Publications by authors named "Dan Liu"

2,481 Publications

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Kim-1 Targeted Extracellular Vesicles: A New Therapeutic Platform for RNAi to Treat AKI.

J Am Soc Nephrol 2021 Jun 14. Epub 2021 Jun 14.

B Liu, Institute of Nephrology, Southeast University Zhongda Hospital, Nanjing, China

Acute kidney injury (AKI) is a significant public health problem with high morbidity and mortality. Unfortunately, no definitive treatment is currently available for AKI. RNA interference (RNAi) provides a new and potent method for gene therapy to tackle this dilemma. We engineered red blood cell-derived extracellular vesicles (REVs) with targeting peptides and therapeutic siRNAs to treat experimental AKI in a mouse model following renal ischemia/reperfusion (I/R) injury and unilateral ureteral obstruction (UUO). Phage display identified peptides that bind to the kidney injury molecule-1 (Kim-1). RNA-sequencing (RNA-seq) characterized the transcriptome of ischemic kidney to explore potential therapeutic targets. REVs targeted with Kim-1-binding LTH peptide (REV) efficiently homed to and accumulated at the injured tubules in kidney following I/R injury. We identified transcription factors and that drive inflammation and fibrosis as potential therapeutic targets. Taking advantage of the established REVLTH, siRNAs targeting P65 and Snai1 were efficiently delivered to ischemic kidney and consequently blocked the expression of P-p65 and Snai1 in tubules. Moreover, dual suppression of and significantly improved I/R- and UUO-induced kidney injury by alleviating tubulointerstitial inflammation and fibrosis, and potently abrogated the transition to chronic kidney disease. A red blood cell-derived extracellular vesicle platform targeted Kim-1 in acutely injured mouse kidney and delivered siRNAs for transcription factors P65 and Snai1, alleviating inflammation and fibrosis in the tubules.
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http://dx.doi.org/10.1681/ASN.2020111561DOI Listing
June 2021

Dysregulated KRAS gene-signaling axis and abnormal chromatin remodeling drive therapeutic resistance in heterogeneous-sized circulating tumor cells in gastric cancer patients.

Cancer Lett 2021 Jun 11;517:78-87. Epub 2021 Jun 11.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China. Electronic address:

The mechanism by which heterogeneous-sized circulating tumor cells (CTCs) in gastric cancer (GC) patients are resistant to the targeted therapy and/or chemotherapy remains unclear. This study investigated prognostic value and genomic variations of size-heterogenous CTCs, in an attempt to unravel the molecular mechanisms underlying the therapeutic resistance, which is relevant to poor prognosis in GC. Aneuploid CTCs, detected in 111 advanced GC patients, were categorized into small (≤white blood cell [WBC], 25.54%) and large (>WBC, 74.46%) cells. Pre-treatment patients possessing ≥3 baseline small CTCs with trisomy 8 (CTCs) or ≥6 large multiploid CTCs (CTCs) showed an inferior median progression-free survival. Moreover, the cut-off value of ≥6 CTCs was also an effective prognosticator for poor median overall survival. Single cell-based DNA sequencing of 50 targeted CTCs indicated that CTCs and CTCs harbored distinct gene variations respectively. Mutations in the KRAS and Rap1 pathway were remarkably abundant in CTCs, whereas several unique mutations in the MET/PI3K/AKT pathway and SMARCB1 gene were identified in CTCs. Obtained results suggested that CTCs and CTCs exhibited different mechanisms to therapy resistance and correlated with patients' poor outcome.
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http://dx.doi.org/10.1016/j.canlet.2021.06.002DOI Listing
June 2021

Dual-Emission Ratiometric Fluorescent Probe Based on Lanthanide-Functionalized Carbon Quantum Dots for White Light Emission and Chemical Sensing.

ACS Omega 2021 Jun 27;6(22):14629-14638. Epub 2021 May 27.

School of Materials Science & Engineering, University of Shanghai for Science and Technology, Shanghai 200093, P. R. China.

Herein, we develop a novel method to synthesize lanthanide-functionalized carbon quantum dots via free-radical copolymerization using the methyl methacrylate (MMA) monomer as a functional monomer and introducing a lanthanide complex to obtain the dual-emission fluorescent composite material FCQDs-Ln(TFA) (Ln = Eu, Tb; TFA: trifluoroacetylacetone). The obtained composites were fully characterized, and their structures were investigated by Fourier transform infrared spectroscopy (FTIR), H NMR spectroscopy, X-ray photoelectron spectroscopy (XPS), and transmission electron microscopy (TEM). Subsequently, a series of white-light-emitting polymer composite films FCQDs- (Eu:Tb)(TFA)/poly(methyl methacrylate) (PMMA) were designed and synthesized by adjusting the ratio of Eu(TFA)/Tb(TFA) under different wavelengths. More significantly, FCQDs-Tb(TFA) was selected as a sensitive probe for sensing metal cations due to excellent photoluminescence properties, revealing a unique capability of FCQDs-Tb(TFA) of detecting Fe(III) cations with high efficiency and selectivity. Furthermore, the sensing experiment results indicated that FCQDs-Tb(TFA) is ideal as a fluorescent nanoprobe for Fe ion detection, and the lowest detection limit for Fe is 0.158 μM, which is superior to many other previous related research studies. This pioneering work provides a new idea and method for constructing a dual-emission ratio sensor based on carbon quantum dots and also extends the potential application in the biological and environmental fields.
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http://dx.doi.org/10.1021/acsomega.1c01745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190926PMC
June 2021

High FAM189B Expression and Its Prognostic Value in Patients with Gastric Cancer.

Biomed Res Int 2021 25;2021:8875971. Epub 2021 May 25.

Department of Gastroenterology, Guangxi International Zhuang Medicine Hospital, Nanning, 530200 Guangxi, China.

The clinical significance of the family with sequence similarity 189 member B (FAM189B) gene remains largely unknown in gastric cancer (GC). A comprehensive investigation combining multiple detection methods was carried out in the current study to unveil the clinical implications and prospective molecular characterization of FAM189B protein and mRNA in GC. The protein level of FAM189B was clearly upregulated in the tumor tissues of GC as compared to noncancerous gastric tissues with 179 GC cases and 147 noncancerous gastric controls assessed by immunohistochemistry. The upregulation of the FAM189B protein was also found in the more deteriorating period of the tumor, as there were increasing trends in the groups of larger tumors, with lymph node metastasis, a further advanced clinical stage, and a higher histological grade. Next, we focused on the mRNA level of FAM189B in GC tissues using various high-throughput data. After the screening of GEO, ArrayExpress, and SRA, we finally achieved 18 datasets, including an RNA sequencing dataset of TCGA. Altogether, 1095 cases of GC tissue samples were collected, with 305 unique examples of noncancerous controls. Concerning the mRNA level of FAM189B in GC, the final standard mean difference (SMD) was 0.46 and the area under the curve (AUC) was 0.79 for the upregulation of FAM189B mRNA, which confirmed that the FAM189B mRNA level was also markedly upregulated in GC tissues and comparable to its protein level. The survival analysis showed that the higher expression of FAM189B was a risk factor for the overall survival, first progression, and postprogression survival of GC. For the Affymetrix ID 1555515_a_at of FAM189B, the higher expression level of FAM189B predicted a lower overall survival, first progression survival, and postprogression survival with the hazard ratio (HR) being 1.56 (1.24, 1.95), 1.69 (1.32, 2.17), and 1.97 (1.5, 2.6), respectively. For the Affymetrix ID 203550_s_at of FAM189B, a similar result could be found with corresponding HR being 1.49 (1.24, 1.8), 1.49 (1.21, 1.83), and 1.66 (1.32, 2.08), respectively. The interaction of MEM, COXPRESdb coexpressed genes, and DEGs of GC finally generated 368 genes, and the pathway of the cell cycle was the top pathway enriched by KEGG. In conclusion, the overexpression of the FAM189B protein and mRNA might enhance the incidence of GC.
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http://dx.doi.org/10.1155/2021/8875971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172284PMC
May 2021

Intersectional analysis of chronic mild stress-induced lncRNA-mRNA interaction networks in rat hippocampus reveals potential anti-depression/anxiety drug targets.

Neurobiol Stress 2021 Nov 25;15:100347. Epub 2021 May 25.

Institute of Neuroscience, Chongqing Medical University, Chongqing, 400016, China.

Despite studies providing insight into the neurobiology of chronic stress, depression and anxiety, long noncoding RNA (lncRNA)-mediated mechanisms underlying the common and distinct pathophysiology of these stress-induced disorders remain nonconclusive. In a previous study, we used the chronic mild stress paradigm to separate depression-susceptible, anxiety-susceptible and insusceptible rat subpopulations. In the current study, lncRNA and messenger RNA (mRNA) expression was comparatively profiled in the hippocampus of the three stress groups using microarray technology. Groupwise comparisons identified distinct sets of lncRNAs and mRNAs associated with the three different behavioral phenotypes of the stressed rats. To investigate the regulatory roles of the dysregulated lncRNAs upon mRNA expression, correlations between the differential lncRNAs and mRNAs were first analyzed by combined use of weighted gene coexpression network analysis and ceRNA theory-based methods. Subsequent functional analysis of strongly correlated mRNAs indicated that the dysregulated lncRNAs were involved in various biological pathways and processes to specifically induce rat susceptibility or resiliency to depression or anxiety. Further intersectional analysis of phenotype-associated and drug-associated lncRNA-mRNA networks and subnetworks assisted in identifying 16 hub lncRNAs as potential targets of anti-depression/anxiety drugs. Collectively, our study established the molecular basis for understanding the similarities and differences in pathophysiological mechanisms underlying stress-induced depression or anxiety and stress resiliency, revealing several important lncRNAs that represent potentially new therapeutic drug targets for depression and anxiety disorders.
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http://dx.doi.org/10.1016/j.ynstr.2021.100347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170419PMC
November 2021

Combination Model of Thyrotrophin Receptor Antibody and Volumetric Orbital Apex Crowding Index as an Indicator of Dysthyroid Optic Neuropathy.

Dis Markers 2021 18;2021:9964232. Epub 2021 May 18.

Eye Center of Xiangya Hospital, Central South University, Changsha, Hunan, China.

Background: Dysthyroid optic neuropathy (DON) is one of the most serious vision-threatening complications of thyroid eye disease (TED); however, accurate and established diagnostic tools for DON are yet lacking. The present study was aimed at identifying new diagnostic factors for the accurate diagnosis of DON.

Methods: This retrospective cross-sectional study included 25 TED patients (50 eyes) with enlarged extraocular muscles, no previous anti-inflammatory therapy, and the absence of other vision-affecting diseases between May 2017 and August 2019. Baseline data, such as gender, age, ophthalmological history, thyroid disease and management, TED history including clinical features, management, and long-term results, ophthalmological examinations, serology examinations, and single-photon emission computed tomography/computed tomography (SPECT/CT) results, were extracted. The diagnostic criteria were as follows: (1) best-corrected visual acuity (BCVA) loss coexisting with either of the following-increased latency or reduction of amplitude on visual evoked potential (VEP), impaired color vision, visual field defects, contrast sensitivity impairment, and optic disk swelling-and (2) Barrett's index ≥ 60% in CT. Univariate and multivariate logistic regression analyses assessed the differences in age, gender, eyes, medical history, clinical activity, thyroid hormone and antibodies, uptake ratio (UR) of extraocular muscles in SPECT/CT, and volumetric orbital apex crowding index (VACI) using the generalized estimation equation. Consequently, the receiver operating characteristic curve (ROC) of the significant factors was constructed.

Results: Univariate analysis revealed significant differences in the clinical activity, free triiodothyronine (FT3), free thyroxine (FT4), thyrotrophin receptor antibody (TRAb) levels, the UR of superior and medial rectus, and VACI between DON and TED (without DON) groups. Multivariate regression analysis revealed that TRAb and VACI were significantly different. ROC analysis showed that the univariate models of TRAb or VACI and the multivariate model were effective indicators of DON, while the multivariate model had the highest area under the ROC curve.

Conclusion: A combination of TRAb and VACI is an effective indicator for DON.
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http://dx.doi.org/10.1155/2021/9964232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154283PMC
May 2021

Direct antiviral agent treatment leads to rapid and significant fibrosis regression after HCV eradication.

J Viral Hepat 2021 Jun 9. Epub 2021 Jun 9.

Departments of Infectious Diseases, Peking University First Hospital, Beijing, People's Republic of China.

Limited data are currently available regarding fibrosis progression after hepatitis C virus (HCV) eradication. The goal of the present study was to evaluate the effects of HCV eradication on liver stiffness measurements (LSMs), aspartate aminotransferase/platelet ratio index (APRI) scores, fibrosis-4(FIB-4) scores, chitinase-3-like protein 1 (CHI3L1) levels and Golgi protein 73 (GP73) levels in patients with chronic hepatitis C (CHC). One hundred and two patients who received direct antiviral agents (DAAs) therapy at Peking University First Hospital participated in the present study. Clinical information and serum samples were collected at baseline, at the end of treatment (EOT), and at the weeks 12, 24 and 48 after treatment (W12, W24 and W48, respectively). Of the 102 patients, 51 had mild-to-moderate fibrosis (F1/F2), and 51 had advanced fibrosis (F3/F4). The LSMs improved for all patients at the EOT, with observed changes of 2.85 kPa, and the decrease continued to W12. However, a more pronounced improvement was noted for the advanced fibrosis (F3/F4) patients, with a change of 3.6 kPa from baseline to the EOT. Significant decreases between the baseline and EOT measurements were observed in the APRI and FIB-4 scores [0.64 (0.39-1.21) vs. 0.35 (0.26-0.52), p<0.001; 2.53 (1.30-3.91) vs. 1.87 (0.89-2.5), p<0.001], after which the values decreased until W12, with no significant difference observed. Serum CHI3L1 and GP73 levels were profoundly decreased at the EOT compared with those at baseline [134.07 (154.49) vs. 103.75 (98.04), p=0.025; 98.24 (64.76) vs. 88.91 (50.89), p=0.002]. DAA treatments could significantly improve liver fibrosis of CHC patients as evidenced by decreased liver stiffness, APRI scores and FIB-4 scores. Improvements in liver fibrosis markers (especially serum CHI3L1 and GP73) were prominent in patients with advanced fibrosis, indicating that serum CHI3L1 and GP73 could be noninvasive markers for monitoring fibrosis in CHC patients. Significance Statement The prospective cohort evaluated the effect of direct antiviral agents (DAAs) on fibrosis regression after hepatitis C virus (HCV) eradication of Chinese people in the real-world study. This study highlighted that rapid and significant fibrosis regression rather than reduction in inflammation was achieved with DAA treatment, and this regression could be detected as early as the end of treatment. We found the serum CHI3L1 and GP73 levels can be used to monitor changes in fibrosis in CHC patients.
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http://dx.doi.org/10.1111/jvh.13558DOI Listing
June 2021

Large-scale investigation of single cell activities and response dynamics in a microarray chip with a microfluidics-fabricated microporous membrane.

Analyst 2021 Jun 9. Epub 2021 Jun 9.

Departments of Biomedical Engineering and Pathology, School of Basic Medical Science, Central South University, Changsha, Hunan 410013, China.

Microengineering technology involving microfabrication, micropatterning and microfluidics enables promising advances in single cell manipulation and analysis. Herein, we describe a parallel, large-scale, and temporal investigation of diverse single cell activities and response dynamics using a facile-assembled microwell array chip with a microfluidics-molded microporous membrane. We demonstrated that the versatility with respect to geometrical homogeneity and diversity of microporous membrane fabrication, as well as the stability, repeatability, and reproducibility rely on the well-improved molding. Serial and practical operations including controllable single cell trapping, array-like culture or chemical stimulation, and temporal monitoring can be smoothly completed in the chip. We confirmed that the microwell array chip allowed an efficient construction of a single cell array. Using the cell array, on-chip detection of single cell behaviours under various culture and drug therapy conditions to explore phenotypic heterogeneity was achieved in massive and dynamic manners. These achievements provide a facile and reliable methodology for fabricating microporous membranes with precise control and for developing universal microplatforms to perform robust manipulation and versatile analysis of single cells. This work also offers an insight into the development of easy to fabricate/use and market-oriented microsystems for single cell research, pharmaceutical development, and high-throughput screening.
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http://dx.doi.org/10.1039/d1an00784jDOI Listing
June 2021

Demethylzeylasteral Exerts Antitumor Effects via Disruptive Autophagic Flux and Apoptotic Cell Death in Human Colorectal Cancer Cells and Increases Cell Chemosensitivity to 5-Fluorouracil.

Anticancer Agents Med Chem 2021 Jun 7. Epub 2021 Jun 7.

Chongqing Engineering Research Center of Antitumor Natural Drugs, Chongqing Three Gorges Medical College, Chongqing, China.

Background: Demethylzeylasteral (ZST93), a pharmacologically active triterpenoid monomer extracted from Tripterygium wilfordii Hook F (TWHF), has been reported to exert antineoplastic effects in several cancer cell types. However, the anti-tumour effects of ZST93 in human colorectal cancer (CRC) cells are unknown.

Objective: The aim of the present study was to evaluate the antitumor effects of ZST93 on cell cycle arrest, disruptive autophagic flux, apoptotic cell death, and enhanced chemosensitivity to 5-FU in humans CRC cells.

Methods: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide(MTT) assay, colony formation assay, flow cytometry, immunoblotting, immunofluorescence, 5-ethynyl-20-deoxyuridine (EdU) incorporation assay, and autophagy analysis were used to evaluate the effects of ZST93 on cell viability, cell cycle progression, apoptosis and autophagy in two human CRC cell lines. Moreover, ZST93's combined anti-tumour effects with 5-fluorouracil (5-FU) were evaluated.

Results: ZST93 inhibited CRC cell proliferation and growth. It was responsible for blocked cell cycle transition by arresting CRC cells in the G0/G1 phase via down-regulation of CDK4, CDK6, Cyclin D1, and c-MYC. Moreover, ZST93 induced suppressive autophagic flux and caspase-3-dependent cell death, which were further strengthened by the blocking of the autophagy process using chloroquine (CQ). Moreover, ZST93 enhanced CRC cells' chemosensitivity to 5-FU via modulation of autophagy and apoptosis.

Conclusion: ZST93 exerts anti-tumour effects via disruptive autophagic flux and apoptotic cell death in human CRC cells and increases cell chemosensitivity to 5-FU. These results provide insights into the utilisation of ZST93 as an adjuvant or direct autophagy inhibitor and suggest ZST93 as a novel therapeutic strategy for treating CRC.
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http://dx.doi.org/10.2174/1871520621666210608104021DOI Listing
June 2021

A nano-predator of pathological MDMX construct by clearable supramolecular gold(I)-thiol-peptide complexes achieves safe and potent anti-tumor activity.

Theranostics 2021 3;11(14):6833-6846. Epub 2021 May 3.

Department of Talent Highland, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.

As alternatives to small-molecular proteolysis-targeting chimeras (PROTAC), peptide-based molecular glues (MG) are a broad range of dual-functional ligands that simultaneously bind with targetable proteins and E3 ligases by mimicking proteinprotein interaction (PPI) partners. Herein, we design a peptide-derived MG to target a tumor-driving protein, MDMX, for degradation, and nanoengineered it into a supramolecular gold(I)-thiol-peptide complex (Nano-MP) to implement the proteolysis recalcitrance, cellular internalization, and glutathione-triggered release. To optimize the tumor targeting, a pH-responsive macromolecule termed polyacryl sulfydryl imidazole (PSI) was synthesized to coat Nano-MP. As expected, [email protected] induced the MDMX degradation by ubiquitination and subsequently restored the anti-cancer function of p53 and p73. [email protected] revealed potent anti-cancer activities in an orthotopic xenograft mouse model of retinoblastoma by intraocular injection and a patient-derived xenograft model of malignant pancreatic cancer by systemic injection, while maintaining a favorable safety profile and showing a highly favorable clearable profile of excretion from the living body. Collectively, this work not only provided a clinically viable paradigm for the treatment of a wide variety of tumors by multiple administration types, but, more importantly, it bridged the chasm between peptides and PROTACs, and likely reinvigorated the development of peptide-derived proteolysis-targeting chimeras for a great variety of diseases.
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http://dx.doi.org/10.7150/thno.59020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171083PMC
May 2021

Design, synthesis and biological evaluation of N-anthraniloyl tryptamine derivatives as pleiotropic molecules for the therapy of malignant glioma.

Eur J Med Chem 2021 May 29;222:113564. Epub 2021 May 29.

School of Pharmaceutical Science, University of South China, Hengyang, 421001, China; School of Pharmacy, Lanzhou University, Lanzhou, 730000, China. Electronic address:

COX-2 and STAT3 are two key culprits in the glioma microenvironment. Herein, to inhibit COX-2 and block STAT3 signaling, we disclosed 27 N-anthraniloyl tryptamine compounds based on the combination of melatonin derivatives and N-substituted anthranilic acid derivatives. Among them, NP16 showed the best antiproliferative activity and moderate COX-2 inhibition. Of note, NP16 decreased the level of p-JAK2 and p-STAT3, and blocked the nuclear translocation of STAT3 in GBM cell lines. Moreover, NP16 downregulated the MMP-9 expression of BV2 cells in a co-culture system of BV2 and C6 glioma cells, abrogated the proliferative/invasive/migratory abilities of GBM cells, induced apoptosis by ROS and the Bcl-2-regulated apoptotic pathway, and induced obvious G/M arrest in glioma cells in vitro. Furthermore, NP16 displayed favorable pharmacokinetic profiles covering long half-life (11.43 ± 0.43 h) and high blood-brain barrier permeability. Finally, NP16 effectively inhibited tumor growth, promoted the survival rate, increased the expression of E-cadherin and reduced overproduction of PGE, MMP-9, VEGF-A and the level of p-STAT3 in tumor tissue, and improved the anxiety-like behavior in C6 glioma model. All these evidences demonstrated N-anthraniloyl tryptamine derivatives as multifunctional anti-glioma agents with high potency could drain the swamp to beat glioma.
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http://dx.doi.org/10.1016/j.ejmech.2021.113564DOI Listing
May 2021

Deep learning for predicting subtype classification and survival of lung adenocarcinoma on computed tomography.

Transl Oncol 2021 Jun 1;14(8):101141. Epub 2021 Jun 1.

Department of Respiratory and Critical Care Medicine, West China Hospital, West China Medical School, Sichuan University, No. 37 Guo Xue Alley, Chengdu 610041, China. Electronic address:

Objectives: The subtype classification of lung adenocarcinoma is important for treatment decision. This study aimed to investigate the deep learning and radiomics networks for predicting histologic subtype classification and survival of lung adenocarcinoma diagnosed through computed tomography (CT) images.

Methods: A dataset of 1222 patients with lung adenocarcinoma were retrospectively enrolled from three medical institutions. The anonymised preoperative CT images and pathological labels of atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, invasive adenocarcinoma (IAC) with five predominant components were obtained. These pathological labels were divided into 2-category classification (IAC; non-IAC), 3-category and 8-category. We modeled the classification task of histological subtypes based on modified ResNet-34 deep learning network, radiomics strategies and deep radiomics combined algorithm. Then we established the prognostic models in lung adenocarcinoma patients with survival outcomes. The accuracy (ACC), area under ROC curves (AUCs) and C-index were primarily performed to evaluate the algorithms.

Results: This study included a training set (n = 802) and two validation cohorts (internal, n = 196; external, n = 224). The ACC of deep radiomics algorithm in internal validation achieved 0.8776, 0.8061 in the 2-category, 3-category classification, respectively. Even in 8 classifications, the AUC ranged from 0.739 to 0.940 in internal set. Further, we constructed a prognosis model that C-index was 0.892(95% CI: 0.846-0.937) in internal validation set.

Conclusions: The automated deep radiomics based triage system has achieved the great performance in the subtype classification and survival predictability in patients with CT-detected lung adenocarcinoma nodules, providing the clinical guide for treatment strategies.
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http://dx.doi.org/10.1016/j.tranon.2021.101141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184655PMC
June 2021

Frequency and risk factors of impaired left ventricular global longitudinal strain in patients with end-stage renal disease: a two-dimensional speckle-tracking echocardiographic study.

Quant Imaging Med Surg 2021 Jun;11(6):2397-2405

Department of Ultrasound, the Second Affiliated Hospital of Nanchang University, Nanchang, China.

Background: It has been identified that two-dimensional speckle-tracking imaging (2D-STI) enables the early detection of left ventricular (LV) systolic dysfunction. This study's objective was to evaluate the frequency of impaired LV global longitudinal strain (GLS) and investigate the factors in end-stage renal disease (ESRD) patients with preserved LV ejection fraction (LVEF) associated with the impaired GLS.

Methods: A total of 100 ESRD patients with preserved LVEF who underwent transthoracic echocardiography (TTE) were studied. The GLS was calculated as the average of peak longitudinal strain from 18 myocardial segments obtained utilizing the three-standard apical imagings. According to a predefined cutoff, a GLS absolute value of less than 18% was considered subclinical LV systolic dysfunction.

Results: Impaired LV GLS <18% was detected in 58 participants (58/100, 58%). Multivariate analysis exhibited that increased LV mass index was independently associated with impaired GLS <18% [odds ratio (OR): 1.028, 95% confidence interval (CI): 1.004-1.052, P=0.020]. For sequential logistic regression models, model 1, based on parameters included in multivariate logistic regression (χ=30.0), was improved by the addition of the LV mass index (χ=37.4, P<0.01).

Conclusions: The frequency of impaired LV GLS in ESRD patients with preserved LVEF was relatively high. An increased LVEF was independently associated with impaired LV GLS.
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http://dx.doi.org/10.21037/qims-20-1034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107319PMC
June 2021

Pharmacophore-inspired discovery of FLT3 inhibitor from kimchi.

Food Chem 2021 Nov 18;361:130139. Epub 2021 May 18.

State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing 210046, China; State Key Laboratory of Pharmaceutical Biotechnology, Institute of Functional Biomolecules, Nanjing University, Nanjing 210023, China. Electronic address:

Globally consumed kimchi is manufactured through fermenting cruciferous vegetables containing indole glucosinolates (IG). But few reports describe the IG metabolism during the fermentation. Here, we show that indole-3-carbinol (I3C), a breakdown product of IG, is transformed during the kimchi fermentation into 3,3'-diindolylmethane (DIM) and 2-(indol-3-ylmethyl)-3,3'-diindolylmethane (LTr1). LTr1 was found to kill the acute myeloid leukemia (AML) cells with FMS-like tyrosine kinase 3 (FLT3) receptor mutations, by inhibiting the FLT3 phosphorylation and the expression of downstream proteins (STAT5, ERK, and AKT). In the immune-depleted mice xenografted with human MV4-11 cells, LTr1 was demonstrated to reduce the tumor growth and synergize with sorafenib, an anti-AML agent in clinic. The work updates the chemical and biological knowledge about kimchi, and in particular establishes LTr1 as an FLT3 inhibitor that is effective and synergistic with sorafenib in treating AML.
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http://dx.doi.org/10.1016/j.foodchem.2021.130139DOI Listing
November 2021

c-Myc Upregulated by High Glucose Inhibits HaCaT Differentiation by S100A6 Transcriptional Activation.

Front Endocrinol (Lausanne) 2021 14;12:676403. Epub 2021 May 14.

Department of Burn, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Keratinocyte differentiation dysfunction in diabetic skin is closely related to impaired skin barrier functions. We investigated the effects of c-Myc and S100A6 on Human immortal keratinocyte line (HaCaT) or keratinocyte differentiation and potential mechanisms. The expression levels of differentiation makers such as transglutaminase 1 (TGM1), loricrin (LOR), and keratin 1 (K1) were significantly reduced, while the expression of c-Myc was significantly increased in HaCaT cells cultured in high glucose and wound margin keratinocytes from diabetic rats and human patients. Overexpression of caused differentiation dysfunction of HaCaT, while knocking down promoted differentiation. High glucose increased the expression of c-Myc and inhibited differentiation in HaCaT cells by activating the WNT/β-catenin pathway. Moreover, inhibition of c-Myc transcriptional activity alleviated the differentiation dysfunction caused by high glucose or overexpression of . c-Myc binds to the promoter to directly regulate expression and high glucose promoted transcription. The expression of S100A6 was increased in HaCaT cultured with high glucose and wound margin keratinocytes from diabetic rats and human patients. However, the expression of S100A6 was decreased during normal HaCaT differentiation. HaCaT cells treated with S100A6 recombinant protein showed differentiation dysfunction. The expressions of TGM1, LOR and K1 in knockdown HaCaT cells were higher than those in the control group. Overexpression of or high glucose caused differentiation dysfunction of HaCaT cells, and was rescued by knocking down . These findings illustrate a new mechanism by which c-Myc upregulated by high glucose inhibits HaCaT differentiation by directly activating transcription. Thus, c-Myc and S100A6 may be potential targets for the treatment of chronic diabetic wounds.
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http://dx.doi.org/10.3389/fendo.2021.676403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163689PMC
May 2021

Therapeutic effects and prognostic factors of I brachytherapy for pelvic recurrence after early cervical cancer surgery.

Sci Rep 2021 May 31;11(1):11356. Epub 2021 May 31.

Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 510080, Guangdong, China.

To investigate the efficacy of I seed implantation in the treatment regimen of pelvic recurrence after early cervical cancer surgery and to analyse prognostic factors. To evaluate efficacy and analyse prognostic factors of I seed implantation for pelvic recurrence after early cervical cancer surgery. A prospective study was conducted on 62 patients who experienced pelvic recurrence after early cervical cancer surgery between August 2005 and September 2015. The 62 patients were treated and assessed in 2 groups (n = 30). All 62 patients were randomized into two groups that received two different treatment regimens: the treatment group (n = 30), which received I particle implantation therapy, and the control group (n = 32), which received whole-pelvic irradiation using the anteroposterior/posteroanterior field and cisplatin-based concurrent chemoradiation therapy. The efficacy/efficiency of I seed implantation and prognostic factors were analysed by logistic regression. Overall survival was determined by Kaplan-Meier analysis. Multivariate analysis results were obtained by the Cox proportional hazards regression model. The effective control rates at 1, 3, 6 and 12 months were 76.7%, 80.0%, 83.3%, and 86.7% in the I particle implantation group. The total effective control rates at 1, 3, 6 and 12 months were 65.6%, 65.5%, 62.5%, and 71.9% in the chemoradiotherapy group. Significant differences were observed between the two groups. The overall survival rates at 1, 2, 3, 4, and 5 years and the median overall were 96.7%, 93.3%, 86.7%, 71.9%, 65.6% and 4.34 years, respectively, in the I seed implantation group and 81.3%, 71.9%, 62.5%, 56.3%, 53.1% and 3.59 years, respectively, in the control group. There were statistically significant differences in survival rates depending on the diameter of the largest recurrent pelvic tumour (χ = 6.611, P = 0.010). The multivariate analysis showed that the survival rates were related to the diameter of the largest recurrent pelvic tumour (χ = 4.538, P = 0.033). I implantation is an effective, safe, and promising method for the treatment of pelvic recurrence after early cervical cancer surgery. The diameter of the recurrent pelvic tumour was identified as a significant independent prognostic factor in patients who received I implantation.
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http://dx.doi.org/10.1038/s41598-021-90007-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166881PMC
May 2021

Long Noncoding RNA SNHG1 Activates Autophagy and Promotes Cell Invasion in Bladder Cancer.

Front Oncol 2021 13;11:660551. Epub 2021 May 13.

Department of Urology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.

LncRNAs play important roles in bladder cancer. However, only a few studies report on the correlation between lncRNAs expression and autophagy in bladder cancer. This study aimed to explore the effect of lncRNA on autophagy in bladder cancer. The findings showed high expression of in the bladder cancer cells and tumor tissues. The high expression of was positively correlated with bladder cancer cell invasion, proliferation, and autophagy. This finding implies that promotes bladder cancer cell invasion and proliferation autophagy. Further analysis of the mechanism of action of showed that it functions as a sponge of miRNA-493 in bladder cancer. miRNA-493 binds on the 3' -UTR of mRNA thus affecting ATG14 protein expression, which is implicated in autophagy. These findings are supported by previous preclinical studies using multiple Bca cell lines and TCGA, which demonstrate that plays an oncogenic role by acting as a sponge of miR-493-5p or as its ceRNA. Upregulation of promotes proliferation, invasion, and autophagy of bladder cancer cells through the miR-493-5p/ATG14/autophagy pathway. Therefore, may act as a potential therapeutic target for the treatment of bladder cancer.
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http://dx.doi.org/10.3389/fonc.2021.660551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158816PMC
May 2021

Transport of Mobile Particles in Heavy Metal Contaminated Soil with Simulated Acid Rain Leaching.

Bull Environ Contam Toxicol 2021 May 27. Epub 2021 May 27.

The Key Nuturing Station for the State Key Laboratory of Subtropical Silviculture, Key Laboratory of Soil Contamination Bioremediation of Zhejiang Province, Zhejiang A & F University, Lin'an, 311300, Zhejiang, China.

The soil contaminated with heavy metals requires special attention due to its adverse effects on health of human and animals. The effects of simulated acid rain with different pH values on transport of heavy metal in contaminated soil of Phyllostachys pubescens forest were studied by indoor leaching column test. The results revealed that particle size of soil was mainly concentrated in range of more than 50 μm. The content of heavy metals in particles less than 50 μm was relatively high. The Pb and Zn were mainly adsorbed on colloidal particles and were transported during simulated acid rain. The release of Fe and Al increased the release of particulate matter in soil leaching solution. The mobility of Zn was increased at low pH.
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http://dx.doi.org/10.1007/s00128-021-03269-6DOI Listing
May 2021

Gender Differences in Job Satisfaction and Work-Life Balance Among Chinese Physicians in Tertiary Public Hospitals.

Front Public Health 2021 10;9:635260. Epub 2021 May 10.

Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, United States.

Gender has been associated with job-related experience, including job satisfaction and work-life balance. This study aimed to identify gender differences in job satisfaction and work-life balance among Chinese physicians in a large, nationally representative sample. A national cross-sectional survey was conducted between March 18 and 31, 2019, using an anonymous online questionnaire. The questionnaire included the short-form MSQ (Chinese version) and a work-life balance item. The demographic and job-related factors were also collected. In total, 22,128 physicians (9,378 males and 12,750 females) from 144 tertiary public hospitals completed the survey. The overall MSQ score (job satisfaction) was 70.31 ± 12.67, and it was 69.89 ± 13.24 in males, and 70.63 ± 12.22 in females, respectively ( < 0.001). Only 931 (4.21%) physicians were very satisfied with WLB (421 males, 510 females), and 2,534 (11.45%) were rated as satisfied. Age, education, monthly income, working hours, specialty, and professional titles were significantly associated with job satisfaction; while number of children, specialty, professional titles, monthly income, age, working hours were significantly associated with WLB. No significant gender differences were observed in job satisfaction or WLB after controlling confounding factors (both > 0.05). While many demographic and work-related factors are significantly associated with job satisfaction and WLB, we found no significant gender differences, which is different from many other studies. To improve Chinese physicians' job satisfaction and work-life balance, interventions should be focused on certain specialties and on other modifiable factors, such as income, working hours.
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http://dx.doi.org/10.3389/fpubh.2021.635260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141628PMC
May 2021

An Integrated Analysis of Network Pharmacology, Molecular Docking, and Experiment Validation to Explore the New Candidate Active Component and Mechanism of Coupled-Herbs in Treating Oligoasthenozoospermia.

Drug Des Devel Ther 2021 17;15:2059-2089. Epub 2021 May 17.

School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, People's Republic of China.

Purpose: One of the most common types of male infertility is recognized as oligoasthenozoospermia (OA), characterized by low sperm count and quality in males. As a traditional Chinese medicine (TCM), coupled-herbs (CSMFCH) has been known to act a curative effect on OA for thousands of years. Nevertheless, the substantial basis and molecular mechanism of CSMFCH in treating OA remain elusive.

Methods: Herein, an integrated approach, including network pharmacology, molecular docking, and experiment validation, was utilized to reveal the new candidate active component and mechanism of CSMFCH in treating OA.

Results: The results show that kaempferol is the most significant bioactive component of CSMFCH on OA. The mechanism and targets of CSMFCH against OA are relevant to hormone regulation, oxidant stress, and reproductive promotion. In order to validate network pharmacology results, molecular docking and experiment validation were conducted. In detail, molecular docking was employed to verify the strong binding interactions between kaempferol and the core targets. UHPLC-Q-Orbitrap-MS was used to identify kaempferol in the CSMFCH extract. In vitro and in vivo experiments further proved CSMFCH and kaempferol could enhance the mouse Leydig (TM3) and mouse Sertoli (TM4) cell viability, improve the male reproductive organ weights, sperm quality, and decrease testis tissue damage in the OA mouse model induced by CP.

Conclusion: Our results not only identify the new candidate active component of CSMFCH in treating OA but also provide new insights into the mechanisms of CSMFCH against OA.
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http://dx.doi.org/10.2147/DDDT.S307015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139735PMC
May 2021

Effects of sepsis and its treatment measures on intestinal flora structure in critical care patients.

World J Gastroenterol 2021 May;27(19):2376-2393

Department of Critical Care Medicine, General Hospital of Ningxia Medical University, Yinchuan 750004, Ningxia Hui Autonomous Region, China.

Background: Sepsis is a common disease in intensive care units, with high morbidity and mortality. Intestinal microecology plays a vital part in the development and progression of this disease, possibly because sepsis and its treatment cause specific changes in the composition of the intestinal flora.

Aim: To investigate the characteristics of intestinal flora disturbance in sepsis patients treated with antibiotics.

Methods: In this prospective comparative study, we enrolled ten patients with sepsis (sepsis group), hospitalized in the Department of Critical Care Medicine of the General Hospital, Ningxia Medical University, China (a class IIIa general hospital) from February 2017 to June 2017; ten patients without sepsis hospitalized in the same period (non-sepsis group) and ten healthy individuals (control group) were also enrolled. Fecal samples collected from the three groups were subjected to gene sequencing and the intestinal flora diversity, structure, and composition were determined. Additionally, the dynamics of the intestinal flora diversity, structure, and composition in sepsis patients were investigated gene sequencing of samples collected 0 d, 3 d, and 7 d after admittance to the intensive care unit. Correlations between the serum levels of procalcitonin, endotoxin, diamine oxidase, and D-lactic acid and the intestinal flora composition of sepsis patients were also investigated.

Results: Compared with the healthy control group, sepsis and non-sepsis patients showed reduced intestinal flora α-diversity and a distinct flora structure, with Firmicutes as the dominant phylum, and significantly decreased proportions of Bacteroidetes, as well as and , among other genera. Of note, the proportion of was significantly increased in the intestinal tract of sepsis patients. Interestingly, the α-diversity in the sepsis group decreased gradually, from days 1 to 7 of treatment. However, pairwise comparisons showed that both the diversity and structure of the intestinal flora were not significantly different considering the three different time points studied. Curiously, the serum levels of procalcitonin, endotoxin, diamine oxidase, and D-lactic acid in sepsis patients correlated with the prevalence of various bacterial genera. For example, the prevalence of was positively correlated with serum procalcitonin, endotoxins, and diamine oxidase; similarly, the prevalence of was positively correlated with serum procalcitonin, endotoxins, and D-lactic acid.

Conclusion: Sepsis patients in intensive care units show dysbiosis, lasting for at least 1 wk.
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http://dx.doi.org/10.3748/wjg.v27.i19.2376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130038PMC
May 2021

Analysis of unigenes involved in lateral root development in Bupleurum chinense and B. scorzonerifolium.

Planta 2021 May 26;253(6):128. Epub 2021 May 26.

Laboratory of Medicinal Plant Cultivation, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China.

Main Conclusion: We identified IAA13 negatively associated with lateral root number by comparing the differential expressed genes between Bupleurum chinense and B. scorzonerifolium. Dried roots of the genus Bupleurum L. are used as a herbal medicine for diseases in Asia. Bupleurum chinense has a greater number of lateral roots than B. scorzonerifolium, but the genetic mechanisms for such differences are largely unknown. We (a) compared the transcriptome profiles of the two species and (b) identified a subset of candidate genes involved in auxin signal transduction and explored their functions in lateral root development. By isoform sequencing (Iso-Seq) analyses of the whole plant, more unigenes were found in B. scorzonerifolium (118,868) than in B. chinense (93,485). Given the overarching role of indole-3-acetic acid (IAA) as one of the major regulators of lateral root development, we identified 539 unigenes associated with auxin signal transduction. Fourteen and 44 unigenes in the pathway were differentially expressed in B. chinense and B. scorzonerifolium, respectively, and 3 unigenes (LAX2, LAX4, and IAA13) were expressed in both species. The number of lateral root primordia increased after exogenous auxin application at 8 h and 12 h in B. scorzonerifolium and B. chinense, respectively. Since overexpression of IAA13 in Arabidopsis reduced the number of lateral roots, we hypothesized that IAA13 is involved in the reduction of the number of lateral roots in B. scorzonerifolium.
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http://dx.doi.org/10.1007/s00425-021-03644-xDOI Listing
May 2021

Tumor Immune Microenvironment Characterization Identifies Prognosis and Immunotherapy-Related Gene Signatures in Melanoma.

Front Immunol 2021 6;12:663495. Epub 2021 May 6.

Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, National Human Genetic Resources Sharing Service Platform, Tianjin, China.

Background: The tumor microenvironment (TME) involves infiltration of multiple immune cell subsets, which could influence the prognosis and clinical characteristics. The increasing evidence on the role of tumor-infiltrating lymphocytes (TILs) in primary and metastatic melanomas supports that the immune system is involved in the progression and outcomes of melanoma. However, the immune infiltration landscape in melanoma has not been systematically elucidated.

Methods: In this study, we used CIBERSORT and ESTIMATE algorithms to analyze immune infiltration pattern of 993 melanoma samples. Then we screened differential expression genes (DEGs) related to immune subtypes and survival. The immune cell infiltration (ICI) score was constructed by using principal-component analysis (PCA) based on immune signature genes from DGEs. Gene set enrichment analysis (GSEA) was applied to explore high and low ICI score related pathways. Finally, the predictive ability of ICI score was evaluated in survival prognosis and immunotherapy benefit.

Result: We identified three ICI clusters and three gene clusters associated with different immune subtypes and survival outcomes. Then the ICI score was constructed, and we found that high ICI score exhibited activated immune characteristics and better prognosis. High ICI score was significantly enriched in immune pathways and highly expressed immune signature genes. More importantly, we confirmed that melanoma patients with high ICI score had longer overall survival and rate of response to immunotherapy.

Conclusion: We presented a comprehensive immune infiltration landscape in melanoma. Our results will facilitate understanding of the melanoma tumor microenvironment and provide a new immune therapy strategy.
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http://dx.doi.org/10.3389/fimmu.2021.663495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134682PMC
May 2021

Ingenane and jatrophane-type diterpenoids from Euphorbia kansui with multidrug resistance reversal activity.

Phytochemistry 2021 Aug 18;188:112775. Epub 2021 May 18.

Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650093, China. Electronic address:

Bioassay-guided purification on the ethanolic extract of the roots of Euphorbia kansui Liou ex S.B.Ho (Euphorbiaceae) led to the isolation of one unreported ingenane-type (euphorksol A) and six unreported jatrophane-type (euphorksjats A-F) diterpenoids, together with twenty-five known diterpenoids. Their structures were elucidated based on extensive NMR analysis and high-resolution mass spectrometry. Euphorksol A is a rare example of an ingenane-type diterpenoid with a 6,7-expoxy fragment. All compounds were examined for cytotoxicity against adriamycin (Adr)-sensitive HepG-2 and Adr-resistant HepG-2/Adr cell lines, but none showed significant activity. Then, all isolates were evaluated for their ability to reverse multidrug resistance (MDR). 6β,7β-Epoxy-3β,4β,5β-trihydroxyl-20- deoxyingenol and 3,5,7,15-tetraacetoxy-9-nicotinoyloxy-14-oxojatropha-6(17),11-diene showed significant MDR reversal activity in HepG-2/Adr cells (reversal fold: RF = 186.4 and 143.8, respectively) versus the positive control verapamil (Ver, RF = 93.7). Euphorksol A and kansuinin B exhibited moderate MDR reversal activity (RF = 57.4 and 68.9, respectively). These compounds are the first ingenane-type diterpenoids reported to show MDR reversal activity, which will provide new insights toward the development of MDR regulatory agents.
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http://dx.doi.org/10.1016/j.phytochem.2021.112775DOI Listing
August 2021

The Pittsburgh Sleep Quality Index (PSQI): Psychometric and clinical risk score applications among college students.

Psychol Assess 2021 May 20. Epub 2021 May 20.

Department of Family Sciences.

Sleep is closely related to physical and mental health problems as well as problem behaviors among adolescents and young adults. Thus, to better understand sleep seems paramount, including how to best measure it. The Pittsburgh Sleep Quality Index (PSQI) is one of the most widely used sleep measures. Some recent psychometric evidence (i.e., inconsistent dimensionality across studies) has called into question the application of this clinically developed measure. The current study sought to rigorously test the dimensionality of the measure, by comparing a psychometric application of it to a clinical application. It also tested correlates of sleep quality measured by the PSQI, including academic achievement, mental health, and substance use (alcohol and drug use) . Data were collected from 820 college students using an online computer-assisted protocol. Results from factor analyses supported a 2-factor solution for the PSQI. Findings from path analyses using scale scores based on the extracted factor structure as the independent variable provided evidence that the psychometric approach worked equally well as the clinical application using the global sleep quality risk score , providing some support for the use of a psychometric approach of the PSQI. Sleep quality scores (both scale and global sleep quality risk scores) were consistently associated with academic achievement, mental health, and substance use problems, thus providing further support on the importance of good sleep for young adults. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/pas0001027DOI Listing
May 2021

A microfluidic-integrated lateral flow recombinase polymerase amplification (MI-IF-RPA) assay for rapid COVID-19 detection.

Lab Chip 2021 05;21(10):2019-2026

The MOE Key Laboratory of Spectrochemical Analysis & Instrumentation, The Key Laboratory of Chemical Biology of Fujian Province, State Key Laboratory of Physical Chemistry of Solid Surfaces, Collaborative Innovation Center of Chemistry for Energy Materials, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China.

The COVID-19 pandemic, caused by SARS-CoV-2, currently poses an urgent global medical crisis for which there remains a lack of affordable point-of-care testing (POCT). In particular, resource-limited areas need simple and easily disseminated testing solutions to manage the outbreak. In this work, a microfluidic-integrated lateral flow recombinase polymerase amplification (MI-IF-RPA) assay was developed for rapid and sensitive detection of SARS-CoV-2, which integrates the reverse transcription recombinase polymerase amplification (RT-RPA) and a universal lateral flow (LF) dipstick detection system into a single microfluidic chip. The single-chamber RT-RPA reaction components are mixed with running buffer, and then delivered to the LF detection strips for biotin- and FAM-labelled amplified analyte sequences, which can provide easily interpreted positive or negative results. Testing requires only a simple nucleic acid extraction and loading, then incubation to obtain results, approximately 30 minutes in total. SARS-CoV-2 armored RNA particles were used to validate the MI-IF-RPA system, which showed a limit of detection of 1 copy per μL, or 30 copies per sample. Chip performance was further evaluated using clinically diagnosed cases of COVID-19 and revealed a sensitivity of 97% and specificity of 100%, highly comparable to current reverse transcription-polymerase chain reaction (RT-PCR)-based diagnostic assays. This MI-IF-RPA assay is portable and comprises affordable materials, enabling mass production and decreased risk of contamination. Without the need for specialized instrumentation and training, MI-IF-RPA assay can be used as a complement to RT-PCR for low-cost COVID-19 screening in resource-limited areas.
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http://dx.doi.org/10.1039/d0lc01222jDOI Listing
May 2021

α7 Nicotinic Acetylcholine Receptor Agonist PNU-282987 Ameliorates Cognitive Impairment Induced by Chronic Intermittent Hypoxia.

Nat Sci Sleep 2021 11;13:579-590. Epub 2021 May 11.

Institute of Respiratory Disease, The First Hospital of China Medical University, Shenyang, People's Republic of China.

Purpose: Cognitive impairment is an important complication of obstructive sleep apnea (OSA). Chronic intermittent hypoxia (CIH), the main pathophysiological characteristics of OSA, is closely related to cognitive dysfunction and may be mediated by alpha-7 nicotinic acetylcholine receptors (α7nAChR). This study investigated the effects and clarified the mechanisms of α7nAChR on the cognitive function of mice with CIH.

Methods: Thirty CD-1 mice were randomly divided into room air (RA), CIH-2 weeks (CIH2W), and CIH-4 weeks (CIH4W) groups. Cognitive function was evaluated by novel object recognition (NOR) and Morris water maze (MWM) tests after exposure. Then, 104 CD-1 mice were exposed to CIH for 4 weeks and randomly divided into four groups: CIH4W (control), with dimethyl sulfoxide (DMSO) (sham), with α7nAChR-specific agonist PNU-282987 (PNU), and with α7nAChR-specific inhibitor methyllycaconitine and PNU-282987 (MLA+PNU). In addition to the evaluation of cognitive function, apoptotic bodies in the hippocampus were detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, changes in p-CREB and BDNF were detected by immunohistochemistry, while those of ERK1/2, CREB, PGC-1α, FNDC5, and BDNF were detected by Western blotting in the hippocampal tissues of the mice.

Results: Compared to the CIH2W and RA groups, the CIH4W group showed cognitive dysfunction in the NOR and MWM tests. The changes in cognitive dysfunction were alleviated by PNU-282987; furthermore, MLA pretreatment offset the effect. In hippocampal tissues, TUNEL assays showed decreased apoptotic cells, immunohistochemical staining showed increased expressions of p-CREB and BDNF. The expression levels of p-ERK1/2/t-ERK1/2, p-CREB/t-CREB, PGC-1α, FNDC5, and BDNF were increased after PNU-282987 injection.

Conclusion: Four weeks of CIH caused cognitive dysfunction in mice. Activating α7nAChR might ameliorate this dysfunction by upregulating the ERK1/2/CREB signaling pathway; enhancing PGC-1α, FNDC5, and BDNF expression levels; and reducing cell apoptosis in the hippocampal tissue of mice.
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http://dx.doi.org/10.2147/NSS.S296701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123952PMC
May 2021

Emerging role of human polyomaviruses 6 and 7 in human cancers.

Infect Agent Cancer 2021 May 17;16(1):35. Epub 2021 May 17.

Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Centre+, Maastricht, the Netherlands.

Background: Currently 12 human polyomaviruses (HPyVs) have been identified, 6 of which have been associated with human diseases, including cancer. The discovery of the Merkel cell polyomavirus and its role in the etiopathogenesis in the majority of Merkel cell carcinomas has drawn significant attention, also to other novel HPyVs. In 2010, HPyV6 and HPyV7 were identified in healthy skin swabs. Ever since it has been speculated that they might contribute to the etiopathogenesis of skin and non-cutaneous human cancers.

Main Body: Here we comprehensively reviewed and summarized the current evidence potentially indicating an involvement of HPyV6 and HPyV7 in the etiopathogenesis of neoplastic human diseases. The seroprevalence of both HPyV6 and 7 is high in a normal population and increases with age. In skin cancer tissues, HPyV6- DNA was far more often prevalent than HPyV7 in contrast to cancers of other anatomic sites, in which HPyV7 DNA was more frequently detected.

Conclusion: It is remarkable to find that the detection rate of HPyV6-DNA in tissues of skin malignancies is higher than HPyV7-DNA and may indicate a role of HPyV6 in the etiopathogenesis of the respected skin cancers. However, the sheer presence of viral DNA is not enough to prove a role in the etiopathogenesis of these cancers.
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http://dx.doi.org/10.1186/s13027-021-00374-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130262PMC
May 2021

Structure basis for AA98 inhibition on the activation of endothelial cells mediated by CD146.

iScience 2021 May 14;24(5):102417. Epub 2021 Apr 14.

State Key Laboratory of Membrane Biology, Laboratory of Molecular Biophysics, School of Life Sciences, Peking University, Beijing 100871, China.

CD146 is an adhesion molecule that plays important roles in angiogenesis, cancer metastasis, and immune response. It exists as a monomer or dimer on the cell surface. AA98 is a monoclonal antibody that binds to CD146, which abrogates the activation of CD146-mediated signaling pathways and shows inhibitory effects on tumor growth. However, how AA98 inhibits the function of CD146 remains unclear. Here, we describe a crystal structure of the CD146/AA98 Fab complex at a resolution of 2.8 Å. Monomeric CD146 is stabilized by AA98 Fab binding to the junction region of CD146 domains 4 and 5. A higher-affinity AA98 variant (here named HA98) was thus rationally designed. Better binding to CD146 and prominent inhibition on cell migration were achieved with HA98. Further experiments on xenografted melanoma in mice with HA98 revealed superior inhibitory effects on tumor growth to those of AA98, which suggested future applications of this antibody in cancer therapy.
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http://dx.doi.org/10.1016/j.isci.2021.102417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093899PMC
May 2021

Retrieval of 30 Lymph Nodes Is Mandatory for Selected Stage II Gastric Cancer Patients.

Front Oncol 2021 30;11:593470. Epub 2021 Apr 30.

Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.

Background: According to the 8th edition AJCC staging manual, a least of 16 lymph nodes retrieval (LNRs) is the minimal requirement for lymph nodes (LNs) dissection of gastric cancer surgery. Previous studies have shown that increasing the number of LNRs (≥30) prolongs survival for selected patients. However, the necessity of retrieving 30 or more LN for stage II gastric cancer patients is still under debate.

Aim: This study aims to explore the impact of retrieving 30 or more lymph nodes on the survival of stage II cancer patients.

Methods: A total of 1,177 patients diagnosed with stage II gastric cancer were enrolled in this study. The clinicopathological parameters and the impact of different LNRs (<30 or ≥30) and positive lymph node ratio (NR) on overall survival (OS) were retrospectively analyzed.

Results: The mean number of LNRs was 34 ± 15. A total of 44% (518/1,177) of patients had an LNRs <30, while 56% (659/1,177) of patients had an LNRs ≥30. The 5-year survival rate was 81% for all patients, 76% for the LNRs <30 group, and 86% for LNRs ≥30 group, respectively (P = 0.003). The survival benefit of retrieving 30 lymph nodes was significant in certain subgroups: age >60 years/male/underwent total gastrectomy/stage IIB. For N+ patients, higher NR was significantly correlated with poor survival.

Conclusion: The survival benefit of retrieving 30 LNs varies in different subgroups. An LNRs of 30 is mandatory for selected stage II gastric cancer patients.
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http://dx.doi.org/10.3389/fonc.2021.593470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121255PMC
April 2021