Publications by authors named "Qiong Wu"

1,498 Publications

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Systematic screening reveals synergistic interactions that overcome MAPK inhibitor resistance in cancer cells.

Cancer Biol Med 2021 Jun 9. Epub 2021 Jun 9.

Department of Cell Biology, Basic Medical College, Army Medical University (Third Military Medical University), Chongqing 400038, China.

Objective: Effective adjuvant therapeutic strategies are urgently needed to overcome MAPK inhibitor (MAPKi) resistance, which is one of the most common forms of resistance that has emerged in many types of cancers. Here, we aimed to systematically identify the genetic interactions underlying MAPKi resistance, and to further investigate the mechanisms that produce the genetic interactions that generate synergistic MAPKi resistance.

Methods: We conducted a comprehensive pair-wise sgRNA-based high-throughput screening assay to identify synergistic interactions that sensitized cancer cells to MAPKi, and validated 3 genetic combinations through competitive growth, cell viability, and spheroid formation assays. We next conducted Kaplan-Meier survival analysis based on The Cancer Genome Atlas database and conducted immunohistochemistry to determine the clinical relevance of these synergistic combinations. We also investigated the MAPKi resistance mechanisms of these validated synergistic combinations by using co-immunoprecipitation, Western blot, qRT-PCR, and immunofluorescence assays.

Results: We constructed a systematic interaction network of MAPKi resistance and identified 3 novel synergistic combinations that effectively targeted MAPKi resistance ( + + , and + ). We next analyzed their clinical relevance and the mechanisms by which they sensitized cancer cells to MAPKi exposure. Specifically, we discovered a novel protein complex, HDGF-LGR5, that adaptively responded to MAPKi to enhance cancer cell stemness, which was up- or downregulated by the inhibitors of ITGB3 + JNK or ITGB3 + IGF1R.

Conclusions: Pair-wise sgRNA library screening provided systematic insights into elucidating MAPKi resistance in cancer cells. ITGB3- + IGF1R-targeting drugs (cilengitide + linsitinib) could be used as an effective therapy for suppressing the adaptive formation of the HDGF-LGR5 protein complex, which enhanced cancer stemness during MAPKi stress.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0560DOI Listing
June 2021

Anlotinib monotherapy for refractory metastatic colorectal cancer: A double-blinded, placebo controlled, randomized Phase III trial (ALTER0703).

Oncologist 2021 Jun 8. Epub 2021 Jun 8.

Department of Medical Oncology, Liuzhou worker's hospital, Liuzhou, China.

Background: Treatment options for refractory metastatic colorectal cancer (mCRC) were limited. Anlotinib is a novel multitarget tyrosine kinase inhibitor. ALTER0703 study was conducted to assess efficacy and safety of anlotinib for refractory mCRC patients.

Patients And Methods: This was a multicenter, double-blinded, placebo-controlled, randomized phase III trial involving 33 hospitals in China. Patients had taken at least 2 lines of therapies were 2:1 randomized to receive oral anlotinib (12 mg/day; days 1-14; 21 days/cycle) or placebo, plus best supportive care. Randomization was stratified by previous VEGF-targeting treatments and time from diagnosis to metastases. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL) and safety.

Results: 419 patients (anlotinib: 282; placebo: 137) were treated from Dec, 2014 to Aug, 2016. The median PFS was improved in anlotinib group (4.1 months; 95% CI 3.4-4.5) over placebo group (1.5 months; 95% CI, 1.4-1.5), with a hazard ratio (HR) of 0.34 (95% CI, 0.27-0.43; P<0.0001). However, median OS was similar between two groups (8.6 months; 95% CI, 7.8-9.7 vs. 7.2 months; 95% CI, 6.2-8.8; HR = 1.02; P=0.870). Improvements of ORR and DCR were observed in anlotinib over placebo. The most common grade ≥3 anlotinib related adverse events were hypertension (20.92%), increased γ-GT (7.09%) and hand-foot skin reaction (6.38%).

Conclusions: Anlotinib was tolerated in Chinese refractory mCRC patients. Although OS did not reach significant difference, anlotinib still provided clinical benefits by substantially prolonged PFS in these patients.

Implications For Practice: In this randomized clinical trial that included 419 patients with refractory metastatic colorectal cancer, substantial prolonged in progression-free survival was noted in patients who received anlotinib compared with those given placebo. Improvements on objective response rate and disease control rate was also observed in anlotinib group. However, overall survival was similar between the two groups. In a word, in third-line or above treatment of Chinese patients with refractory metastatic colorectal cancer, anlotinib provided clinical benefit by significantly prolonged progression-free survival.
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http://dx.doi.org/10.1002/onco.13857DOI Listing
June 2021

Guanosine and uridine alleviate airway inflammation via inhibition of the MAPK and NF-κB signals in OVA-induced asthmatic mice.

Pulm Pharmacol Ther 2021 Jun 5:102049. Epub 2021 Jun 5.

Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, P. R. China; Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, P. R. China; Frontiers Science Center for Disease-related Molecular Network, Sichuan University, 65292, Chengdu, Sichuan, P. R. China. Electronic address:

Asthma is one of the most common respiratory diseases. Lack of response or poor adherence to corticosteroids demands the development of new drug candidates for asthma. Endogenous nucleosides could be potential options since uridine has been reported to have an anti-inflammatory effect in asthma model. However, its molecular pathways and whether other nucleosides have similar therapeutic effects remain untouched. Thus, we herein report our investigation into the anti-inflammatory effects of guanosine and uridine, and the related inner signaling pathways in asthma model. Present study shows that administration of guanosine or uridine can reduce lung inflammation in OVA-challenged mice. Total cell counts in BALF, cytokines such as IL-4, IL-6, IL-13, OVA-specific IgE and mRNA level of Cxcl1, Cxlc3, IL-17 and Muc5ac were decreased in asthmatic mice after treatment. Besides, the production of IL-6 in LPS/IFN-γ induced THP-1 cells was also decreased by both nucleosides. In vivo and in vitro expressions of key molecules in the MAPK and NF-κB pathways were reduced after the treatment of both compounds. These findings suggest that guanosine has a similar potential therapeutic value in asthma as uridine and they exert anti-inflammatory effects through suppression of the MAPK and NF-κB pathways.
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http://dx.doi.org/10.1016/j.pupt.2021.102049DOI Listing
June 2021

A link between protein acetylation and mitochondrial dynamics under energy metabolism: A comprehensive overview.

J Cell Physiol 2021 Jun 8. Epub 2021 Jun 8.

Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.

Cells adjust mitochondrial morphologies to coordinate between the cellular demand for energy and the availability of resources. Mitochondrial morphology is regulated by the balance between two counteracting mitochondrial processes of fusion and fission. Fission and fusion are dynamic and reversible processes that depend on the coordination of a number of proteins and are primarily regulated by posttranslational modifications. In the mitochondria, more than 20% of proteins are acetylated in proteomic surveys, partly involved in the dynamic regulation of mitochondrial fusion and fission. This article focuses on the molecular mechanism of the mitochondrial dynamics of fusion and fission, and summarizes the related mechanisms and targets of mitochondrial protein acetylation to regulate the mitochondrial dynamics of fusion and fission in energy metabolism.
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http://dx.doi.org/10.1002/jcp.30461DOI Listing
June 2021

Multi-Functional Liposome: A Powerful Theranostic Nano-Platform Enhancing Photodynamic Therapy.

Adv Sci (Weinh) 2021 Jun 3:e2100876. Epub 2021 Jun 3.

Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials (IAM), Nanjing Tech University (NanjingTech), Nanjing, 211816, P. R. China.

Although photodynamic therapy (PDT) has promising advantages in almost non-invasion, low drug resistance, and low dark toxicity, it still suffers from limitations in the lipophilic nature of most photosensitizers (PSs), short half-life of PS in plasma, poor tissue penetration, and low tumor specificity. To overcome these limitations and enhance PDT, liposomes, as excellent multi-functional nano-carriers for drug delivery, have been extensively studied in multi-functional theranostics, including liposomal PS, targeted drug delivery, controllable drug release, image-guided therapy, and combined therapy. This review provides researchers with a useful reference in liposome-based drug delivery.
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http://dx.doi.org/10.1002/advs.202100876DOI Listing
June 2021

Decitabine Sensitizes the Radioresistant Lung Adenocarcinoma to Pemetrexed Through Upregulation of Folate Receptor Alpha.

Front Oncol 2021 17;11:668798. Epub 2021 May 17.

Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Cancer Center, Zhejiang University, Hangzhou, China.

Chemotherapy is the backbone of subsequent treatment for patients with lung adenocarcinoma (LUAD) exhibiting radiation resistance, and pemetrexed plays a critical role in this chemotherapy. However, few studies have assessed changes in the sensitivity of LUAD cells to pemetrexed under radioresistant circumstances. Therefore, the objectives of this study were to delineate changes in the sensitivity of radioresistant LUAD cells to pemetrexed and to elucidate the related mechanisms and then develop an optimal strategy to improve the cytotoxicity of pemetrexed in radioresistant LUAD cells. Our study showed a much lower efficacy of pemetrexed in radioresistant cells than in parental cells, and the mechanism of action was the significant downregulation of folate receptor alpha (FRα) by long-term fractionated radiotherapy, which resulted in less cellular pemetrexed accumulation. Interestingly, decitabine effectively reversed the decrease in FRα expression in radioresistant cells through an indirect regulatory approach. Thereafter, we designed a combination therapy of pemetrexed and decitabine and showed that the activation of FRα by decitabine sensitizes radioresistant LUAD cells to pemetrexed both and in xenografts. Our findings raised a question regarding the administration of pemetrexed to patients with LUAD exhibiting acquired radioresistance and accordingly suggested that a combination of pemetrexed and decitabine would be a promising treatment strategy.
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http://dx.doi.org/10.3389/fonc.2021.668798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165306PMC
May 2021

Raman Spectroscopy Study on Ternary Model Coal Mine Methane Hydrates.

ACS Omega 2021 Apr 14;6(16):10709-10714. Epub 2021 Apr 14.

School of Safety Engineering, Heilongjiang University of Science and Technology, Harbin 150022, China.

The microfeatures of coal mine methane (CMM) hydrates, synthesized with three gas samples (CH/CH/N, G1 = 43 : 47 : 10, G2 = 60 : 30 : 10, and G3 = 74 : 16 : 10) in a self-made transparent high-pressure cell at 275.15 K and 5 MPa were investigated using Raman spectroscopy. As a discriminator, the vibrational band frequencies in the C-C regions of the recorded hydrate Raman spectra for CH show that G1∼G3 hydrates are structure I. The three principal parameters used to study the microfeatures of the model CMM hydrates, including cavity occupancies, hydrate guest compositions, and hydration numbers, were calculated. The large cavity occupancies for CH constantly decrease from 85.12 to 79.32%, while the small cavity occupancies for CH have a continuous increase from 73.75 to 96.42%. However, CH competes with CH on entering the large cavities for their large cavity occupancies of 12.79-17.31%. The cavity occupancies of N are less than 1.2%. The hydrate composition calculations show that the molar fractions of CH are the maximum. The hydration numbers range from 6.221 to 6.00. Based on the hydrate guest compositions and hydration numbers, the molecular formulas of the three CMM hydrates are presented.
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http://dx.doi.org/10.1021/acsomega.1c00216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153790PMC
April 2021

Spontaneous Patterning during Frontal Polymerization.

ACS Cent Sci 2021 Apr 24;7(4):603-612. Epub 2021 Mar 24.

Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois, United States.

Complex patterns integral to the structure and function of biological materials arise spontaneously during morphogenesis. In contrast, functional patterns in synthetic materials are typically created through multistep manufacturing processes, limiting accessibility to spatially varying materials systems. Here, we harness rapid reaction-thermal transport during frontal polymerization to drive the emergence of spatially varying patterns during the synthesis of engineering polymers. Tuning of the reaction kinetics and thermal transport enables internal feedback control over thermal gradients to spontaneously pattern morphological, chemical, optical, and mechanical properties of structural materials. We achieve patterned regions with two orders of magnitude change in modulus in poly(cyclooctadiene) and 20 °C change in glass transition temperature in poly(dicyclopentadiene). Our results suggest a facile route to patterned structural materials with complex microstructures without the need for masks, molds, or printers utilized in conventional manufacturing. Moreover, we envision that more sophisticated control of reaction-transport driven fronts may enable spontaneous growth of structures and patterns in synthetic materials, inaccessible by traditional manufacturing approaches.
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http://dx.doi.org/10.1021/acscentsci.1c00110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155460PMC
April 2021

Fluorescent hollow [email protected] nanoparticles-based lateral flow assay for simultaneous detection of C-reactive protein and troponin T.

Mikrochim Acta 2021 May 28;188(6):209. Epub 2021 May 28.

Laboratory of Controllable Preparation and Application of Nanomaterials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing, 100190, China.

Highly fluorescent hollow [email protected] nanoparticles (NPs) were synthesized efficiently via the hydrothermal method. By changing the hydrothermal time of [email protected] NP, the peaks of fluorescence spectra measured at fluorescent excitation of 330 nm were at 540 nm, 590 nm, and 640 nm, respectively. Hollow ZrO NPs have a uniform core-shell structure with the size of 178 ± 10 nm and shell of 19 ± 4 nm. The as-prepared [email protected] NPs were used to develop lateral flow assay (LFA) for the sensitive and qualitative detection of C-reactive protein (CRP). The visual limit of detection of the LFA for the CRP antigen was 1 μg/L within 20 min, which is 1000-fold lower than that of colloidal gold-based LFA. In addition, a multiplex lateral flow assay (mLFA) was developed using the as-prepared green and [email protected] NPs for the simultaneous, specific, sensitive, and qualitative detection of CRP and troponin T (cTnT). The visual limits of detection of CRP and cTnT in mLFA were 10 μg/L and 0.1 mg/L, respectively. The excellent performance of [email protected] NPs should facilitate their application in point-of-care technology for the detection of other biomarkers.
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http://dx.doi.org/10.1007/s00604-021-04865-3DOI Listing
May 2021

A biopsychosocial perspective on maternal parenting in the first two years of infant life.

Authors:
Qiong Wu

Behav Brain Res 2021 May 21;411:113375. Epub 2021 May 21.

Department of Human Development & Family Science, Florida State University, Sandels 322, 120 Convocation Way, Tallahassee, FL, 32306, United States. Electronic address:

Guided by a biopsychosocial perspective of mothering, this study investigated the interplay among biological (maternal cortisol reactivity), psychological (maternal depressive symptoms), and social (infant emotion and regulation) factors in contributing to early changes in maternal parenting. Participants were 1292 low-income, mother-infant pairs, assessed when the infants were 6-months (T1), 15-months (T2), and 24-months old (T3). Maternal parenting was observed at all assessment points. At T1, infant emotion expression and orienting towards mothers were observed, when maternal cortisol reactivity was assessed. Mothers reported their depressive symptoms at T1. Exploratory factor analysis revealed two parenting factors across time points: positive engagement and negative intrusiveness. Second-order latent growth curve models revealed interactions among maternal cortisol reactivity, depressive symptoms, and child negative emotion/orienting at T1 in predicting intercepts and slopes of two parenting factors. T1 maternal cortisol reactivity was associated with a higher positive engagement intercept for infants having high negative emotion at T1, but a lower positive engagement intercept for infants with low negative emotion at T1, under low T1 maternal depressive symptoms. T1 maternal cortisol reactivity was also related to a lower negative intrusiveness intercept for infants showing high orienting at T1. Longitudinally, maternal cortisol reactivity at T1 predicted a faster decline in positive engagement when infants showed high negative emotion at T1, but a slower decline when infants were less negative at T1. This study reveals a bivalent adaptation process in maternal sensitivity and enhances the current understanding of how biopsychosocial factors contribute to maternal parenting in low-income families.
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http://dx.doi.org/10.1016/j.bbr.2021.113375DOI Listing
May 2021

Downregulation of CD151 restricts VCAM-1 mediated leukocyte infiltration to reduce neurobiological injuries after experimental stroke.

J Neuroinflammation 2021 May 22;18(1):118. Epub 2021 May 22.

Department of Neurology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China.

Background: Translational failures in anti-adhesion molecule therapies after stroke reveal the necessity of developing new strategies that not only interrupt leukocyte recruitment but also consider the inhibition of endothelial cell inflammation, verification of therapeutic time window, and normal function maintenance of circulating leukocytes. Our study focused on the potential therapeutic value of CD151 downregulation in improving current anti-adhesion molecule therapies.

Methods: Lentivirus intracerebroventricular administration was conducted to inhibit the CD151 expression and observe its functional influence on neurological injuries and outcomes. Then, immunohistochemistry and myeloperoxidase activity assessment were performed to explore the effects of CD151 expression on neutrophil and monocyte recruitment after rat cerebral ischemia. Primary rat brain microvascular endothelial cells were subjected to oxygen glucose deprivation and reoxygenation to elucidate the underlying working mechanisms between CD151 and VCAM-1.

Results: The CD151 downregulation remarkably reduced neurological injuries and improved neurological outcomes, which were accompanied with reduced neutrophil and monocyte infiltration after the CD151 downregulation. The VCAM-1 expression was remarkably decreased among the adhesion molecules on the endothelial cell responsible for neutrophil and monocyte infiltration. The activation of p38 MAPK and NF-κB pathways was restricted after the CD151 downregulation. p38 MAPK and NF-κB inhibitors decreased the VCAM-1 expression, and p38 acted as an upstream regulator of NF-κB. However, CD151 downregulation did not directly influence the neutrophil and monocyte activation.

Conclusions: Overall, CD151 regulated the expression of adhesion molecules. It also played a critical role in suppressing VCAM-1-mediated neutrophil and monocyte infiltration via the p38/NF-κB pathway. This study possibly provided a new basis for improving current anti-adhesion molecule therapies.
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http://dx.doi.org/10.1186/s12974-021-02171-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140507PMC
May 2021

Effectiveness of acupuncture therapy for postherpetic neuralgia: an umbrella review protocol.

BMJ Open 2021 05 21;11(5):e043064. Epub 2021 May 21.

Department of Pain, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China.

Introduction: Several systematic reviews and meta-analysis indicate that acupuncture and related therapies may be a valuable adjunctive technique to pharmacological interventions for pain management of postherpetic neuralgia (PHN). However, the robustness of the results of these studies has not been evaluated. The aim of this proposed umbrella review is to provide more reliable evidence of the effectiveness of acupuncture therapy for PHN based on medical references for healthcare decision makers.

Methods And Analysis: PubMed, EMBASE, The Cochrane Library, Web of Science, Chinese BioMedical Literature Database, VIP Database for Chinese Technical Periodicals, China National Knowledge Infrastructure and Wan fang Database will be used to retrieve reviews. The time of publication will be limited from inception to March 2021. Two reviewers will screen all retrieved articles independently to identify their eligibility and extract the data. The quality will be assessed independently by two trained reviewers using Assessment of Multiple Systematic Reviews-2 for methodological quality, Risk of Bias in Systematic Review for level of bias, Preferred Reporting Items for Systematic Reviews and Meta-Analysis for reporting quality and Grading of Recommendations Assessment, Development and Evaluation for the quality of evidence. Any disagreements will be settled by discussion or the involvement of a third reviewer.

Ethics And Dissemination: The protocol of this review does not require ethical approval because the research will be based on publicly available data. The findings will be disseminated through publication in peer-reviewed international journals or presentation in academic conference.

Prospero Registration Number: CRD42020173341.

Reporting Checklist: PRISMA-P, 2015.
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http://dx.doi.org/10.1136/bmjopen-2020-043064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144037PMC
May 2021

AKT1 is positively regulated by G-quadruplexes in its promoter and 3'-UTR.

Biochem Biophys Res Commun 2021 Jul 18;561:93-100. Epub 2021 May 18.

Key Laboratory of Saline-alkali Vegetation Ecology Restoration, Ministry of Education, College of Life Science, Northeast Forestry University, Harbin, 150040, China. Electronic address:

AKT1 plays a key role in cell growth and survival, and its activation in cancers is mediated by different mechanisms. In this study, we investigated the potential of G-quadruplex (G4) formation by multiple consecutive G-tracts in the AKT1 promoter and its 3'-UTR. In circular dichroism analyses, synthetic oligonucleotides based on these G-tract regions showed molar ellipticity peaks at specific wavelengths of G4 structures. We verified G4 forming potential of these oligonucleotides using dimethyl sulfate footprinting, gel-shift and immunostaining assays. In reporter assays, mutations of the G-tracts in either the promoter or the 3'-UTR of AKT1 reduced expression mediated by these G-rich regions, suggesting positive regulation of AKT1 gene expression by these G4 structures. Furthermore, SP1 bound to its consensus sites regardless of the presence of G4 motifs in the AKT1 promoter, and both the G4 motifs and SP1 binding sites were needed to reach the strongest promoter strength.
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http://dx.doi.org/10.1016/j.bbrc.2021.05.029DOI Listing
July 2021

Genetically predicted selenium is negatively associated with serum TC, LDL-C and positively associated with HbA1C levels.

J Trace Elem Med Biol 2021 May 13;67:126785. Epub 2021 May 13.

Department of Epidemiology & Biostatistics, School of Public Health, Zhejiang University, Hangzhou, 310058, Zhejiang, China; Department of Respiratory Diseases, Sir Run Run Shaw Hospital Affiliated to School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310060, China; Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, 310058, Zhejiang, China. Electronic address:

Background & Aims: Pervious epidemiological evidence on the associations of selenium, zinc with lipid profile and glycemic indices was contradictory. The aim of this study was to investigate whether selenium and zinc were casually associated with lipid profile and glycemic indices using mendelian randomization (MR) analysis.

Method: A two-sample MR was used to evaluate the causal-effect estimations. Summary statistics for selenium, zinc, lipids and glycemic indices were retrieved from previous large-scale genome-wide association study (GWAS). Single nucleotide polymorphisms (SNPs) that independently and strongly associated with the selenium and zinc were selected as the instrumental variables. The casual estimates were calculated using inverse variance weighted method (IVW), with weighted median, MR-Egger, and MR-PRESSO test as sensitivity analysis, respectively.

Results: In the standard IVW analysis, per SD increment in selenium was associated with an 0.077 mmol/L decrease of TC (95 %CI: -0.102,-0.052) and 0.074 mmol/L of LDL-C (95 %CI: -0.1,-0.048). Suggestive casual associations were found between selenium and insulin or HbA1c. With IVW method, per SD increase in selenium was associated with an 0.023 mmol/L increase of insulin (95 %CI: 0.001,0.045), and an 0.013 mmol/L increase of HbA1c (95 %CI: 0.003,0.023). The results were robust in the sensitivity analysis. Zinc was not casually associated with any of lipid and glycemic markers.

Conclusion: Our MR analysis provides evidence of the potential causal effect of Se on beneficial lipid profile, including decreased TC and LDL-C. Furthermore, suggestive casual evidence was suggested between Se and increased serum HbA1c levels. Careful consideration is required for the protective effects of Se supplementation. No casual-effect association was found between Zn and any indices of the lipid and glucose parameters.
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http://dx.doi.org/10.1016/j.jtemb.2021.126785DOI Listing
May 2021

3D bioactive cell-free-scaffolds for in-vitro/in-vivo capture and directed osteoinduction of stem cells for bone tissue regeneration.

Bioact Mater 2021 Nov 21;6(11):4083-4095. Epub 2021 Apr 21.

Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Department of Life Sciences and Medicine, Northwest University, Xi'an, 710069, China.

Hydrophilic bone morphogenetic protein 2 (BMP2) is easily degraded and difficult to load onto hydrophobic carrier materials, which limits the application of polyester materials in bone tissue engineering. Based on soybean-lecithin as an adjuvant biosurfactant, we designed a novel cell-free-scaffold of polymer of poly(ε-caprolactone) and poly(lactide-co-glycolide)-co-polyetherimide with abundant entrapped and continuously released BMP2 for stem cell-capture and osteogenic induction, avoiding the use of exogenous cells. The optimized bioactive osteo-polyester scaffold (BOPSC), i.e. SBMP-10SC, had a high BMP2 entrapment efficiency of 95.35%. Due to its higher porosity of 83.42%, higher water uptake ratio of 850%, and sustained BMP2 release with polymer degradation, BOPSCs were demonstrated to support excellent capture, proliferation, migration and osteogenic differentiation of mouse adipose derived mesenchymal stem cells (mADSCs), and performed much better than traditional BMP-10SCs with unmodified BMP2 and single polyester scaffolds (10SCs). Furthermore, capture and migration of stem cells and differentiation into osteoblasts was observed in mice implanted with BOPSCs without exogenous cells, which enabled allogeneic bone formation with a high bone mineral density and ratios of new bone volume to existing tissue volume after 6 months. The BOPSC is an advanced 3D cell-free platform with sustained BMP2 supply for stem cell capture and osteoinduction in bone tissue engineering with potential for clinical translation.
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http://dx.doi.org/10.1016/j.bioactmat.2021.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091180PMC
November 2021

Evaluating the Consistency of Gene Methylation in Liver Cancer Using Bisulfite Sequencing Data.

Front Cell Dev Biol 2021 29;9:671302. Epub 2021 Apr 29.

Department of Critical Medicine, Shenzhen People's Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medicine College of Jinan University, Shenzhen, China.

Bisulfite sequencing is considered as the gold standard approach for measuring DNA methylation, which acts as a pivotal part in regulating a variety of biological processes without changes in DNA sequences. In this study, we introduced the most prevalent methods for processing bisulfite sequencing data and evaluated the consistency of the data acquired from different measurements in liver cancer. Firstly, we introduced three commonly used bisulfite sequencing assays, i.e., reduced-representation bisulfite sequencing (RRBS), whole-genome bisulfite sequencing (WGBS), and targeted bisulfite sequencing (targeted BS). Next, we discussed the principles and compared different methods for alignment, quality assessment, methylation level scoring, and differentially methylated region identification. After that, we screened differential methylated genes in liver cancer through the three bisulfite sequencing assays and evaluated the consistency of their results. Ultimately, we compared bisulfite sequencing to 450 k beadchip and assessed the statistical similarity and functional association of differentially methylated genes (DMGs) among the four assays. Our results demonstrated that the DMGs measured by WGBS, RRBS, targeted BS and 450 k beadchip are consistently hypo-methylated in liver cancer with high functional similarity.
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http://dx.doi.org/10.3389/fcell.2021.671302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116545PMC
April 2021

A novel Tembusu virus isolated from goslings in China form a new subgenotype 2.1.1.

Transbound Emerg Dis 2021 May 16. Epub 2021 May 16.

Anhui Province Key Laboratory of Veterinary Pathobiology and Disease Control, Anhui Agricultural University, Hefei, China.

Since 2010, several duck Tembusu viruses (DTMUVs) have been isolated from infected ducks in China, and these virus strains have undergone extensive variation over the years. Although the infection rate is high, the mortality rate is usually relatively low-~5%-30%; however, since fall 2019, an infectious disease similar to DTMUV infection but with a high mortality rate of ~50% in goslings has been prevalent in Anhui Province, China. The present study identified a new Tembusu virus, designated DTMUV/Goose/China/2019/AQ-19 (AQ-19), that is believed to be responsible for the noticeably high mortality in goslings. To investigate the genetic variation of this strain, its entire genome was sequenced and analysed for specific variations, and goslings and mice were challenged with the isolated virus to investigate its pathogenicity. The AQ-19 genome shared only 94.3%-96.9% and 90.9% nucleotide identity with other Chinese and Malaysian DTMUVs, respectively; however, AQ-19 has high homology with Thailand DTMUVs (97.2%-98.1% nucleotide identity). Phylogenetic analysis of the E gene revealed that AQ-19 and most of Thailand DTMUVs form a branch separate from any of the previously reported DTMUV strains in China. After the challenge, some goslings and mice showed typical clinical signs of DTMUV, particularly severe neurological dysfunction. AQ-19 has high virulence in goslings and mice, resulting in 60% and 70% mortality through intramuscular and intracerebral routes, respectively. Pathological examination revealed severe histological lesions in the brain and liver of the infected goslings and mice. Taken together, these results demonstrated the emergence of a novel Tembusu virus with high virulence circulating in goslings in China for the first time, and our findings highlight the high genetic diversity of DTMUVs in China. Further study of the pathogenicity and host range of this novel Tembusu virus is particularly important.
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http://dx.doi.org/10.1111/tbed.14155DOI Listing
May 2021

Effects of Tourniquet Application on Faster Recovery after Surgery and Ischemia-Reperfusion Post-Total Knee Arthroplasty, Cementation through Closure versus Full-Course and Nontourniquet Group.

J Knee Surg 2021 May 15. Epub 2021 May 15.

Department of Orthopaedic Surgery, Jinling Hospital, Nanjing, China.

Pneumatic tourniquets are used in total knee arthroplasty (TKA) for surgical field visualization and improved cementation; however, their use is controversial. This study aimed to assess the effects of tourniquet application on faster recovery post-TKA. Our hypothesis was that inflammation and limb function would be similar with different tourniquet applications. A prospective randomized double-blinded trial assessed tourniquets effects on postoperative pain, swelling, and early outcome in TKA. In present study, 50 TKAs were enrolled in each group as follows: full course (FC), cementation through closure (CTC), and no tourniquet (NT), CTC as treatment group while FC and NT as control groups. Topical blood samples of 3 mL from the joint cavity and drainage bags were obtained at special time point. At last, all samples such as tumor necrosis factor-a (TNF-a), C-C motif chemokine ligand 2 (CCL2), pentraxin 3 (PTX3), prostaglandin E2 (PGE2), superoxide dismutase 1 (SOD1), and myoglobin (Mb) were detected by ELISA. Active and passive range of motion (ROM) values, pain score by the visual analog scale (VAS), change of thigh circumference were recorded at special time point as well. In topical blood, the change of inflammatory factors, such as TNF-a, PTX3, CCL2, PGE2, SOD1, and Mb, was lower in CTC and NT groups than in FC group ( < 0.01 and 0.05). Although VAS and ROM were comparable preoperatively in three groups ( > 0.05), the perimeter growth rate was lower, pain scores (VAS) were reduced, and ROM values were improved in CTC and NT groups compared with FC group at T4, T5, and T6 postoperatively ( < 0.01 and 0.05). Improved therapeutic outcome was observed in the CTC group, indicating patients should routinely undergo TKA with cementation through closure tourniquet application.
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http://dx.doi.org/10.1055/s-0041-1728814DOI Listing
May 2021

Recovering chemical sludge from the zero liquid discharge system of flue gas desulfurization wastewater as flame retardants by a stepwise precipitation process.

J Hazard Mater 2021 May 7;417:126054. Epub 2021 May 7.

Shanghai Engineering Research Center of Energy - Saving in Heat Exchange Systems, College of Environmental and Chemical Engineering, Shanghai University of Electric Power, Shanghai 200090, China.

In this study, a five-stage stepwise precipitation process, including pre-sedimentation, magnesium removal, gypsum precipitation, ettringite precipitation and calcium removal, was proposed as a softening pretreatment for zero liquid discharge system for flue gas desulfurization wastewater. Batch tests and long-term bench-scale experiment showed that magnesium, sulfate and calcium were efficiently removed with efficiencies all above 98.0%, leaving a clean effluent majorly containing NaCl and NaOH. The precipitated CaSO, CaCO, Mg(OH) and ettringite were completely separated by stepwise precipitation, and the purity of Mg(OH) and ettringite were further enhanced by washing and soaking treatment. CaSO and CaCO can be directly recycled as gypsum product and desulfurizing agent within the power plant, while Mg(OH) and ettringite presented proper particle size and excellent thermal properties as a synergistic flame retardant. The flame retardancy of ethylene vinyl acetate copolymer were greatly improved when blended with recovered Mg(OH) and ettringite, and possessed better performance by blending them together because ettringite could act as a dispersing and compatible agent of Mg(OH), and relieve the intensity of smoke releasing. Chemical sludge recovery compensates the total cost of the five-stage process by 45.0%, and makes the process technically versatile, economically beneficial and environmentally friendly without solid waste production.
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http://dx.doi.org/10.1016/j.jhazmat.2021.126054DOI Listing
May 2021

Recovering chemical sludge from the zero liquid discharge system of flue gas desulfurization wastewater as flame retardants by a stepwise precipitation process.

J Hazard Mater 2021 May 7;417:126054. Epub 2021 May 7.

Shanghai Engineering Research Center of Energy - Saving in Heat Exchange Systems, College of Environmental and Chemical Engineering, Shanghai University of Electric Power, Shanghai 200090, China.

In this study, a five-stage stepwise precipitation process, including pre-sedimentation, magnesium removal, gypsum precipitation, ettringite precipitation and calcium removal, was proposed as a softening pretreatment for zero liquid discharge system for flue gas desulfurization wastewater. Batch tests and long-term bench-scale experiment showed that magnesium, sulfate and calcium were efficiently removed with efficiencies all above 98.0%, leaving a clean effluent majorly containing NaCl and NaOH. The precipitated CaSO, CaCO, Mg(OH) and ettringite were completely separated by stepwise precipitation, and the purity of Mg(OH) and ettringite were further enhanced by washing and soaking treatment. CaSO and CaCO can be directly recycled as gypsum product and desulfurizing agent within the power plant, while Mg(OH) and ettringite presented proper particle size and excellent thermal properties as a synergistic flame retardant. The flame retardancy of ethylene vinyl acetate copolymer were greatly improved when blended with recovered Mg(OH) and ettringite, and possessed better performance by blending them together because ettringite could act as a dispersing and compatible agent of Mg(OH), and relieve the intensity of smoke releasing. Chemical sludge recovery compensates the total cost of the five-stage process by 45.0%, and makes the process technically versatile, economically beneficial and environmentally friendly without solid waste production.
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http://dx.doi.org/10.1016/j.jhazmat.2021.126054DOI Listing
May 2021

Case Report: A Case of Eyelid Myoclonic Status With Tonic-Clonic Seizure and Literature Review.

Front Pediatr 2021 22;9:671732. Epub 2021 Apr 22.

Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.

Eyelid myoclonus with or without absence epilepsy is a rare and usually misdiagnosed disease in the neurology department. It is an idiopathic general epileptic syndrome, the onset period is 6-8 years, and is more common in girls. It is characterized by rapid abnormal eye blinking, accompanied by upward rolling of the eye and slight backward movement of the head, with eye closure sensitivity and photosensitivity. The seizure is frequent and short, dozens or even hundreds of times a day; a small number of patients may have eyelid myoclonus status. We report a patient who visits the hospital for the first time with eyelid myoclonic problem; the patient continued to wink the eyes, eye rolled up, and backward movement of the head, accompanied by impairment of consciousness. Video electroencephalography (VEEG) suggests continued spike slow-wave, polyspike slow-wave. After the patient had 2, 4, 6, 8, 10, 12, and 14 Hz of intermittent photic stimulation (IPS), her seizures and epileptic discharges reduced or stopped. Seven min after giving stimulation at 20 Hz, the child developed an occipital-initiated tonic-clonic seizure, which demonstrated that after sufficient IPS stimulation, the occiput cortex became excited and initiated a brain network, leading to diffuse brain discharge and tonic-clonic seizures. At 1 h after onset, the child developed a nonconvulsive state, with impairment of consciousness despite no eyelid myoclonic movements, and VEEG suggested a large number of epileptic discharges. After 10 min of administrating midazolam, the patient's EEG immediately became normal, and the patient regained consciousness. Therefore, this paper presents an eyelid myoclonus status patient with occipital origin seizure, we recorded the whole course of the disease and the treatment effect, and reviewed the literature accordingly.
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http://dx.doi.org/10.3389/fped.2021.671732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100049PMC
April 2021

Working memory task induced neural activation: A simultaneous PET/fMRI study.

Neuroimage 2021 May 2;237:118131. Epub 2021 May 2.

Department of Nuclear Medicine, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany; TUM-Neuroimaging Center (TUM-NIC), Technical University of Munich, Munich, Germany; Graduate School of Systemic Neurosciences, Ludwig-Maximilians-Universität, Martinsried, Germany.

Purpose: Positron emission tomography (PET) with [F]fluorodeoxyglucose (FDG) is a powerful method for mapping cerebral glucose metabolism as a proxy of neural activity, assuming a steady-state during the recording interval. We asked if a clinical FDG-PET imaging protocol might also capture changes in neural activity associated with performance of a working memory (WM) task.

Methods: To test this concept, we examined hybrid PET/MR data for FDG-PET and simultaneous functional magnetic resonance imaging (fMRI) in a sample of healthy volunteers. The PET image acquisition started 30 min after a bolus injection of approximately 100 MBq FDG, and the WM task was undertaken starting at approximately 60 min post-injection. We reconstructed FDG-PET sum images corresponding to baseline (44-60 min p.i.) and WM tasks (63- 71 min p.i.), each with intensity scaling to the corresponding global mean.

Results: Compared to the baseline resting condition, relative FDG uptake increased during WM task performance in brain regions previously associated with WM. Furthermore, these metabolically active regions partly overlapped with the regions showing task-dependent increases in BOLD signal in simultaneous fMRI.

Conclusion: We find evidence for WM task-induced neural activation using a clinical FDG-PET imaging protocol. These findings encourage the development of dedicated protocols for tracking neural correlates of cognitive function.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118131DOI Listing
May 2021

Circ-140/chi-miR-8516/- Regulates αs1-/β-Casein Secretion and Lipid Formation in Goat Mammary Epithelial Cells.

Genes (Basel) 2021 Apr 29;12(5). Epub 2021 Apr 29.

College of Animal Science and Technology, Northwest A&F University, No. 22 Xinong Road, Xianyang 712100, China.

MicroRNAs play an essential role in mammary gland development, and involution is a factor that limits lactation. Chi-miR-8516 is one of the validated microRNAs that regulates the expression of and , which surge during the involution of the mammary gland. This study aims to explore the direct or indirect regulation of and by chi-miR-8516 and the regulation of chi-miR-8516 by circ-140. In goat mammary epithelial cells, we found that chi-miR-8516 takes circ-140 as a sponge and regulates expression by targeting and promoting the phosphorylation of MAPK. The examination of αs1-/β-casein and lipid showed the modulation of the circ-140/chi-miR-8516/- axis in casein secretion and lipid formation, which was regulated by the phosphorylation of mTOR and STAT5. This study illustrates an axis that regulates the synthesis of milk components, and explores the pathways in which the axis participates.
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http://dx.doi.org/10.3390/genes12050671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146108PMC
April 2021

Body image and hopelessness among early-stage breast cancer survivors after surgery in China: A cross-sectional study.

Nurs Open 2021 May 3. Epub 2021 May 3.

The Second Surgical Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.

Aim: To examine the body image and hopelessness status of early-stage breast cancer survivors who received a one-time dressing change after surgery and were ready to be discharged from a hospital in China.

Design: A cross-sectional study.

Methods: Participants were 211 women with breast cancer who had received a one-time dressing change postsurgery. Spearman's correlation and structural equation modelling were used for data analysis.

Results: Participants in the 35-45 age group and those who underwent bilateral mastectomy presented higher scores for hopelessness. Married participants showed lower scores for the feelings about the future subscale compared to other subscales. Body image was significantly and positively associated with and had a positive effect on hopelessness. Women with a more positive appraisal of their body image tended to report lower levels of hopelessness. Healthcare providers should evaluate patients' distress levels after a mastectomy to identify women who may require early psychosocial intervention.
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http://dx.doi.org/10.1002/nop2.884DOI Listing
May 2021

A target-triggered and self-calibration aptasensor based on SERS for precise detection of a prostate cancer biomarker in human blood.

Nanoscale 2021 Apr;13(16):7574-7582

Key Laboratory of OptoElectronic Science and Technology for Medicine, Ministry of Education, Fujian Provincial Key Laboratory for Photonics Technology, Fujian Normal University, Fuzhou 350007, China.

Sensitive and precise detection of prostate-specific antigen (PSA) is critical for prostate cancer screening and monitoring. Herein, a target-triggered and self-calibration aptasensor based on a core-satellite nanostructure using surface-enhanced Raman spectroscopy (SERS) technology was developed for the sensitive and reliable determination of PSA protein, with a limit of detection of 0.38 ag mL-1 and a dynamic detection range of 10-2 to 10-15 mg mL-1. Furthermore, the proposed approach for the detection of PSA in patient blood samples was performed, and results showed that it is capable of providing comparable detection accuracy associated with a larger dynamic detection range and a lower detection limit as well as less sample requirement (only 5 μL) in comparison with the clinical commonly used method. Therefore, this SERS-based aptasensor for the detection of PSA in human blood samples has promising potential to be an alternative tool for clinical application in the accurate screening of prostate cancer.
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http://dx.doi.org/10.1039/d1nr00480hDOI Listing
April 2021

Identification of Differentially Expressed Genes and Lipid Metabolism Signaling Pathways between Muscle and Fat Tissues in Broiler Chickens.

J Poult Sci 2021 Apr;58(2):131-137

College of Life Science, Longyan University, Longyan, Fujian 364012, China.

In this study, signaling pathways and key differentially expressed genes (DEGs) involved in lipid metabolism in muscle and fat tissues were investigated. Muscle and abdominal fat tissues were obtained from 35-day-old female broilers for RNA sequencing. DEGs between muscle and fat tissues were identified. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of DEGs were performed. A total of 6130 DEGs were identified to be significantly enriched in 365 GO terms, most of which were involved in biological processes, cellular components, and molecular functions in muscle and fat tissues. Three important lipid signaling pathways (pyruvate metabolism, the insulin signaling pathway, and the adipocytokine signaling pathway) were identified among the fat and muscle tissues of broilers. The key common DEGs in these pathways included phosphoenolpyruvate carboxykinase 2 (), acetyl-CoA carboxylase 1 alpha and beta ( and ), and the mitogen-activated protein kinase () gene family. Hence, our findings revealed the pathways and key genes and gene families involved in the regulation of fat deposition in the muscle and fat tissues of broilers.
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http://dx.doi.org/10.2141/jpsa.0200040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076620PMC
April 2021

Plasmids Expressing shRNAs Specific to the Nucleocapsid Gene Inhibit the Replication of Porcine Deltacoronavirus In Vivo.

Animals (Basel) 2021 Apr 23;11(5). Epub 2021 Apr 23.

Department of Preventive Veterinary Medicine, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China.

Porcine deltacoronavirus (PDCoV) is a novel enteric coronavirus and is becoming one of the major causative agents of diarrhea in pig herds in recent years. To date, there are no commercial vaccines or antiviral pharmaceutical agents available to control PDCoV infection. Therefore, developing a reliable strategy against PDCoV is urgently needed. In this study, to observe the antiviral activity of RNA interference (RNAi), four short hairpin RNAs (shRNAs) specific to the nucleocapsid (N) gene of PDCoV were designed and tested in vitro. Of these, a double-shRNA-expression vector, designated as pSil-double-shRNA-N1, was the most effectively expressed, and the inhibition of PDCoV replication was then further evaluated in neonatal piglets. Our preliminary results reveal that plasmid-based double-shRNA-expression targeting the N gene of PDCoV can significantly protect LLC-PK1 cells and piglets from pathological lesions induced by PDCoV. Our study could benefit the investigation of the specific functions of viral genes related to PDCoV infection and offer a possible methodology of RNAi-based therapeutics for PDCoV infection.
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http://dx.doi.org/10.3390/ani11051216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145914PMC
April 2021

Exploring effects of DNA methylation and gene expression on pan-cancer drug response by mathematical models.

Exp Biol Med (Maywood) 2021 Apr 28:15353702211007766. Epub 2021 Apr 28.

Guangzhou Institute of Respiratory health, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou 51000, China.

Since genetic alteration only accounts for 20%-30% in the drug effect-related factors, the role of epigenetic regulation mechanisms in drug response is gradually being valued. However, how epigenetic changes and abnormal gene expression affect the chemotherapy response remains unclear. Therefore, we constructed a variety of mathematical models based on the integrated DNA methylation, gene expression, and anticancer drug response data of cancer cell lines from pan-cancer levels to identify genes whose DNA methylation is associated with drug response and then to assess the impact of epigenetic regulation of gene expression on the sensitivity of anticancer drugs. The innovation of the mathematical models lies in: Linear regression model is followed by logistic regression model, which greatly shortens the calculation time and ensures the reliability of results by considering the covariates. Second, reconstruction of prediction models based on multiple dataset partition methods not only evaluates the model stability but also optimizes the drug-gene pairs. For 368,520 drug-gene pairs with  < 0.05 in linear models, 999 candidate pairs with both AUC ≥ 0.8 and  < 0.05 were obtained by logistic regression models between drug response and DNA methylation. Then 931 drug-gene pairs with 45 drugs and 491 genes were optimized by model stability assessment. Integrating both DNA methylation and gene expression markedly increased predictive power for 732 drug-gene pairs where 598 drug-gene pairs including 44 drugs and 359 genes were prioritized. Several drug target genes were enriched in the modules of the drug-gene-weighted interaction network. Besides, for cancer driver genes such as , , and , synergistic effects of DNA methylation and gene expression can predict certain anticancer drugs' responses. In summary, we identified potential drug sensitivity-related markers from pan-cancer levels and concluded that synergistic regulation of DNA methylation and gene expression affect anticancer drug response.
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http://dx.doi.org/10.1177/15353702211007766DOI Listing
April 2021

M6ADD: a comprehensive database of mA modifications in diseases.

RNA Biol 2021 Apr 27:1-9. Epub 2021 Apr 27.

School of Life Science and Technology, Computational Biology Research Center, Harbin Institute of Technology, Harbin, Heilongjiang, China.

N6-methyladenosine (mA) modification is an important regulatory factor affecting diseases, including multiple cancers and it is a developing direction for targeted disease therapy. Here, we present the M6ADD (mA-diseases database) database, a public data resource containing manually curated data on potential mA-disease associations for which some experimental evidence is available; the related high-throughput sequencing data are also provided and analysed by using different computational methods. To give researchers a tool to query the m6A modification data, the M6ADD was designed as a web-based comprehensive resource focusing on the collection, storage and online analysis of m6A modifications, aimed at exploring the associations between m6A modification and gene disorders and diseases. The M6ADD includes 222 experimentally confirmed mA-disease associations, involving 59 diseases from a review of more than 2000 published papers. The M6ADD also includes 409,229 mA-disease associations obtained by computational and statistical methods from 30 high-throughput sequencing datasets. In addition, we provide data on 5239 potential mA regulatory proteins related to 24 cancers based on network analysis prediction methods. In addition, we have developed a tool to explore the function of mA-modified genes through the protein-protein interaction networks. The M6ADD can be accessed at http://m6add.edbc.org/.
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http://dx.doi.org/10.1080/15476286.2021.1913302DOI Listing
April 2021