Publications by authors named "Lei Fan"

566 Publications

Extracellular Matrix-based Conductive Interpenetrating Network Hydrogels with Enhanced Neurovascular Regeneration Properties for Diabetic Wounds Repair.

Adv Healthc Mater 2021 Oct 14:e2101556. Epub 2021 Oct 14.

School of Materials Science and Engineering & National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, 510641, China.

The critical effects that impair diabetic wound healing are characterized by poor vascularization and severe peripheral neuropathy. Current management strategies for diabetic wound healing are unsatisfactory, due to the paucity of neurovascular regeneration at the wound site. Importantly, conductivity in skin tissue has been reported to be essential for modulating myriad biological processes especially vascular and nerve regeneration. Herein, we synthesized an extracellular matrix (ECM)-based conductive dressing from an interpenetrating polymer network hydrogel composed of gelatin methacryloyl (GM), oxidized chondroitin sulfate (OCS), and OCS-polypyrrole (OCS-P) conductive nanoparticles that could promote diabetic wound repairing by enhancing local neurovascular regeneration. The conductive hydrogels combined the advantageous features of water-swollen hydrogels with conductive polymers (CPs) to provide tissue-matching electrical conductivity and mechanical properties for neurovascular regeneration. In vitro and in vivo studies showed that the conductive hydrogel can promote neurovascular regeneration by increasing intracellular Ca concentration, which subsequently promoted phosphorylation of proteins in the PI3K/AKT and MEK/ERK pathways. Furthermore, our conductive hydrogel stimulated full-thickness diabetic wound repair on day 14 by promoting local neurovascular regeneration and collagen deposition. These findings corroborated that our ECM-based conductive interpenetrating network hydrogel dressing significantly promoted wound repairing due to its neurovascular regeneration properties, suggesting that they are suitable candidates for diabetic wound repair. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/adhm.202101556DOI Listing
October 2021

Intrauterine administration of peripheral blood mononuclear cells (PBMCs) improves embryo implantation in mice by regulating local Treg/Th17 cell balance.

J Reprod Dev 2021 Oct 7. Epub 2021 Oct 7.

Department of Obstetrics & Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China.

Immune imbalance of Treg/Th17 cells may contribute to recurrent implantation failure (RIF) during in vitro fertilization and embryo transfer (IVF-ET). In this study, we sought to determine the effect of intrauterine administration of mouse PBMCs prior to embryo implantation on endometrial receptivity and embryo implantation, and examine the underlying mechanism of Treg/Th17 cell balance following intrauterine administration of PBMCs. Pregnant mice were randomly divided into three groups: control group, embryo implantation dysfunction (EID) group, and EID with PBMCs group, and the number of embryo implantation sites was recorded during early pregnancy (Pd7.5). The balance of Treg/Th17 cells in the peripheral blood, spleen, and local implantation sites was detected during the peri-implantation period (Pd4.0) and early pregnancy (Pd7.5). The EID group demonstrated a significant decrease in the number of embryo implantation sites, while the EID with PBMCs group demonstrated higher number of embryo implantation sites compared to the EID group. The balance of Treg/Th17 cells in the peripheral blood and spleen tissues was not significantly different between the aforementioned groups. However, the local uterine ratio of the Treg/Th17 cells increased in the EID with PBMCs group compared to that in the EID group. Collectively, we found that intrauterine administration of PBMCs prior to embryo implantation effectively promotes embryo implantation rates. This may be attributed to the improvement in the local immune balance of Treg and Th17 cells compared with the overall immune balance.
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http://dx.doi.org/10.1262/jrd.2021-006DOI Listing
October 2021

Association of Derived Neutrophil-To-Lymphocyte Ratio With Prognosis of Coronary Heart Disease After PCI.

Front Cardiovasc Med 2021 17;8:705862. Epub 2021 Sep 17.

Department of Cardiology, Key Laboratory of Cardiac Injury and Repair of Henan Province, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

The present study aimed to investigate the prognostic role of derived neutrophil-to-lymphocyte ratio (dNLR) in patients with coronary heart disease (CHD) after PCI. A total of 3,561 post-PCI patients with CHD were retrospectively enrolled in the CORFCHD-ZZ study from January 2013 to December 2017. The patients (3,462) were divided into three groups according to dNLR tertiles: the first tertile (dNLR < 1.36; = 1,139), second tertile (1.36 ≥ dNLR < 1.96; = 1,166), and third tertile(dNLR ≥ 1.96; = 1,157). The mean follow-up time was 37.59 ± 22.24 months. The primary endpoint was defined as mortality (including all-cause death and cardiac death), and the secondary endpoint was major adverse cardiovascular events (MACEs) and major adverse cardiovascular and cerebrovascular events (MACCEs). There were 2,644 patients with acute coronary syndrome (ACS) and 838 patients with chronic coronary syndrome (CCS) in the present study. In the total population, the all-cause mortality (ACM) and cardiac mortality (CM) incidence was significantly higher in the third tertile than in the first tertile [hazard risk (HR) = 1.8 (95% CI: 1.2-2.8), = 0.006 and HR = 2.1 (95% CI: 1.23-3.8), = 0.009, respectively]. Multivariate Cox regression analyses suggested that compared with the patients in the first tertile than those in the third tertile, the risk of ACM was increased 1.763 times (HR = 1.763, 95% CI: 1.133-2.743, = 0.012), and the risk of CM was increased 1.763 times (HR = 1.961, 95% CI: 1.083-3.550, = 0.026) in the higher dNLR group during the long-term follow-up. In both ACS patients and CCS patients, there were significant differences among the three groups in the incidence of ACM in univariate analysis. We also found that the incidence of CM was significantly different among the three groups in CCS patients in both univariate analysis (HR = 3.541, 95% CI: 1.154-10.863, = 0.027) and multivariate analysis (HR = 3.136, 95% CI: 1.015-9.690, = 0.047). The present study suggested that dNLR is an independent and novel predictor of mortality in CHD patients who underwent PCI.
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http://dx.doi.org/10.3389/fcvm.2021.705862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484317PMC
September 2021

A metabolomics study: Reveals the protective effect and mechanism of Terminalia chebula Retz on the cardiotoxicity induced by radix Aconiti kusnezoffii Reichb.

Pak J Pharm Sci 2021 May;34(3(Special)):1233-1241

Department of Pharmacy, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, PR China/State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China.

To reveal the protective effect of Terminalia chebula Retz (TCR) on cardiotoxicity induced by radix of Aconitum kusnezoffii Reichb (AKR). Control, AKR, AKR-TCR 1:3, AKR-TCR 1:1, AKR-TCR 3:1 and TCR-prepared AKR groups were set up. After treatment, the heart tissues were observed by H&E staining and transmission electron microscope. Serum myoglobin (MB) and troponin (cTn) were detected by ELISA. UPLC-Q Exactive/MS analysis was performed to detect the metabolic difference among the groups. ELISA results showed that the MB and cTn values of AKR group were significantly higher than Control group (P<0.05), while those of the other groups were lower than AKR group. TCR-prepared AKR group had similar MB and cTn contents to the Control group. Histopathological examination also indicated better detoxifying effects in the TCR-prepared AKR and AKR-TCR 1:1 group. The serum metabolomics analysis showed obvious distinction between the AKR and Control groups, while AKR-TCR combination reversed the metabolomics changes induced by AKR. Through multivariate statistical analysis, 9 metabolic markers related to energy, nucleic acid and amino acid metabolism were identified. Conclusively, AKR-induced cardiotoxicity may be related to energy, nucleic acid and amino acid metabolism, and TCR can reduce the cardiotoxicity by regulating the relative metabolism pathways.
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May 2021

Fast Self-Healing Superhydrophobic Thermal Energy Storage Coatings Fabricated by Bio-Based Beeswax and Artificially Cultivated Diatom Frustules.

ACS Appl Mater Interfaces 2021 Oct 28;13(40):48088-48100. Epub 2021 Sep 28.

Guangdong Provincial Key Laboratory of Functional Oxide Materials and Devices, Department of Materials Science and Engineering, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.

Diatom frustules (DFs) with delicate hierarchical pores and a large specific surface area are extracted from artificially cultured diatoms, showing their utilization potential as shape-stabilized phase change materials (ss-PCMs). Herein, we successfully prepared a fully biomass-based ss-PCM, superhydrophobic thermal energy storage (STES) coating by employing beeswax (BW) as phase change materials (PCMs) and DFs as supporting materials via a facile spraying method. DFs can adsorb as much as 65 wt % BW without leakage, accompanied with a high heat storage capacity of 112.57 J/g. The thermal stability test demonstrates that the DF/BW coating can undergo 500 heating-freezing cycles with the reduction of the phase change enthalpy being less than 5%. Simultaneously, the DF also endows BW with a higher thermal degradation temperature (from ∼200 to ∼250 °C). In addition, the DF/BW coating shows superhydrophobicity due to the incorporation of the low surface energy of BW and the micro/nanostructures of DFs. This superhydrophobic surface can quickly and repeatedly recover its excellent water repellency through a simple heat treatment (80 °C, 20 min) after being damaged by a water impact or strong acid and alkali corrosion. This self-healing ability can effectively overcome the poor durability of traditional superhydrophobic materials. Our research can expand the application of DFs in the field of ss-PCMs and guide the preparation of durable superhydrophobic surfaces with rapid self-healing performance.
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http://dx.doi.org/10.1021/acsami.1c14065DOI Listing
October 2021

LncRNA landscape analysis identified LncRNA LEF-AS1 as an oncogene that upregulates LEF1 and promotes survival in chronic lymphocytic leukemia.

Leuk Res 2021 Sep 9;110:106706. Epub 2021 Sep 9.

Department of Hematology, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. Electronic address:

Chronic lymphocytic leukemia (CLL) is a malignant disorder of mature B lymphocytes, and the precise pathogenesis is largely unknown at present. This study set out to screen the differential expression profile of long non-coding RNA (lncRNA) by microarray and explore the underlying mechanism, biological function, and clinical significance of lncRNA in CLL cells. Compared to the lncRNA expression profiles of the control group, we picked lncRNA LEF1-AS1 for further exploration. By quantitative real-time polymerase chain reaction (qRT-PCR), we validated that primary CLL cells harbor higher lncRNA LEF1-AS1 levels than normal B cells. In the two cell lines with stable overexpression of LEF1-AS1, expression of LEF1 elevated on RNA and protein level, proliferation rates increased, and apoptosis rates decreased. In primary CLL cells, mRNA expression of LEF1 decreased by qRT-PCR after negatively regulating the expression of LEF1-AS1. RNA Binding Protein Immunoprecipitation and RNA pull-down demonstrated that LncRNA LEF1-AS1 and LEF1 protein could combine especially. This thesis concludes LEF1-AS1 may be an oncogenic lncRNA that regulates the target gene LEF1 by interacting with protein LEF1. However, the prognostic significance of lncRNA LEF1-AS1 in CLL patients is still unclear.
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http://dx.doi.org/10.1016/j.leukres.2021.106706DOI Listing
September 2021

Identification of a Novel Prognostic Gene Signature From the Immune Cell Infiltration Landscape of Osteosarcoma.

Front Cell Dev Biol 2021 6;9:718624. Epub 2021 Sep 6.

Charité - Universitätsmedizin Berlin, Berlin, Germany.

The tumor microenvironment (TME) mainly comprises tumor cells and tumor-infiltrating immune cells mixed with stromal components. Latestresearch hasdisplayed that tumor immune cell infiltration (ICI) is associated with the clinical outcome of patients with osteosarcoma (OS). This work aimed to build a gene signature according to ICI in OS for predicting patient outcomes. The TARGET-OS dataset was used for model training, while the GSE21257 dataset was taken forvalidation. Unsupervised clustering was performed on the training cohort based on the ICI profiles. The Kaplan-Meier estimator and univariate Cox proportional hazards models were used to identify the differentially expressed genes between clusters to preliminarily screen for potential prognostic genes. We incorporated these potential prognostic genes into a LASSO regression analysis and produced a gene signature, which was next assessed with the Kaplan-Meier estimator, Cox proportional hazards models, ROC curves, IAUC, and IBS in the training and validation cohorts. In addition, we compared our signature to previous models. GSEAswere deployed to further study the functional mechanism of the signature. We conducted an analysis of 22 TICsfor identifying the role of TICs in the gene signature's prognosis ability. Data from the training cohort were used to generate a nine-gene signature. The Kaplan-Meier estimator, Cox proportional hazards models, ROC curves, IAUC, and IBS validated the signature's capacity and independence in predicting the outcomes of OS patients in the validation cohort. A comparison with previous studies confirmed the superiority of our signature regarding its prognostic ability. Annotation analysis revealed the mechanism related to the gene signature specifically. The immune-infiltration analysis uncoveredkey roles for activated mast cells in the prognosis of OS. We identified a robust nine-gene signature (ZFP90, UHRF2, SELPLG, PLD3, PLCB4, IFNGR1, DLEU2, ATP6V1E1, and ANXA5) that can predict OS outcome precisely and is strongly linked to activated mast cells.
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http://dx.doi.org/10.3389/fcell.2021.718624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450587PMC
September 2021

Development of surrogate models in reliability-based design optimization: A review.

Math Biosci Eng 2021 07;18(5):6386-6409

Henan Key Laboratory of Mechanical Equipment Intelligent Manufacturing, School of Mechanical and Electrical Engineering, Zhengzhou University of Light Industry, Zhengzhou, MO 450002, China.

Reliability-based design optimization (RBDO) is applied to handle the unavoidable uncertainties in engineering applications. To alleviate the huge computational burden in reliability analysis and design optimization, surrogate models are introduced to replace the implicit objective and performance functions. In this paper, the commonly used surrogate modeling methods and surrogate-assisted RBDO methods are reviewed and discussed. First, the existing reliability analysis methods, RBDO methods, commonly used surrogate models in RBDO, sample selection methods and accuracy evaluation methods of surrogate models are summarized and compared. Then the surrogate-assisted RBDO methods are classified into global modeling methods and local modeling methods. A classic two-dimensional RBDO numerical example are used to demonstrate the performance of representative global modeling method (Constraint Boundary Sampling, CBS) and local modeling method (Local Adaptive Sampling, LAS). The advantages and disadvantages of these two kinds of modeling methods are summarized and compared. Finally, summary and prospect of the surrogate-assisted RBDO methods are drown.
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http://dx.doi.org/10.3934/mbe.2021317DOI Listing
July 2021

Prognostic Score for Metastatic Breast Cancer With Liver Metastasis and Its Predictive Value of Locoregional Treatment Benefit.

Front Oncol 2021 27;11:651636. Epub 2021 Aug 27.

Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.

Background: There is a significant survival difference and lack of effective treatment among breast cancer patients with liver metastasis. This present study aimed to construct a novel prognostic score for predicting the prognosis and locoregional treatment benefit of metastatic breast cancer with liver metastasis (BCLM).

Methods: In total, 2,398 eligible patients between 2010 and 2016 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. They were assigned to the training set including 1,662 patients (2010-2014) and validation set comprising 736 patients (2015-2016) depending on the time of diagnosis. The prognostic score was based on regression coefficients in the multivariate Cox regression analysis. And then, patients were stratified into low-, intermediate-, and high-risk groups by the prognostic score. The discrimination and calibration of prognostic score were evaluated using time-dependent receiver operating characteristic (ROC) curves analysis and calibration curves, respectively. Subgroup analysis was performed to evaluate locoregional surgery and chemotherapy benefit in different risk groups.

Results: Age, race, insurance and marital status, T stage, pathological grade, molecular subtypes, and extrahepatic metastasis were identified as independent prognostic variables in the prognostic score. The prognostic score showed high discrimination power with an area under the curve (AUC) of 0.77 and 0.72 and excellent agreement suggested by calibration plots in the training and validation sets, respectively. Intermediate-risk [hazard ratio (HR) 2.39, 95% confidence interval (CI) 2.09-2.73, <0.001] and high-risk groups (HR 4.88; 95% CI 4.13-5.76; <0.001) had significantly worse prognosis in comparison with the low-risk group. The median overall survival (OS) in three prognostic groups were 44, 18, and 7 months, with a 3-year survival rate of 56, 23, and 7%, respectively. Apart from the high-risk group (HR 0.79; 95% CI 0.56-1.10; =0.157), the low-risk (HR 0.64; 95% CI 0.49-0.84; =0.001) and intermediate-risk groups (HR 0.68; 95% CI 0.55-0.85; =0.001) could benefit from the surgery of primary site, while chemotherapy improved prognosis in all risk groups.

Conclusions: A prognostic score was developed to accurately predict the prognosis of BCLM patients. Moreover, it may be useful for further subdividing them into different risk groups and helping guide clinicians in treatment decisions.
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http://dx.doi.org/10.3389/fonc.2021.651636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432710PMC
August 2021

GADD45β stabilized by direct interaction with HSP72 ameliorates insulin resistance and lipid accumulation.

Pharmacol Res 2021 Sep 8;173:105879. Epub 2021 Sep 8.

Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China. Electronic address:

Growth arrest and DNA damage-inducible 45β (GADD45β) belongs to the GADD45 family which is small acidic proteins in response to cellular stress. GADD45β has already been reported to have excellent capabilities against cancer, innate immunity and neurological diseases. However, there is little information regard GADD45β and non-alcoholic fatty liver disease (NAFLD). In the current work, we found that the expression of GADD45β was markedly decreased in the livers of NAFLD patients via analyzing Gene Expression Omnibus (GEO) dataset and in mouse model through detecting its mRNA in high-fat-high-fructose diet (HFHFr)-fed mice. Moreover, the results from in vivo experiment demonstrated that overexpression of GADD45β by AAV8-mediated gene transfer in HFHFr-fed mouse model could reduce the level of serum and hepatic triglyceride (TG), and alleviate insulin resistance. Subsequently, by combining immunoprecipitation (IP) and mass spectrometry, we identified that HSP72 directly interacted with GADD45β to prevent GADD45β from being degraded by the proteasome pathway. Finally, the benefits of GADD45β in regulating key factors of TG synthesis and insulin signaling pathway were abolished after HSP72 knockdown. In conclusion, GADD45β stabilized by the interaction with HSP72 could alleviate the NAFLD-related pathologies, suggested it might be a potential target for the treatment of NAFLD.
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http://dx.doi.org/10.1016/j.phrs.2021.105879DOI Listing
September 2021

An injectable, self-healing, electroconductive extracellular matrix-based hydrogel for enhancing tissue repair after traumatic spinal cord injury.

Bioact Mater 2022 Jan 1;7:98-111. Epub 2021 Jun 1.

School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, 510006, China.

Injectable biomaterial-based treatment is a promising strategy to enhance tissue repair after traumatic spinal cord injury (SCI) by bridging cavity spaces. However, there are limited reports of injectable, electroconductive hydrogels with self-healing properties being employed for the treatment of traumatic SCI. Hence, a natural extracellular matrix (ECM) biopolymer (chondroitin sulphate and gelatin)-based hydrogel containing polypyrrole, which imparted electroconductive properties, is developed for traumatic SCI repair. The resulting hydrogels showed mechanical (~928 Pa) and conductive properties (4.49 mS/cm) similar to natural spinal cord tissues. Moreover, the hydrogels exhibited shear-thinning and self-healing abilities, which allows it to be effectively injected into the injury site and to fill the lesion cavity to accelerate the tissue repair of traumatic SCI. electroconductive ECM hydrogels promoted neuronal differentiation, enhanced axon outgrowth, and inhibited astrocyte differentiation. The electroconductive ECM hydrogel activated endogenous neural stem cell neurogenesis (n = 6), and induced myelinated axon regeneration into the lesion site via activation of the PI3K/AKT and MEK/ERK pathways, thereby achieving significant locomotor function restoration in rats with spinal cord injury (p < 0.001, compared to SCI group). Overall, the injectable self-healing electroconductive ECM-based hydrogels developed in this study are ideal biomaterials for treatment of traumatic SCI.
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http://dx.doi.org/10.1016/j.bioactmat.2021.05.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8379448PMC
January 2022

Automated Optical Tweezers Manipulation to Transfer Mitochondria from Fetal to Adult MSCs to Improve Antiaging Gene Expressions.

Small 2021 Sep 19;17(38):e2103086. Epub 2021 Aug 19.

Department of Biomedical Engineering, City University of Hong Kong, Hong Kong, 99907, China.

Mitochondrial dysfunction is considered to be an important factor that leads to aging and premature aging diseases. Transferring mitochondria to cells is an emerging and promising technique for the therapy of mitochondrial deoxyribonucleic acid (mtDNA)-related diseases. This paper presents a unique method of controlling the quality and quantity of mitochondria transferred to single cells using an automated optical tweezer-based micromanipulation system. The proposed method can automatically, accurately, and efficiently collect and transport healthy mitochondria to cells, and the recipient cells then take up the mitochondria through endocytosis. The results of the study reveal the possibility of using mitochondria from fetal mesenchymal stem cells (fMSCs) as a potential source to reverse the aging-related phenotype and improve metabolic activities in adult mesenchymal stem cells (aMSCs). The results of the quantitative polymerase chain reaction analysis show that the transfer of isolated mitochondria from fMSCs to a single aMSC can significantly increase the antiaging and metabolic gene expression in the aMSC. The proposed mitochondrial transfer method can greatly promote precision medicine for cell therapy of mtDNA-related diseases.
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http://dx.doi.org/10.1002/smll.202103086DOI Listing
September 2021

The Impact of the SARS-COV-2 Pandemic on the Mental Health and Employment Decisions of Medical Students in North China.

Front Psychiatry 2021 19;12:641138. Epub 2021 Jul 19.

Institute of Pharmacy, Inner Mongolia Medical University, Inner Mongolia Jinshan Development Area, Hohhot, China.

The outbreak of severe respiratory syndrome coronavirus 2 (SARS-COV-2) has led to long periods of social isolation for individuals across the world. Although medical students generally have a high prevalence of mental health problems, they have received less attention than other groups concerning the impact of SARS-COV-2. Therefore, the present study investigated the mental health status, risk factors, and protective factors for mental health problems in medical students in North China during the SARS-COV-2 pandemic. A WeChat-based survey, which included the Depression Anxiety Stress Scale-21 and measures of social demographics, was performed twice. Risk and protective factors were identified by binary logistic regression analysis. A total of 702 effective questionnaires were collected in two separate surveys. In total, 24.55% of medical students were suffering anxiety to different degrees of severity, 13.18% were suffering depression in the first survey, and 3.71% wanted to give up working in primary medical care during the SARS-COV-2 pandemic in the second survey. In contrast, during the SARS-COV-2 pandemic, a risk factor for anxiety and depression was gender which is male, while being knowledgeable about the SARS-COV-2 pandemic and having a lower academic burden were both protective factors. Measures are required to prevent increases in mental health problems in medical students. Our findings suggest that increasing knowledge about the SARS-COV-2 pandemic and reducing academic burden in medical students is extremely important during the SARS-COV-2 pandemic.
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http://dx.doi.org/10.3389/fpsyt.2021.641138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326451PMC
July 2021

Continuous input of organic ultraviolet filters and benzothiazoles threatens the surface water and sediment of two major rivers in the Pearl River Basin.

Sci Total Environ 2021 Dec 27;798:149299. Epub 2021 Jul 27.

Environmental Research Institute, School of Environment, Guangdong Provincial Key Laboratory of Chemical Pollution and Environmental Safety, MOE Key Laboratory of Theoretical Chemistry of Environment, South China Normal University, Guangzhou 510006, China.

The extensive usage of organic ultraviolet filters (UV filters) and benzothiazoles (BTs) has caused continuous and widespread pollution in the aquatic environment. This study investigated the occurrence of nine organic UV filters and eight BTs in the surface water and sediment of two major drinking water source rivers in the Pearl River Basin (PRB). The detection frequencies of six organic UV filters and seven BTs were above 50% in surface water, while eight target compounds were as high as 100%. Composition profiles revealed that 2-Hydroxybenzothiazole (2-OH-BTH, 1112 ng/L) and 2-Mercaptobenzothiazole (2-SH-BTH, 426.3 ng/L) were the predominant compounds in surface water, while Octyl 4-methoxycinnamate (OMC, maximum concentration, 68.3 ng/g) and UV-329 (18.8 ng/g) were predominant in sediment. Significant positive correlations were observed between water quality parameters (temperature, total phosphorus (TP) and total nitrogen (TN)) and organic UV filters (UV-327 and UV-P), indicating the domestic discharge. The calculated annual flux of targets compounds indicated that West River (WR) promoted more BTs and UV filters to the PRB than North River (NR) (BTs: WR22, 88,517 kg/year; NR13, 15,660 kg/year; UV filters: WR22, 28,332 kg/year; NR13, 1128 kg/year). Significant relationship between the Gross Domestic Product (GDP) and annual flux of BTs (R = 0.96, p < 0.001), and UV filters (R = 0.88, p < 0.001) in the rivers were found by regression analysis. UV-329 was detected with medium risk (RQ > 0.1) in all WR surface water samples, and 2-SH-BTH was detected with high risk (RQ > 1) in half of the WR sediment samples. This study provides the first time reports on the organic UV filters and BTs in two major rivers in the Pearl River Basin, and further showed that these two types of contaminants are ubiquitous and with potential risks in surface water and sediment of PRB.
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http://dx.doi.org/10.1016/j.scitotenv.2021.149299DOI Listing
December 2021

Anthracycline-free or short-term regimen as adjuvant chemotherapy for operable breast cancer: A phase III randomized non-inferiority trial.

Lancet Reg Health West Pac 2021 Jun 13;11:100158. Epub 2021 May 13.

Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: De-escalating anthracycline is gaining popularity for breast cancer patients. We aim to evaluate the non-inferiority of an anthracycline-free or short-term regimen to the standard anthracycline-based regimen for operable patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer.

Methods: It is a prospective, open-label, phase 3, randomized non-inferiority trial from June 1, 2010 to June 1, 2017. Follow-up had been kept until July 2019. This trial was conducted at Fudan University Shanghai Cancer Center. Patients with pT1-3N+ or pT2-3N0 but high-risk (grade II/III, lymphovascular invasion, ≤35 years of age or hormone-receptor negative) HER2-negative operable breast cancer were eligible and stratified by age, pathological tumour stage, pathological node status and hormone-receptor status. Patients were randomized to 6 cycles of docetaxel and cyclophosphamide (TC,  = 524), 3 cycles of cyclophosphamide/epirubicin/fluorouracil followed by 3 cycles of docetaxel (CEF-T,  = 523) or epirubicin and cyclophosphamide for 4 cycles followed by paclitaxel for 12 weeks (EC-P,  = 524) as the intention-to-treat population. Of these patients, 94% completed allocated therapy. Difference in disease-free survival (DFS) compared to EC-P. The prespecified non-inferiority margin was 4.5%, corresponding to the hazard ratio (HR) of 1.44 (one-sided α = 0.05), with an assumed 5-year DFS of 89% for EC-P.

Findings: Included in the intention-to-treat population were 1571 patients (median [IQR] age, 50 [45-57] years; 92% estrogen receptor [ER]-positive; 59% pN+). Through a median follow-up of 5.5 years, HR for TC EC-P was 1.05 (5-year DFS: 85.0% . 85.9%; 90% confidence interval [CI]: 0.79-1.39, non-inferior  = 0.048) and for CEF-T EC-P, 0.99 (5-year DFS: 85.1% . 85.9%; 90% CI: 0.75-1.30, non-inferior  = 0.045). Grade 3 or 4 adverse events for TC included rash (3.9%) and peripheral neuropathy (2.8%) and for CEF-T and EC-P diarrhea and nausea/vomiting were predominant. Results of per-protocol analyses were similar.

Interpretation: Both TC and CEF-T are non-inferior adjuvant regimen to EC-P mainly in patients with ER+HER2- breast cancer. TC is a safe regimen that avoids anthracycline-related side effects.

Funding: This work was supported by grants from the National Natural Science Foundation of China (Grants 81672600, 81722032, 82072916, and 91959207), the 2018 Shanghai Youth Excellent Academic Leader, the Fudan ZHUOSHI Project, the Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals (grant SHDC12010116), the Cooperation Project of Conquering Major Diseases in the Shanghai Municipality Health System (grant 2013ZYJB0302), the Innovation Team of the Ministry of Education (grant IRT1223), and the Shanghai Key Laboratory of Breast Cancer (grant 12DZ2260100) and the National Cancer Institute (grant P30 CA16058).
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http://dx.doi.org/10.1016/j.lanwpc.2021.100158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315472PMC
June 2021

Circulating PD-L1 is associated with T cell infiltration and predicts prognosis in patients with CRLM following hepatic resection.

Cancer Immunol Immunother 2021 Jul 28. Epub 2021 Jul 28.

State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Department of Medical Oncology, Sun Yat-Sen University Cancer Center, 651# Dongfeng Road East, Guangzhou, 510060, People's Republic of China.

Background: Exosomal PD-L1 (exoPD-L1) could induce immunosuppression functionally, thus impairing patients' survival in melanoma, NSCLC, and gastric cancer. However, no evidence demonstrates the feasibility of circulating exoPD-L1 and soluble PD-L1 (sPD-L1) as biomarkers for prognosis and early recurrence in colorectal liver metastasis (CRLM) patients following hepatectomy or their association with T cell infiltration at liver metastases.

Methods: In cohort 1, exoPD-L1 and sPD-L1 were preoperatively tested using ELISA. CD3, CD8, granzyme B (GB) and PD1 expressed at liver metastases were evaluated using immunohistochemistry. In cohort 2, exoPD-L1 and sPD-L1 were detected at baseline, before hepatectomy, after hepatectomy, and after disease progression.

Results: In cohort 1, higher preoperative exoPD-L1 or sPD-L1 significantly impaired RFS (exoPD-L1, P = 0.0043; sPD-L1, P = 0.0041) and OS (exoPD-L1, P = 0.0034; sPD-L1, P = 0.0061). Furthermore, preoperative exoPD-L1 was negatively correlated with CD3 + T-lymphocytes infiltrated at tumor center (CT), and GB and PD1 were expressed at tumor invasive margin (IM). Preoperative sPD-L1 was negatively correlated with CD3 + and CD8 + T-lymphocytes' infiltration at IM and CT, GB and PD1 expression at IM. In cohort 2, exoPD-L1 and sPD-L1 levels decreased following hepatectomy but increased when tumor progressed. Moreover, higher postoperative exoPD-L1 and sPD-L1 or a small reduction in exoPD-L1 and sPD-L1 levels after hepatectomy suggested higher early recurrence rate.

Conclusions: Both preoperative exoPD-L1 and sPD-L1 had promising prognostic values and were associated with T cell infiltration at liver metastases in CRLM patients following hepatectomy. Dynamically tracking exoPD-L1 and sPD-L1 levels could monitor disease status and detect early recurrence.
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http://dx.doi.org/10.1007/s00262-021-03021-3DOI Listing
July 2021

The Choline Metabolite TMAO Inhibits NETosis and Promotes Placental Development in GDM of Humans and Mice.

Diabetes 2021 Oct 27;70(10):2250-2263. Epub 2021 Jul 27.

Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

Choline metabolite trimethylamine N-oxide (TMAO) has been recognized as a risk factor of gestational diabetes mellitus (GDM), but its exact role in GDM has not been reported. In this study, we focused on the placenta development to reveal the role of TMAO in GDM. We found that the TMAO levels in peripheral and cord plasma were increased in women with GDM and that TMAO levels were positively correlated with newborn weight and placental thickness. Neutrophil extracellular traps (NETs) in the peripheral and cord plasma and the myeloperoxidase expression in the placenta of women with GDM also increased. NETs could inhibit the proliferation, migration, invasion, and angiogenesis of HTR-8/Svneo cells. However, TMAO not only could inhibit the formation of NETs but also could enhance the biological function of HTR-8/Svneo cells. With induction of GDM in NETs-deficient PAD4 and wild-type mice, the placental weight of PAD4 mice increased significantly. TMAO feeding also inhibited the formation of NETs and further increased the weight of the placenta and fetuses, and this increase did not affect the placental structure. Our data indicate that higher TMAO levels and the formation of abnormal NETs were associated with GDM. TMAO not only could promote the development of the placenta and fetuses but also could inhibit the formation of NETs.
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http://dx.doi.org/10.2337/db21-0188DOI Listing
October 2021

Rapid Secondary Recrystallization of the Goss Texture in FeGa Sheets Using Nanosized NbC Particles.

Materials (Basel) 2021 Jul 8;14(14). Epub 2021 Jul 8.

Key Laboratory for Anisotropy and Texture of Materials, Ministry of Education, Northeastern University, Shenyang 110819, China.

Herein, a simple and efficient method is proposed for fabricating FeGa alloy thin sheets with a high magnetostriction coefficient. Sharp Goss texture ({110}<001>) was successfully produced in the sheets by rapid secondary recrystallization induced by nanosized NbC particles at low temperatures. Numerous NbC precipitates (size ~90 nm) were obtained after hot rolling, intermediate annealing, and primary recrystallization annealing. The relatively higher quantity of nanosized NbC precipitates with 0.22 mol% resulted in finer and uniform grains (~10 μm) through thickness after primary recrystallization annealing. There was a slow coarsening of the NbC precipitates, from 104 nm to 130 nm, as the temperature rose from 850 °C to 900 °C in a pure nitrogen atmosphere, as well as a primary recrystallization textured by strong γ fibers with a peak at {111} <112> favoring the development of secondary recrystallization of Goss texture at a temperature of 850 °C. Matching of the appropriate inhibitor characteristics and primary recrystallization texture guaranteed rapid secondary recrystallization at temperatures lower than 950 °C. A high magnetostriction coefficient of 304 ppm was achieved for the FeGa sheet after rapid secondary recrystallization.
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http://dx.doi.org/10.3390/ma14143818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306011PMC
July 2021

Enhanced dispersion of nickel nanoparticles on SAPO-5 for boosting hydroisomerization of n-hexane.

J Colloid Interface Sci 2021 Dec 10;604:727-736. Epub 2021 Jul 10.

State Key Laboratory of Heavy Oil Processing, China University of Petroleum, Qingdao 266555, China.

The nickel based bifunctional catalyst with enhanced hydroisomerization performance was developed using an in-situ solid synthesis method. It was achieved to stabilize smaller Ni active sites on SAPO-5 using ethylenediaminetetraacetic acid (EDTA) ligands. The role of EDTA ligands was clarified by controlling the molar ratio of EDTA to Ni (EDTA/Ni) over Ni/SAPO-5 catalysts. EDTA ligands inhibited the formation of nickel aluminate spinel and aggregation of NiO species during calcination, which dispersed Ni nanoparticles in a mean size of 4.7 nm on SAPO-5. The size of Ni nanoparticles could be controlled by regulating EDTA/Ni ratio in [Ni-EDTA] complex. The prepared catalyst exhibited high yield of isomers (54.0%) and di-branched isomers selectivity (18.0%) in the n-hexane hydroisomerization, which was approximately 2 times higher than that of the Ni/SAPO-5 catalyst without EDTA ligands at similar conversion. These results are important to propose a facile approach for the preparation of highly dispersed non-noble metal based bifunctional catalysts at a high loading.
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http://dx.doi.org/10.1016/j.jcis.2021.07.039DOI Listing
December 2021

MEK inhibition by trametinib overcomes chemoresistance in preclinical nasopharyngeal carcinoma models.

Anticancer Drugs 2021 Oct;32(9):978-985

Department of Neurology, Xiangyang No. 1 People's Hospital, Affiliated Hospital of Hubei University of Medicine, Xiangyang, Hubei, People's Republic of China.

The development of chemoresistance is the major cause of treatment failure in nasopharyngeal carcinoma (NPC). Although 'paradoxical' activation of extracellular signal-regulated kinase (ERK) has been shown to contribute resistance to anticancer treatment, the role of ERK in NPC chemoresistance has not been yet revealed. In this work, we report that trametinib, a clinically available mitogen-activated protein kinase inhibitor for melanoma treatment, overcomes NPC chemoresistance via suppressing ERK activation induced by chemotherapy. We first showed that trametinib at nanomolar concentrations was active against NPC cells and acted synergistically with cisplatin. Trametinib remarkably decreased phosphorylation of ERK and its downstream effector in NPC cells. We next showed that cisplatin treatment stimulates ERK signaling, and furthermore that this can be abolished by trametinib. We finally generated cisplatin-resistant NPC models and demonstrated that trametinib was effective in inhibiting cisplatin-resistant NPC growth, colony formation and survival via suppressing ERK signaling in vitro and in vivo. Our work demonstrates the potential of trametinib in overcoming chemoresistance in preclinical NPC models and provides evidence of initializing clinical trials of using trametinib for NPC treatment.
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http://dx.doi.org/10.1097/CAD.0000000000001092DOI Listing
October 2021

Low prevalence and independent prognostic role of del(11q) in Chinese patients with chronic lymphocytic leukemia.

Transl Oncol 2021 Oct 14;14(10):101176. Epub 2021 Jul 14.

Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China; Key Laboratory of Hematology of Nanjing Medical University, Nanjing 210029, China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing 210029, China; Pukou CLL Center, Nanjing 210000, China. Electronic address:

The 11q deletion (del(11q)) is a conventional cytogenetic aberration observed in chronic lymphocytic leukemia (CLL) patients. However, the prevalence and the prognostic value of del(11q) are still controversial. In this research, we retrospectively explored the prevalence, association, and prognostic significance of del(11q) in 352 untreated and 99 relapsed/refractory Chinese CLL patients. Totally 11.4% of untreated and 19.2% of relapsed/refractory patients harbored del(11q). Del(11q) was more common in patients with β2-microglobulin > 3.5 mg/L, positive CD38, positive zeta-chain associated protein kinase 70, unmutated immunoglobulin heavy variable-region gene and ataxia telangiectasia mutated mutation. Kaplan-Meier method and univariate Cox regression indicated that del(11q) was an independent prognostic factor for overall survival (OS). Based on the results of univariate Cox regression analysis, two nomograms that included del(11q) were established to predict survival. Desirable area under curve of receiver operating characteristic curves was obtained in the training and validation cohorts. In addition, the calibration curves for the probability of survival showed good agreement between the prediction by nomogram and actual observation. In summary, the prevalence of del(11q) is relatively low in our cohort and del(11q) is an unfavorable prognostic factor for untreated CLL patients. Besides, these two nomograms could be used to accurately predict the prognosis of untreated CLL patients.
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http://dx.doi.org/10.1016/j.tranon.2021.101176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287238PMC
October 2021

Prognostic nutritional index, a novel biomarker which predicts worse prognosis in diffuse large B cell lymphoma.

Leuk Res 2021 Jul 7;110:106664. Epub 2021 Jul 7.

Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China; Key Laboratory of Hematology of Nanjing Medical University, Nanjing 210029, China; Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing 210029, China. Electronic address:

The prognostic nutritional index (PNI), an indicator of nutritional status and systemic inflammation, is associated with survival in several types of lymphoma. The purpose of this study was to investigate the prognostic value of PNI in diffuse large B cell lymphoma (DLBCL). With three hundred and ten patients were enrolled, the median level of PNI was 45.90 (range 25.30-139.70). According to the receiver operating characteristic (ROC) curve, 44.85 was determined to be the best cutoff value to divide patients into two different groups. With a median follow-up of 33.3 months (range 3.5-118.5), compared with the high PNI group, the 3-year and adjusted 3-year progression-free survival (PFS) and overall survival (OS) were worse in the low PNI group (all P < 0.050). Multivariate Cox analysis suggested that low PNI was an independent risk factor for PFS (hazard ratio (HR) 2.196, 95 % CI 1.197-4.030, P = 0.011) and showed a tendency to predict inferior OS (HR 1.918, 95 % CI 0.932-3.948, P = 0.077). Furthermore, PNI combined with other significant prognostic factors to build a novel prognostic index, namely NPI, was more accurate than the National Comprehensive Cancer Network international prognostic index (NCCN-IPI) to predict worse PFS and had a similar effect on predicting OS. All these findings suggested that PNI, as a novel available biomarker, was of prognostic significance in DLBCL patients.
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http://dx.doi.org/10.1016/j.leukres.2021.106664DOI Listing
July 2021

Regulation of redox balance using a biocompatible nanoplatform enhances phototherapy efficacy and suppresses tumor metastasis.

Chem Sci 2020 Oct 22;12(1):148-157. Epub 2020 Oct 22.

Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), College of Chemistry and Molecular Sciences, Wuhan University Wuhan Hubei 430072 P. R. China

Many cancer treatments including photodynamic therapy (PDT) utilize reactive oxygen species (ROS) to kill tumor cells. However, elevated antioxidant defense systems in cancer cells result in resistance to the therapy involving ROS. Here we describe a highly effective phototherapy through regulation of redox homeostasis with a biocompatible and versatile nanotherapeutic to inhibit tumor growth and metastasis. We systematically explore and exploit methylene blue adsorbed polydopamine nanoparticles as a targeted and precise nanocarrier, oxidative stress amplifier, photodynamic/photothermal agent, and multimodal probe for fluorescence, photothermal and photoacoustic imaging to enhance anti-tumor efficacy. Remarkably, following the glutathione-stimulated photosensitizer release to generate exogenous ROS, polydopamine eliminates the endogenous ROS scavenging system through depleting the primary antioxidant, thus amplifying the phototherapy and effectively suppressing tumor growth and . Furthermore, this approach enables a robust inhibition against breast cancer metastasis, as oxidative stress is a vital impediment to distant metastasis in tumor cells. Innovative, safe and effective nanotherapeutics regulation of redox balance may provide a clinically relevant approach for cancer treatment.
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http://dx.doi.org/10.1039/d0sc04983bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178807PMC
October 2020

Monocyte-to-albumin ratio as a novel predictor of long-term adverse outcomes in patients after percutaneous coronary intervention.

Biosci Rep 2021 Jul;41(7)

Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.

Background: Monocyte count and serum albumin (Alb) have been proven to be involved in the process of systemic inflammation. Therefore, we investigated the prognostic value of monocyte-to-albumin ratio (MAR) in patients who underwent percutaneous coronary intervention (PCI).

Methods: We enrolled a total of 3561 patients in the present study from January 2013 to December 2017. They were divided into two groups according to MAR cut-off value (MAR < 0.014, n=2220; MAR ≥ 0.014, n=1119) as evaluated by receiver operating characteristic (ROC) curve. The average follow-up time was 37.59 ± 22.24 months.

Results: The two groups differed significantly in the incidences of all-cause mortality (ACM; P<0.001), cardiac mortality (CM; P<0.001), major adverse cardiovascular events (MACEs; P=0.038), and major adverse cardiovascular and cerebrovascular events (MACCEs; P=0.037). Multivariate Cox regression analyses revealed MAR as an independent prognostic factor for ACM and CM. The incidence of ACM increased by 56.5% (hazard ratio [HR] = 1.565; 95% confidence interval [CI], 1.086-2.256; P=0.016) and that of CM increased by 76.3% (HR = 1.763; 95% CI, 1.106-2.810; P=0.017) in patients in the higher-MAR group. Kaplan-Meier survival analysis suggested that patients with higher MAR tended to have an increased accumulated risk of ACM (Log-rank P<0.001) and CM (Log-rank P<0.001).

Conclusion: The findings of the present study suggested that MAR was a novel independent predictor of long-term mortality in patients who underwent PCI.
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http://dx.doi.org/10.1042/BSR20210154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243340PMC
July 2021

Alkaline phosphatase-to-albumin ratio as a novel predictor of long-term adverse outcomes in coronary artery disease patients who underwent PCI.

Biosci Rep 2021 Jul;41(7)

Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.

Background: Alkaline phosphatase (ALP) and albumin (ALB) have been shown to be associated with coronary artery disease (CAD), and it has been reported that alkaline phosphatase-to-albumin ratio (AAR) is associated with the liver damage and poorer prognosis of patients with digestive system malignancy. Moreover, several previous studies showed that there was a higher incidence of malignancy in CAD patients. However, to our knowledge, the relationship between AAR and long-term adverse outcomes in CAD patients after undergoing percutaneous coronary intervention (PCI) has not been investigated. Therefore, we aim to access the relation between AAR and long-term adverse outcomes in post-PCI patients with CAD.

Methods: A total of 3378 post-PCI patients with CAD were enrolled in the retrospective Clinical Outcomes and Risk Factors of Patients with Coronary Heart Disease after PCI (CORFCHD-ZZ) study from January 2013 to December 2017. The median duration of follow-up was 37.59 ± 22.24 months. The primary end point was long-term mortality including all-cause mortality (ACM) and cardiac mortality (CM). The secondary end points were major adverse cardiac events (MACEs) and major adverse cardiac and cerebrovascular events (MACCEs).

Results: Kaplan-Meier analyses showed that an increased AAR was positively correlated with incidences of long-term ACM (log-rank, P=0.014), CM (log-rank, P=0.011), MACEs (log-rank, P=0.013) and MACCEs (log-rank, P=0.006). Multivariate Cox regression analyses showed that the elevated AAR was an independent predictor of long-term ACM (adjusted HR = 1.488 [1.031-2.149], P=0.034), CM (adjusted HR = 1.837 [1.141-2.959], P=0.012), MACEs (adjusted HR = 1.257 [1.018-1.551], P=0.033) and MACCEs (adjusted HR = 1.237 [1.029-1.486], P=0.024).

Conclusion: An elevated AAR is a novel independent predictor of long-term adverse outcomes in CAD patients following PCI.
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http://dx.doi.org/10.1042/BSR20203904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243337PMC
July 2021

The interaction of MYB, bHLH and WD40 transcription factors in red pear (Pyrus pyrifolia) peel.

Plant Mol Biol 2021 Jul 11;106(4-5):407-417. Epub 2021 Jun 11.

Biotechnology Research Centre, Faculty of Life Science and Biotechnology, Chenggong Campus, Kunming University of Science and Technology, Chenggong, 650500, Kunming, China.

Key Message: Sunlight enhanced peel color and significantly up-regulated the expression of PyMYB10 and PybHLH genes. MYB-bHLH-WD40 transcriptional complex forms in the light and is involved in regulating anthocyanin accumulation in the peel. Anthocyanin is the major pigment in the peel of Yunnan red pear (Pyrus pyrifolia (Burm.) Nak.). A transcriptional activation protein complex, involving members of the transcription factor classes of MYB, bHLH and WD40, regulates anthocyanin biosynthesis. This complex was examined in the peel of red pear. In order to clarify the interaction of PyMYB10, PybHLH and PyWD40, fruit were bagged then peel samples collected 0, 3, 5, and 7 days after bag removal. Samples were used for Western blotting and protein interaction analysis. The results showed that sunlight enhanced peel color and significantly up-regulated the expression of both PyMYB10 and PybHLH genes. Co-immunoprecipitation (Co-IP) analysis showed that PybHLH interacted with PyMYB10 or PyWD40, and PyMYB10 interacted with PyWD40. Using onion cells as a model system, bimolecular fluorescence complementation (BiFC) confirmed these interactions and showed that the interaction localized to the nuclei. GST Pull down and Far-Western blotting assays demonstrated that PybHLH interacted with PyMYB10 or PyWD40, respectively, and PyMYB10 interacted with PyWD40 in vitro. In addition, EMSA assay showed that PyMYB10 can directly bind to the promoter of the gene encoding the anthocyanin biosynthesis enzyme anthocyanidin synthase (PyANS). Taken together, these results showed that the ternary complex of PyMYB10, PybHLH and PyWD40 transcription factors forms to regulate anthocyanin biosynthesis and accumulation in Yunnan red pear.
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http://dx.doi.org/10.1007/s11103-021-01160-wDOI Listing
July 2021

Magnesium treatment on methylation changes of transmembrane serine protease 2 (TMPRSS2).

Nutrition 2021 09 7;89:111340. Epub 2021 May 7.

Department of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA. Electronic address:

Objectives: The viral entry of SARS-CoV-2 requires host-expressed TMPRSS2 to facilitate the viral spike protein priming. This study aims to test the hypothesis that magnesium (Mg) treatment leads to DNA methylation changes in TMPRSS2.

Methods: This study is nested within the Personalized Prevention of Colorectal Cancer Trial, a double-blind 2 × 2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center.

Results: We found that 12 wk of personalized Mg treatment significantly increased 5-methylcytosine methylation at cg16371860 (TSS1500, promoter) by 7.2% compared to the placebo arm (decreased by 0.1%) in those ages < 65 y. The difference remained statistically significant after adjusting for age, sex, and baseline methylation as well as correction for false discovery rate (adjusted P = 0.014). Additionally, Mg treatment significantly reduced 5-hydroxymethylcytosine levels at cg26337277 (close proximity to TSS200 and the 5' untranslated region, promoter) by 2.3% compared to an increase of 7.1% in the placebo arm after adjusting for covariates in those ages < 65 y (P = 0.003). The effect remained significant at a false discovery rate of 0.10 (adjusted P = 0.088).

Conclusions: Among individuals ages < 65 y with calcium-to-magnesium intake ratios equal to or over 2.6, reducing the ratio to around 2.3 increased 5-methylcytosine modifications (i.e., cg16371860) and reduced 5-hydroxymethylcytosine modifications (i.e., cg26337277) in the TMPRSS2 gene. These findings, if confirmed, provide another mechanism for the role of Mg intervention in the prevention of COVID-19 and treatment of early and mild disease by modifying the phenotype of the TMPRSS2 genotype.
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http://dx.doi.org/10.1016/j.nut.2021.111340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102075PMC
September 2021

Effects of Gene Delivery Approaches on Differentiation Potential and Gene Function of Mesenchymal Stem Cells.

IEEE Trans Biomed Eng 2021 Jun 8;PP. Epub 2021 Jun 8.

Introduction of a gene to mesenchymal stem cells (MSCs) is a well-known strategy to purposely manipulate the cell fate and further enhance therapeutic performance in cell-based therapy. Viral and chemical approaches for gene delivery interfere with differentiation potential. Although microinjection as a physical delivery method is commonly used for transfection, its influence on MSC cell fate is not fully understood. The current study aimed to evaluate the effects of four nonviral gene delivery methods on stem cell multi-potency. The four delivery methods are robotic microinjection, polyethylenimine (PEI), cationic liposome (cLipo), and calcium phosphate nanoparticles (CaP). Among the four methods, microinjection has exhibited the highest transfection efficiency of ~60%, while the three others showed lower efficiency of 10-25%. Robotic microinjection preserved fibroblast-like cell morphology, stress fibre intactness, and mature focal adhesion complex, while PEI caused severe cytotoxicity. No marked differentiation bias was observed after microinjection and cLipo treatment. By contrast, CaP-treated MSCs exhibited excessive osteogenesis, while PEI-treated MSCs showed excessive adipogenesis. Robotic microinjection system was used to inject the CRISPR/Cas9-encoding plasmid to knock out PPAR gene in MSCs, and the robotic microinjection did not interfere with PPAR function in differentiation commitment. Meanwhile, the bias in osteo-adipogenic differentiation exhibited in CaP and PEI-treated MSCs after PPAR knockout via chemical carriers. Our results indicate that gene delivery vehicles variously disturb MSCs differentiation and interfere with exogenous gene function. Our findings further suggest that robotic microinjection offers a promise of generating genetically modified MSCs without disrupting stem cell multi-potency and therapeutic gene function.
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http://dx.doi.org/10.1109/TBME.2021.3087129DOI Listing
June 2021

Lubrication and Dynamically Controlled Drug Release Properties of Tween 85/Tween 80/HO Lamellar Liquid Crystals.

Langmuir 2021 06 3;37(23):7067-7077. Epub 2021 Jun 3.

School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, P. R. China.

Lamellar liquid crystals have amazing lubricating and drug-solubilizing properties. Hence, the combination of drug molecules with lamellar liquid crystals is expected to be used in joint lubrication and treatment. In this study, the partial phase diagram of the Tween 85/Tween 80/HO three-component system was determined. The phase structure of the system changed from a hexagonal liquid crystal to a lamellar liquid crystal with the increase of Tween 85 content. The lamellar liquid crystals showed superior lubricating properties due to their unique lamellar structure. Furthermore, the model of drug release during friction was established for the first time. It was found that the order of the lamellar liquid crystals increased with the increase of the mass ratio of Tween 85/Tween 80, leading to the decrease of the ibuprofen release rate. In addition, the release rate of ibuprofen increased progressively with the increase of the friction frequency, but the load had little effect on it. Therefore, the lamellar liquid crystals consisting of nonionic surfactants with good biocompatibility have potential application prospects for joint lubrication and treatment of arthritis.
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http://dx.doi.org/10.1021/acs.langmuir.1c00659DOI Listing
June 2021

Association of heart rate and diabetes among 0.5 million adults in the China Kadoorie biobank: Results from observational and Mendelian randomization analyses.

Nutr Metab Cardiovasc Dis 2021 07 27;31(8):2328-2337. Epub 2021 Apr 27.

Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China; Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, China. Electronic address:

Background And Aims: Observational studies have associated resting heart rate with incident diabetes. Whether the associations are causal remains unclear. We aimed to examine the shape and strength of the associations and assessed the causal relevance of such associations in Chinese adults.

Methods And Results: The China Kadoorie Biobank enrolled 512,891 adults in China. Cox proportional hazard regression models was conducted to estimate hazard ratios (HRs) for the associations of resting heart rate with type 2 diabetes and total diabetes. Among 92,724 participants, 36 single-nucleotide polymorphisms (SNPs) related to resting heart rate were used to construct genetic risk score. We used Mendelian randomization analyses to make the causal inferences. During a median follow-up of 9 years, 7872 incident type 2 diabetes and 13,349 incident total diabetes were documented. After regression dilution bias adjustment, each 10 bpm higher heart rate was associated with about a 26% higher risk of type 2 diabetes (HR, 1.26 [95% CI, 1.23, 1.29]) and 23% higher risk of total diabetes (HR, 1.23 [95% CI, 1.20, 1.26]). Instrumental variable analyses showed participants at top quintile compared with those at bottom quintile had 30% higher risk for type 2 diabetes (HR, 1.30 [95% CI, 1.17, 1.43]), and 10% higher risk for total diabetes (HR, 1.10 [95% CI, 1.02, 1.20]).

Conclusions: This study provides evidence that resting heart rate is an important risk factor for diabetes risk. The results suggest that novel treatment approaches targeting reduction of high heart rate for incidence of diabetes may be worth further investigation.
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http://dx.doi.org/10.1016/j.numecd.2021.04.015DOI Listing
July 2021
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