Publications by authors named "Lijie Wang"

166 Publications

Plasma exchange therapy for acute necrotizing encephalopathy of childhood.

Pediatr Investig 2021 Jun 18;5(2):99-105. Epub 2021 Jun 18.

Department of Pediatric Intensive Care Unit Beijing Children's Hospital Capital Medical University National Center for Children's Health China.

Importance: Acute necrotizing encephalopathy (ANE) is a rare disease with high mortality. Plasma exchange (PLEX) has recently been reported to treat ANE of childhood (ANEC), but its efficacy is uncertain.

Objective: This study aimed to investigate the effectiveness of PLEX on ANEC.

Methods: A retrospective study was conducted in four pediatric intensive care units from December 2014 to December 2020. All patients who were diagnosed with ANEC were included; however, these patients were excluded if their length of stay was less than 24 h. Participants were classified into PLEX and non-PLEX groups.

Results: Twenty-nine patients with ANEC were identified, 10 in the PLEX group and 19 in the non-PLEX group. In the PLEX group, C-reactive protein, procalcitonin, alanine aminotransferase, and aspartate aminotransaminase levels were significantly lower after 3 days of treatment than before treatment (13.1 . 8.0, = 0.043; 9.8 . 1.5, = 0.028; 133.4 . 31.9, = 0.028; 282.4 . 50.5, = 0.046, respectively). Nine patients (31.0%, 9/29) died at discharge, and a significantly difference was found between the PLEX group and non-PLEX group [0 . 47.4% (9/19), = 0.011]. The median follow-up period was 27 months, and three patients were lost to follow-up. Thirteen patients (50.0%, 13/26) died at the last follow-up, comprising three (33.3%, 3/9) in the PLEX group and ten (58.8%, 10/17) in the non-PLEX group, but there was no significant difference between the two groups ( = 0.411). Three patients (10.3%, 3/29) fully recovered.

Interpretation: PLEX may reduce serum C-reactive protein and procalcitonin levels and improve liver function in the short term. PLEX may improve the prognosis of ANEC, and further studies are needed.
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http://dx.doi.org/10.1002/ped4.12280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212728PMC
June 2021

Integrative analysis of immune molecular subtypes and microenvironment characteristics of bladder cancer.

Cancer Med 2021 Jun 24. Epub 2021 Jun 24.

Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, People's Republic of China.

The emergence of immunotherapy has provided an option of treatment methods for bladder cancer (BC). However, the beneficiaries of immunotherapy are still limited to small-scale patients, and immunotherapy-related adverse events often occur. It is a major challenge for clinical work to study the immune subtypes of BC and the molecular mechanism of immune escape, and identify the immune responders accurately. Here, we explore the immune molecular subtypes of bladder cancer and potential escape mechanisms. First, we screened the expression profiles of 303 differentially expressed immune-related genes in BC patients from the Cancer Genome Atlas (TCGA) database, and successfully identified 4 molecular subtypes of BC. By comparing the clinical characteristics, immune cells infiltration, the expression of checkpoint genes, human leukocyte antigen (HLA) genes, and gene mutation status of different subtypes, we identified different clinical and immunological characteristics of 4 subtypes. Among 4 subtypes, Cluster 2 met the general characteristics of immunotherapy responders and responded well to immunotherapy, while Cluster 4 had the highest expression of immune characteristics, and is similar to the immune environment of normal bladder tissue. Then, the weighted gene co-expression network analysis (WGCNA) of immune-related genes revealed that brown module was positively correlated with subtypes. Pathway enrichment analysis explored the major pathways associated with subtypes, which are also associated with immune escape mechanisms. Moreover, the decision tree model, which was constructed by the principle of random forest screening factors, was also validated in internal validation set and external validation set from the Gene Expression Omnibus (GEO) cohort (GSE133624), and could achieve accurate subtypes prediction for BC patients with high-throughput sequencing. Taken together, we explored the immune molecular subtypes and their mechanisms of BC, and these results may provide guidance for the development of new BC immunotherapy strategies.
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http://dx.doi.org/10.1002/cam4.4071DOI Listing
June 2021

Compact dual-wavelength vertical-external-cavity surface-emitting laser with simple elements.

Opt Express 2021 May;29(11):16572-16583

Dual-wavelength lasers with separation from several nanometers to tens of nanometers at 1 µm waveband are attractive light sources for terahertz generation. This work reports a compact dual-wavelength vertical-external-cavity surface-emitting laser with simple elements. The gain chip is regularly designed and epitaxially grown, and the laser cavity is the most common straight line cavity. By the use of a blade as the tuning element in cavity, the laser wavelength can be tuned continuously, and the stable dual-wavelength oscillation can be obtained when the blade is situated at a certain position. The total output power of 85 mW, which is limited by our pump source, is produced when the laser wavelengths are at 961 nm and 970 nm. We have also analyzed the evolution mechanism and the stability of this dual-wavelength laser.
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http://dx.doi.org/10.1364/OE.423074DOI Listing
May 2021

Constitutive activation of the NEAT1/miR-22-3p/Ltb4r1 signaling pathway in mice with myocardial injury following acute myocardial infarction.

Aging (Albany NY) 2021 06 3;13(11):15307-15319. Epub 2021 Jun 3.

Department of Cardiology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, P.R. China.

Coronary heart disease (CHD) with myocardial infarction (MI) being the manifestation of its advanced manifestation, remains the primary cause of mortality and disability worldwide. Aberrant expression of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) can affect the occurrence of MI in CHD. The present study aimed to explore whether NEAT1 sponging with miR-22-3p affected MI in CHD and its related mechanism. We established that the NEAT1 and Ltb4r1 expressions were increased, while miR-22-3p expression was down-regulated in MI mice following CHD. NEAT1 could competitively bind to miR-22-3p and positively regulate Ltb4r1 expression. Ltb4r1 was the downstream target of miR-22-3p. Moreover, silencing NEAT1 or downregulating Ltb4rl expression resulted in improved cardiac function, reduced infarct size, and declined levels of IL-1β, IL-6, and IL-18. Furthermore, silencing of NEAT1 also inhibited apoptosis by decreasing levels of Cleaved caspase-3 and Bax, and increasing Bcl-2 level through sponging miR-22-3p, resulting in reduced myocardial injury in CHD. Altogether, the activation of the NEAT1/miR-22-3p/Ltb4r1 signaling pathway appears to aggravate myocardial injury following a MI, which suggested that this signaling may be a useful target for improved and more individualized treatments for MI.
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http://dx.doi.org/10.18632/aging.203089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221362PMC
June 2021

Eliminating base-editor-induced genome-wide and transcriptome-wide off-target mutations.

Nat Cell Biol 2021 05 10;23(5):552-563. Epub 2021 May 10.

School of Life Science and Technology and Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China.

The fusion of CRISPR-Cas9 with cytidine deaminases leads to base editors (BEs) capable of programmable C-to-T editing, which has potential in clinical applications but suffers from off-target (OT) mutations. Here, we used a cleavable deoxycytidine deaminase inhibitor (dCDI) domain to construct a transformer BE (tBE) system that induces efficient editing with only background levels of genome-wide and transcriptome-wide OT mutations. After being produced, the tBE remains inactive at OT sites with the fusion of a cleavable dCDI, therefore eliminating unintended mutations. When binding at on-target sites, the tBE is transformed to cleave off the dCDI domain and catalyses targeted deamination for precise base editing. After delivery into mice through a dual-adeno-associated virus (AAV) system, the tBE system created a premature stop codon in Pcsk9 and significantly reduced serum PCSK9, resulting in a ~30-40% decrease in total cholesterol. The development of tBE establishes a highly specific base editing system and its in vivo efficacy has potential for therapeutic applications.
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http://dx.doi.org/10.1038/s41556-021-00671-4DOI Listing
May 2021

Prognostic value of baseline and change in neutrophil-to-lymphocyte ratio for survival in advanced non-small cell lung cancer patients with poor performance status receiving PD-1 inhibitors.

Transl Lung Cancer Res 2021 Mar;10(3):1397-1407

Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China.

Background: Advanced non-small cell lung cancer (NSCLC) patients with poor performance status (PS) are likely to receive programmed cell death 1 (PD-1) inhibitors, despite limited evidence. The aim of the present study was to report the clinical outcomes and potential prognostic biomarkers in advanced NSCLC patients with poor PS receiving PD-1 inhibitors.

Methods: We conducted a retrospective study enrolling 101 advanced NSCLC patients from our hospital. Data of patients with poor PS 2-4 receiving PD-1 inhibitors were retrieved from medical records. Patients were stratified based on dichotomized baseline neutrophil-to-lymphocyte ratio (NLR), change in NLR (ΔNLR; 6 weeks post-treatment NLR minus baseline NLR), and their combination. The receiver-operating characteristic curve was used to assess the best cutoff for NLR. Multivariate Cox analysis was used to evaluate the prognostic value of NLR and ΔNLR for patients' survival.

Results: The optimal cutoff for NLR was 4.5. The median follow-up was 25.7 months, baseline NLR ≥4.5, and ΔNLR ≥0, which were independently and significantly associated with shorter overall survival (both P=0.002) and progression-free survival (P=0.004 for NLR and P<0.001 for ΔNLR). Furthermore, simultaneous elevation of the 2 factors was associated with worsened prognosis; patients with both NLR ≥4.5 and ΔNLR ≥0 had significantly increased risk of death [hazards ratio (HR): 10.79, 95% confidence interval (CI): 4.30-27.10] and disease progression (HR: 10.49, 95% CI: 4.39-25.09), compared with both low NLR and ΔNLR patients. Patients with either NLR ≥4.5 or ΔNLR ≥0 showed an intermediate risk for death (HR: 3.12, 95% CI: 1.35-7.21) and progression (HR: 3.45, 95% CI: 1.62-7.36).

Conclusions: High baseline NLR and increased post-treatment NLR might aid in the stratification of high progression and death risk groups in advanced NSCLC patients with poor PS receiving PD-1 inhibitors.
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http://dx.doi.org/10.21037/tlcr-21-43DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044483PMC
March 2021

SCD leads to the development and progression of acute myocardial infarction through the AMPK signaling pathway.

BMC Cardiovasc Disord 2021 Apr 20;21(1):197. Epub 2021 Apr 20.

Department of General Practice, The Second Affiliated Hospital of Shenyang Medical College, Shenyang, China.

Background: Acute myocardial infarction (AMI) is myocardial necrosis caused by acute coronary ischemia and hypoxia. It can be complicated by arrhythmia, shock, heart failure and other symptoms that can be life-threatening. A multi-regulator driven dysfunction module for AMI was constructed. It is intended to explore the pathogenesis and functional pathways regulation of acute myocardial infarction.

Methods: Combining differential expression analysis, co-expression analysis, and the functional enrichment analysis, a set of expression disorder modules related to AMI was obtained. Hypergeometric test was performed to calculate the potential regulatory effects of multiple factors on the module, identifying a range of non-coding RNA and transcription factors.

Results: A total of 4551 differentially expressed genes for AMI and seven co-expression modules were obtained. These modules are primarily involved in the metabolic processes of prostaglandin transport processes, regulating DNA recombination and AMPK signal transduction. Based on this set of functional modules, 3 of 24 transcription factors (TFs) including NFKB1, MECP2 and SIRT1, and 3 of 782 non-coding RNA including miR-519D-3P, TUG1 and miR-93-5p were obtained. These core regulators are thought to be involved in the progression of AMI disease. Through the AMPK signal transduction, the critical gene stearoyl-CoA desaturase (SCD) can lead to the occurrence and development of AMI.

Conclusions: In this study, a dysfunction module was used to explore the pathogenesis of multifactorial mediated AMI and provided new methods and ideas for subsequent research. It helps researchers to have a deeper understanding of its potential pathogenesis. The conclusion provides a theoretical basis for biologists to design further experiments related to AMI.
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http://dx.doi.org/10.1186/s12872-021-02011-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059031PMC
April 2021

Efficacy and safety of crizotinib plus bevacizumab in positive non-small cell lung cancer: an open-label, single-arm, prospective observational study.

Am J Transl Res 2021 15;13(3):1526-1534. Epub 2021 Mar 15.

School of Medicine, Nankai University Weijin Road 94#, Nankai District, Tianjin 300071, China.

Background: Crizotinib is a tyrosine kinase inhibitor (TKI) effective in positive non-small cell lung cancer (NSCLC) patients. Bevacizumab is an antiangiogenic monoclonal antibody, and improves clinical benefit of NSCLC in combination with EGFR-TKIs or chemotherapy. However, the efficacy and safety of crizotinib plus bevacizumab in treating naive positive NSCLC patients have not been studied.

Methods: In this open-label, single-arm, prospective observational study, locally advanced or metastatic rearrangement/ fusion/ amplification NSCLC patients were treated with crizotinib (250 mg orally twice daily) and bevacizumab (7.5 mg/kg intravenous every three weeks) until disease progression or intolerant toxicity or death. Primary end point was progressive free survival (PFS), secondary end points were duration of response (DOR), overall response rate (ORR), disease control rate (DCR) and safety. Patients receiving ≥1 cycle of treatment were evaluated.

Findings: Fourteen patients were eligible for analyzing between June 2016 and October 2017. There were 12 patients with rearrangement, 1 patient with fusion, and 1 patient with amplification. The median follow-up time was 42.8 months. The median PFS and DOR of the patients with rearrangement were 13.9 and 14.8 months respectively. Of the 12 patients, 7 gained partial response, 5 gained stable disease. The ORR and DCR were 58.3% and 100%. The PFS were 12.9 months and 1.9 months for patient with fusion or amplification. The most two common treatment-related adverse events were fatigue (28.6%) and rash (21.4%). 3 patients discontinued therapy because of liver damage or hemoptysis.

Interpretation: This study demonstrated that crizotinib plus bevacizumab showed benefit in treating naive rearrangement NSCLC patients, and the toxicity was relatively tolerant. Our results suggested that crizotinib plus bevacizumab might be a promising treatment strategy in positive NSCLC patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014364PMC
March 2021

Stability of Engineered Ferritin Nanovaccines Investigated by Combined Molecular Simulation and Experiments.

J Phys Chem B 2021 04 7;125(15):3830-3842. Epub 2021 Apr 7.

School of Chemical Engineering and Advanced Materials, The University of Adelaide, Adelaide, South Australia 5005, Australia.

Human ferritin is regarded as an attractive and promising vaccine platform because of its uniform structure, good plasticity, and desirable thermal and chemical stabilities. Besides, it is biocompatible and presumed safe when used as a vaccine carrier. However, there is a lack of knowledge of how different antigen insertion sites on the ferritin nanocage impact the resulting protein stability and performance. To address this question, we selected Epstein-Barr nuclear antigen 1 as a model epitope and fused it at the DNA level with different insertion sites, namely, the N- and C-termini of ferritin, to engineer proteins E1F1 and F1E1, respectively. Protein properties including hydrophobicity and thermal, pH, and chemical stability were investigated both by molecular dynamics (MD) simulation and by experiments. Both methods demonstrate that the insertion site plays an important role in protein properties. The C-terminus insertion (F1E1) leads to a less hydrophobic surface and more tolerance to the external influence of high temperature, pH, and high concentration of chemical denaturants compared to N-terminus insertion (E1F1). Simulated protein hydrophobicity and thermal stability by MD were in high accordance with experimental results. Thus, MD simulation can be used as a valuable tool to engineer nanovaccine candidates, cutting down costs by reducing the experimental effort and accelerating vaccine design.
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http://dx.doi.org/10.1021/acs.jpcb.1c00276DOI Listing
April 2021

Analysis of Mechanical Characteristics of Bionic Artificial Skin Using Different Suturing Patterns.

Appl Bionics Biomech 2021 20;2021:6696612. Epub 2021 Mar 20.

Tianjin Key Lab of High Speed Cutting and Precision Machining, Tianjin University of Technology and Education, China 300222.

Artificial bionic skin material is playing an increasingly important role in the field of medicine and bionic engineering and becoming a research hotspot in many disciplines in recent years. In this work, the digital moiré method was used to measure the mechanical field of the bionic skin material under different suturing conditions. Through the digital image process, the deformation characteristics and the stress distribution near the contact area between the bionic skin material and the suture were obtained and discussed. The different healing effects caused by suturing mode were further explored, which can provide mechanical guidance for wound suturing in clinical medicine.
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http://dx.doi.org/10.1155/2021/6696612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007379PMC
March 2021

Systemic Immune-Inflammation Index and Changes of Neutrophil-Lymphocyte Ratio as Prognostic Biomarkers for Patients With Pancreatic Cancer Treated With Immune Checkpoint Blockade.

Front Oncol 2021 24;11:585271. Epub 2021 Feb 24.

Department of Oncology, Chinese People's Liberation Army General Hospital, People's Liberation Army School of Medicine, Beijing, China.

The efficacy of current treatment regimens for pancreatic cancer (PC) remains unsatisfactory. In recent years, immune checkpoint blockade (ICB) therapy has shown promising anti-tumor outcomes in many malignancies, including PC. Inexpensive and readily available biomarkers which predict therapeutic responses and prognosis are in critical need. Systemic immune-inflammation index (SII) and neutrophil-lymphocyte ratio (NLR) are emerging predictors for prognosis of various tumors. We aim to investigate the prognostic significance of baseline SII, NLR, and their changes in PC patients treated with ICB. Our retrospective analysis included PC patients treated with ICB therapy in the Chinese PLA General Hospital. All demographic, biological, and clinical data were extracted from medical records. Relative changes of SII after two doses of ICB were defined as ΔSII% and calculated as (SII-SII)/SII, and so was the case for ΔNLR%. Overall survival (OS) and progression-free survival (PFS) were compared using Kaplan-Meier curves. The prognostic significance of baseline SII, NLR, and their changes was assessed in univariate and multivariate analyses using the Cox proportional hazard regression model. In total, 122 patients with PC treated with ICB were included in the present analysis. Elevated baseline SII (HR=3.28; 95% CI:1.98-5.27; =0.03) and ΔNLR% (HR=2.21; 95% CI:1.03-4.74; =0.04) were significantly correlated with an increased risk of death. For PC patients receiving ICB combined with chemotherapies or radiotherapies as the first-line treatment, increased baseline SII was a negative predictor for both OS (HR=8.06; 95% CI:1.71-37.86; =0.01) and PFS (HR=2.84; 95%CI:1.37-10.38; =0.04). Our study reveals the prognostic value of baseline SII and NLR changes in PC patients receiving ICB therapy. The clinical utility of these prognostic biomarkers needs to be further studied in prospective studies.
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http://dx.doi.org/10.3389/fonc.2021.585271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943876PMC
February 2021

Genetic and environmental determinants of O-methylguanine DNA-methyltransferase (MGMT) gene methylation: a 10-year longitudinal study of Danish twins.

Clin Epigenetics 2021 02 15;13(1):35. Epub 2021 Feb 15.

Epidemiology, Biostatistics and Biodemography, Department of Public Health, University of Southern Denmark, J.B. Winsløws Vej 9 B., 5000, Odense C, Denmark.

Background: Epigenetic inactivation of O-methylguanine DNA-methyltransferase (MGMT) is associated with increased sensitivity to alkylating chemotherapeutic agents in glioblastoma patients. The genetic background underlying MGMT gene methylation may explain individual differences in treatment response and provide a clue to a personalized treatment strategy. Making use of the longitudinal twin design, we aimed, for the first time, to estimate the genetic contributions to MGMT methylation in a Danish twin cohort.

Methods: DNA-methylation from whole blood (18 monozygotic (MZ) and 25 dizygotic (DZ) twin pairs) repeated 10 years apart from the Longitudinal Study of Aging Danish Twins (LSADT) were used to search for genetic and environmental contributions to DNA-methylation at 170 CpG sites of across the MGMT gene. Both univariate and bivariate twin models were applied. The intraclass correlations, performed on cross-sectional data (246 MZ twin pairs) from an independent study population, the Middle-Aged Danish Twins (MADT), were used to assess the genetic influence at each CpG site of MGMT for replication.

Results: Univariate twin model revealed twelve CpG sites showing significantly high heritability at intake (wave 1, h > 0.43), and seven CpG sites with significant heritability estimates at end of follow-up (wave 2, h > 0.5). There were six significant CpG sites, located at the gene body region, that overlapped among the two waves (h > 0.5), of which five remained significant in the bivariate twin model, which was applied to both waves. Within MZ pair correlation in these six CpGs from MADT demarks top level of genetic influence. There were 11 CpGs constantly have substantial common environmental component over the 10 years.

Conclusions: We have identified 6 CpG sites linked to the MGMT gene with strong and persistent genetic control based on their DNA methylation levels. The genetic basis of MGMT gene methylation could help to explain individual differences in glioblastoma treatment response and most importantly, provide references for mapping the methylation Quantitative Trait Loci (meQTL) underlying the genetic regulation.
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http://dx.doi.org/10.1186/s13148-021-01009-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885436PMC
February 2021

[Ginsenoside 20(S)-Rg3 upregulates tumor suppressor VHL gene expression by suppressing DNMT3A-mediated promoter methylation in ovarian cancer cells].

Nan Fang Yi Ke Da Xue Xue Bao 2021 Jan;41(1):100-106

Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.

Objective: To explore the mechanism by which ginsenoside 20(S)-Rg3 upregulates the expression of tumor suppressor von Hippel-Lindau (VHL) gene in ovarian cancer cells.

Methods: Ovarian cancer cell line SKOV3 treated with 20(S)-Rg3 were examined for mRNA and protein levels of VHL, DNMT1, DNMT3A and DNMT3B by real-time PCR and Western blotting, respectively. The changes in VHL mRNA expression in SKOV3 cells in response to treatment with 5-Aza-CdR, a DNA methyltransferase inhibitor, were detected using real-time PCR. VHL gene promoter methylation was examined with methylation-specific PCR and VHL expression levels were determined with real-time PCR and Western blotting in non-treated or 20(S)-Rg3-treated SKOV3 cells and in 20(S)-Rg3-treated DNMT3A-overexpressing SKOV3 cells. VHL and DNMT3A protein levels were detected by immunohistochemistry in subcutaneous SKOV3 cell xenografts in nude mice.

Results: Treatment of SKOV3 cells with 20(S)-Rg3 significantly upregulated VHL and downregulated DNMT3A expressions at both the mRNA and protein levels ( < 0.05) and upregulated DNMT3B expression only at the mRNA level, but did not cause significant changes in either the mRNA or protein level of DNMT1. Treatment of the cells with 2 and 5 μmol/L 5-Aza-CdR obviously increased VHL mRNA expression by by over 3 folds ( < 0.05). 20(S)-Rg3 significantly decreased the methylation level in the promoter region of VHL gene, and this effect was abrogated by DNMT3A overexpression in the cells ( < 0.05). Immunohistochemisty showed a significantly increased VHL expression but a lowered DNMT3A expression in subcutaneous SKOV3 cell xenografts in 20 (S)-Rg3-treated nude mice.

Conclusions: Ginsenoside 20(S)-Rg3 upregulates VHL expression in ovarian cancer cells by suppressing DNMT3A-mediated DNA methylation.
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http://dx.doi.org/10.12122/j.issn.1673-4254.2021.01.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867494PMC
January 2021

Immunotherapy beyond progression in patients with advanced non-small cell lung cancer.

Transl Lung Cancer Res 2020 Dec;9(6):2391-2400

Department of Oncology, the Second Medical Center, Chinese PLA General Hospital, Beijing, China.

Background: Immune checkpoint inhibitors (ICIs) represent a great breakthrough in the treatment of advanced non-small cell lung cancer (aNSCLC). However, whether immunotherapy beyond progression (IBP) is effective for aNSCLC has yet to be established. Therefore, a retrospective clinical study was conducted to investigate the efficacy of IBP in patients with aNSCLC under real-world conditions.

Methods: A total of 125 Chinese patients with aNSCLC who experienced progressive disease (PD) after receiving monotherapy or combination therapy (combined with chemotherapy or/and antiangiogenic therapy) with programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors between January 2015 and March 2019 were enrolled. Patients who were treated with ICIs for more than 6 weeks after PD were defined as IBP (n=39), while those who received ICI treatment for less than 6 weeks or discontinued it due to PD were defined as non-IBP (n=86). Patient clinical characteristics were evaluated. An optimization-based method was applied to balance the clinical baseline characteristics between the two groups.

Results: In total population, the IBP group had longer overall survival (median OS, 26.6 9.5 months; HR, 0.40; 95% CI: 0.23-0.69; P<0.001) and progression-free survival (median PFS, 8.9 4.1 months; HR, 0.41; 95% CI: 0.26-0.65; P<0.001), compared with the non-IBP group. Despite no significant difference in objective response rate (ORR, 15.4% 11.6%, P=0.560), disease control rate (DCR) was significantly higher in the IBP group (89.7% 61.6%, P<0.001). After balancing baseline covariates, the IBP group also had longer OS (median: 26.6 10.7 months; HR, 0.40; 95% CI: 0.19-0.84; P=0.015) and PFS (median: 9.7 4.3 months; HR, 0.28; 95% CI: 0.15-0.51; P<0.001), with a benefit in either of patients previously treated with ICI monotherapy or in combination therapy and with non-response to the previously ICI.

Conclusions: IBP is associated with longer OS and PFS in patients with aNSCLC. Our findings may suggest new therapeutic options for patients with aNSCLC who experienced disease progression after initial immunotherapy.
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http://dx.doi.org/10.21037/tlcr-20-1252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815351PMC
December 2020

Increase in HIV-1-transmitted drug resistance among ART-naïve youths at the China-Myanmar border during 2009 ~ 2017.

BMC Infect Dis 2021 Jan 21;21(1):93. Epub 2021 Jan 21.

State Key Laboratory of Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Chinese Center for Disease Control and Prevention, 155 Changbai Road, Changping District, Beijing, 102206, China.

Background: HIV-transmitted drug resistance (TDR) is found in antiretroviral therapy (ART)-naïve populations infected with HIV-1 with TDR mutations and is important for guiding future first- and second-line ART regimens. We investigated TDR and its effect on CD4 count in ART-naïve youths from the China-Myanmar border near the Golden Triangle to better understand TDR and effectively guide ART.

Methods: From 2009 to 2017, 10,832 HIV-1 infected individuals were newly reported along the Dehong border of China, 573 ART-naïve youths (16 ~ 25 y) were enrolled. CD4 counts were obtained from whole blood samples. HIV pol gene sequences were amplified from RNA extracted from plasma. The Stanford REGA program and jpHMM recombination prediction tool were used to determine genotypes. TDR mutations (TDRMs) were analyzed using the Stanford Calibrated Population Resistance tool.

Results: The most common infection route was heterosexuals (70.51%), followed by people who inject drugs (PWID, 19.20%) and men who have sex with men (MSM) (8.90%). The distribution of HIV genotypes mainly included the unique recombinant form (URF) (44.08%), 38.68% were CRFs, 13.24% were subtype C and 4.04% were subtype B. The prevalence of TDR increased significantly from 2009 to 2017 (3.48 to 9.48%) in ART-naïve youths (4.00 to 13.16% in Burmese subjects, 3.33 to 5.93% in Chinese subjects), and the resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), and protease inhibitors (PIs) were 3.49, 2.62, and 0.52%, respectively. Most (94.40%, n = 34) of HIV-1-infected patients with TDRM had mutation that conferred resistance to a single drug class. The most common mutations Y181I/C and K103N, were found in 7 and 9 youths, respectively. The mean CD4 count was significantly lower among individuals with TDRMs (373/mm vs. 496/mm, p = 0.013).

Conclusions: The increase in the prevalence of HIV-1 TDR increase and a low CD4 count of patients with TDRMs in the China-Myanmar border suggests the need for considering drug resistance before initiating ART in HIV recombination hotspots.
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http://dx.doi.org/10.1186/s12879-021-05794-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818912PMC
January 2021

A real-world study of the efficacy and safety of anti-programmed cell death-1 therapy combined with chemotherapy or targeted therapy in patients with advanced biliary tract cancer.

J Gastrointest Oncol 2020 Dec;11(6):1421-1430

Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China.

Background: Immune checkpoint inhibitors (ICIs) represent a breakthrough in cancer treatment. However, they have rarely been used to treat biliary tract cancer (BTC). In the current study, we aimed to evaluate and compare the efficacy and safety of anti-programmed cell death-1 (PD-1) therapy used alone or in combination with chemotherapy or targeted therapy in the treatment of advanced BTC.

Methods: Patients with advanced BTC who were treated either with anti-PD-1 therapy alone or anti-PD-1 therapy plus chemotherapy or targeted therapy between December, 2015 and October, 2017 were retrospectively screened for eligibility. Patients who had previously received treatment with any agent targeting T-cell co-stimulation or immune checkpoints were excluded. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were evaluated.

Results: A total of 37 patients were included in this study (15 cases in the monotherapy group and 22 cases in the combination group). Patients in the combination group had significantly longer OS [median, 8.2 3.6 months, HR 0.47 (0.20-1.10), P=0.011] and PFS (median, 3.9 2.0 months, HR 0.58 (0.28-1.19), P=0.034) than patients in the monotherapy group. The ORR was 18.2% (4/22) and 0% in the combination group and monotherapy group, respectively, and the difference was not significant (P=0.131). Furthermore, no significant difference was found between the two groups with respect to the incidence of grade 3-4 treatment-related adverse events (P=0.388).

Conclusions: Anti-PD-1 therapy plus chemotherapy or targeted therapy is an effective and tolerable treatment for patients with advanced BTC and is promising as a first-line treatment or beyond.
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http://dx.doi.org/10.21037/jgo-20-562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807271PMC
December 2020

Transcriptomics analysis for the identification of potential age-related genes and cells associated with three major urogenital cancers.

Sci Rep 2021 01 12;11(1):641. Epub 2021 Jan 12.

Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China.

Age is one of the most important risk factors of the occurrence for tumor patients. The majority of patients with urogenital cancers are the elderly, whose clinical characteristics are greatly affected by age and ageing. Our study aimed to explore age-related genes, cells, and biological changes in three common urogenital cancers via integrative bioinformatics analysis. First, mRNA (count format) and clinical data for bladder cancer, prostate cancer and renal cell carcinoma were downloaded from the Cancer Genome Atlas (TCGA). Through the comparison of clinicopathological characteristics, genes expression and cells infiltration between the old group and the young group, it was found that the clinical characteristics, genes and cells in the tumor microenvironment of different ages were quite different. And 4 key cells, 14 hub genes and some potential pathways were identified and considered as important factors. More importantly, we analyzed the differential landscape of the genes and cells from different perspectives, and confirmed its importance. In conclusion, we identified genes and cell types associated with age-related changes in the tumour microenvironment in urogenital cancer patients. These genes and cell types may play a critical role in the age-associated differences in clinicopathological characteristics among urogenital cancers, thus providing a link between ageing and cancer occurrence. The findings of this study may pave the way for the development of age-tailored approaches to treat cancer and other age-related diseases.
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http://dx.doi.org/10.1038/s41598-020-80065-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803945PMC
January 2021

Three-Dimensional (3D)-Printed Zero-Order Released Platform: a Novel Method of Personalized Dosage Form Design and Manufacturing.

AAPS PharmSciTech 2021 Jan 6;22(1):37. Epub 2021 Jan 6.

School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China.

In 2017, there are 451 million people with diabetes worldwide. These figures were expected to increase to 693 million by 2045. The research and development of hypoglycemic drugs has become a top priority. Among them, sulfonylurea hypoglycemic drugs such as glipizide are commonly used in non-insulin-dependent type II diabetes. In order to adapt to the wide range of hypoglycemic drugs and the different individual needs of patients, this topic used glipizide as a model drug, and prepared glipizide preparations with 3D printing technology. The purpose of this study was to investigate the prescription applicability and control-release behavior of structure and explore the application prospects of 3D printing personalized drug delivery formulations. This article aims to establish a production process for personalized preparations based on 3D printing technology. The process is easy to obtain excipients, universal prescriptions, flexible dosages, exclusive customization, and integrated automation. In this paper, the UV method was used to determine the in vitro release and content analysis method of glipizide; the physical and chemical properties of the glipizide were investigated. The established analysis method was inspected and evaluated, and the experimental results met the methodological requirements. Glipizide controlled-release tablets were prepared by the semisolid extrusion (SSE) method using traditional pharmaceutical excipients combined with 3D printing technology. The formulation composition, in vitro release, and printing process parameters of the preparation were investigated, and the final prescription and process parameters (traveling speed 6.0-7.7 mm/s and extruding speed 0.0060-0.0077 mm/s) were selected through comprehensive analysis. The routine analysis results of the preparation showed that the performance of the preparation meets the requirements. In order for 3D printing technology to play a better role in community medicine and telemedicine, this article further explored the universality of the above prescription and determined the scope of application of prescription drugs and dosages. Glipizide, gliclazide, lornoxicam, puerarin, and theophylline were used as model drugs, and the range of drug loading percentage was investigated. The results showed when the solubility of the drug is 9.45 -8.34 mg/mL, and the drug loading is 3-43%; the release behavior is similar.
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http://dx.doi.org/10.1208/s12249-020-01886-8DOI Listing
January 2021

An MRI-based radiomics signature as a pretreatment noninvasive predictor of overall survival and chemotherapeutic benefits in lower-grade gliomas.

Eur Radiol 2021 Apr 6;31(4):1785-1794. Epub 2021 Jan 6.

Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxi Road, Jinan, 250012, Shandong, China.

Objectives: The aim of this study was to develop and validate a radiomics signature for predicting survival and chemotherapeutic benefits of patients with lower-grade gliomas (LGG).

Methods: Radiomics features were extracted from precontrast axial fluid-attenuated inversion recovery (FLAIR) and contrast-enhanced axial T-1 weighted (CE-T1-w) sequence. Lasso Cox regression model was used for feature selection and radiomics signature building. The radiomics signature was developed in a primary cohort that consisted of 149 LGG patients and was then validated on an entirely new validation cohort that contained 66 LGG patients. A radiomics nomogram for the prediction of OS was established by adding the radiomics to clinicopathologic nomogram which developed with clinical data.

Results: A radiomics signature derived from joint CE-T1-w and FLAIR images showed better prognostic performance (C-index, 0.798) than signatures derived from CE-T1-w (C-index, 0.744) or FLAIR (C-index, 0.736) sequences alone. Multivariable Cox regression revealed that the radiomics signature was an independent prognostic factor. One radiomics nomogram integrated the radiomics signature from joint CE-T1-w and FLAIR sequences with the clinicopathologic nomogram outperformed the clinicopathologic nomogram based on clinicopathologic data alone in predicting OS of LGG (C-index, 0.821 vs. 0.692; p < 0.001). Further analysis revealed that patients with higher radiomics signature were prone to benefit from chemotherapy.

Conclusions: The radiomics signature was independent with clinicopathologic data and was a noninvasive pretreatment predictor for LGG patients' survival. Moreover, it could predict which patients with LGG benefit from chemotherapy.

Key Points: • A radiomics signature derived from joint CE-T1-w and FLAIR sequences showed better prognostic performance than signatures derived from either single imaging modality. • The radiomics signature is an independent prognostic factor and outperformed clinicopathologic features in predicting overall survival of LGG patients. • The radiomics signature could help preoperatively identify LGG patients who may benefit from chemotherapy.
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http://dx.doi.org/10.1007/s00330-020-07581-3DOI Listing
April 2021

Macrophage-mediated vascular permeability via VLA4/VCAM1 pathway dictates ascites development in ovarian cancer.

J Clin Invest 2021 Feb;131(3)

Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China.

The development of ascites correlates with advanced stage disease and poor prognosis in ovarian cancer. Vascular permeability is the key pathophysiological change involved in ascites development. Previously, we provided evidence that perivascular M2-like macrophages protect the vascular barrier through direct contact with endothelial cells (ECs). Here, we investigated the molecular mechanism and its clinical significance in the ovarian cancer setting. We found that upon direct coculture with the endothelium, M2 macrophages tuned down their VLA4 and reduced the levels of VCAM1 in ECs. On the other hand, ectopically overexpressing VLA4 in macrophages or VCAM1 in ECs induced hyperpermeability. Mechanistically, downregulation of VLA4 or VCAM1 led to reduced levels of RAC1 and ROS, which resulted in decreased phosphorylation of PYK2 (p-PYK2) and VE-cadherin (p-VE-cad), hence enhancing cell adhesion. Furthermore, targeting the VLA4/VCAM1 axis augmented vascular integrity and abrogated ascites formation in vivo. Finally, VLA4 expression on the macrophages isolated from ascites dictated permeability ex vivo. Importantly, VLA4 antibody acted synergistically with bevacizumab to further enhance the vascular barrier. Taking these data together, we reveal here that M2 macrophages regulate the vascular barrier though the VCAM1/RAC1/ROS/p-PYK2/p-VE-cad cascade, which provides specific therapeutic targets for the treatment of malignant ascites.
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http://dx.doi.org/10.1172/JCI140315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843216PMC
February 2021

Pretreatment hemoglobin level as a predictor to evaluate the efficacy of immune checkpoint inhibitors in patients with advanced non-small cell lung cancer.

Ther Adv Med Oncol 2020 5;12:1758835920970049. Epub 2020 Nov 5.

Department of Oncology, The Second Medical Center of Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, China.

Background: Targeting immune checkpoints represents an immense breakthrough in cancer therapeutics. The prognostic value of hemoglobin (Hb) has been investigated in many malignancies including non-small cell lung cancer (NSCLC). However, the prognostic impact of pretreatment Hb count for immune checkpoint inhibitors (ICIs) in advanced NSCLC patients remains unclear.

Methods: A total of 310 late-stage NSCLC patients who received ICI therapies between January 2015 and March 2019 were prospectively enrolled. We used a propensity score-matched cohort analysis for this study. Patients' clinicopathological characteristics and pretreatment Hb concentration were assessed against the progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method and Cox proportional hazards regression.

Results: A propensity score (PS)-matched cohort analysis was applied to adjust for potential bias and to create two comparable groups according to patients' clinicopathological characteristics. The patients with normal baseline Hb levels (⩾110 g/L) had significantly longer PFS [median: 10.0 4.0 months, hazard ratio (HR): 0.63, 95% confidence interval (CI): 0.46-0.86;  = 0.001] and OS [median: 17.6 10.5 months, HR (95% CI): 0.56 (0.40-0.79);  < 0.001] than those with decreased Hb count (<110 g/L) in a PS-matched cohort ( = 255). For patients with normal pretreatment Hb levels, ICI combination therapy was significantly associated with better PFS [median: 11.1 8.0 months, HR (95% CI): 0.74 (0.50-1.06);  = 0.09] and OS [median: 26.0 12.9 months, HR (95% CI): 0.56 (0.37-0.86);  = 0.008] than monotherapy, but there was no such trend for patients with decreased baseline Hb levels.

Conclusion: Our findings showed that normal pretreatment Hb count served as a favorable prognostic marker in advanced NSCLC patients treated with ICIs, representing an economical biomarker with readily measuring performance among all reported ones.
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http://dx.doi.org/10.1177/1758835920970049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649885PMC
November 2020

Efflux mechanism and pathway of verapamil pumping by human P-glycoprotein.

Authors:
Lijie Wang Yan Sun

Arch Biochem Biophys 2020 12 13;696:108675. Epub 2020 Nov 13.

Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300350, China; Key Laboratory of Systems Bioengineering and Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin, 300350, China. Electronic address:

Multidrug resistance (MDR) caused by overexpressed permeability-glycoprotein (P-gp) in cancer cells is the main barrier for the cure of cancers. P-gp can pump many chemotherapeutic drugs, which is a viable target to overcome P-gp-mediated MDR by efficient inhibitors of P-gp. However, limited understanding of the efflux mechanism by human P-gp hinders the development of efficient inhibitors. Herein, the transport of a P-gp inhibitor, verapamil, by human P-gp has been investigated using targeted molecular dynamics simulations and energetics analysis based on our previous research on the transport of a drug (doxorubicin). The energetics analysis identifies that the driving forces for the transport of verapamil are electrostatic repulsions contributed by the positively charged residues in the initial stage and then hydrophobic interactions contributed by the important residues in the later stage. This scenario is generally consistent with that in the transport of doxorubicin. However, the positively charged residues and the important residues for the transport of verapamil are incompletely consistent with the relative residues for the transport of doxorubicin. Moreover, the binding free energy contributions of the positively charged residues for the transport of verapamil are generally higher than them for the transport of doxorubicin, while the important residues constitute significantly different binding free energy compositions in the transports of the two substrates. Consequently, the pathway for the transport of verapamil is identified, which shares only two residues (F336 and M986) with the pathway of doxorubicin. This may imply the weak competitiveness of verapamil with doxorubicin in the substrate efflux. Taken together, this work provided new insights into the efflux mechanisms by human P-gp and would be beneficial in the design of potent P-gp inhibitors.
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http://dx.doi.org/10.1016/j.abb.2020.108675DOI Listing
December 2020

Association of the Pretreatment Lung Immune Prognostic Index with Survival Outcomes in Advanced Hepatocellular Carcinoma Patients Treated with PD-1 Inhibitors.

J Hepatocell Carcinoma 2020 2;7:289-299. Epub 2020 Nov 2.

Department of Medical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China.

Purpose: At present, there are no validated biomarkers that can predict whether patients with advanced hepatocellular carcinoma (aHCC) are likely to benefit from anti-PD-1 therapy. We aimed to determine whether lung immune prognostic index (LIPI) is associated with outcomes in patients with aHCC treated with PD-1 inhibitors.

Patients And Methods: Patients undergoing initial treatment with PD-1 inhibitors for aHCC at a single center from January 1, 2015 to August 31, 2019 were included. The patients were stratified according to pretreatment LIPI based on a derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) ≥ 3 and a lactate dehydrogenase (LDH) level ≥ the upper limit of normal (ULN). Kaplan-Meier analysis and the Log rank test were used to calculate and compare survival between good LIPI and intermediate/poor LIPI scores. The prognostic values of LIPI for survival and disease control rate were evaluated using Cox proportional hazard and logistic regression models, respectively.

Results: Of the 108 study patients, 53 (49%) had a good LIPI (dNLR < 3 and LDH normal) and 55 (51%) had intermediate/poor LIPI (dNLR ≥ 3 or/and LDH ≥ ULN). With a median follow-up of 12.4 months, intermediate/poor LIPI was independently associated with shorter overall survival (OS) (hazard ratio [HR] 4.00; 95% CI, 2.00-8.03) and progression-free survival (PFS) (HR 2.65; 95% CI, 1.61-4.37). The median OS for good and intermediate/poor LIPI was not reached and was 13.7 (95% CI, 8.2-19.1) months, respectively, and the median PFS was 10.9 (95% CI, 8.9-12.9) and 4.0 (95% CI, 2.2-5.8) months (both P < 0.001), respectively.

Conclusion: Pretreatment LIPI combined with a dNLR ≥ 3 and/or LDH ≥ ULN is associated with poor outcomes in patients with aHCC treated with PD-1 inhibitors. Further validation in large, prospective studies are warranted.
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http://dx.doi.org/10.2147/JHC.S277453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646485PMC
November 2020

Mixing of plant litters strengthens their remediation effects on crude oil-contaminated soil.

Environ Sci Pollut Res Int 2021 Mar 22;28(10):12753-12765. Epub 2020 Oct 22.

College of Natural Resources and Environment, Northwest A&F University, Yangling, 712100, China.

To investigate the effects of the mixing of litters on their remediation efficiency in petroleum-contaminated soil, litters from two common plants in the petroleum-contaminated region of Northern Shaanxi, China, Bothriochloa ischaemum (L.) Keng and Sophora davidii Kom. ex Pavol., and their mixture were mixed with 45 g/kg petroleum-contaminated soil. Based on these, a 150-day simulated remediation experiment was conducted at 25 °C and consistent moisture conditions. The effects on the degradation of petroleum components and the restoration of nutrient contents, pH, and enzymatic activity in the disturbed soil were detected. The effects of the litter treatments on the community structure and carbon source utilization characteristics of soil microorganisms were also studied. The results indicated that all litter treatments significantly accelerated the degradation of petroleum components, while the mixing of litter exhibited significant synergistic effects, leading to significantly higher degradation rates of saturated hydrocarbons, aromatic hydrocarbons, and nonhydrocarbon substances than the observed rates in the single-litter treatments and the predicted rates based on the single-litter treatments. Litter treatment significantly increased the N and P contents and enzymatic activity of contaminated soil. The effects of mixed litter on soil chemical and biological properties fell between the effects of the 2 types of single-litter treatments. However, the mixing of litters exhibited significant synergistic effects in supplementing available P and increasing sucrase, dehydrogenase, lignin peroxidase, and laccase activity, while it exhibited significant antagonistic effects in supplementing nitrate nitrogen and increasing urease, phosphatase, polyphenol oxidase, and manganese peroxidase activity. Litter treatment significantly altered the community structure of soil microorganisms. The relative abundances of some petroleum-degrading microbial phyla or genera in mixed litter-treated soil were significantly different from those in single litter-treated soils, which might contribute to the strengthened remediation effects of mixed litter treatment. The results might provide a theoretical basis for the more effect utilization of biomass resources in the remediation of petroleum-contaminated soil.
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http://dx.doi.org/10.1007/s11356-020-11299-6DOI Listing
March 2021

The negative feedback between miR-143 and DNMT3A regulates cisplatin resistance in ovarian cancer.

Cell Biol Int 2021 Jan 22;45(1):227-237. Epub 2020 Oct 22.

Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.

Emerging evidence suggests that miR-143 plays an important role in the regulation of tumor sensitivity to chemotherapeutic agents. The study explores the underlying mechanism of miR-143 in reversing cisplatin resistance in ovarian cancer. The cisplatin-resistant ovarian cancer cell line A2780/CDDP was induced and established via treating A2780 cells by gradually increasing cisplatin concentrations. The IC values of A2780/CDDP and A2780 to cisplatin were 218.10 ± 1.12 and 21.99 ± 1.12 μM, respectively. Quantitative real-time polymerase chain reaction (qRT-PCR) results showed that miR-143 was significantly decreased in A2780/CDDP cells compared with A2780 cells. miR-143 overexpression decreased cisplatin resistance in A2780/CDDP, and miR-143 inhibition decreased A2780 sensitivity to cisplatin. Results of qRT-PCR, Western blot analysis, and luciferase reporter assay indicated that the direct target of miR-143 was DNMT3A, which, in turn, was upregulated in A2780/CDDP. DNMT3A overexpression antagonized the sensitizing effect of miR-143 on A2780/CDDP to cisplatin. Knocking down of DNMT3A reduced cisplatin resistance in A2780/CDDP, while overexpression of DNMT3A increased cisplatin resistance in A2780. Methylation-specific polymerase chain reaction results showed that the methylation level in the promoter region of the miR-143 precursor gene was higher in A2780/CDDP cells than in A2780 cells. DNMT3A mediated the hypermethylation of the miR-143 precursor gene, resulting in miR-143 downregulation in A2780/CDDP. miR-143 inhibited cell growth of A2780/CDDP cell in nude mice. Our findings indicated the negative feedback between miR-143 and DNMT3A as a crucial epigenetic modifier of cisplatin resistance in ovarian cancer.
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http://dx.doi.org/10.1002/cbin.11486DOI Listing
January 2021

Analysis of the global situation of COVID-19 research based on bibliometrics.

Health Inf Sci Syst 2020 Dec 30;8(1):30. Epub 2020 Sep 30.

Department of Epidemiology and Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, 250012 Shandong China.

With the rapid global spread of the COVID-19 pandemic, researchers have contributed several important advances. The WHO and countries with severe outbreaks have developed diagnosis and treatment guidelines. Here, we analyze the current transformation and application of scientific research to global epidemic prevention and control. We described and analyzed current COVID-19 research from the perspectives of international cooperation, interdisciplinary cooperation, and research hotspots using a bibliometric clustering algorithm. Using the diagnosis and treatment guidelines of the WHO and the United States and China as examples, we evaluate the transformation of scientific results from basic research to applications. Scientific research results that have not yet been incorporated into these guidelines are summarized to encourage updates and improvements by applying scientific research to prevention and control. COVID-19 has fostered interdisciplinary cooperative research, and the current results are mainly focused on the origin, epidemiological characteristics, clinical research, and diagnosis and treatment methods for the virus. Due to the ongoing publication of new research, diagnosis and treatment guidelines are constantly improving. However, some research gaps still exist, and some results have not yet been incorporated into the guidelines. The current research is still in the preliminary exploratory stage, and some problems, such as weak international cooperation, unbalanced interdisciplinary cooperation, and the lack of coordination between research and applications, exist. Therefore, countries around the world must improve the International Public Health Emergency Management System and prepare for major public health emergencies in the future.
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http://dx.doi.org/10.1007/s13755-020-00120-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526071PMC
December 2020

Using SSVEP-BCI to Continuous Control a Quadcopter with 4-DOF Motions

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:4745-4748

Brain-computer interfaces (BCIs) allow for translating electroencephalogram (EEG) into control commands, e.g., to control a quadcopter. This study, we developed a practical BCI based on steady-state visually evoked potential (SSVEP) for continuous control of a quadcopter from the first-person perspective. Users watched with the video stream from a camera on the quadcopter. An innovative user interface was developed by embedding 12 SSVEP flickers into the video stream, which corresponded to the flight commands of 'take-off,' 'land,' 'hover,' 'keep-going,' 'clockwise,' 'counter-clockwise' and rectilinear motions in six directions, respectively. The command was updated every 400ms by decoding the collected EEG data using a combined classification algorithm based on task-related component analysis (TRCA) and linear discriminant analysis (LDA). The quadcopter flew in the 3-D space according to the control vector that was determined by the latest four commands. Three novices participated in this study. They were asked to control the quadcopter by either the brain or hands to fly through a circle and land on the target zone. As a result, the time consumption ratio of brain-control to hand-control was as low as 1.34, which means the BCI performance was close to hands. The information transfer rate reached a peak of 401.79 bits/min in the simulated online experiment. These results demonstrate the proposed SSVEP-BCI system is efficient for controlling the quadcopter.
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http://dx.doi.org/10.1109/EMBC44109.2020.9176131DOI Listing
July 2020

Enhancing performance of SSVEP-based BCI by unsupervised learning information from test trials

Annu Int Conf IEEE Eng Med Biol Soc 2020 07;2020:3359-3362

Steady-State Visual Evoked Potentials (SSVEPs) have become one of the most used neural signals for brain- computer interfaces (BCIs) due to their stability and high signal- to-noise rate. However, the performance of SSVEP-based BCIs would degrade with a few training samples. This study was proposed to enhance the detection of SSVEP by combining the supervised learning information from training samples and the unsupervised learning information from the trial to be tested. A new method, i.e. cyclic shift trials (CST), was proposed to generate new calibration samples from the test data, which were furtherly used to create the templates and spatial filters of task- related component analysis (TRCA). The test-trial templates and spatial filters were combined with training-sample templates and spatial filters to recognize SSVEP. The proposed algorithm was tested on a benchmark dataset. As a result, it reached significantly higher classification accuracy than traditional TRCA when only two training samples were used. Speciflcally, the accuracy was improved by 9.5% for 0.7s data. Therefore, this study demonstrates CST is effective to improve the performance of SSVEP-BCI.
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http://dx.doi.org/10.1109/EMBC44109.2020.9176851DOI Listing
July 2020

Familial dilated cardiomyopathy caused by a novel variant in the Lamin A/C gene: a case report.

BMC Cardiovasc Disord 2020 09 22;20(1):423. Epub 2020 Sep 22.

Department of Cardiology, Shanghai East Hospital, Shanghai Tongji University School of Medicine, No. 150 Jimo Road, Shanghai, 200120, China.

Background: Familial dilated cardiomyopathy (FDCM) is most commonly inherited as an autosomal dominant trait. The Lamin A/C (LMNA) gene variants have been identified to be associated with DCM, conductive system disorders, type 2 Emery-Dreifuss muscular dystrophy and several other disorders. Here, we reported a novel variant in the LMNA gene that might be related to FDCM.

Case Presentation: A 30-year-old young man was hospitalized for chest tightness, extreme fatigue, palpitation and impaired activity tolerance. He had clinical characteristics including cardiac dilatation, atrial tachyarrhythmia, severe conductive system disorders, and dyskinesia of both upper limbs and the neck. Genetic sequence analysis indicated that the patient carried a novel c.1325 T>C heterozygous LMNA gene variant. Catheter ablation and cardiac resynchronization therapy with pacing function (CRT-P) were performed to treat the arrhythmia.

Conclusion: The variant c.1325 T>C is a novel variant in the LMNA gene that has not been previously reported. Young patients with DCM, conductive system disorders and skeletal myopathy should be alert to the possibility of LMNA gene variant. Cardiac resynchronization therapy (CRT) may be a reasonable choice for patient carrying a LMNA gene variant with third-degree atrioventricular block even if the left ventricular ejection fraction is preserved in order to prevent the deterioration of cardiac function caused by right ventricular pacing dependency.
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http://dx.doi.org/10.1186/s12872-020-01695-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509919PMC
September 2020

Electroconvulsive therapy modulates functional interactions between submodules of the emotion regulation network in major depressive disorder.

Transl Psychiatry 2020 08 5;10(1):271. Epub 2020 Aug 5.

Department of Neurology, The First Hospital of Anhui Medical University, Hefei, 230022, China.

An increasing number of neuroimaging studies have consistently revealed that disrupted functional interactions within the cognitive emotion regulation network (ERN) contribute to the onset of major depressive disorders (MDD). To disentangle the functional reorganization of ERN after electroconvulsive therapy (ECT) in MDD is curial for understanding its neuropathology. Resting-state functional magnetic resonance imaging data was collected from 23 MDD patients before and after ECT, as well as 25 healthy controls. Network modularity analysis was used to identify the submodules and functional connectivity (FC) was used to investigate the functional reorganization of ERN in the MDD patients after ECT. Four submodules of ERN were identified, including emotion response module (ERM), emotion integration module (EIM), emotion generation module (EGM), and emotion execution module (EEM). The increased intra-modular FC of EEM and inter-modular FCs of EEM with EIM\ERM were found in MDD patients after ECT. Modular transition analysis revealed that left ventrolateral prefrontal cortex, supplementary motor area, posterior cingulate cortex, right angular gyrus, and right precentral gyrus were transferred across different submodules across the three groups. Further analyses showed correlations between changed FC and clinical symptoms in the MDD patients after ECT. Finally, we also identified 11 increased connections between nodes belonging to different submodules of ERN in MDD patients after ECT. These results showed that ECT could induce functional reorganization of intra- and inter-modules within the ERN, and the functional changes were related to therapeutic efficacy or memory impairments of ECT in MDD patients.
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http://dx.doi.org/10.1038/s41398-020-00961-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406501PMC
August 2020
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