Publications by authors named "Jun Yan"

1,401 Publications

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MIL-1, a novel antitumor agent derived from natural product millepachine, acts as tubulin polymerization inhibitor for the treatment of hepatocellular carcinoma.

Eur J Pharmacol 2021 Feb 26:173975. Epub 2021 Feb 26.

Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, Guangdong, China. Electronic address:

Natural products are a large source of clinically effective antitumor drugs. Millepachine is a natural product derived from leguminous plants that was reported to display antitumor activity. In this study, the novel compound, (1H-indol-5-yl)(5-methoxy-2,2-dimethyl-2H-chromen-8-yl)methanone (MIL-1), was designed and synthesized by fusing millepachine and indole rings. MIL-1 exerted much better antitumor activity than millepachine, manifesting as a 24- to 201-fold increase in vitro cytotoxicity and a 2.4-fold increase in in vivo antitumor activity in hepatocellular cell lines-derived models. The immunofluorescence and HPLC detection revealed that MIL-1 was a potent microtubule targeting agent by interfering with the equilibrium of tubulin-microtubule dynamics and irreversibly binding to tubulin. MIL-1 displayed remarkable antitumor activity with an IC of 31-207 nM towards various human cancer cell lines derived from various organs and tissues, and it exerted no evidence of toxicity against normal cells. Mechanistic studies showed that MIL-1 arrested the cell cycle at G2/M phase and induced apoptosis by activating caspase-3 activity and reactive oxygen species (ROS) accumulation. Nevertheless, the superior antitumor effect of MIL-1 is worthy of further detailed study for the treatment of hepatocellular carcinoma (HCC).
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http://dx.doi.org/10.1016/j.ejphar.2021.173975DOI Listing
February 2021

A Prognostic Model Based on RNA Binding Protein Predicts Clinical Outcomes in Hepatocellular Carcinoma Patients.

Front Oncol 2020 12;10:613102. Epub 2021 Feb 12.

Center of Hepatobiliary Pancreatic Disease, Beijing Tsinghua Changgung Hospital, Beijing, China.

Dysregulation of RNA binding proteins (RBPs) is closely associated with tumor events. However, the function of RBPs in hepatocellular carcinoma (HCC) has not been fully elucidated. The RNA sequences and relevant clinical data of HCC were retrieved from the The Cancer Genome Atlas (TCGA) database to identify distinct RBPs. Subsequently, univariate and multivariate cox regression analysis was performed to evaluate the overall survival (OS)-associated RBPs. The expression levels of prognostic RBP genes and survival information were analyzed using a series of bioinformatics tool. A total of 365 samples with 1,542 RBPs were included in this study. One hundred and eighty-seven differently RBPs were screened, including 175 up-regulated and 12 down-regulated. The independent OS-associated RBPs of , and were used to develop a prognostic model. Survival analysis showed that low-risk patients had a significantly longer OS and disease-free survival (DFS) when compared to high-risk patients (: 2.577, : 1.793-3.704, < 0.001 and : 1.599, : 1.185-2.159, = 0.001, respectively). The International Cancer Genome Consortium (ICGC) database was used to externally validate the model, and the OS of low-risk patients were found to be longer than that of high-risk patients ( < 0.001). The Nomograms of OS and DFS were plotted to help in clinical decision making. These results showed that the model was effective and may help in prognostic stratification of HCC patients. The prognostic prediction model based on RBPs provides new insights for HCC diagnosis and personalized treatment.
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http://dx.doi.org/10.3389/fonc.2020.613102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907500PMC
February 2021

Microwave-Assisted Synthesis of Tris-Anderson Polyoxometalates for Facile CO Cycloaddition.

Inorg Chem 2021 Feb 24. Epub 2021 Feb 24.

School of Chemistry and Chemical Engineering, Central South University, Changsha 410000, P. R. China.

Four new tris-Anderson polyoxometalates (POMs), (NH)[ZnMoO(CHNO)(OH)]·4HO (), (NH)[CuMoO(CHNO)(OH)]·4HO (), (TBA)(NH)[ZnMoO(CHO)(OH)]·10HO () (TBA = -CHN), and (NH)[CuMoO(CHO)]·16HO (), were synthesized by a microwave-assisted method. Single-crystal X-ray diffraction revealed that and contained a tris (trihydroxyl organic compounds) ligand grafted on one side, while two tris ligands were grafted on two sides to form χ/δ and δ/δ isomers in and , respectively. H and C NMR spectra of the χ/δ isomer were obtained for the first time, with six methylenes showing six peaks in the H NMR spectrum and only four peaks in the C NMR spectrum. Mass spectrometry monitoring revealed that during the microwave-assistant process the tris ligand can graft onto POMs to form , while tris directly coordinates with metallic heteroatoms to form isopolymolybdates during the conventional reflux synthesis process. In addition, - can catalyze CO with epoxides into cyclic carbonates with high selectivity and yields at an atmospheric pressure of CO, which is lower than the pressure of CO in other catalysis using POMs as catalysts. Furthermore, - showed good catalytic stability and cycling properties. Mechanism studies substantiated POMs cocatalyzed with Br to improve the catalytic yields.
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http://dx.doi.org/10.1021/acs.inorgchem.1c00019DOI Listing
February 2021

Exosome-mediated delivery of RNA and DNA for gene therapy.

Cancer Lett 2021 Feb 18;505:58-72. Epub 2021 Feb 18.

3P Biotechnologies, Inc., Louisville, KY, 40202, USA; James Graham Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, 40202, USA. Electronic address:

Gene therapy promises to revolutionize biomedicine and personalized medicine by modulating or compensating the expression of abnormal genes. The biggest obstacle for clinical application is the lack of an effective, non-immunogenic delivery system. We show that bovine colostrum exosomes and polyethyleneimine matrix (EPM) delivers short interfering RNA (siRNA) or plasmid DNA (pDNA) for effective gene therapy. KRAS, a therapeutic focus for many cancers, was targeted by EPM-delivered KRAS siRNA (siKRAS) and inhibited lung tumor growth (>70%) and reduced KRAS expression (50%-80%). Aberrant p53 is another therapeutic focus for many cancers. EPM-mediated introduction of wild-type (WT) p53 pDNA (pcDNA-p53) resulted in p53 expression in p53-null H1299 cells in culture, subcutaneous lung tumor, and tissues of p53-knockout mice. Additionally, chemo-sensitizing effects of paclitaxel were restored by exogenous WT p53 in lung cancer cells. Together, this novel EPM technology represents an effective 'platform' for delivery of therapeutic nucleic acids to treat human disease.
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http://dx.doi.org/10.1016/j.canlet.2021.02.011DOI Listing
February 2021

Accurate assembly of ferrocene-functionalized {Ti22Fc4} clusters with photocatalytic amine oxidation activity.

Chem Commun (Camb) 2021 Feb 18. Epub 2021 Feb 18.

Hunan Provincial Key Laboratory of Chemical Power Sources, College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, Hunan, P. R. China.

We report here the synthesis of a ferrocene-functionalized {Ti22Fc4} cluster with a 'dimer-of-clusters' topology, which represents the largest Ti-oxo cluster (TOC) modified with organometallic groups ever reported. The exact assembly path of {Ti22Fc4} can be inferred from its two substructures, {Ti11Fc2} and {Ti5Fc}, which can also be synthesized independently through subtle changes in reaction conditions. Furthermore, we used these clusters as photocatalysts, and have studied, for the first time, the photocatalytic activity of TOCs in the oxidative coupling of amines.
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http://dx.doi.org/10.1039/d1cc00019eDOI Listing
February 2021

EXPRESS: A Piecewise Model for In Situ Raman Measurement of the Chlorinity of Deep-Sea High-Temperature Hydrothermal Fluids.

Appl Spectrosc 2021 Feb 18:3702821999114. Epub 2021 Feb 18.

nstitute of Oceanology, Chinese Academy of Sciences, Key Lab of Marine Geology and Environment, 7 Nanhai Road, Qingdao, Shandong 266071,PR China, Qingdao, Shandong, China.

The chlorinity of deep-sea hydrothermal fluids, representing one of the crucial deep-sea hydrothermal indicators, indicates the degree of deep phase separation of hydrothermal fluids and water/rock reactions. However, accurately measuring the chlorinity of high-temperature hydrothermal fluids is still a significant challenge. In this paper, a piecewise chlorinity model to measure the chlorinity of high-temperature hydrothermal fluids was developed based on the OH stretching band of water, exhibiting an accuracy of 96.20%. The peak position, peak area ratio and F value were selected to establish the chlorinity piecewise calibration model within the temperature ranges of 0-50°C, 50-200°C and 200-300°C. Compared with that of the chlorinity calibration model built based on a single parameter, the accuracy of this piecewise model increased by approximately 4.83-12.33%. This chlorinity calibration model was applied to determine the concentrations of Cl for high-temperature hydrothermal fluids in the Okinawa Trough hydrothermal field.
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http://dx.doi.org/10.1177/0003702821999114DOI Listing
February 2021

Effects of cold air dehydration on icefish water dynamics and macromolecular oxidation measured by low-field nuclear magnetic resonance and magnetic resonance imaging.

Food Sci Nutr 2021 Feb 3;9(2):736-746. Epub 2020 Dec 3.

Arg & Forestry Prod Deep Proc Technol & Equipment Co-Innovation Center for the Sustainable Forestry in Southern China College of Forestry Nanjing Forestry University Nanjing China.

We have used low-field nuclear magnetic resonance (LF-NMR) and magnetic resonance imaging to measure water dynamics and migration, color, and texture profile (TPA) of icefish dried with hot and cold air methods. Relaxation time of T, T and T, and the peak area of A and A decreased significantly during drying. The water signal intensity decreased from the surface to inner regions during drying. Color parameters of L* and b* values increased significantly, TPA parameters of hardness increased, cohesiveness decreased significantly, and moisture content decreased significantly during drying. We observed correlations between the moisture content, TPA, color, and NMR parameters. In addition, we found lower thiobarbituric acid reactive substances and carbonyl content of the dried icefish with cold air compared with hot air. The cold air drying method yielded better sensory quality, and LF-NMR was a useful nondestructive method to determine the degree of drying and the quality of icefish.
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http://dx.doi.org/10.1002/fsn3.2039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866611PMC
February 2021

Minimal right vertical infra-axillary incision for repair of congenital heart defects.

Ann Thorac Surg 2021 Feb 13. Epub 2021 Feb 13.

Pediatric Cardiac Surgery Center, National Center for Cardiovascular Disease and Fuwai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China. Electronic address:

Background: The present study evaluated the surgical results of a diverse array of congenital heart defects through minimal right vertical infra-axillary incision (RVIAI).

Methods: A retrospective review of consecutive patients using minimal RVIAI for congenital heart defects between 2015 to 2019 was performed. The study included 1672 patients and the minimal RVIAI was utilized for 13 primary procedures. The length of incision ranged from 2.0 to 4.0 cm in all patients.

Results: Median age was 2.3 years (range, 0.2-6.0 years) and median weight was 12.5 kg (range, 5.0-34.0 kg). There was no in-hospital death or conversion to median sternotomy. Five patients (0.3%) underwent early reoperations (three had postoperative bleeding, one had coarctation of ascending aorta due to cannulation, and one had major residual shunt). Other postoperative complications included trivial residual shunt in 16 patients (1.0%), pleural effusion in 3 patients (0.2%), and wound infection in 4 patients (0.2%). Median follow-up was 3.2 years (range, 0.2-4.9 years). There were no late deaths or late reoperations. During the follow-up period, no surgery-related thoracic deformity or breast asymmetry were noted. One patient had mild scoliosis. We randomly chose 100 patients to complete questionnaire regarding patient satisfaction with minimal RVIAI. Results showed that all patients and their parents were satisfied with the cosmetic results.

Conclusions: Minimal RVIAI can be safely performed for a wide range of congenital heart defects with excellent cosmetic results. It may serve as a good alternative to median sternotomy, especially for very young female patients.
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http://dx.doi.org/10.1016/j.athoracsur.2021.01.052DOI Listing
February 2021

Clinical Outcome of Patients with Transposition of the Great Arteries and Intramural Coronary Artery.

Pediatr Cardiol 2021 Feb 16;42(2):417-424. Epub 2021 Feb 16.

Department of Cardiovascular Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167# Beilishi Road, Xicheng District, Beijing, 100037, China.

To review the early and intermediate outcomes of patients with transposition of the great arteries (TGA) and intramural coronary artery (IMCA) who underwent arterial switch operation (ASO) at our center. Among 450 patients with TGA who underwent an ASO between 2010 and 2018, 26 (5.8%) patients were identified with IMCA. The left coronary artery was intramural in 21 of 26 patients. We adopted coronary transfer using double coronary buttons with unroofed intramural course for all 26 patients. Early mortality for patients with IMCA was 3 of 26 (11.5%) compared with 10 of 424 (2.4%) for those without IMCA (p = 0.007). Six patients suffered major adverse events, including extracorporeal membrane oxygenation support in 3 patients, delayed sternal closure in 6 patients. The follow-up was available for all 23 survivors, with the mean follow-up period of 73.5 ± 28.7 months. There was no late death and reinterventions, and all patients were asymptomatic at last follow-up. One patient exhibited moderate neopulmonary regurgitation, and 1 patient presented with distal stenosis of the right pulmonary artery. Coronary transfer using double coronary buttons with unroofed intramural course was a good option for patients with TGA and IMCA. With this technique, ASO could be performed with optimal early and intermediate outcomes.
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http://dx.doi.org/10.1007/s00246-020-02499-5DOI Listing
February 2021

microRNA-130b-3p Contained in MSC-Derived EVs Promotes Lung Cancer Progression by Regulating the FOXO3/NFE2L2/TXNRD1 Axis.

Mol Ther Oncolytics 2021 Mar 20;20:132-146. Epub 2020 Sep 20.

Department of Thoracic Surgery, Shenzhen Hospital, Southern Medical University, Shenzhen 518101, P.R. China.

This study aimed to explore the molecular mechanism by which mesenchymal stem cells (MSCs) mediate lung cancer progression. Extracellular vesicles (EVs) were isolated from transfected or untransfected MSCs, and were co-cultured with lung cancer cells with/without microRNA-130b-3p (miR-130b-3p) inhibitor, mimic, overexpression plasmids of FOXO3/NFE2L2, or shRNAs. CCK-8 assay, colony formation, transwell assay, and flow cytometry were carried out to determine the biological functioning of lung cancer cells. Furthermore, FOXO3, Keap1, NFE2L2, and TXNRD1 expression was determined by qRT-PCR and western blot analysis. A tumor xenograft mouse model was used to determine role of EVs-miR-130b-3p and its target FOXO3 in lung cancer progression . miR-130b-3p was highly expressed in lung cancer tissues and MSC-derived EVs. Moreover, the MSC-derived EVs transferred miR-130b-3p to lung cancer cells to promote cell proliferation, migration, and invasion while repress cell apoptosis. miR-130b-3p directly targeted FOXO3, and FOXO3 elevated Keap1 expression to downregulate NFE2L2, thus inhibiting TXNRD1. FOXO3 overexpression or silencing of NFE2L2 or TXNRD1 diminished lung cancer cell proliferation, invasion, and migration but enhanced apoptosis. EV-delivered miR-130b-3p or FOXO3 silencing promoted lung cancer progression . In summary, MSC-derived EVs with upregulated miR-130b-3p suppressed FOXO3 to block the NFE2L2/TXNRD1 pathway, thus playing an oncogenic role in lung cancer progression.
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http://dx.doi.org/10.1016/j.omto.2020.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851484PMC
March 2021

Antitumor γδ T cells need oxygen to function.

Authors:
Jun Yan

Nat Immunol 2021 Mar;22(3):268-269

Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.

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http://dx.doi.org/10.1038/s41590-021-00874-9DOI Listing
March 2021

Regulation of tumor immune suppression and cancer cell survival by CXCL1/2 elevation in glioblastoma multiforme.

Sci Adv 2021 Jan 27;7(5). Epub 2021 Jan 27.

Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The invasiveness and high immune suppression of glioblastoma multiforme (GBM) produce poor survival of afflicted patients. Unfortunately, in the past decades, no therapeutic approach has remarkably improved the survival time of patients with GBM. Our analysis of the TCGA database and brain tumor tissue arrays indicated that and overexpression is closely associated with GBM's aggressiveness. Our results showed that elevation of CXCL1 or CXCL2 facilitated myeloid cell migration and simultaneously disrupted CD8 T cell accumulation at tumor sites, causing accelerated tumor progression. Yet, blockade of CXCL1/2 significantly prevented myeloid-derived suppressor cell migration and thereby increased CD8 T cell accumulation in vitro and in vivo. CXCL1/2 also promoted the paracrine factor S100A9 and further activated Erk1/2 and p70S60k, whereas blocking CXCL1/2 down-regulated these prosurvival factors. The combination of targeting CXCL1/2 and standard temozolomide chemotherapy improved upon the antitumor efficacy of chemotherapy alone, extending the overall survival time in GBM.
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http://dx.doi.org/10.1126/sciadv.abc2511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840139PMC
January 2021

Impacts of land-use changes on the variability of microbiomes in soil profiles.

J Sci Food Agric 2021 Feb 11. Epub 2021 Feb 11.

Key Laboratory of Mollisols Agroecology, Northeast Institute of Geography and Agroecology, Chinese Academy of Sciences, Harbin, 150081.

Background: The conversion of arable land to grassland and/or forested land is a common strategy of restoration, because the development of plant communities can inhibit the erosion of soil, increase biodiversity and improve associated ecosystem services. The vertical profiles of microbial communities, however, have not been well characterized, and their variability after land conversion is not well understood. We assessed the effects of the conversion of arable land (AL) to grassland (GL) and forested land (FL) on bacterial communities as old as 29 years in 0-200 cm profiles of a Chinese Mollisol.

Results: The soil in AL has been a stable ecosystem, and changes in assembly of soil microbiomes tended to be larger in the topsoil. The soil properties and microbial biodiversity of arable land were larger following revegetation and reforestation. The conversion caused a more complex coupling among microbes, and negative interactions and average connectivity were stronger in the 0-20 cm layers in GL and in the 20-60 cm layers in FL. The land use dramatically influenced the assembly of the microbial communities more in GL than AL and FL. The bacterial diversity was an important component of soil multinutrient cycling in the profiles and that microbial functions were not as affected by changes in land use.

Conclusion: The spatial variation of the microbiomes provided critical information on belowground soil ecology and the ability of the soil to provide crucial ecosystem services. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/jsfa.11150DOI Listing
February 2021

Association of the Collagen Signature in the Tumor Microenvironment With Recurrence and Survival of Patients With T4N0M0 Colon Cancer.

Dis Colon Rectum 2021 Feb 1. Epub 2021 Feb 1.

Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China. School of Science, Jimei University, Xiamen, Fujian, 361021, China. Department of Radiology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, China. Key Laboratory of OptoElectronic Science and Technology for Medicine of the Ministry of Education & Fujian Provincial Key Laboratory of Photonics Technology, Fujian Normal University, Fuzhou, Fujian, 350007, China.

Background: The current clinicopathological risk factors do not accurately predict disease recurrence in patients with T4N0M0 colon cancer. We hypothesized that the collagen signature combined with clinicopathological risk factors (new model) had a better prognostic value than clinicopathological risk factors alone (clinicopathological model).

Objective: This study aimed to establish a collagen signature in the tumor microenvironment and to validate its role in predicting the recurrence of T4N0M0 colon cancer.

Design: This was a retrospective study.

Settings: This study took place at a tertiary medical center.

Patients: Patients with T4N0M0 colon cancer who underwent surgery at our center between 2009 and 2015 (n=416) were included.

Intervention: A total of 142 collagen features were analyzed in the tumor microenvironment in specimens of colon cancer using second harmonic generation imaging. A collagen signature was constructed using a LASSO Cox regression model.

Main Outcome Measures: Disease-free survival and overall survival.

Results: The training and testing cohorts consisted of 291 and 125 randomly assigned samples, with recurrence rates of 19.9% and 22.4%, respectively. A 3-feature-based collagen signature predicted the recurrence risk at 1, 3, and 5 years, with the area under the receiver-operating characteristic curves of 0.808, 0.832, and 0.791 in the training cohort and 0.836, 0.807, and 0.794 in the testing cohort, respectively. Multivariate analysis revealed that the collagen signature could independently predict the disease-free survival (HR=7.17, p<0.001) and overall survival rates (HR=5.03, p<0.001). The new model had a better prognostic value than the clinicopathological model, which included four clinicopathological risk factors: obstruction or perforation, lymphovascular invasion, tumor budding, and no chemotherapy.

Limitations: This study was limited by its retrospective design.

Conclusions: The collagen signature in the tumor microenvironment may be a new prognostic marker that can effectively predict the recurrence and survival of patients with T4N0M0 colon cancer. See Video Abstract at http://links.lww.com/DCR/B503 .
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http://dx.doi.org/10.1097/DCR.0000000000001907DOI Listing
February 2021

Oligomer β-amyloid Induces Hyperactivation of Ras to Impede NMDA Receptor-Dependent Long-Term Potentiation in Hippocampal CA1 of Mice.

Front Pharmacol 2020 10;11:595360. Epub 2020 Dec 10.

Department of Physiology, Nanjing Medical University, Nanjing, China.

The activity of Ras, a small GTPase protein, is increased in brains with Alzheimer's disease. The objective of this study was to determine the influence of oligomeric Aβ on the activation of Ras, and the involvement of the Ras hyperactivity in Aβ-induced deficits in spatial cognition and hippocampal synaptic plasticity. Herein, we show that intracerebroventricular injection of Aβ in mice (Aβ-mice) enhanced hippocampal Ras activation and expression, while 60 min incubation of hippocampal slices in Aβ (Aβ-slices) only elevated Ras activity. Aβ-mice showed deficits in spatial cognition and NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) in hippocampal CA1, but basal synaptic transmission was enhanced. The above effects of Aβ were corrected by the Ras inhibitor farnesylthiosalicylic acid (FTS). ERK2 phosphorylation increased, and Src phosphorylation decreased in Aβ-mice and Aβ-slices. Both were corrected by FTS. In CA1 pyramidal cells of Aβ-slices, the response of AMPA receptor and phosphorylation of GluR1 were enhanced with dependence on Ras activation rather than ERK signaling. In contrast, NMDA receptor (NMDAR) function and GluN2A/2B phosphorylation were downregulated in Aβ-slices, which was recovered by application of FTS or the Src activator ouabain, and mimicked in control slices treated with the Src inhibitor PP2. The administration of PP2 impaired the spatial cognition and LTP induction in control mice and FTS-treated Aβ-mice. The treatment of Aβ-mice with ouabain rescued Aβ-impaired spatial cognition and LTP. Overall, the results indicate that the oligomeric Aβ hyperactivates Ras and thereby causes the downregulation of Src which impedes NMDAR-dependent LTP induction resulting in cognitive deficits.
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http://dx.doi.org/10.3389/fphar.2020.595360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848859PMC
December 2020

Capsule carbohydrate structure determines virulence in Acinetobacter baumannii.

PLoS Pathog 2021 Feb 2;17(2):e1009291. Epub 2021 Feb 2.

LAC+USC Medical Center, Los Angeles, California, United States of America.

Acinetobacter baumannii is a highly antibiotic-resistant bacterial pathogen for which novel therapeutic approaches are needed. Unfortunately, the drivers of virulence in A. baumannii remain uncertain. By comparing genomes among a panel of A. baumannii strains we identified a specific gene variation in the capsule locus that correlated with altered virulence. While less virulent strains possessed the intact gene gtr6, a hypervirulent clinical isolate contained a spontaneous transposon insertion in the same gene, resulting in the loss of a branchpoint in capsular carbohydrate structure. By constructing isogenic gtr6 mutants, we confirmed that gtr6-disrupted strains were protected from phagocytosis in vitro and displayed higher bacterial burden and lethality in vivo. Gtr6+ strains were phagocytized more readily and caused lower bacterial burden and no clinical illness in vivo. We found that the CR3 receptor mediated phagocytosis of gtr6+, but not gtr6-, strains in a complement-dependent manner. Furthermore, hypovirulent gtr6+ strains demonstrated increased virulence in vivo when CR3 function was abrogated. In summary, loss-of-function in a single capsule assembly gene dramatically altered virulence by inhibiting complement deposition and recognition by phagocytes across multiple A. baumannii strains. Thus, capsular structure can determine virulence among A. baumannii strains by altering bacterial interactions with host complement-mediated opsonophagocytosis.
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http://dx.doi.org/10.1371/journal.ppat.1009291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880449PMC
February 2021

Transposition of the Great Arteries, Ventricular Septal Defect, and Pulmonary Stenosis: Modified REV versus Rastelli.

Pediatr Cardiol 2021 Jan 28. Epub 2021 Jan 28.

Pediatric Cardiac Surgery Center, National Center for Cardiovascular Disease and Fuwai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 167 North Lishi Rd, Beijing, People's Republic of China.

The objective of this study was to evaluate and compare the results of the modified réparation à l'ètage ventriculaire (REV) and the Rastelli operation for the treatment of transposition of the great arteries (TGA), ventricular septal defect (VSD), and pulmonary stenosis (PS). Records of 38 patients who underwent the modified REV (n = 16) or the Rastelli operation (n = 22) for the treatment of TGA, VSD, and PS between 2010 and 2019 were reviewed. The median age was 2.2 years (range 0.6-8.0 years) and the median weight was 11.3 kg (range 6.4-22.0 kg). No in-hospital death occurred and there were 4 early reoperations (two in each group). Overall survival at 10 years was 97.4% (100% in Modified REV group and 95.5% in Rastelli group, P = 0.39). Freedom from left ventricular outflow tract (LVOT) reoperation was 100% in both groups. Freedom from right ventricular outflow tract (RVOT) reoperation was 100% in Modified REV group and 75.4% in Rastelli group (P = 0.073). Event-free survival was 100% in Modified REV group and 72.0% in Rastelli group (P = 0.048). The most recent echocardiography showed that LVOT peak gradient was less than 10 mmHg in all patients. In Modified REV group, 30.8% of patients (4/13) had either RVOT obstruction (RVOT peak gradient more than 40 mmHg) or moderate or severe pulmonary insufficiency, while conduit stenosis (peak gradient more than 40 mmHg) was found in 25.0% of patients (3/12) in Rastelli group. The modified REV and the Rastelli operation provide satisfactory early results, as well as long-term survival and LVOT performance. However, the modified REV has better RVOT performance.
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http://dx.doi.org/10.1007/s00246-021-02538-9DOI Listing
January 2021

Absence of CCR2 reduces spontaneous intestinal tumorigenesis in the Apc mouse model.

Int J Cancer 2021 Jan 26. Epub 2021 Jan 26.

Department of Microbiology and Immunology, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA.

The biological activities of chemokine (C-C motif) ligand 2 (CCL2) are mediated via C-C chemokine receptor-2 (CCR2). Increased CCL2 level is associated with metastasis of many cancers. In our study, we investigated the role of the CCL2/CCR2 axis in the development of spontaneous intestinal tumorigenesis using the Apc mouse model. Ablation of CCR2 in Apc mice significantly increased the overall survival and reduced intestinal tumor burden. Immune cell analysis showed that CCR2 Apc mice exhibited significant reduction in the myeloid cell population and increased interferon γ (IFN-γ) producing T cells both in spleen and mesenteric lymph nodes compared to Apc mice. The CCR2 Apc tumors showed significantly reduced levels of interleukin (IL)-17 and IL-23 and increased IFN-γ and Granzyme B compared to Apc tumors. Transfer of CCR2 Apc CD4 T cells into Rag2 mice led to development of colitis phenotype with increased CD4 T cells hyper proliferation and IL-17 production. In contrast, adoptive transfer of CCR2 Apc CD4 T cells into Rag2 mice failed to enhance colonic inflammation or IL-17 production. These results a suggest novel additional role for CCR2, where it regulates migration of IL-17 producing cells mediating tumor-promoting inflammation in addition to its role in migration of tumor associated macrophages.
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http://dx.doi.org/10.1002/ijc.33477DOI Listing
January 2021

KIF11 Promotes Proliferation of Hepatocellular Carcinoma among Patients with Liver Cancers.

Biomed Res Int 2021 4;2021:2676745. Epub 2021 Jan 4.

Department of Pathology in Tianjin First Central Hospital, Number 24, Convalescent Road, Nankai, Tianjin 300192, China.

Background: Hepatocellular carcinoma (HCC) lacks effective treatments and has a poor prognosis. Therefore it is needed to develop more effective drug targets. Kinesin family member 11 (KIF11) has been reported to affect the progression of several cancers, and its high expression associates with the prognosis of patients. However, the relevant mechanisms of KIF11 in HCC progression have not been studied.

Method: Through the cancer genome atlas (TCGA) database and immunohistochemical (IHC) staining of patients' specimens, we determined that KIF11 was highly expressed in HCC tissues and associated with prognosis. We established a KIF11 stably depleted hepatoma cell line, through cell-cloning experiments and cell counting kit-8 (CCK-8) assays to detect the effects on proliferation . The role of KIF11 in promoting cell proliferation was verified in mice.

Result: The expression of KIF11 was negatively correlated with the overall survival (OS) and disease-free survival (DFS) and positively correlated with tumor size of HCC patients. KIF11 depletion inhibits cell proliferation and tumor growth and . KIF11 can be used as a positive correlation marker for HCC prognosis and served as a potential therapeutic target.
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http://dx.doi.org/10.1155/2021/2676745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801104PMC
January 2021

Acute Exposure of Atmospheric Ultrafine Particles Induced Inflammation Response and Dysregulated TGFβ/Smads Signaling Pathway in ApoE Mice.

Cardiovasc Toxicol 2021 Jan 21. Epub 2021 Jan 21.

Department of Toxicology, Tianjin Institute of Environmental and Operational Medicine, No. 1, Dali Road, Heping District, Tianjin, 300050, China.

Ultrafine particles (UFPs) referred to particular matters with aerosol diameter less than 100 nm. Because of the lightweight and small size, UFPs have become an occupational inhalation risk. The UFPs will be accumulated in the deep lung through inhalation, and then reach into all the organs via circulation system; some UFPs even stay in the brain. As previous study reported, UFPs exposure is usually associated with cardiovascular disease, such as atherosclerosis (AS). In our study, we tried to understand how acute UFP exposure caused the biological dysregulation in atherosclerosis. Acute exposure of UFPs were applied to mice for 6 consecutive days, mice were sacrificed after 3, 5, 7, and 10 days post-exposure. Aorta and serum were collected for histological and biomarkers analysis. Mice aortic adventitial fibroblasts (MAFs) were isolated from mice and used to further study to understand the mechanism of UFPs induced atherosclerosis. Compared to the untreated control, the inflammation responses and nitrate stress were observed after acute exposure of UFPs, with increased IL-6, MCP-1, p47phox, and 3-NT levels in the mice serum. Besides, upregulation of microRNAs: miR-301b-3p and Let-7c-1-3p, and their downstream target: Smad2, Smad3, and TGFβ1 were also observed in mouse aorta after acute exposure of UFPs. Similar results were identified in vitro as well. Acute exposure of UFPs induced the systematic nitrate stress and inflammation responses, along with the changes of vascular permeability. Dysregulated miRNAs and TGFβ/Smads signaling pathway indicated the higher risk of atherosclerosis/vasculature remodeling when exposed to UFPs.
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http://dx.doi.org/10.1007/s12012-021-09633-6DOI Listing
January 2021

Synergistic rifabutin and colistin reduce emergence of resistance when treating .

Antimicrob Agents Chemother 2021 Jan 19. Epub 2021 Jan 19.

Department of Molecular Microbiology and Immunology, Keck School of Medicine at USC, Los Angeles, CA

Recently, we reported rifabutin hyper-activity against We sought to characterize potential interactions between rifabutin and colistin, the last resort drug for carbapenem-resistant infections. Rifabutin and colistin were synergistic and , and low dose colistin significantly suppressed emergence of resistance to rifabutin. Thus, this combination is a promising therapeutic option for highly resistant infections.
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http://dx.doi.org/10.1128/AAC.02204-20DOI Listing
January 2021

Hybrid wireframe DNA nanostructures with scaffolded and scaffold-free modules.

Angew Chem Int Ed Engl 2021 Jan 15. Epub 2021 Jan 15.

Tsinghua University, School of Life Sciences, Tsinghua University, School of Life Sciences, 100084, Beijing, CHINA.

Scaffolded DNA origami approach and scaffold-free LEGO approach both demonstrate extraordinary self-assembly capability for the construction of all kinds of complex DNA nanostructures. Combining the construction elements of the two approaches, we introduce a hybrid framework to build wireframe structures in this study. A collection of two-dimensional (2D) and three-dimensional (3D) wireframe structures are presented to showcase the simple and versatile design scheme. Our development reveals more of the ever-expanding design space of structural DNA nanotechnology.
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http://dx.doi.org/10.1002/anie.202015564DOI Listing
January 2021

Musculin is highly enriched in Th17 and IL-22-producing ILC3s and restrains pro-inflammatory cytokines in murine colitis.

Eur J Immunol 2021 Jan 15. Epub 2021 Jan 15.

Antagen (Beijing) Biotechnologies, Co. Ltd, Beijing, China.

Transcription suppressor Musculin (MSC) is enriched in pro-inflammatory Th17 and IL-22-producing ILC3s. While MSC mice survived DSS-induced colitis, MSC mice showed elevated pro-inflammatory cytokines with severer pathology, reduced body weight, and earlier death. Reversal of colitis symptoms in MSC mice by IL-22 antagonism suggests the existence of MSC:IL-22 regulatory axis.
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http://dx.doi.org/10.1002/eji.202048573DOI Listing
January 2021

Complete Genome Sequence of sp. Strain ACS, an Anaerobic Bacterium That Respires Tetrachloroethene under Acidic pH Conditions.

Microbiol Resour Announc 2021 Jan 14;10(2). Epub 2021 Jan 14.

Center for Environmental Biotechnology, University of Tennessee, Knoxville, Tennessee, USA

sp. strain ACS couples growth with reductive dechlorination of tetrachloroethene to -1,2-dichloroethene at pH values as low as 5.5. The genome sequence of strain ACS consists of a circular 2,737,849-bp chromosome and a 39,868-bp plasmid and carries 2,737 protein-coding sequences, including two reductive dehalogenase genes.
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http://dx.doi.org/10.1128/MRA.01360-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849710PMC
January 2021

Deep learning-based automatic delineation of the hippocampus by MRI: geometric and dosimetric evaluation.

Radiat Oncol 2021 Jan 14;16(1):12. Epub 2021 Jan 14.

Department of Radiation Oncology, The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, China.

Background: Whole brain radiotherapy (WBRT) can impair patients' cognitive function. Hippocampal avoidance during WBRT can potentially prevent this side effect. However, manually delineating the target area is time-consuming and difficult. Here, we proposed a credible approach of automatic hippocampal delineation based on convolutional neural networks.

Methods: Referring to the hippocampus contouring atlas proposed by RTOG 0933, we manually delineated (MD) the hippocampus on the MRI data sets (3-dimensional T1-weighted with slice thickness of 1 mm, n = 175), which were used to construct a three-dimensional convolutional neural network aiming for the hippocampus automatic delineation (AD). The performance of this AD tool was tested on three cohorts: (a) 3D T1 MRI with 1-mm slice thickness (n = 30); (b) non-3D T1-weighted MRI with 3-mm slice thickness (n = 19); (c) non-3D T1-weighted MRI with 1-mm slice thickness (n = 11). All MRIs confirmed with normal hippocampus has not been violated by any disease. Virtual radiation plans were created for AD and MD hippocampi in cohort c to evaluate the clinical feasibility of the artificial intelligence approach. Statistical analyses were performed using SPSS version 23. P < 0.05 was considered significant.

Results: The Dice similarity coefficient (DSC) and Average Hausdorff Distance (AVD) between the AD and MD hippocampi are 0.86 ± 0.028 and 0.18 ± 0.050 cm in cohort a, 0.76 ± 0.035 and 0.31 ± 0.064 cm in cohort b, 0.80 ± 0.015 and 0.24 ± 0.021 cm in cohort c, respectively. The DSC and AVD in cohort a were better than those in cohorts b and c (P < 0.01). There is no significant difference between the radiotherapy plans generated using the AD and MD hippocampi.

Conclusion: The AD of the hippocampus based on a deep learning algorithm showed satisfying results, which could have a positive impact on improving delineation accuracy and reducing work load.
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http://dx.doi.org/10.1186/s13014-020-01724-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807715PMC
January 2021

A guideline for screw fixation of coracoid process base fracture by 3D simulation.

J Orthop Surg Res 2021 Jan 14;16(1):58. Epub 2021 Jan 14.

Department of Orthopaedics, Liaocheng People's Hospital, 67 Dongchang West Road, Liaocheng, 252000, Shandong, China.

Background: Fractures of the base of the coracoid process are relatively rare, but an increasing number of studies have reported using screws to fix coracoid process base fractures. This study was performed to simulate the surgical procedure and obtain the ideal diameter, length, insertion point and angle of the screw from a 3-D axial perspective in Chinese patients.

Methods: We randomly collected right scapula computed tomography (CT) scans from 100 adults. DICOM-formatted CT scan images were imported into Mimics software. A 3D digital model of the right scapula was established. Two virtual cylinders representing two screws were placed from the top of the coracoid process to the neck of the scapula and across the base of the coracoid process to fix the base of the coracoid process. The largest secure diameters and lengths of the virtual screws were measured. The positions of the insertion points and the directions of the screws were also examined.

Results: The screw insertion safe zone can exhibit an irregular fusiform shape according to the reconstructed scapula model. The mean maximum diameters of the medial and lateral screws were 7.08 ± 1.19 mm and 7.34 ± 1.11 mm, respectively. The mean maximum lengths of the medial and lateral screws were 43.11 ± 6.31 mm and 48.16 ± 6.94 mm, respectively. A screw insertion corridor with a diameter of at least 4.5 mm was found in all patients. We found sex-dependent differences in the mean maximum diameters and maximum lengths of the two screws. The positions of the two insertion points were statistically different across sexes.

Conclusions: The study provides a valuable guideline for determining the largest secure corridor for two screws in fixing a fracture at the base of the coracoid process. For ideal screw placement, we suggest individualised preoperative 3D reconstruction simulations. Further biomechanical studies are needed to verify the function of the screws.
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http://dx.doi.org/10.1186/s13018-021-02203-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809839PMC
January 2021

Genome-wide distribution and functions of the AAE complex in epigenetic regulation in Arabidopsis.

J Integr Plant Biol 2021 Jan 12. Epub 2021 Jan 12.

Shanghai Center for Plant Stress Biology and CAS Center of Excellence for Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai, 201602, China.

Heterochromatin is widespread in eukaryotic genomes and has diverse impacts depending on its genomic context. Previous studies have shown that a protein complex, the ASI1-AIPP1-EDM2 (AAE) complex, participates in polyadenylation regulation of several intronic heterochromatin-containing genes. However, the genome-wide functions of AAE are still unknown. Here, we show that the ASI1 and EDM2 mostly target the common genomic regions on a genome-wide level and preferentially interacts with genetic heterochromatin. Polyadenylation [(poly(A)] sequencing reveals that AAE complex has a substantial influence on poly(A) site usage of heterochromatin-containing genes, including not only intronic heterochromatin-containing genes but also the genes showing overlap with heterochromatin. Intriguingly, AAE is also involved in the alternative splicing regulation of a number of heterochromatin-overlapping genes, such as the disease resistance gene RPP4. We provided evidence that genic heterochromatin is indispensable for the recruitment of AAE in polyadenylation and splicing regulation. In addition to conferring RNA processing regulation at genic heterochromatin-containing genes, AAE also targets some transposable elements (TEs) outside of genes (including TEs sandwiched by genes and island TEs) for epigenetic silencing. Our results reveal new functions of AAE in RNA processing and epigenetic silencing, and thus represent important advances in epigenetic regulation. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/jipb.13068DOI Listing
January 2021

High-fat diet-induced upregulation of exosomal phosphatidylcholine contributes to insulin resistance.

Nat Commun 2021 01 11;12(1):213. Epub 2021 Jan 11.

James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, 40202, USA.

High-fat diet (HFD) decreases insulin sensitivity. How high-fat diet causes insulin resistance is largely unknown. Here, we show that lean mice become insulin resistant after being administered exosomes isolated from the feces of obese mice fed a HFD or from patients with type II diabetes. HFD altered the lipid composition of exosomes from predominantly phosphatidylethanolamine (PE) in exosomes from lean animals (L-Exo) to phosphatidylcholine (PC) in exosomes from obese animals (H-Exo). Mechanistically, we show that intestinal H-Exo is taken up by macrophages and hepatocytes, leading to inhibition of the insulin signaling pathway. Moreover, exosome-derived PC binds to and activates AhR, leading to inhibition of the expression of genes essential for activation of the insulin signaling pathway, including IRS-2, and its downstream genes PI3K and Akt. Together, our results reveal HFD-induced exosomes as potential contributors to the development of insulin resistance. Intestinal exosomes thus have potential as broad therapeutic targets.
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http://dx.doi.org/10.1038/s41467-020-20500-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801461PMC
January 2021

Development and external evaluation of predictions models for mortality of COVID-19 patients using machine learning method.

Neural Comput Appl 2021 Jan 5:1-10. Epub 2021 Jan 5.

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

To predict the mortality of patients with coronavirus disease 2019 (COVID-19). We collected clinical data of COVID-19 patients between January 18 and March 29 2020 in Wuhan, China . Gradient boosting decision tree (GBDT), logistic regression (LR) model, and simplified LR were built to predict the mortality of COVID-19. We also evaluated different models by computing area under curve (AUC), accuracy, positive predictive value (PPV), and negative predictive value (NPV) under fivefold cross-validation. A total of 2924 patients were included in our evaluation, with 257 (8.8%) died and 2667 (91.2%) survived during hospitalization. Upon admission, there were 21 (0.7%) mild cases, 2051 (70.1%) moderate case, 779 (26.6%) severe cases, and 73 (2.5%) critically severe cases. The GBDT model exhibited the highest fivefold AUC, which was 0.941, followed by LR (0.928) and LR-5 (0.913). The diagnostic accuracies of GBDT, LR, and LR-5 were 0.889, 0.868, and 0.887, respectively. In particular, the GBDT model demonstrated the highest sensitivity (0.899) and specificity (0.889). The NPV of all three models exceeded 97%, while their PPV values were relatively low, resulting in 0.381 for LR, 0.402 for LR-5, and 0.432 for GBDT. Regarding severe and critically severe cases, the GBDT model also performed the best with a fivefold AUC of 0.918. In the external validation test of the LR-5 model using 72 cases of COVID-19 from Brunei, leukomonocyte (%) turned to show the highest fivefold AUC (0.917), followed by urea (0.867), age (0.826), and SPO2 (0.704). The findings confirm that the mortality prediction performance of the GBDT is better than the LR models in confirmed cases of COVID-19. The performance comparison seems independent of disease severity.

Supplementary Information: The online version contains supplementary material available at(10.1007/s00521-020-05592-1).
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http://dx.doi.org/10.1007/s00521-020-05592-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783503PMC
January 2021

Predicting postoperative peritoneal metastasis in gastric cancer with serosal invasion using a collagen nomogram.

Nat Commun 2021 01 8;12(1):179. Epub 2021 Jan 8.

Department of General Surgery, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China.

Accurate prediction of peritoneal metastasis for gastric cancer (GC) with serosal invasion is crucial in clinic. The presence of collagen in the tumour microenvironment affects the metastasis of cancer cells. Herein, we propose a collagen signature, which is composed of multiple collagen features in the tumour microenvironment of the serosa derived from multiphoton imaging, to describe the extent of collagen alterations. We find that a high collagen signature is significantly associated with a high risk of peritoneal metastasis (P < 0.001). A competing-risk nomogram including the collagen signature, tumour size, tumour differentiation status and lymph node metastasis is constructed. The nomogram demonstrates satisfactory discrimination and calibration. Thus, the collagen signature in the tumour microenvironment of the gastric serosa is associated with peritoneal metastasis in GC with serosal invasion, and the nomogram can be conveniently used to individually predict the risk of peritoneal metastasis in GC with serosal invasion after radical surgery.
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http://dx.doi.org/10.1038/s41467-020-20429-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794254PMC
January 2021