Publications by authors named "Qiyue Zhang"

32 Publications

Anchoring red blood cell with tetrahedral DNA nanostructure: Electrochemical biosensor for the sensitive signage of circulating tumor DNA.

Talanta 2022 Aug 5;251:123793. Epub 2022 Aug 5.

Key Laboratory for Biobased Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou, 510642, China. Electronic address:

Circulating tumor cells (CTCs), as a type of tumor, have attracted wide attention because of their characteristics of shedding from the primary tumor and spreading to other tissues and organs through peripheral blood. The circulating tumor DNA (ctDNA), the DNA released by CTCs and other tumor cells into the peripheral blood, was considered as a promising detection substance for clinical application. By utilizing the biocompatibility of red blood cells to realize the attachment of tetrahedral DNA (TDN), as well as the specific target recognition ability of TDN to enable efficient recognition of targets, a biocompatible electrochemical biosensor for effective and rapid detection of ctDNA was developed using methylene blue (MB) as the signal probe. The current signal and the logarithm of ctDNA concentration were linearly correlated in the range from 1 fM to 100 pM with the detection limit of 0.66 fM. With high specificity, the TDN-based biosensor can detect ctDNA efficiently in the real biological environment such as serum, which provided a potential opportunity for the early clinical diagnosis.
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http://dx.doi.org/10.1016/j.talanta.2022.123793DOI Listing
August 2022

CREB is a potential marker associated with drug-induced liver injury: Identification and validation through transcriptome database analysis.

J Toxicol Sci 2022 ;47(8):337-348

Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University.

Drug-induced liver injury (DILI) is the main cause of failure in drug development and postapproval withdrawal. Although toxicogenomic techniques provide an unprecedented opportunity for mechanistic assessment and biomarker discovery, they are not suitable for the screening of large numbers of exploratory compounds in early drug discovery. Using a comprehensive analysis of toxicogenomics (TGx) data, we aimed to find DILI-relevant transcription factors (TFs) that could be incorporated into a reporter gene assay system. Gene set enrichment analysis (GSEA) of the Open TG-GATEs dataset highlighted 4 DILI-relevant TFs, including CREB, NRF2, ELK-1, and E2F. Using ten drugs with already assigned idiosyncratic toxicity (IDT) risks, reporter gene assays were conducted in HepG2 cells in the presence of the S9 mix. There were weak correlations between NRF2 activity and IDT risk, whereas strong correlations were observed between CREB activity and IDT risk. In addition, CREB activation associated with 3 Withdrawn/Black box Warning drugs was reversed by pretreatment with a PKA inhibitor. Collectively, we suggest that CREB might be a sensitive biomarker for DILI prediction, and its response to stress induced by high-risk drugs might be primarily regulated by the PKA/CREB signaling pathway.
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http://dx.doi.org/10.2131/jts.47.337DOI Listing
August 2022

DFO treatment protects against depression-like behaviors and cognitive impairment in CUMS mice.

Brain Res Bull 2022 09 30;187:75-84. Epub 2022 Jun 30.

College of Life Sciences and Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, 300071 Tianjin, PR China. Electronic address:

Depression has several negative effects on emotion as well as learning and memory abilities. Previous studies showed that depression could exacerbate inflammation, which in turn further aggravated depression. Deferoxamine (DFO) is a chelating agent binding iron and aluminium, and is clinically applied to treat acute ion poisoning and hemochromatosis. Researches showed that it could reduce inflammation via increasing the expression of hypoxia-inducible factor-1alpha (HIF-1α). Here, we established a chronic unpredictable mild stress (CUMS) model to investigate whether DFO exerted a neuroprotective function in depression. The results demonstrated that CUMS (4 weeks) effectively induced depression-like behaviors in mice based on sucrose preference test (SPT), forced swim test (FST), tail suspension test (TST), open field test (OFT), and elevated plus-maze test (EPT). It also brought cognitive deficits based on Morris water maze (MWM) test and the impairment of synaptic plasticity based on in vivo electrophysiological recordings. Additionally, CUMS exposure significantly decreased the expression of hippocampal synapse related proteins and the spine density of neurons in the DG region, accompanied by increasing the expression of hippocampal inflammatory cytokines, and promoted the activation of microglia in the hippocampus. The expression of HIF-1α was down-regulated as expected. However, DFO distinctly reversed the CUMS-induced impairments. The mechanism is associated with the DFO inhibition of inflammation by upregulating HIF-1 expression, thereby alleviating a series of pathology changes. Together, these findings suggest that DFO likely plays a protective role in cognitive impairments and synaptic plasticity deficits resulting from depression.
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http://dx.doi.org/10.1016/j.brainresbull.2022.06.016DOI Listing
September 2022

Case Report: Mucous Membrane Pemphigoid With IgG and IgA Anti-Laminin γ1 Antibodies and IgA Anti-Laminin α5 Antibodies.

Front Immunol 2022 1;13:903174. Epub 2022 Jun 1.

Dermatology Hospital of Jiangxi Province, Jiangxi Provincial Clinical Research Center for Skin Diseases, Candidate Branch of National Clinical Research Center for Skin Diseases, Dermatology Institute of Jiangxi Province, The Affiliated Dermatology Hospital of Nanchang University, Nanchang, China.

Mucous membrane pemphigoid (MMP) and anti-laminin (LM) γ1 pemphigoid, two subtypes of subepidermal autoimmune bullous diseases characterized by autoantibodies against epidermal basement membrane zone proteins, mainly show mucosal and skin lesions, respectively. The known autoantigens of MMP includes BP180, BP230, LM332, integrin α6β4 and type VII collagen, and anti-LMγ1 pemphigoid targets LMγ1. In this study, we present an unique MMP case with oral mucosal lesions, which showed positive IgA signals on basement membrane zone in indirect immunofluorescence using normal human skin and on dermal side in indirect immunofluorescence using salt-split skin, positive IgA autoantibodies against LMγ1 by immunoblotting of epidermal extracts, positive IgA autoantibodies against LMα5 by immunoblotting of LM521 recombinant protein (rLM521) and positive IgG autoantibodies against LMγ1 by immunoblotting of rLM111 and rLM521 at first visit (Day 0). After therapy, further serological analyses of serum samples collected at Day 30 and Day 50 indicated that IgA autoantibodies against LMγ1 were likely to be pathogenic. These results suggest that LMγ1 is another autoantigen of MMP, and our patient might be the first reported case of anti-LMγ1 MMP.
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http://dx.doi.org/10.3389/fimmu.2022.903174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9198329PMC
June 2022

Study on Meso-Material Parameters of Submarine Weathered Granite Based on Parallel Bond Model.

Materials (Basel) 2022 May 29;15(11). Epub 2022 May 29.

School of Civil Engineering, Shandong University, Jinan 250061, China.

In order to study the mechanical properties of submarine weathered granite under marine geological conditions, uniaxial compression tests were carried out on the original medium weathered granite of the seafloor of an offshore area in Pingtan, Fujian Province by using triaxial experimental apparatus to analyze the fracture characteristics, stress-strain characteristics, and compressive strength indexes. Based on the theory of discontinuous medium, the uniaxial compression and uniaxial tensile tests of rocks were simulated, and the microscopic mechanical parameters of discrete elements of granite samples were determined based on the indoor macroscopic mechanical tests: effective modulus E, compressive elastic modulus E, macro Poisson's ratio μ, and uniaxial compressive strength . The results show that the parallel bond model has good simulation results for the uniaxial compression test, but the tensile strength and tensile-compression ratio were quite different from the experimental values. When the confining pressure is large, the calibrated parameter adaptability by uniaxial compression is poor. The reason for certain errors is a large resistance of the parallel bond model to particle rotation and the influence of normal stress on shear strength is not considered. The cementation model can be modified by adding coefficients based on laboratory test results.
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http://dx.doi.org/10.3390/ma15113878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9181947PMC
May 2022

Photodynamic therapy for extensive oral verrucous/granular leukoplakia with moderate-to-severe dysplasia: A case study.

Photodiagnosis Photodyn Ther 2022 May 22;39:102910. Epub 2022 May 22.

Emergency Department, State Key Laboratory of Oral Diseases, National Center of Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 14, Sec. 3 Renminnan Road, Chengdu, Sichuan 610041, PR China. Electronic address:

Non-homogeneous oral verrucous/granular leukoplakia is a potentially malignant disorder with a higher malignant transformation rate than homogeneous leukoplakia. Surgical resection is commonly performed since the disease is often malignant and refractory. However, surgical intervention is painful and heavily impairs the patients' quality of life. Photodynamic therapy is minimally invasive, can be administered repeatedly, and is widely used to treat potentially malignant disorders and cancers. We report a case of oral verrucous/granular leukoplakia with extensive lesions in a 58-year-old man. Histopathological examination showed moderate-to-severe dysplasia and a tendency of malignant transformation in the focal area. At this stage, the patient was recommended for surgery by the oncology department. With the patient's consent, photodynamic therapy was performed at our department while he awaited the surgery. In the absence of any auxiliary measures, eight treatments with 5-aminolevulinic acid-mediated photodynamic therapy achieved favorable results, and there no recurrence was observed after 7 months of follow-up. This result suggests that photodynamic therapy should be considered when treating potentially malignant disorders such as oral verrucous/granular leukoplakia, or as pre-treatment before surgical resection.
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http://dx.doi.org/10.1016/j.pdpdt.2022.102910DOI Listing
May 2022

MST1 mediates neuronal loss and cognitive deficits: A novel therapeutic target for Alzheimer's disease.

Prog Neurobiol 2022 07 4;214:102280. Epub 2022 May 4.

College of Life Sciences, Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, 300071 Tianjin, PR China. Electronic address:

Alzheimer's disease (AD) is the most prevalent form of dementia in the old adult and characterized by progressive cognitive decline and neuronal damage. The mammalian Ste20-like kinase1/2 (MST1/2) is a core component in Hippo signaling, which regulates neural stem cell proliferation, neuronal death and neuroinflammation. However, whether MST1/2 is involved in the occurrence and development of AD remains unknown. In this study we reported that the activity of MST1 was increased with Aβ accumulation in the hippocampus of 5xFAD mice. Overexpression of MST1 induced AD-like phenotype in normal mice and accelerated cognitive decline, synaptic plasticity damage and neuronal apoptosis in 2-month-old 5xFAD mice, but did not significantly affect Aβ levels. Mechanistically, MST1 associated with p53 and promoted neuronal apoptosis by phosphorylation and activation of p53, while p53 knockout largely reversed MST1-induced AD-like cognitive deficits. Importantly, either genetic knockdown or chemical inactivation of MST1 could significantly improve cognitive deficits and neuronal apoptosis in 7-month-old 5xFAD mice. Our results support the idea that MST1-mediated neuronal apoptosis is an essential mechanism of cognitive deficits and neuronal loss for AD, and manipulating the MST1 activity as a potential strategy will shed light on clinical treatment for AD or other diseases caused by neuronal injury.
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http://dx.doi.org/10.1016/j.pneurobio.2022.102280DOI Listing
July 2022

Antioxidant activity of SSeCAHK in HepG2 cells: a selenopeptide identified from selenium-enriched soybean protein hydrolysates.

RSC Adv 2021 Oct 18;11(54):33872-33882. Epub 2021 Oct 18.

National Soybean Processing Industry Technology Innovation Center, Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Technology and Business University Beijing 100048 China

This paper is aimed at purifying and identifying selenium (Se)-containing antioxidative peptides from Se-enriched soybean peptides (SSP). In this work, the SSP was separated into five fractions (F1 to F5). Fraction F4, displaying the highest antioxidative activity, was further separated, and sub-fractions F4-1 to F4-5 were selected for antioxidative activity evaluation using 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2-azino-bis-(3-ethylbenzo-thiazoline-6-sulphonic acid)diammonium salt (ABTS), and OH radical scavenging assays. The Se-containing antioxidative peptides with sequence Ser-SeC-Ala-His-Lys (SSeCAHK) were identified in sub-fraction F4-1 and chemically synthesized. This Se-containing pentapeptide showed a preventive effect against hydrogen peroxide (HO)-induced oxidative stress in HepG2 cells. Pretreating the cells for 2 h with SSeCAHK (0.13-0.50 mg mL) induced strong intracellular, reactive oxygen species (ROS) scavenging activity while preventing a decrease in reduced glutathione (GSH) and an increase in malondialdehyde (MDA). Therefore, SSeCAHK treatment improved HO-induced oxidative stress in HepG2 cells, demonstrating the significant potential of SSeCAHK as a natural antioxidative functional material for dietary supplementation.
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http://dx.doi.org/10.1039/d1ra06539dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9042330PMC
October 2021

Goal Disruption and Psychological Disequilibrium During the Outbreak of COVID-19: The Roles of Uncertainty, Information Seeking and Social Support.

Health Commun 2022 Mar 13:1-8. Epub 2022 Mar 13.

School of Journalism and Communication, The Chinese University of Hong Kong.

Using panel data from mainland China, this study incorporates uncertainty, information seeking, and social support into the goal disruption theoretical model to examine the indirect influence of goal disruption on psychological disequilibrium through uncertainty and the moderating roles of information seeking and social support in this relationship. The results demonstrate that goal disruption causes uncertainty and then leads to psychological disequilibrium. Information seeking can reduce uncertainty and social support can attenuate psychological disequilibrium as well. Limitations and further directions are discussed.
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http://dx.doi.org/10.1080/10410236.2022.2049046DOI Listing
March 2022

New troodontid theropod specimen from Inner Mongolia, China clarifies phylogenetic relationships of later-diverging small-bodied troodontids and paravian body size evolution.

Cladistics 2022 02 23;38(1):59-82. Epub 2021 Jul 23.

Long Hao Institute of Geology and Paleontology, Hohhot, Nei Mongol, 010010, China.

A new troodontid (LH PV39) recovered from the Upper Cretaceous Wulansuhai Formation, Inner Mongolia, China, is described, highlighting the dorsoventrally compressed sacral centra. The completely fused neurocentral junctions indicate that LH PV39 had reached adulthood at the time of death, but its size is nevertheless 20% smaller than that of the sympatric Philovenator, demonstrating that it is the second small-bodied troodontid recovered from the Wulansuhai Formation. Phylogenetic analyses scoring LH PV39 using different strategies and performed with different algorithms unambiguously recovered it as a troodontid. While the parsimony-based analysis scoring LH PV39 as an independent OTU with all of its available characteristics included recovered it as a basal troodontid, the Bayesian analysis suggests a closer relationship of LH PV39 to Almas and an unnamed troodontid from Ukhaa Tolgod, Mongolia (MPC-D100/1126+D100/3500). Body size analysis confirmed a single trend of gigantism throughout the evolution of troodontids, and suggests that the Late Cretaceous troodontids evolved in two directions: (i) several size-independent characteristics evolved while retaining the small sizes that are typical of the Early Cretaceous relatives, resulting in the Late Cretaceous small-bodied troodontids; and (ii) size-dependent characteristics (e.g., the elongation of the rostrum) evolved accompanying the size increase, resulting in large-bodied derived troodontids. The mosaic features of the Late Cretaceous small-bodied troodontids place them intermediate between their Early Cretaceous basal relatives and the Late Cretaceous large-bodied taxa in a well-resolved phylogeny, which is crucial for understanding the size and morphological evolution of troodontids.
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http://dx.doi.org/10.1111/cla.12467DOI Listing
February 2022

MST1-knockdown protects against impairment of working memory via regulating neural activity in depression-like mice.

Genes Brain Behav 2022 02 19;21(2):e12782. Epub 2022 Jan 19.

College of Life Sciences and Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, Tianjin, China.

We reported that over-expression of MST1 induced the impairment of spatial memory via disturbing neural oscillation patterns in mice. Meanwhile, the P-MST1 is increased in the hippocampus after chronic unpredictable mild stress (CUMS). However, it is unclear if MST1 knockdown protects against stress-induced memory deficits via modulating neural activities. In the study, a CUMS mouse model was established and an intrahippocampal injection of AAV-shMST1 was used to knockdown MST1 in the hippocampus. The data showed that there were memory deficits with over-expressed P-MST1 level in CUMS mice. However, MST1 knockdown can significantly prevent the damages of CUMS-induced working memory and synaptic plasticity via regulating neural oscillation patterns. It suggests that MST1 down-regulation effectively protected against stress-induced behavioral dysfunctions. Moreover, as a more convenient way, neural oscillation analysis could provide some assistance for the auxiliary diagnosis and treatment of depression.
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http://dx.doi.org/10.1111/gbb.12782DOI Listing
February 2022

Thermogravimetric analysis of the pyrolysis and combustion kinetics of surface dead combustibles in the Daxing'an Mountains.

PLoS One 2021 2;16(12):e0260790. Epub 2021 Dec 2.

Forestry College of Inner Mongolia Agricultural University, Hohhot, China.

In boreal regions, the frequency of forest fires is increasing. In this study, thermogravimetric analysis was used to analyze the pyrolysis kinetics of dead surface combustibles in different forest types within the Daxing'an Mountains, China. The results show that the combustible material load of forest types, the Larix forest (LG) is relatively high. Base on the E of kinetic parameters, the LG, and Quercus forest (QM) forest types had relatively high combustibility values and comprehensive combustibility values for 1-, 10-, and 100-h time lags. According to the obtained P values, the pyrolysis of dead surface fuels with 1-, 10-, and 100-h time lags is relatively difficult in the Larix / Betula mixed forest (L-B) and QM forest types. Therefore, mixed forests of the LG, L-B, and QM tree species can be established as fire-resistant forests to establish a fire barrier, reduce the combustibility of forest stands, and reduce the possibility of forest fires.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0260790PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8638970PMC
January 2022

Complete Genome Sequencing and Comparative Analysis of Citrobacter koseri CKNJ, a Strain Isolated from a Patient with Endogenous Endophthalmitis.

Jpn J Infect Dis 2022 Mar 31;75(2):148-155. Epub 2021 Aug 31.

Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, China.

Citrobacter koseri (C. koseri) is an opportunistic pathogen that can cause a variety of diseases. Although the mortality rate of C. koseri infections is high, there is a paucity of clinical information. Furthermore, the genomic features of this species are poorly understood. Herein, we present a patient with endogenous endophthalmitis secondary to septicemia, and collected a C. koseri isolate, CKNJ, from the blood of the patient. Whole genome sequencing revealed that CKNJ harbors no plasmids and codes for 67 putative virulence factors. Whole genome single nucleotide polymorphism-based phylogenetic analysis revealed that the CKNJ strain was close to strains with the same isolation sites. Compared to the other sequenced C. koseri chromosomes, CKNJ contains several strain-variable regions, including one prophage and 2 large genomic islands. Sequencing of the first complete genome of a clinical strain from China should reinforce our understanding of the genomic features and pathogenicity of this invasive infection-causing C. koseri with clinical significance.
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http://dx.doi.org/10.7883/yoken.JJID.2021.334DOI Listing
March 2022

α-Chaconine Affects the Apoptosis, Mechanical Barrier Function, and Antioxidant Ability of Mouse Small Intestinal Epithelial Cells.

Front Plant Sci 2021 9;12:673774. Epub 2021 Jun 9.

College of Animal Science and Technology, Jilin Agricultural Science and Technology University, Jilin City, China.

α-Chaconine is the most abundant glycoalkaloid in potato and toxic to the animal digestive system, but the mechanisms underlying the toxicity are unclear. In this study, mouse small intestinal epithelial cells were incubated with α-chaconine at 0, 0.4, and 0.8 μg/mL for 24, 48, and 72 h to examine apoptosis, mechanical barrier function, and antioxidant ability of the cells using a cell metabolic activity assay, flow cytometry, Western blot, immunofluorescence, and fluorescence quantitative PCR. The results showed that α-chaconine significantly decreased cell proliferation rate, increased apoptosis rate, decreased transepithelial electrical resistance (TEER) value, and increased alkaline phosphatase (AKP) and lactate dehydrogenase (LDH) activities, and there were interactions between α-chaconine concentration and incubation time. α-Chaconine significantly reduced the relative and mRNA expressions of genes coding tight junction proteins zonula occludens-1 (ZO-1) and occludin, increased malondialdehyde (MDA) content, decreased total glutathione (T-GSH) content, reduced the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and γ-glutamylcysteine synthetase (γ-GCS) and the mRNA expressions of SOD, CAT, GSH-Px, and γ-GCS genes. In conclusion, α-chaconine disrupts the cell cycle, destroys the mechanical barrier and permeability of mucosal epithelium, inhibits cell proliferation, and accelerates cell apoptosis.
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http://dx.doi.org/10.3389/fpls.2021.673774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220139PMC
June 2021

rTMS alleviates cognitive and neural oscillatory deficits induced by hindlimb unloading in mice via maintaining balance between glutamatergic and GABAergic systems.

Brain Res Bull 2021 07 22;172:98-107. Epub 2021 Apr 22.

College of Life Sciences and Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, 300071, Tianjin, PR China. Electronic address:

Microgravity, as a part of the stress of space flight, has several negative effects on cognitive functions. Repetitive transcranial magnetic stimulation (rTMS), as a novel non-invasive technique, could be an effective approach to alleviated cognitive decline, applied in both preclinical and clinical studies. Neural oscillations and their interactions are involved in cognitive functions and support the communication of neural information. The neural oscillation could be a window from which we may understand what happens in the brain. The current study aimed to explore if 15 Hz rTMS plays a neural modulation role in a mouse model of hindlimb unloading. We hypothezed that rTMS can improve the cognitive and neural oscillatory deficits induced by hindlimb unloading via maintaining the balance between glutamatergic and GABAergic systems. Our data show that rTMS can significantly alleviate behavior deficits, modulate theta oscillation, improve the disturbed power distribution of theta oscillation and the decreased strength of Cross-Frequency Coupling in the dentate gyrus region, and effectively mitigated the blocked communication of neural information in the perforant pathway (PP)-dentate gyrus (DG) neural pathway in Hu mice. Furthermore, biochemical analysis using high-performance liquid chromatography and Western blot assay confirmed that rTMS increases the low expression of glutamate (Glu) and N-Methyl d-Aspartate receptor subtype 2B (NR2B) and decreases the high expression of γ-aminobutyric acid (GABA), 67 KDa isoform of glutamate decarboxylase (GAD67), and GABA type A receptor subunit alpha1 (GABAAR) in the hippocampus of Hu mice. Taken together, the results suggest that rTMS plays a significant neural modulation role in the hippocampal neural activity disorders induced by Hu, which possibly depends on rTMS maintaining the balance of glutamatergic and gamma-aminobutyric acidergic (GABAergic) systems.
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http://dx.doi.org/10.1016/j.brainresbull.2021.04.013DOI Listing
July 2021

Recent progress in metabolic engineering of Saccharomyces cerevisiae for the production of malonyl-CoA derivatives.

J Biotechnol 2021 Jan 2;325:83-90. Epub 2020 Dec 2.

National Engineering Laboratory for Cereal Fermentation Technology (NELCF), School of Biotechnology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China; Jiangsu Provincial Research Center for Bioactive Product Processing Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu 214122, China. Electronic address:

To reduce dependence on petroleum, the biosynthesis of important chemicals from simple substrates using industrial microorganisms has attracted increased attention. Metabolic engineering of Saccharomyces cerevisiae offers a sustainable and flexible alternative for the production of various chemicals. As a key metabolic intermediate, malonyl-CoA is a precursor for many useful compounds. However, the productivity of malonyl-CoA derivatives is restricted by the low cellular level of malonyl-CoA and enzymatic performance. In this review, we focused on how to increase the intracellular malonyl-CoA level and summarize the recent advances in different metabolic engineering strategies for directing intracellular malonyl-CoA to the desired malonyl-CoA derivatives, including strengthening the malonyl-CoA supply, reducing malonyl-CoA consumption, and precisely controlling the intracellular malonyl-CoA level. These strategies provided new insights for further improving the synthesis of malonyl-CoA derivatives in microorganisms.
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http://dx.doi.org/10.1016/j.jbiotec.2020.11.014DOI Listing
January 2021

Legumain Knockout Protects Against Aβ-Induced AD-like Cognitive Deficits and Synaptic Plasticity Dysfunction Via Inhibiting Neuroinflammation Without Cleaving APP.

Mol Neurobiol 2021 Apr 21;58(4):1607-1620. Epub 2020 Nov 21.

College of Life Sciences and Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, Tianjin, 300071, People's Republic of China.

Neuroinflammation is the important pathological feature of Alzheimer's disease (AD). Legumain, a lysosomal cysteine protease, plays an important role in neuroinflammation during ischemic stroke and depressive disorder. Legumain is involved in AD process through cleaving APP; however, it is unclear if legumain can possibly modulate neuroinflammation without cleaving APP in AD. Thus, we established a mouse model of AD by single intracerebroventricular injections of Aβ in legumain knockout (KO) mice. The behavioral tests showed that legumain-KO effectively ameliorated cognitive impairment induced by Aβ. Moreover, legumain deprivation significantly improves the synaptic plasticity damages in Aβ-treated mice. Moreover, legumain-KO considerably inhibited the activation of microglia and reduced the expression of inflammatory cytokines in the hippocampus of Aβ-treated mice. Interestingly, we found that legumain-KO inhibited TLR4/MyD88/NF-κB pathway, which was activated by Aβ in the hippocampus. In conclusion, our results suggested that legumain-KO reduced the level of neuroinflammation that was associated with inhibiting TLR4/MyD88/NF-κB pathways, thereby improving the hippocampal synaptic plasticity and reducing the cognitive impairments in Aβ-treated mice. Legumain knockout blocked microglia activation by inhibiting TLR4/MyD88/NF-κB signaling pathways, and further reduced inflammatory cytokine expression. As a result, legumain knockout alleviated synaptic damage and cognitive impairment induced by Aβ1--42.
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http://dx.doi.org/10.1007/s12035-020-02219-3DOI Listing
April 2021

[Role of miRNA and lncRNA in animal fat deposition-a review].

Sheng Wu Gong Cheng Xue Bao 2020 Aug;36(8):1504-1514

College of Animal Science and Technology, Northwest A & F University, Yangling 712100, Shaanxi, China.

MicroRNA (miRNA) is a type of highly conserved nucleotide sequence composed of 18 to 25 nucleotides, which can specifically bind to the 3'-noncoding regions of mRNA, and then play a negative regulatory role in degrading mRNA or inhibiting translation. Long non-coding RNA (lncRNA) is a type of nucleotide sequence that exceeds 200 nucleotides in length and cannot encode proteins or can only encode protein peptides. It regulates gene expression at the levels of epigenetic, transcriptional and post-transcriptional. As an important energy storage organ, fat plays an important role in regulating the energy balance of animals, and is closely related to meat production traits such as meat production and meat quality. And the disorder of fat function can lead to hyperlipidemia, type 2 diabetes and a series of cardiovascular diseases, so the molecular regulation mechanism of animal fat deposition has attracted more attention. In recent years, more and more studies have found that miRNA and lncRNA play a crucial role in animal fat deposition. We review here the current research progresses in the role of miRNA and lncRNA in animal fat deposition, to provide theoretical guidance and new ideas for further revealing the molecular regulation mechanism of animal fat deposition.
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http://dx.doi.org/10.13345/j.cjb.200232DOI Listing
August 2020

Variations of Mesozoic feathers: Insights from the morphogenesis of extant feather rachises.

Evolution 2020 09 11;74(9):2121-2133. Epub 2020 Jul 11.

Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, 90033.

The rachises of extant feathers, composed of dense cortex and spongy internal medulla, are flexible and light, yet stiff enough to withstand the load required for flight, among other functions. Incomplete knowledge of early feathers prevents a full understanding of how cylindrical rachises have evolved. Bizarre feathers with unusually wide and flattened rachises, known as "rachis-dominated feathers" (RDFs), have been observed in fossil nonavian and avian theropods. Newly discovered RDFs embedded in early Late Cretaceous Burmese ambers (about 99 million year ago) suggest the unusually wide and flattened rachises mainly consist of a dorsal cortex, lacking a medulla and a ventral cortex. Coupled with findings on extant feather morphogenesis, known fossil RDFs were categorized into three morphotypes based on their rachidial configurations. For each morphotype, potential developmental scenarios were depicted by referring to the rachidial development in chickens, and relative stiffness of each morphotype was estimated through functional simulations. The results suggest rachises of RDFs are developmentally equivalent to a variety of immature stages of cylindrical rachises. Similar rachidial morphotypes documented in extant penguins suggest that the RDFs are not unique to Mesozoic theropods, although they are likely to have evolved independently in extant penguins.
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http://dx.doi.org/10.1111/evo.14051DOI Listing
September 2020

The relationship between serum triglyceride levels and acute pancreatitis in an animal model and a 14-year retrospective clinical study.

Lipids Health Dis 2019 Oct 23;18(1):183. Epub 2019 Oct 23.

Department of Gastroenterology, First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, Guangxi, China.

Objectives: The aim of the current study was to evaluate influence of serum triglyceride levels on the course of acute pancreatitis (AP).

Methods: Rats models of hypertriglyceridemic were used in animal experiments. Following induction of acute pancreatitis, amylase, and pancreas histological scores were all compared. In addition, in a clinical study, clinical data were collected from 1681 AP patients admitted from 2003 to 2016 who were divided into 4 groups based on their serum triglyceride (TG) levels. The clinical features among these 4 groups were compared, and a receiver operating characteristic (ROC) curve analysis was also performed on TG values to estimate their relationship with severity.

Results: In animal experiments, the hypertriglyceridemic pancreatitis (HTGP) group had markedly higher serum amylase, and histological scores relative to the other animal groups. In the clinical study, we identified significant differences in gender, age, body mass index (BMI), cost, and incidence of partial complications among the 4 TG-based groups. Importantly, the TG levels on day 3-4 after admission could be used to accurately predict disease severity.

Conclusions: Hypertriglyceridemia (HTG) can aggravate pancreatic injury, and hypertriglyceridemia patients are more likely to suffer from severe pancreatic injury with a higher possibility of complications. In addition, triglyceride levels are correlated with the severity of AP positively.
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http://dx.doi.org/10.1186/s12944-019-1126-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813107PMC
October 2019

MicroRNA-323-3p promotes myogenesis by targeting Smad2.

J Cell Biochem 2019 11 19;120(11):18751-18761. Epub 2019 Jun 19.

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

Skeletal muscle is an important and complex organ with multiple biological functions in humans and animals. Proliferation and differentiation of myoblasts are the key steps during the development of skeletal muscle. MicroRNA (miRNA) is a class of 21-nucleotide noncoding RNAs regulating gene expression by combining with the 3'-untranslated region of target messenger RNA. Many studies in recent years have suggested that miRNAs play a critical role in myogenesis. Through high-throughput sequencing, we found that miR-323-3p showed significant changes in the longissimus dorsi muscle of Rongchang pigs in different age groups. In this study, we discovered that overexpression of miR-323-3p repressed myoblast proliferation and promoted differentiation, whereas the inhibitor of miR-323-3p displayed the opposite results. Furthermore, we predicted Smad2 as the target gene of miR-323-3p and found that miR-323-3p directly modulated the expression level of Smad2. Then luciferase reporter assays verified that Smad2 was a target gene of miR-323-3p during the differentiation of myoblasts. These findings reveal that miR-323-3p is a positive regulator of myogenesis by targeting Smad2. This provides a novel mechanism of miRNAs in myogenesis.
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http://dx.doi.org/10.1002/jcb.29187DOI Listing
November 2019

Polymorphism of the Gene and Dynamic Balance Performance in Han Chinese Children.

Hereditas 2019 23;156:15. Epub 2019 May 23.

1Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, 200030 China.

Background: Athletic performances are complex traits with heritability of ~66%. Dynamic balance is one of the most important athletic performances, and there has been little studies for it in sports genomics. The candidate gene was reported to be able to affect muscle development for balance predisposition and influence the athletic performance including skiing triumph in the Caucasian population. This study aims to investigate whether the gene is a susceptibility gene for dynamic balance performance in Han Chinese children.

Results: A total 2244 children were recruited and their balance beam performances were measured. Five polymorphisms in the gene were genotyped through the MassARRAY Sequenom platform. Rs2016520 exerted significant association with dynamic balance performance (minor allele C, P = 0.015, P < 0.05) and was affirmed in a meta-analysis by combining previously reported Caucasian cohorts (OR = 1.57, 95% CI = [1.30, 1.91], P < 10 ) . Another polymorphism, rs2267668, was also significantly associated with dynamic balance performance (minor allele G, P = 0.015, P < 0.05). In the dichotomous study, 321 cases (61% boys and 39% girls) and 370 controls (49% boys and 51% girls) in our samples were selected as representatives, and the thresholds were the mean velocity (0.737 m/s) ± standard deviation (0.264 m/s), in which rs2016520-C and rs2267668-G still remained significant (CI =1.41 [1.11~1.79], P = 0.004, P < 0.016; CI =1.45 [1.14~1.86], P = 0.002, P < 0.016). In different genders, consistent OR direction was observed for each variant.

Conclusions: Our results suggested that the gene is associated with dynamic balance performance of human being, and further studies to reveal its etiology is strongly suggested.
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http://dx.doi.org/10.1186/s41065-019-0092-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533762PMC
December 2019

ACTN3 is associated with children's physical fitness in Han Chinese.

Mol Genet Genomics 2019 Feb 30;294(1):47-56. Epub 2018 Aug 30.

Human Sports Science Department, Shanghai University of Sports, Shanghai, 200438, China.

The ACTN3 gene locates on 11q13-q14 and encodes the α-actinin-3 protein, which is only expressed in human skeletal muscle and influenced muscle function and metabolism. The previous studies reported that SNP rs1815739 is associated with elite power athletes' performance. In this study, we investigated the association between five SNPs within the ACTN3 gene and Chinese children physical fitness. We recruited 2244 Han Chinese children participants, and measured their 25-m run, stand broad jump, 10-m shuttle run, handgrip, BMI (calculated by weight and height) data. SNPs rs1671064, rs2275998, rs2290463, rs10791881, and rs1815739 of ACTN3 gene were genotyped and analyzed in five physical fitness data. QTL analysis on genotype and physical fitness data was carried out in all samples. Furthermore, a dichotomous division of samples into an overweight group (543) and a normal group (1701) was used for an association study of overweight. In the QTL analysis, we found rs2290463 was significantly associated with stand broad jump (corrected P value = 0.009, beta = 2.692). After added age and gender as covariates in the regression test, the association became more significant (P value = 5.80 × 10, corrected P value = 4.06 × 10); when we used BMI as a covariate, the association still existed (P value = 4.65 × 10, corrected P value = 0.001). In the association study of overweight, rs2275998 was found to be significant (OR, 95% CI = 0.733 [0.6-0.895]; P = 0.011, P = 0.024) after the Bonferroni correction, and the association did not change much after a further correction for gender, age, and stand broad jump performance. Our results showed that common variants in ACTN3 are significantly associated with both stand broad jump performance and overweight in Han Chinese children.
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http://dx.doi.org/10.1007/s00438-018-1485-7DOI Listing
February 2019

A prospective study on the changes and clinical significance of pre-operative and post-operative circulating tumor cells in resectable gastric cancer.

J Transl Med 2018 06 20;16(1):171. Epub 2018 Jun 20.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of GI Oncology, Peking University Cancer Hospital & Institute, Fucheng Road 52, Haidian District, Beijing, 100142, China.

Background: Circulating tumor cells (CTCs) have been suggested as potential prognostic indicators for multiple tumors, including gastric cancer; however, pre- and post-operative CTC changes in resectable gastric cancer and possible correlations to post-operative recurrence have not been evaluated.

Methods: Subjects (n = 93) with resectable gastric cancer were prospectively reviewed from July 2013 to December 2014 at Peking University Cancer Hospital. The proportion of CTCs were evaluated before (n = 93) and after (n = 63) radical operation using a standardized CellSearch system.

Results: CTCs ≥ 1 were measured in the pre-operative blood of 31 (33.3%) patients and in the post-operative blood of 21 patients (33.3%). Patients with relatively poor clinicopathological features had more pre- and post-operative CTCs. The 3-year disease-free survival (DFS) rate for patients with CTCs ≥ 5/7.5 ml was significantly lower than for patients with CTCs < 5/7.5 ml (40.0% vs 66.4%, p < 0.001 for pre-surgery; 25.0% vs 62.2%, p < 0.001 for post-surgery). Patients with CTCs ≥ 5/7.5 ml in post-operative blood had significantly shorter mean DFS (1.28 vs 31.6 months; p = 0.002) and overall survival (OS; 10.0 vs 34.9 months; p = 0.001) than other patients. Among the 10 patients with hematogenous recurrence, 3 had post-operative CTCs ≥ 2/7.5 ml and had early recurrence (DFS 1.1, 1.1, 1.4 months). Moreover, DFS for the seven patients was 20.2, 11.9, 20.0, 6.0, 15.5, 25.9, 30.0 months, respectively. DFS for the three patients with increased CTCs after surgery was shorter than for patients with mildly increased, stable, or decreased CTCs.

Conclusions: Pre- and post-operative CTCs are promising prognostic markers for resectable gastric cancer. Our study further suggests that increased post-operative CTCs may be correlated with hematogenous recurrence. Trial registration (ClinicalTrials.gov Identifier: NCT01848015). Registered 7 May 2013. https://clinicaltrials.gov/ct2/show/NCT01848015.
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http://dx.doi.org/10.1186/s12967-018-1544-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011408PMC
June 2018

miR-34a increases the sensitivity of colorectal cancer cells to 5-fluorouracil and .

Am J Cancer Res 2018 1;8(2):280-290. Epub 2018 Feb 1.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and InstituteBeijing, China.

This study was designed to investigate the significance of the effect of miR-34a on 5-fluorouracil (5-FU) sensitivity and . miR-34a expression in tumor tissues or serum was determined by quantitative polymerase chain reaction. CRC cell lines HCT116 and SW480 were used to evaluate cell viability, cell apoptosis, and the cell cycle using a cell proliferation assay, flow cytometry, and Western blotting, respectively. For the studies, xenografts derived from SW480 cells were established to assess the antitumor activity between miR-34a and 5-FU. Patients with high levels of miR-34a expression were found to benefit more from 5-FU-based chemotherapy than patients with low levels of miR-34a expression, regardless of disease stage. Ectopic expression of miR-34a alone or 5-FU alone was found to inhibit CRC cell growth and . Moreover, cell growth and was further inhibited when miR-34a combined with 5-FU through increasing the rate of cell apoptosis. The potential targets of miR-34a, including CREB1, Bcl-2, Notch 1, Sirt1, and E2F3, were predicted and preliminarily validated and merit further study.

Conclusion: miR-34a might function as a predictor of fluorouracil chemosensitivity in CRC, and a combination strategy of miR-34a with fluorouracil was expected to be more beneficial for CRC patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835695PMC
February 2018

Reevaluation of the Dentary Structures of Caenagnathid Oviraptorosaurs (Dinosauria, Theropoda).

Sci Rep 2018 01 10;8(1):391. Epub 2018 Jan 10.

Laboratory of Vertebrate Evolution, College of Life Science, Capital Normal University, Beijing, 100048, China.

Among the characters of caenagnathid oviraptorosaurians, the lateral occlusal grooves and ridges on the occlusal surface of the jaw bones often receive special attention. Recent studies demonstrated that ontogenetic edentulism is present in caenagnathids, and therefore the lateral occlusal grooves and ridges are vestigial alveoli and interdental septa, respectively. In the present paper, the dentary structures of caenagnathids were reevaluated based on CT images of Caenagnathiasia sp. IVPP V20377. Several previously unknown features including crateriform vestigial alveoli, the morphology of the dentary interior hollow space, and the paired blind tubes beneath the dentary symphyseal shelf are recognized. Current lines of evidence suggest different jaw bone morphologies are likely produced by various tooth reduction patterns, which indicates ontogenetic dietary shift, if once presented in caenagnathids and Sapeornis, may have been different from the condition seen in Limusaurus. The 3D images of dentary interior spaces suggest that while tooth reduction progresses, the empty alveoli are partially modified into structures accommodating blood vessels that nourish the rhamphotheca, probably representing a functional compensation for the insufficient blood supply in toothed jaw bones.
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http://dx.doi.org/10.1038/s41598-017-18703-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762635PMC
January 2018

Exceptional appendage and soft-tissue preservation in a Middle Triassic horseshoe crab from SW China.

Sci Rep 2017 10 26;7(1):14112. Epub 2017 Oct 26.

Institute of Neuroscience, Xiamen University, Xiamen, 361005, China.

Horseshoe crabs are classic "living fossils", supposedly slowly evolving, conservative taxa, with a long fossil record back to the Ordovician. The evolution of their exoskeleton is well documented by fossils, but appendage and soft-tissue preservation is extremely rare. Here we analyse details of appendage and soft-tissue preservation in Yunnanolimulus luopingensis, a Middle Triassic (ca. 244 million years old) horseshoe crab from Yunnan Province, SW China. The remarkable preservation of anatomical details including the chelicerae, five pairs of walking appendages, opisthosomal appendages with book gills, muscles, and fine setae permits comparison with extant horseshoe crabs. The close anatomical similarity between the Middle Triassic horseshoe crabs and their recent analogues documents anatomical conservatism for over 240 million years, suggesting persistence of lifestyle. The occurrence of Carcinoscorpius-type claspers on the first and second walking legs in male individuals of Y. luopingensis indicates that simple chelate claspers in males are plesiomorphic for horseshoe crabs, and the bulbous claspers in Tachypleus and Limulus are derived.
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http://dx.doi.org/10.1038/s41598-017-13319-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658423PMC
October 2017

Aneuploidy of chromosome 8 in circulating tumor cells correlates with prognosis in patients with advanced gastric cancer.

Chin J Cancer Res 2016 Dec;28(6):579-588

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.

Objective: Previous work indicated that aneuploidy of chromosome 8 in circulating tumor cells (CTCs) correlated with therapeutic efficacy for advanced gastric cancer (AGC) patients. In this follow-up study performed on the same population of AGC patients, we investigated whether and how aneuploidy of chromosome 8 in CTCs correlates with patients' clinical prognosis.

Methods: The prospective study was performed on 31 patients with newly diagnosed AGC. Previously established integrated subtraction enrichment (SE) and immunostaining-fluorescence hybridization (iFISH) platform was applied to identify, enumerate and characterize CTCs. Quantification of CTCs and analysis of their aneuploidy of chromosome 8 were performed on patients before and after therapy.

Results: CTCs were measured in 93.5% of AGC patients, and two CTC subtypes with diverse threshold values were identified, multiploid CTCs with the threshold of ≥2 per 7.5 mL and multiploid plus triploid CTCs with the threshold of ≥4, which were found to significantly correlate with poor progression-free survival (PFS) and overall survival (OS). In particular, patients with ≥10% increased multiploid CTCs after an initial 6 weeks of therapy had poor PFS and OS, whereas improved PFS and OS were observed on those who had ≥10% decreased multiploid CTCs. After adjusting for clinically significant factors, ≥10% increased post-therapy multiploid CTCs was the only independent predictor of PFS and OS.

Conclusions: Aneuploidy of CTCs correlates with prognosis of AGC patients. Quantitative comparison monitoring multiploid CTCs before and after therapy may help predict improved or inferior prognosis and chemoresistance.
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http://dx.doi.org/10.21147/j.issn.1000-9604.2016.06.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242452PMC
December 2016

Famitinib exerted powerful antitumor activity in human gastric cancer cells and xenografts.

Oncol Lett 2016 Sep 25;12(3):1763-1768. Epub 2016 Jul 25.

Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China.

Famitinib (SHR1020), a novel multi-targeted tyrosine kinase inhibitor, has antitumor activity against several solid tumors via targeting vascular endothelial growth factor receptor 2, c-Kit and platelet-derived growth factor receptor β. The present study investigated famitinib's activity against human gastric cancer cells and . Cell viability and apoptosis were measured, and cell cycle analysis was performed following famitinib treatment using 3-(4,5-dimethylthiazol -2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, flow cytometry, terminal deoxynucleotidyl transferase dUTP nick end labeling assay and western blotting. Subsequently, cluster of differentiation 34 staining was used to evaluate microvessel density. BGC-823-derived xenografts in nude mice were established to assess drug efficacy . Famitinib inhibited cell proliferation by inducing cell cycle arrest at the G2/M phase and caused cell apoptosis in a dose-dependent manner in gastric cancer cell lines. In BGC-823 xenograft models, famitinib significantly slowed tumor growth via inhibition of angiogenesis. Compared with other chemotherapeutics such as 5-fluorouracil, cisplatin or paclitaxel alone, famitinib exhibited the greatest tumor suppression effect (>85% inhibition). The present study demonstrated for the first time that famitinib has efficacy against human gastric cancer and , which may lay the foundations for future clinical trials.
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http://dx.doi.org/10.3892/ol.2016.4909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998225PMC
September 2016

Dynamic monitoring of circulating tumour cells to evaluate therapeutic efficacy in advanced gastric cancer.

Br J Cancer 2016 Jan;114(2):138-45

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.

Background: This study was intended to determine the clinical significance of circulating tumour cells (CTCs) in patients with advanced gastric cancer (AGC), particularly the potential role of CTCs for dynamic monitoring of the therapeutic response.

Methods: A single-centre, prospective study was undertaken in 136 patients with newly diagnosed AGC. The patients' CTCs were enumerated using CellSearch at baseline and at the first response evaluation. In 15 patients whose clinical condition permitted longitudinal study, CTCs were longitudinally enumerated during treatment.

Results: Following 6 weeks of chemotherapy, an unfavourable post-therapy CTC level (⩾3 CTCs per 7.5 ml) was closely correlated with the objective response rate (P=0.016) and the disease control rate (P=0.013), and it also independently predicted a shorter progression-free survival and overall survival. Particularly, conversion to a favourable CTC level following therapy improved the prognosis, but patients who changed to an unfavourable CTC level fared significantly worse. Elevated CTCs during therapy may be associated with a poor prognosis.

Conclusions: Post-therapy CTC level may help in evaluating therapeutic response in patients with AGC and predicting their prognosis. In addition, changes in CTCs following therapy may be useful in rapidly identifying ineffective treatments and poor prognosis.
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http://dx.doi.org/10.1038/bjc.2015.417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815805PMC
January 2016
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