbiota, and and human health, described the microbial composition of the human, the relationship between intestinal flora disorders and disease occurrence, and summarized the interactions between polysaccharides and intestinal microorganisms.
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http://dx.doi.org/10.1016/j.foodres.2020.109858DOI Listing
February 2021

Combinational Antibacterial Activity of Nisin and 3-Phenyllactic Acid and Their Co-production by Engineered .

Front Bioeng Biotechnol 2021 5;9:612105. Epub 2021 Feb 5.

Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, China.

Nisin produced by certain strains is commercially used in meat and dairy industries because of its effective antibacterial activity and food safety characteristics. It has been proved that the antibacterial activity could be enhanced when combined with other antimicrobial agents. In this study, we demonstrated that nisin and 3-phenyllactic acid (PLA) in combination displayed excellent combinational antibacterial activity against foodborne pathogens including and . The potential application in food preservation was further verified microbial analysis during the storage of meat and milk, and determination of strawberry rot rate. Scanning electron microscopy observation indicated a distinct mode of PLA with nisin, which may target at the dividing cell, contributing to their combinational antibacterial effect of nisin and PLA. Considering the positive results, a nisin-PLA co-producing strain was constructed based on the food-grade strain F44, a nisin Z producer. By the knockout of two L-lactate dehydrogenase (LDH) and overexpression of D-LDH , the yield of PLA was significantly increased 1.77-fold in comparison with the wild type. Anti-bacterial assays demonstrated that the fermentation product of the recombinant strain performed highly effective antibacterial activity. These results provided a promising prospect for the nisin-PLA co-expressing in food preservation on account of its considerable antibacterial activity and cost-effective performance.
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http://dx.doi.org/10.3389/fbioe.2021.612105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901885PMC
February 2021

DNA primase subunit 1 deteriorated progression of hepatocellular carcinoma by activating AKT/mTOR signaling and UBE2C-mediated P53 ubiquitination.

Cell Biosci 2021 Feb 23;11(1):42. Epub 2021 Feb 23.

Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, China.

Background: DNA primase subunit 1 (PRIM1) has been reported as a novel oncogene in several cancer types. However, its roles in hepatocellular carcinoma (HCC) remain unclear. This study aimed to investigate underlying mechanisms of PRIM1 and identify it as a potential molecular target for HCC.

Methods: Hub genes were screened between HCC tissues and normal liver tissues in 3 gene expression omnibus (GEO) datasets and the cancer genome atlas (TCGA). The expression features and prognostic value of one of the hub genes PRIM1 were analyzed by bioinformatic analyses and immunohistochemistry. Loss-of-function and gain-of-function studies were used to investigate the regulatory role of PRIM1 in HCC cells. Real-time (RT)-qPCR, western blotting, and ubiquitin immunoprecipitation assays were performed to explore the underlying mechanisms. The xenograft model was employed to detect the roles of PRIM1 in tumor growth in vivo. Finally, the 3D spheroid model was conducted to validate the role of PRIM1 in tumor growth and sorafenib resistance.

Results: The hub genes of HCC were screened in multiple bioinformatic datasets. PRIM1, as one of the hub genes, was significantly overexpressed in HCC tissues in mRNA and protein levels. In addition, high expression of PRIM1 indicated poor prognosis of HCC patients in TCGA, ICGC, and Nantong cohorts. Overexpression of PRIM1 promoted the proliferation, migration/invasion, and sorafenib resistance of HCC cells, with the decrease in apoptosis and cell cycle arrest. Mechanically, PRIM1 facilitated epithelial-mesenchymal transition (EMT) process and the activity of PI3K/AKT/mTOR signaling of HCC cells. Additionally, PRIM1 could cause the ubiquitination and degradation of P53 by upregulating Ubiquitin Conjugating Enzyme E2 C (UBE2C). Furthermore, knockdown of PRIM1 significantly inhibited the growth of xenograft tumors and HCC cells-derived spheroids with enhanced sorafenib resistance.

Conclusion: This study implies that PRIM1 may play a key role in the progression of HCC and may serve as a potential target for HCC treatment.
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http://dx.doi.org/10.1186/s13578-021-00555-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903777PMC
February 2021

Cullin-RING Ligases as Promising Targets for Gastric Carcinoma Treatment.

Pharmacol Res 2021 Aug 15;170:105493. Epub 2021 Feb 15.

School of Pharmaceutical Sciences, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, Zhengzhou University, Zhengzhou 450001, PR China. Electronic address:

Gastric carcinoma has serious morbidity and mortality, which seriously threats human health. The studies on gastrointestinal cell biology have shown that the ubiquitination modification that occurs after protein translation plays an essential role in the pathogenesis of gastric carcinoma. Protein ubiquitination is catalyzed by E3 ubiquitin ligase and can regulate various substrate proteins in different cellular pathways. Cullin-RING E3 ligase (CRLs) is a representative of the E3 ubiquitin ligase family, which requires cullin (CUL) neddylation modification for activation to regulate homeostasis of ~20% of cellular proteins. The substrate molecules regulated by CRLs are often involved in many cell progressions such as cell cycle progression, cell apoptosis, DNA damage and repair. Given that CRLs play an important role in modulation of biological activities, so targeting a certain CULs member neddylation may be an attractive strategy for selectively controlling the cellular proteins levels to achieve the goal of cancer treatment. In this review, we will discuss the roles of CULs and Ring protein in gastric carcinoma and summarize the current neddylation modulators for gastric carcinoma treatment.
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http://dx.doi.org/10.1016/j.phrs.2021.105493DOI Listing
August 2021

Rac Family Small GTPase 3 Correlates with Progression and Poor Prognosis in Bladder Cancer.

DNA Cell Biol 2021 Mar 17;40(3):469-481. Epub 2021 Feb 17.

Department of Urology, Third Hospital of Hebei Medical University, Shijiazhuang, China.

Bladder cancer (BC) is a common genitourinary malignancy worldwide. However, the molecular pathogenesis of BC remains unclear. The current study conducted bioinformatic analyses to discover key genes involved in BC progression. A total of 375 differentially expressed genes (DEGs) were screened in the GEO database and The Cancer Genome Atlas (TCGA) database, which were further evaluated by the core level in the protein-protein interaction network. (Rac family small GTPase 3), one of the top hub genes, was focused on for its gene expression and prognostic value in BC. Immunohistochemical assays indicated elevated levels in BC tissues compared with normal tissues. Overexpression of expression was closely associated with poor differentiation ( = 0.035), advanced TNM stage ( = 0.014), lymph metastasis ( = 0.033), and recurrence ( < 0.001). Kaplan-Meier and Cox proportional hazards analyses demonstrated that high expression indicated poor survival of BC patients, which could serve as an independent prognostic factor for overall survival (HR = 3.159,  = 0.023) and disease-free survival (HR = 4.633,  = 0.002). Moreover, bioinformatic analyses indicated that might be correlated with malignant phenotypes and immune infiltration of BC. Taken together, could be a novel prognostic biomarker for BC.
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http://dx.doi.org/10.1089/dna.2020.5613DOI Listing
March 2021

Chaperone-mediated autophagy affects tumor cell proliferation and cisplatin resistance in esophageal squamous cell carcinoma.

Thorac Cancer 2021 04 10;12(7):1048-1057. Epub 2021 Feb 10.

National Center for International Research in Cell and Gene Therapy, Sino-British Research Centre for Molecular Oncology, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.

Background: Chaperone-mediated autophagy (CMA) is a lysosomal degradation pathway of selective soluble proteins. Lysosomal membrane associated protein 2a (LAMP2a) is the lysosomal membrane receptor of CMA and influences CMA activity. Although it has been suggested that higher expression of LAMP2a is associated with more advanced tumor node metastasis (TNM) stages and shorter survival time in patients with esophageal squamous cell carcinoma (ESCC), the underlying mechanism has not been known yet.

Methods: In this study, we modulated the activity of CMA through LAMP2a or small molecular compounds in human ESCC cells to investigate its role in ESCC.

Results: We found that down-regulating the activity of CMA could inhibit the proliferation and colony formation of ESCC cells as well as increase their sensitivity to cisplatin.

Conclusions: Our results promote better understanding of how CMA affects human ESCC and provide a new therapeutic target against ESCC through down-regulating LAMP2a.
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http://dx.doi.org/10.1111/1759-7714.13849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017246PMC
April 2021

Transferable Active Centers of Strongly Coupled [email protected] and Molybdenum Co-doped g-CN Heterostructure Electrocatalysts for Boosting Hydrogen Evolution Reaction in Both Acidic and Alkaline Media.

Inorg Chem 2021 Feb 4;60(4):2604-2613. Epub 2021 Feb 4.

School of Materials Science and Engineering, Shaanxi Key Laboratory of Green Preparation and Functionalization for Inorganic Materials, Shaanxi University of Science and Technology, Xi'an 710021, P. R. China.

Designing an excellent acidic and alkaline general-purpose hydrogen evolution electrocatalyst plays an important role in promoting the development of the energy field. Here, a feasible strategy is reported to use the strongly coupled [email protected] and molybdenum co-doped g-CN ([email protected]) heterostructure with transferable active centers for catalytic reactions in acidic and alkaline media. Research studies have shown that the unsaturated S site at the edge of MoS and the active N atom on the Mo-S-CN substrate are, respectively, the active centers of acidic and alkaline hydrogen evolution reaction. Specifically, Mo-S-CN is regarded as a synergistic catalyst for the active species MoS in acidic hydrogen evolution, while MoS acts as a co-catalyst when the alkaline active species are transferred to Mo-S-CN. The coordination of the electrons between the interfaces achieves a synergistic balance, which provides the optimal sites for the adsorption of the reactants. Such an electrocatalyst exhibits overpotentials of 193 and 290 mV at 10 mA cm in 0.5 M HSO and 1 M KOH, respectively, which was better than numerous previous reports. This research provides an outstanding avenue to realize multifunctional electrocatalysts.
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http://dx.doi.org/10.1021/acs.inorgchem.0c03485DOI Listing
February 2021

DSTG: deconvoluting spatial transcriptomics data through graph-based artificial intelligence.

Brief Bioinform 2021 Jan 22. Epub 2021 Jan 22.

Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Recent development of spatial transcriptomics (ST) is capable of associating spatial information at different spots in the tissue section with RNA abundance of cells within each spot, which is particularly important to understand tissue cytoarchitectures and functions. However, for such ST data, since a spot is usually larger than an individual cell, gene expressions measured at each spot are from a mixture of cells with heterogenous cell types. Therefore, ST data at each spot needs to be disentangled so as to reveal the cell compositions at that spatial spot. In this study, we propose a novel method, named deconvoluting spatial transcriptomics data through graph-based convolutional networks (DSTG), to accurately deconvolute the observed gene expressions at each spot and recover its cell constitutions, thus achieving high-level segmentation and revealing spatial architecture of cellular heterogeneity within tissues. DSTG not only demonstrates superior performance on synthetic spatial data generated from different protocols, but also effectively identifies spatial compositions of cells in mouse cortex layer, hippocampus slice and pancreatic tumor tissues. In conclusion, DSTG accurately uncovers the cell states and subpopulations based on spatial localization. DSTG is available as a ready-to-use open source software (https://github.com/Su-informatics-lab/DSTG) for precise interrogation of spatial organizations and functions in tissues.
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http://dx.doi.org/10.1093/bib/bbaa414DOI Listing
January 2021

Mineral Element Deposition and Gene Expression across Different Tissues of Cherry Valley Ducks.

Animals (Basel) 2021 Jan 19;11(1). Epub 2021 Jan 19.

Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou 225009, China.

This study was conducted to investigate the deposition of several mineral elements and the mRNA levels of mineral-related genes across different tissues of cherry valley ducks. The contents of magnesium (Mg), potassium (K), zinc (Zn), and selenium (Se) in ducks' breast muscle, thigh muscle, liver, skin, and tibia at the age of 0, 21, 35, 49, and 63 days, respectively, were measured using an atomic fluorescence spectrophotometer, while the mRNA levels of mineral-related genes were detected by qRT-PCR. The results revealed that the dynamics of Mg and K were generally similar in each tissue, with a significant positive correlation ( < 0.05). In the breast muscle, thigh muscle, and liver, the contents of almost all mineral elements reached their peak values ( < 0.05) at the age of 49 to 63 days. Interestingly, the expression of most mineral-related genes was the highest at birth ( < 0.05). In addition, there was a significant negative correlation between the expression of and the deposition of K (r = -0.957, < 0.05), and a similar result was found for the expression of and the deposition of Zn (r = -0.905, < 0.05). Taken together, Mg and K could be used as joint indicators for the precise breeding of the high-quality strain of cherry valley ducks, while the age of 49 to 63 days could be used as the reference for the best marketing age. In addition, and could be used as the key genes to detect K and Zn, respectively. Hence, the findings of this study can be used to improve the production and breeding efficiency of high-quality meat ducks.
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http://dx.doi.org/10.3390/ani11010238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832843PMC
January 2021

3D scaffold-free microlivers with drug metabolic function generated by lineage-reprogrammed hepatocytes from human fibroblasts.

Biomaterials 2021 02 8;269:120668. Epub 2021 Jan 8.

Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, USA. Electronic address:

Generating microliver tissues to recapitulate hepatic function is of increasing importance in tissue engineering and drug screening. But the limited availability of primary hepatocytes and the marked loss of phenotype hinders their application. Human induced hepatocytes (hiHeps) generated by direct reprogramming can address the shortage of primary hepatocytes to make personalized drug prediction possible. Here, we simplify preparation of reprogramming reagents by expressing six transcriptional factors (HNF4A, FOXA2, FOXA3, ATF5, PROX1, and HNF1) from two lentiviral vectors, each expressing three factors. Transducing human fetal and adult fibroblasts with low vector dosage generated human induced hepatocyte-like cells (hiHeps) displaying characteristics of mature hepatocytes and capable of drug metabolism. To mimic the physiologic liver microenvironment and improve hepatocyte function, we prepared 3D scaffold-free microliver spheroids using hiHeps and human liver nonparenchymal cells through self-assembly without exogenous scaffolds. We then introduced the microliver spheroids into a two-organ microfluidic system to examine interactions between hepatocytes and tumor cells. The hiHeps-derived spheroids metabolized the prodrug capecitabine into the active metabolite 5-fluorouracil and induced toxicity in downstream tumor spheroids. Our results demonstrate that hiHeps can be used to make microliver spheroids and combined with a microfluidic system for drug evaluation. Our work could make it possible to use patient-specific hepatocyte-like cells to predict drug efficacy and side effects in various organs from the same patient.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120668DOI Listing
February 2021

Identification and Validation of the N6-Methyladenosine RNA Methylation Regulator YTHDF1 as a Novel Prognostic Marker and Potential Target for Hepatocellular Carcinoma.

Front Mol Biosci 2020 10;7:604766. Epub 2020 Dec 10.

Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China.

N6-methyladenosine (mA) RNA methylation has been implicated in various malignancies. This study aimed to identify the mA methylation regulator-based prognostic signature for hepatocellular carcinoma (HCC) as well as provide candidate targets for HCC treatment. The least absolute shrinkage and selection operator (LASSO) analyses were performed to identify a risk signature in The Cancer Genome Atlas (TCGA) datasets. The risk signature was further validated in International Cancer Genome Consortium (ICGC) and Pan-Cancer Analysis of Whole Genomes (PCAWG) datasets. Following transfection of short hairpin RNA (shRNA) targeting YTHDF1, the biological activities of HCC cells were evaluated by Cell Counting Kit-8 (CCK-8), wound-healing, Transwell, flow cytometry, and xenograft tumor assays, respectively. The potential mechanisms mediated by YTHDF1 were predicted by overrepresentation enrichment analysis (ORA)/gene set enrichment analysis (GSEA) and validated by Western blotting. Overexpression of mA RNA methylation regulators was correlated with malignant clinicopathological characteristics of HCC patients. The Cox regression and LASSO analyses identified a risk signature with five mA methylation regulators (KIAA1429, ZC3H13, YTHDF1, YTHDF2, and METTL3). In accordance with HCC cases in TCGA, the prognostic value of risk signature was also determined in ICGC and PCAWG datasets. Following analyzing the expression and clinical implications in TCGA and Gene Expression Omnibus (GEO), YTHDF1 was chosen for further experimental validation. Knockdown of YTHDF1 significantly inhibited the proliferation, migration, and invasion of HCC cells, as well as enhanced the apoptosis . Moreover, silencing YTHDF1 repressed the growth of xenograft tumors . Mechanism investigation indicated that YTHDF1 might promote the aggressive phenotypes by facilitating epithelial-mesenchymal transition (EMT) and activating AKT/glycogen synthase kinase (GSK)-3β/β-catenin signaling. The current study identified a robust risk signature consisting of mA RNA methylation regulators for HCC prognosis. In addition, YTHDF1 was a potential molecular target for HCC treatment.
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http://dx.doi.org/10.3389/fmolb.2020.604766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758441PMC
December 2020

scLM: Automatic Detection of Consensus Gene Clusters Across Multiple Single-cell Datasets.

Genomics Proteomics Bioinformatics 2020 Dec 23. Epub 2020 Dec 23.

Center for Cancer Genomics and Precision Oncology, Wake Forest Baptist Comprehensive Cancer Center, Wake Forest Baptist Medical Center, Winston Salem, NC 27157, USA; Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA. Electronic address:

In gene expression profiling studies, including single-cell RNA-seq (scRNA-seq) analyses, the identification and characterization of co-expressed genes provides critical information on cell identity and function. Gene co-expression clustering in scRNA-seq data presents certain challenges. We show that commonly used methods for single cell data are not capable of identifying co-expressed genes accurately, and produce results that substantially limit biological expectations of co-expressed genes. Herein, we present single-cell Latent-variable Model (scLM), a gene co-clustering algorithm tailored to single cell data that performs well at detecting gene clusters with significant biologic context. Importantly, scLM can simultaneously cluster multiple single-cell datasets, i.e., consensus clustering, enabling users to leverage single cell data from multiple sources for novel comparative analysis. scLM takes raw count data as input and preserves biological variation without being influenced by batch effects from multiple datasets. Results from both simulation data and experimental data demonstrate that scLM outperforms the existing methods with considerably improved accuracy. To illustrate the biological insights of scLM, we apply it to our in-house and public experimental scRNA-seq datasets. scLM identifies novel functional gene modules and refines cell states, which facilitates mechanism discovery and understanding of complex biosystems such as cancers. A user-friendly R package with all the key features of the scLM method is available at https://github.com/QSong-github/scLM.
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http://dx.doi.org/10.1016/j.gpb.2020.09.002DOI Listing
December 2020

Organoid: Current Implications and Pharmaceutical Applications in Liver Diseases.

Curr Mol Pharmacol 2020 Dec 16. Epub 2020 Dec 16.

Department of Radiology, Wake Forest School of Medicine, One Medical Center Boulevard, WinstonSalem, 27157 NC. United States.

Background: Understanding organogenesis, disorders, and repairing processes particularly important for understanding disease occurrence and developing treatment approaches. At present, liver-related studies are mainly conducted using in vivo models and cell lines, making it difficult to generalize the full picture of the structural characteristics and functions of human organs. Organoid is a three-dimensional (3D) culture system in vitro, which holds the promise to establish various disease models and conduct in-depth research by generating organ-like tissues in a dish. Recent advances of human liver organoids have provided us a deeper understanding of this complex organ.

Conclusion: In this review, we provide a systematic overview of the construction methods of organoids, focusing on their applications in the hepatic organogenesis and various liver disease models, as well as the limitations of current models. The development of organoid models is proving to be crucial in future liver research.
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http://dx.doi.org/10.2174/1874467213666201217115854DOI Listing
December 2020

IGFBP2 promotes tumor progression by inducing alternative polarization of macrophages in pancreatic ductal adenocarcinoma through the STAT3 pathway.

Cancer Lett 2021 03 10;500:132-146. Epub 2020 Dec 10.

Department of Cancer Biology, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Winston-Salem, NC, 27157, USA. Electronic address:

Tumor-associated macrophages (TAMs) represent the M2-like phenotype with potent immunosuppressive activity, and play a pro-tumor role in pancreatic ductal adenocarcinoma (PDAC) biology. In this study, we investigated the role of the insulin-like growth factor binding protein 2 (IGFBP2) as a determinant of TAM polarity. Clinical data revealed that the levels of IGFBP2 correlated with M2 TAMs accumulation and disease progression in human PDAC. In vivo mouse model experiments showed that IGFBP2 promoted an immunosuppressive microenvironment and tumor growth in a macrophage dependent manner. Bioinformatics analysis of PDAC transcriptomes revealed a significant association between IGFBP2 expression and M2 macrophage polarization and signal transducer and activator of transcription 3 (STAT3) activation. Mechanistic investigations demonstrated that IGFBP2 augmented the expression and secretion of IL-10 through STAT3 activation in PDAC cells, which induced TAM polarization toward an M2 phenotype. IGFBP2-polarized M2 macrophages significantly increased Tregs infiltration and impaired antitumor T-cell immunity in a mouse model. Thus, our investigations have illuminated the IGFBP2 signaling pathway that contributes to the macrophage-based immunosuppressive microenvironment in PDAC, suggesting that blocking the IGFBP2 axis constitutes a potential treatment strategy to reset TAM polarization toward an antitumor state in PDAC.
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http://dx.doi.org/10.1016/j.canlet.2020.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923838PMC
March 2021

Identifying cancer-associated fibroblasts as emerging targets for hepatocellular carcinoma.

Cell Biosci 2020 Oct 31;10(1):127. Epub 2020 Oct 31.

Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, China.

The tumor microenvironment (TME) is a complex multicellular functional compartment that includes fibroblasts, myofibroblasts, endothelial cells, immune cells, and extracellular matrix (ECM) elements. The microenvironment provides an optimum condition for the initiation, growth, and dissemination of hepatocellular carcinoma (HCC). As one of the critical and abundant components in tumor microenvironment, cancer-associated fibroblasts (CAFs) have been implicated in the progression of HCC. Through secreting various growth factors and cytokines, CAFs contribute to the ECM remodeling, stem features, angiogenesis, immunosuppression, and vasculogenic mimicry (VM), which reinforce the initiation and development of HCC. In order to restrain the CAFs-initiated HCC progression, current strategies include targeting specific markers, engineering CAFs with tumor-suppressive phenotype, depleting CAFs' precursors, and repressing the secretions or downstream signaling. In this review, we update the emerging understanding of CAFs in HCC, with particular emphasis on cellular origin, phenotypes, biological functions and targeted strategies. It provides insights into the targeting CAFs for HCC treatment.
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http://dx.doi.org/10.1186/s13578-020-00488-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603733PMC
October 2020

Multiregion whole-exome sequencing of intraductal papillary mucinous neoplasms reveals frequent somatic mutations predominantly in low-grade regions.

Gut 2021 May 7;70(5):928-939. Epub 2020 Oct 7.

Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Objective: Intraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions that can progress to invasive pancreatic cancer and are classified as low-grade or high-grade based on the morphology of the neoplastic epithelium. We aimed to compare genetic alterations in low-grade and high-grade regions of the same IPMN in order to identify molecular alterations underlying neoplastic progression.

Design: We performed multiregion whole exome sequencing on tissue samples from 17 IPMNs with both low-grade and high-grade dysplasia (76 IPMN regions, including 49 from low-grade dysplasia and 27 from high-grade dysplasia). We reconstructed the phylogeny for each case, and we assessed mutations in a novel driver gene in an independent cohort of 63 IPMN cyst fluid samples.

Results: Our multiregion whole exome sequencing identified , a previously unreported genetic driver of IPMN tumorigenesis, with hotspot mutations in one of two codons identified in >50% of the analyzed IPMNs. Mutations in were significantly more prevalent in low-grade regions in our sequenced cases. Phylogenetic analyses of whole exome sequencing data demonstrated diverse patterns of IPMN initiation and progression. Hotspot mutations in were also identified in an independent cohort of IPMN cyst fluid samples, again with a significantly higher prevalence in low-grade IPMNs.

Conclusion: Hotspot mutations in occur at high prevalence in IPMNs. Unique among pancreatic driver genes, mutations are enriched in low-grade IPMNs. These data highlight distinct molecular features of low-grade and high-grade dysplasia and suggest diverse pathways to high-grade dysplasia via the IPMN pathway.
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http://dx.doi.org/10.1136/gutjnl-2020-321217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262510PMC
May 2021

Genome-wide mutation analysis in precancerous lesions of endometrial carcinoma.

J Pathol 2021 01 13;253(1):119-128. Epub 2020 Nov 13.

Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China.

Clinicopathological evidence supports endometrial atypical hyperplasia (AH) or endometrial intraepithelial neoplasia as the precursor of uterine endometrioid carcinoma (EC), the most common gynecologic malignancy. However, the pathogenic progression from AH to EC remains unclear. Here, we employed whole-exome sequencing to identify somatic mutations and copy number changes in micro-dissected lesions from 30 pairs of newly diagnosed AH and EC. We found that all but one pair of AHs shared the same DNA mismatch repair status as their corresponding ECs. The percentage of common mutations between AH lesions and corresponding ECs varied significantly, ranging from 0.1% to 82%. Microsatellite stable AHs had fewer cancer driver mutations than ECs (5 versus 7, p = 0.017), but among microsatellite unstable AHs and ECs there was no difference in mutational numbers (36 versus 38, p = 0.65). As compared to AH specimens, 19 (79%) of 24 microsatellite stable EC tumors gained new cancer driver mutations, most of which involved PTEN, ARID1A, PIK3CA, CTNNB1, or CHD4. Our results suggest that some AH lesions are the immediate precursor of ECs, and progression depends on acquisition of additional cancer driver mutations. However, a complex clonal relationship between AH and EC can also be appreciated, as in some cases both lesions diverge very early or arise independently, thus co-developing with distinct genetic trajectories. Our genome-wide profile of mutations in AH and EC shines new light on the molecular landscape of tumor progression. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5566DOI Listing
January 2021

Organocatalytic Regio- and Enantioselective 1,8-Additions of Nitrogen and Sulfur Nucleophiles to 6-Methylene-6-indoles.

Org Lett 2020 10 29;22(20):7859-7863. Epub 2020 Sep 29.

Department of Medicinal Chemistry, School of Pharmacy, Qingdao University, Qingdao 266021, China.

Remote stereocontrolled 1,8-addition of heteroatom nucleophiles to 6-methylene-6-indoles generated from 6-indolylmethanols has been developed for the first time. With the aid of a chiral phosphoric acid, 6-indolylmethanols reacted with benzotriazoles to furnish 1,8-adducts with a nitrogen-containing tertiary carbon stereocenter in 54-80% yield with 76-92% ee. Importantly, the stereoselective 1,8-addition of benzotriazoles featured N selectivity. Furthermore, using thioacids as nucleophiles enabled the formation of 1,8-adducts with a sulfur-containing tertiary carbon stereocenter in 70-78% yield with 75-94% ee.
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http://dx.doi.org/10.1021/acs.orglett.0c02769DOI Listing
October 2020

Telomere Maintenance Associated Mutations in the Genetic Landscape of Gynecological Mucosal Melanoma.

Front Oncol 2020 2;10:1707. Epub 2020 Sep 2.

Department of Gynecological Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Purpose: Gynecological melanomas (GMs) are rare tumors with a poor prognosis. Here, we performed exome sequencing to generate the mutational landscape of GMs.

Methods: Next-generation sequencing was carried out on mucosal melanoma samples ( = 35) obtained from gynecological sites. The alternative telomere lengthening (ALT) phenotype was verified by fluorescence hybridization and the C-circle assay. Immunohistochemistry was performed to detect ATRX protein. Copy number variations in were detected by droplet digital polymerase chain reaction.

Results: In the 58 formalin-fixed paraffin-embedded samples, we identified 33 (56.9%) ALT-positive cases, with 23 showing loss of ATRX protein. promoter mutation was not detected in GMs ( = 40), but copy number variations in the region were observed in 20% (7/35) of the samples. amplification was mutually exclusive with ALT ( < 0.05). Kaplan-Meier revealed that ALT relative to amplification was associated with longer overall survival in GM patients without metastasis.

Conclusion: These findings indicate that telomere maintenance mechanisms play a critical role in the tumorigenesis of GMs and may aid in the prediction of clinical prognosis and the development of targeted therapy for the treatment of GM.
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http://dx.doi.org/10.3389/fonc.2020.01707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492295PMC
September 2020

Targeted GSH-exhausting and hydroxyl radical self-producing manganese-silica nanomissiles for MRI guided ferroptotic cancer therapy.

Nanoscale 2020 Aug;12(32):16738-16754

Department of Pharmacy, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.

Ferroptosis, a cell death path induced by the generation of reactive oxygen species (ROS), will cause the accumulation of lipid peroxides (PL-PUFA-OOH) and achieve potent tumor-regression. However, glutathione (GSH)-dependent glutathione peroxidase 4 (GPx4) can reduce PL-PUFA-OOH and antagonize the ferroptosis inducing effect of ROS. Herein, folate-PEG modified dihydroartemisinin (DHA) loaded manganese doped mesoporous silica nanoparticles (described as nanomissiles) were constructed for integrating the effect of GSH exhaustion and ROS generation. After endocytosis by tumor cells, intracellular GSH triggered the degradation of nanomissiles, which allowed the simultaneous release of DHA and Fenton catalytic Mn2+ due to the redox reaction between the manganese-oxygen bonds and GSH. The degradation would lead to GSH exhaustion, activation of Mn2+-based magnetic resonance imaging (MRI), and DHA-driven ˙OH generation. The GSH-free environment inhibited the activity of GPx4 and enhanced the accumulation of PL-PUFA-OOH oxidized by ˙OH. Furthermore, the cooperative effects suppressed tumor metastasis by destroying the structure of polyunsaturated fatty acids in the cell membranes and showed potent antitumor activity. This innovative ferroptotic therapy integrating the GSH exhaustion and ROS generation will be a promising strategy for cancer therapy.
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http://dx.doi.org/10.1039/d0nr02396eDOI Listing
August 2020

Spreading of benquitrione droplets on superhydrophobic leaves through pillar[5]arene-based host-guest chemistry.

Chem Commun (Camb) 2020 Jul 9;56(55):7593-7596. Epub 2020 Jun 9.

Key Laboratory of Pesticide and Chemical Biology (CCNU), Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China.

Spreading of agricultural sprays on plant surfaces is a significant task as it helps decrease pesticide usage and thereby reduces the risk of environmental pollution. Here, we report a method of increasing the spreading of herbicide benquitrione droplets on superhydrophobic surfaces through its selective dynamic self-assembly with amino pillar[5]arenes. Supramolecular interaction such as host-guest interaction was utilized for the complete diffusion of benquitrione over the hydrophobic plant surface. Furthermore, molecular dynamics simulations were used to verify that AP5A improved the spreading of benquitrione droplets on superhydrophobic interfaces. Moreover, complexation of benquitrione did not affect its biological activity. The present work provides a new method for improving the utilization rate of pesticides and reducing pesticide use.
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http://dx.doi.org/10.1039/d0cc02187cDOI Listing
July 2020

Construction of arsenic-metal complexes loaded nanodrugs for solid tumor therapy: A mini review.

Int J Pharm 2020 Jun 4;583:119385. Epub 2020 May 4.

Department of Pharmacy, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China. Electronic address:

Arsenic trioxide (AsO), a front-line therapeutic agent against acute promyelocytic leukemia, has a broad spectrum against malignancies. Unfortunately, the clinical application of AsO in treating hematological cancers has not been transformed to solid tumors, for its dose-limited toxicity and undesirable pharmacokinetics. The ordinary AsO loaded nanodrugs (such as liposomes, polymer micelles, albumin-based nanodrugs, and silica-based nanodrugs, etc.) still could not fuel up pharmaceuticals and eradicate toxicity for low delivery efficiency caused by the instability and severe drug leakage of formulations during circulation. Recently, the approach of forming and delivering arsenic-metal complexes which will dissociate in the tumoral environment caught our mind. This is the most effective strategy to reduce drug leakage in circulation and accumulate arsenite ions in tumor sites, therefore promote the anti-tumor effect and lighten the toxicity of the drug. This review aims to explain the formation mechanism of arsenic-metal nanocomposites and summarize the constructing strategies of the arsenic-metal nanocomplexes (arsenic-nickel, arsenic-manganese, arsenic-platinum, arsenic-gadolinium, arsenic-zinc, and arsenic-iron nanobins) loaded nanodrugs for solid tumor therapy. Furthermore, the expectations and challenges of arsenic-metal complexes containing nanodrugs for cancer therapy in the future were discussed.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119385DOI Listing
June 2020

The Metastasis Potential Promoting Capacity of Cancer-Associated Fibroblasts Was Attenuated by Cisplatin via Modulating KRT8.

Onco Targets Ther 2020 1;13:2711-2723. Epub 2020 Apr 1.

Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, People's Republic of China.

Background: Cancer-associated fibroblasts (CAFs) are an essential component of tumor microenvironment. They are attracting increasing attentions due to their crucial role in tumor growth, drug-resistance and metastasis. Cisplatin is a first-line chemotherapy drug applying in various types of cancer. There are intensive studies on cisplatin's effect on tumor cells, however, its effect on CAFs remains poorly understood. In the present study, we investigated the effect of cisplatin on CAFs.

Methods: Cell migration was detected by wound healing assay. Cell invasion was performed by the transwell assay. mRNA expression was detected by quantitative PCR, and protein expression was detected by Western blotting. Tumor growth was measured using BALB/c nude mice tumor models.

Results: Cisplatin attenuated the promoting capacity of CAFs on lung cancer cell migration and invasion, via suppressing CAFs' effect on metastasis-related genes including Twist1, vascular endothelial growth factor receptor (VEGFR), MMP2, and AKT signaling pathway. Keratin 8 (KRT8) was identified as a target of cisplatin. KRT8 upregulation in CAFs is responsible for the inhibitory effect of cisplatin on lung cancer cells metastasis potential through AKT pathway suppression. The stimulation of AKT by AKT activator SC79 reversed KRT8's effect on cell migration. Importantly, in vivo study also showed that CAFs enhanced tumor growth significantly, and cisplatin effectively abrogated the promoting effect of CAFs on tumor growth.

Conclusion: Our results revealed a novel mechanism that cisplatin attenuated the metastasis promoting effect of CAFs via KRT8/AKT signaling pathway. This finding highlights KRT8 in CAFs as a potential therapeutic candidate for metastasis treatment.
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http://dx.doi.org/10.2147/OTT.S246235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132007PMC
April 2020

Secretory Clusterin: A Promising Target for Chemoresistance of Hepatocellular Carcinoma.

Mini Rev Med Chem 2020 ;20(12):1153-1165

Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, 226001 Nantong, Jiangsu, China.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Chemoresistance remains the major factor for limited efficacy of the HCC treatment. Thus, exploring the mechanisms underlying drug resistance is of great importance. Secretory clusterin (sCLU), a stressactivated and ATP-independent molecular chaperone, is up-regulated in numerous tumors and correlated with malignant phenotypes. For HCC, the implication of sCLU was previously addressed in tumor growth, metastasis, as well as early diagnosis and poor prognosis. Notably, accumulating studies have emphasized its vital role in drug resistance of HCC. Depletion of sCLU synergistically could enhance the sensitivity of HCC cells to a variety of chemotherapy agents. Herein, we summarized the potential mechanisms accounting for the sCLU-induced chemoresistance, including promoting apoptosis evasion, facilitating epithelial-mesenchymal transition (EMT), maintaining the viability of cancer stem cell (CSC), enhancing drug efflux capacity, and regulating autophagic activities. The current evidence suggest that targeting sCLU might be a promising approach in overcoming chemoresistance of HCC.
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http://dx.doi.org/10.2174/1389557520666200331072122DOI Listing
February 2021

TMT-Based Quantitative Proteomic Analysis Reveals the Crucial Biological Pathways Involved in Self-Incompatibility Responses in .

Int J Mol Sci 2020 Mar 14;21(6). Epub 2020 Mar 14.

Forestry College, Fujian Agriculture and Forestry University, Fuzhou 350002, Fujian, China.

is a valuable woody oil plant belonging to the Theaceae, oil extracted from the seed is an excellent edible oil source. Self-incompatibility (SI) in results in low fruit set, and our knowledge about the mechanism remains limited. In the present study, the Tandem mass tag (TMT) based quantitative proteomics was employed to analyze the dynamic change of proteins response to self- and cross-pollinated in . A total of 6,616 quantified proteins were detected, and differentially abundant proteins (DAPs) analysis identified a large number of proteins. Combined analysis of differentially expressed genes (DEGs) and DAPs of self- and cross-pollinated pistils based on transcriptome and proteome data revealed that several candidate genes or proteins involved in SI of , including polygalacturonase inhibitor, UDP-glycosyltransferase 92A1-like, beta-D-galactosidase, S-adenosylmethionine synthetase, xyloglucan endotransglucosylase/hydrolase, ABC transporter G family member 36-like, and flavonol synthase. Venn diagram analysis identified 11 proteins that may participate in pollen tube growth in . Our data also revealed that the abundance of proteins related to peroxisome was altered in responses to SI in . Moreover, the pathway of lipid metabolism-related, flavonoid biosynthesis and splicesome were reduced in self-pollinated pistils by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. In summary, the results of the present study lay the foundation for learning the regulatory mechanism underlying SI responses as well as provides valuable protein resources for the construction of self-compatibility through genetic engineering in the future.
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http://dx.doi.org/10.3390/ijms21061987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139391PMC
March 2020
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