Publications by authors named "Xuefeng Gao"

86 Publications

Construction of an AuHQ nano-sensitizer for enhanced radiotherapy efficacy through remolding tumor vasculature.

J Mater Chem B 2021 Jun;9(21):4365-4379

Key Laboratory of Functional Polymer Materials, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China.

As a radiotherapy sensitizer, gold-based nanomaterials can significantly enhance radiotherapy efficacy. However, the severe hypoxia and the low accumulation of nanomedicine at the tumor site caused by poor perfusion have seriously affected the effect of radiotherapy. Tumor vascular normalization has emerged as a new strategy for increasing the efficacy of radiotherapy due to its ability to relieve hypoxia and increase perfusion. However, a commonly used approach of blocking a single growth factor to induce vascular normalization is limited by the compensation effect of evasive drug resistance. In this work, we developed a strategy to simultaneously reduce the expression of multi-angiogenic growth factors by suppressing the oxidative stress effects in tumor. Herein, gold nanoparticles (Au NPs) were modified with 8-hydroxyquinoline (HQ) to obtain AuHQ. This system has a simple structure and could inhibit the production of reactive oxygen species in tumor cells by chelating iron ions, and attenuating the expression of angiopoietin-2, vascular endothelial growth factor and basic fibroblast growth factor in human umbilical vein endothelial cells. In vivo, AuHQ treatment increased pericyte coverage, modulated tumor leakage while alleviating tumor hypoxia and increased blood perfusion, thereby inducing tumor vascular normalization. Consequently, Au accumulation of the AuHQ group increased by 1.94 fold compared to that in the control group. Furthermore, the antitumor efficacy of radiotherapy was increased by 38% compared to the Au NPs-treated group. Therefore, AuHQ may be a promising nanomedicine for future cancer treatment.
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http://dx.doi.org/10.1039/d1tb00515dDOI Listing
June 2021

The fecal microbiota of patients with pancreatic ductal adenocarcinoma and autoimmune pancreatitis characterized by metagenomic sequencing.

J Transl Med 2021 05 18;19(1):215. Epub 2021 May 18.

Micriobiota Division, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.

Background: The fecal microbiota in pancreatic ductal adenocarcinoma (PDAC) and in autoimmune pancreatitis (AIP) patients remains largely unknown. We aimed to characterize the fecal microbiota in patients with PDAC and AIP, and explore the possibility of fecal microbial biomarkers for distinguishing PDAC and AIP.

Methods: 32 patients with PDAC, 32 patients with AIP and 32 age- and sex-matched healthy controls (HC) were recruited and the fecal microbiotas were analyzed through high-throughput metagenomic sequencing. Alterations of fecal short-chain fatty acids were measured using gas chromatographic method.

Results: Principal coordinate analysis (PCoA) revealed that microbial compositions differed significantly between PDAC and HC samples; whereas, AIP and HC individuals tended to cluster together. Significant reduction of phylum Firmicutes (especially butyrate-producing bacteria, including Eubacterium rectale, Faecalibacterium prausnitzii and Roseburia intestinalis) and significant increase of phylum Proteobacteria (especially Gammaproteobacteria) were observed only among PDAC samples. At species level, when compared with HC samples, we revealed 24 and 12 differently enriched bacteria in PDAC and AIP, respectively. Functional analysis showed a depletion of short-chain fatty acids synthesis associated KO modules (e.g. Wood-Ljungdahl pathway) and an increase of KO modules associated with bacterial virulence (e.g. type II general secretion pathway). Consistent with the downregulation of butyrate-producing bacteria, gas chromatographic analysis showed fecal butyrate content was significantly decreased in PDAC group. Eubacterium rectale, Eubacterium ventrisum and Odoribacter splanchnicus were among the most important biomarkers in distinguishing PDAC from HC and from AIP individuals. Receiver Operating Characteristic analysis showed areas under the curve of 90.74% (95% confidence interval [CI] 86.47-100%), 88.89% (95% CI 73.49-100%), and 76.54% (95% CI 52.5-100%) for PDAC/HC, PDAC/AIP and AIP/HC, respectively.

Conclusions: In conclusion, alterations in fecal microbiota and butyrate of patients with PDAC suggest an underlying role of gut microbiota for the pathogenesis of PDAC. Fecal microbial and butyrate as potential biomarkers may facilitate to distinguish patients with PDAC from patients with AIP and HCs which worth further validation.
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http://dx.doi.org/10.1186/s12967-021-02882-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130326PMC
May 2021

Ramulus Mori (Sangzhi) Alkaloids (SZ-A) Ameliorate Glucose Metabolism Accompanied by the Modulation of Gut Microbiota and Ileal Inflammatory Damage in Type 2 Diabetic KKAy Mice.

Front Pharmacol 2021 15;12:642400. Epub 2021 Apr 15.

Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

The novel Traditional Chinese Medicine Ramulus Mori (Sangzhi) alkaloid tablets (SZ-A) are approved by The China National Medical Products Administration for the treatment of type 2 diabetes mellitus (T2DM). However, the extensive pharmacological characteristics and the underlying mechanism are unknown. This study investigated the mechanisms by which SZ-A ameliorates glucose metabolism in KKAy mice, an animal model of T2DM. Diabetic KKAy mice were treated intragastrically with SZ-A once daily for 8 weeks, after which glucose levels, lipid metabolism, gut microbiome, systemic inflammatory factors, luminal concentrations of short-chain fatty acids (fecal samples), and ileal proteomic changes were evaluated. The ileum tissues were collected, and the effects of SZ-A on pathological inflammatory damage were evaluated by hematoxylin and eosin staining, immunofluorescence, and immunohistochemistry. The mRNA and protein expression levels of various inflammatory markers, including monocyte chemoattractant protein-1 and phosphorylated nuclear factor kappa B p65, were detected in the ileum tissues. SZ-A improved glucose metabolism with enhanced insulin response and elevated glucagon-like peptide 1 (GLP-1) nearly 2.7-fold during the glucose tolerance test in diabetic KKAy mice. Gut microbiota analysis demonstrated that SZ-A administration elevated the abundance of and , reduced the levels of and and increased the concentrations of fecal acetic and propionic acids compared to the diabetic model group. Additionally, SZ-A markedly improved ileal inflammatory injury and pro-inflammatory macrophage infiltration and improved intestinal mucosal barrier function in diabetic KKAy mice. SZ-A also attenuated the levels of circulating endotoxin, pro-inflammatory cytokines, and chemokines in the mice sera. Collectively, SZ-A ameliorated the overall metabolic profile including glucose and lipid metabolism in KKAy mice, which may be associated with an improvement in GLP-1 and insulin secretion, at least in part by modulating the gut microbiome and relieving the degree of ileal and systemic inflammation.
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http://dx.doi.org/10.3389/fphar.2021.642400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082153PMC
April 2021

Characteristics of Cohesin Mutation in Acute Myeloid Leukemia and Its Clinical Significance.

Front Oncol 2021 13;11:579881. Epub 2021 Apr 13.

Department of Hematology and Oncology, International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen University Health Science Center, Shenzhen, China.

The occurrence of gene mutation is a major contributor to the initiation and propagation of acute myeloid leukemia (AML). Accumulating evidence suggests that genes encoding cohesin subunits have a high prevalence of mutations in AML, especially in the t(8;21) subtype. Therefore, it is important to understand how cohesin mutations contribute to leukemogenesis. However, the fundamental understanding of cohesin mutation in clonal expansion and myeloid transformation in hematopoietic cells remains ambiguous. Previous studies briefly introduced the cohesin mutation in AML; however, an in-depth summary of mutations in AML was not provided, and the correlation between cohesin and AML1-ETO in t (8;21) AML was also not analyzed. By summarizing the major findings regarding the cohesin mutation in AML, this review aims to define the characteristics of the cohesin complex mutation, identify its relationships with co-occurring gene mutations, assess its roles in clonal evolution, and discuss its potential for the prognosis of AML. In particular, we focus on the function of cohesin mutations in RUNX1-RUNX1T1 fusion.
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http://dx.doi.org/10.3389/fonc.2021.579881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076553PMC
April 2021

Expanding of ST11 Carbapenemase-Producing Subclones in a Chinese Hospital, Shenzhen, China.

Infect Drug Resist 2021 13;14:1415-1422. Epub 2021 Apr 13.

Shenzhen People's Hospital, Shenzhen Institute of Respiratory Diseases, Shenzhen, Guangdong, People's Republic of China.

Background: ST11 is the most prevalent sequence type of clinical in China.

Methods: We investigated the characteristics of the ST11 subclones using core genome multi-locus sequence typing (cgMLST). Ninety-three carbapenemase-producing isolates were collected at Shenzhen People's Hospital. Then, whole-genome sequencing and cgMLST were used to discriminate apparent subclones within the ST11 group.

Results: We analyzed the prevalence and genetic relationships of these subclones. ST11 and carbapenemase (KPC-2) were the predominant genotype and carbapenemase, respectively, in the clinical carbapenemase-producing strains. cgMLST scheme genotyping divided the ST11 group into two clades across seven complex types (CTs). CT1313 was the most prevalent subclone. The deletion of and a high frequency of SNPs in genes associated with the stress- and SOS-responses were found in CT1291 and CT2405 over time, respectively.

Conclusion: Our results indicated that the subclones of the ST11 group had different patterns of prevalence. Highly discriminatory genotyping techniques, such as cgMLST scheme, should be used in further molecular epidemiology investigations.
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http://dx.doi.org/10.2147/IDR.S299478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053513PMC
April 2021

Evaluation of acute myeloid leukemia blast percentage on MethylC-Capture Sequencing results.

Exp Hematol Oncol 2021 Mar 31;10(1):26. Epub 2021 Mar 31.

Department of Hematology and Oncology, International Cancer Center, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen University Health Science Center, Shenzhen University, Xueyuan AVE 1098, Nanshan District, Shenzhen, Guangdong, 518000, People's Republic of China.

Aberrant DNA methylation is often related to the diagnosis, prognosis, and therapeutic response of acute myeloid leukemia (AML); however, relevant studies on the relationship between bone marrow myeloblast percentage and the DNA methylation level in AML have not been reported. We evaluated the effects of AML blast percentage on DNA methylation level using the MethylC-capture sequencing (MCC-Seq) approach based on next-generation sequencing (NGS) and found that the methylation level of both genome-wide and promoter regions significantly increased when the percentage of AML blasts reached ≥ 40%, indicating that an accurate DNA methylation level in cancer cells can be obtained when the bone marrow samples of AML patients have more than 40% myeloblasts.
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http://dx.doi.org/10.1186/s40164-021-00219-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011402PMC
March 2021

Salivary Microbiota for Gastric Cancer Prediction: An Exploratory Study.

Front Cell Infect Microbiol 2021 10;11:640309. Epub 2021 Mar 10.

Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Medical School of Chinese PLA, Beijing, China.

To characterize the salivary microbiota in patients at different progressive histological stages of gastric carcinogenesis and identify microbial markers for detecting gastric cancer, two hundred and ninety-three patients were grouped into superficial gastritis (SG; n = 101), atrophic gastritis (AG; n = 93), and gastric cancer (GC; n = 99) according to their histology. 16S rRNA gene sequencing was used to access the salivary microbiota profile. A random forest model was constructed to classify gastric histological types based on the salivary microbiota compositions. A distinct salivary microbiota was observed in patients with GC when comparing with SG and AG, which was featured by an enrichment of putative proinflammatory taxa including and . Among the significantly decreased oral bacteria in GC patients including , , , , , and , , and are known to reduce nitrite, which may consequently result in an accumulation of carcinogenic N-nitroso compounds. We found that GC can be distinguished accurately from patients with AG and SG (AUC = 0.91) by the random forest model based on the salivary microbiota profiles, and taxa belonging to and have potential as diagnostic biomarkers for GC. Remarkable changes in the salivary microbiota functions were also detected across three histological types, and the upregulation in the isoleucine and valine is in line with a higher level of these amino acids in the gastric tumor tissues that reported by other independent studies. Conclusively, bacteria in the oral cavity may contribute gastric cancer and become new diagnostic biomarkers for GC, but further evaluation against independent clinical cohorts is required. The potential mechanisms of salivary microbiota in participating the pathogenesis of GC may include an accumulation of proinflammatory bacteria and a decline in those reducing carcinogenic N-nitroso compounds.
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http://dx.doi.org/10.3389/fcimb.2021.640309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988213PMC
March 2021

Depicting the composition of gut microbiota in children with tic disorders: an exploratory study.

J Child Psychol Psychiatry 2021 Mar 18. Epub 2021 Mar 18.

School of Medicine, Nankai University, Tianjin, China.

Background: Symptom improvement in children with tic disorder (TD) following fecal microbiota transplantation led us to investigate the gut microbiota in TD. This exploratory study aims to depict the gut microbial profile in patients with TD and explore the impact of dopamine receptor antagonist (DRA) drugs on the composition and metabolic function of the gut microbiota.

Methods: The gut microbiota were profiled in fecal samples of 49 children with TD and 50 matched healthy controls (HC) using shotgun metagenomic sequencing. A random forest (RF) model was constructed using the gut bacterial species to distinguish TD from HC. Associations between clinical metadata and microbial abundance or function were analyzed using MaAsLin2 and Spearman correlation.

Results: The gut microbiota in children with TD was featured by higher abundances of Bacteroides plebeius and Ruminococcus lactaris (a potential pro-inflammatory taxon) and lower abundances of Prevotella stercorea and Streptococcus lutetiensis compared to HC. The constructed RF model accurately distinguished TD from HC based on the gut microbiota profile, resulting in an AUC of 0.884. Significant correlations were observed between tic symptom severity and the abundances of multiple bacterial species and gut microbiota metabolic functions. Multivariate analysis identified an upregulation of 4-aminobutanoate (GABA) degradation in the gut microbiota associated with TD status. The gut microbiota of DRA-treated TD children showed a distinct gut microbiota compared to the treatment-naïve group, represented by an increase in some potential enteric pathogens such as Escherichia coli, a decline in several species including Akkermansia muciniphila, and alterations in various metabolic functions.

Conclusions: Bacterial species promoting inflammatory responses and those modulating neurotransmitters such as GABA may be involved in the pathogenesis of TD. The use of DRA drugs is likely to induce overgrowth of some enteric pathogens and alter the gut microbiota metabolism.
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http://dx.doi.org/10.1111/jcpp.13409DOI Listing
March 2021

The Advances and Challenges of NK Cell-Based Cancer Immunotherapy.

Curr Oncol 2021 Feb 26;28(2):1077-1093. Epub 2021 Feb 26.

Department of Hematology and Oncology, Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies, International Cancer Center, Shenzhen University General Hospital, Shenzhen University Health Science Center, Shenzhen University, Xueyuan AVE 1098, Nanshan District, Shenzhen 518000, Guangdong, China.

Natural killer (NK) cells can be widely applied for cancer immunotherapy due to their ability to lyse tumor targets without prior sensitization or human leukocyte antigens-matching. Several NK-based therapeutic approaches have been attempted in clinical practice, but their efficacy is not sufficient to suppress tumor development mainly because of lacking specificity. To this end, the engineering of NK cells with T cell receptor along with CD3 subunits (TCR-NK) has been developed to increase the reactivity and recognition specificity of NK cells toward tumor cells. Here, we review recent advances in redirecting NK cells for cancer immunotherapy and discuss the major challenges and future explorations for their clinical applications.
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http://dx.doi.org/10.3390/curroncol28020105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025748PMC
February 2021

Diversity of plant and soil microbes mediates the response of ecosystem multifunctionality to grazing disturbance.

Sci Total Environ 2021 Jul 8;776:145730. Epub 2021 Feb 8.

Key Laboratory of Grassland Resources of the Ministry of Education, Key Laboratory of Forage Cultivation, Processing and High Efficient Utilization of the Ministry of Agriculture and Rural Affairs, Inner Mongolia Key Laboratory of Grassland Management and Utilization, College of Grassland, Resources and Environment, Inner Mongolia Agricultural University, No. 29 Erdos St., Hohhot, Inner Mongolia 010011, China.

Biodiversity drives ecosystem functioning across grassland ecosystems. However, few studies have examined how grazing intensity affects ecosystem multifunctionality (EMF) via its effects on plant diversity and soil microbial diversity in dry grasslands. We conducted a 12-year experiment manipulating sheep grazing intensity in a desert steppe of northern China. Through measuring plant species diversity, soil microbial diversity (bacteria diversity) and multiple ecosystem functions (i.e., aboveground net primary productivity, belowground biomass of plant community, temporal stability of ANPP, soil organic matter, moisture, available nitrogen and phosphorus, ecosystem respiration and gross ecosystem productivity), we aimed to understand how grazing intensity affected EMF via changing the diversity of plants and microbes. Our results showed that increasing grazing intensity significantly reduced EMF and most individual ecosystem functions, as well as the diversity of plants and microbes, while EMF and most individual functions were positively related to plant diversity and soil microbial diversity under all grazing intensities. In particular, soil microbial diversity in shallow soil layers (0-5 cm depth) had stronger positive correlations with plant diversity and EMF than in deeper soil layers. Furthermore, structural equation modeling (SEM) showed that grazing reduced EMF mainly via reducing plant diversity, rather than by reducing soil microbial diversity. Thus, plant diversity played a more important role in mediating the response of EMF to grazing disturbance. This study highlights the critical role of above- and belowground diversity in mediating the response of EMF to grazing intensity, which has important implications for biodiversity conservation and sustainability in arid grasslands.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145730DOI Listing
July 2021

Multiscale Modeling of Germinal Center Recapitulates the Temporal Transition From Memory B Cells to Plasma Cells Differentiation as Regulated by Antigen Affinity-Based Tfh Cell Help.

Front Immunol 2020 5;11:620716. Epub 2021 Feb 5.

Bioinformatics Laboratory, Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam Institute for Infection and Immunity, Amsterdam, Netherlands.

Germinal centers play a key role in the adaptive immune system since they are able to produce memory B cells and plasma cells that produce high affinity antibodies for an effective immune protection. The mechanisms underlying cell-fate decisions are not well understood but asymmetric division of antigen, B-cell receptor affinity, interactions between B-cells and T follicular helper cells (triggering CD40 signaling), and regulatory interactions of transcription factors have all been proposed to play a role. In addition, a temporal switch from memory B-cell to plasma cell differentiation during the germinal center reaction has been shown. To investigate if antigen affinity-based Tfh cell help recapitulates the temporal switch we implemented a multiscale model that integrates cellular interactions with a core gene regulatory network comprising BCL6, IRF4, and BLIMP1. Using this model we show that affinity-based CD40 signaling in combination with asymmetric division of B-cells result in switch from memory B-cell to plasma cell generation during the course of the germinal center reaction. We also show that cell fate division is unlikely to be (solely) based on asymmetric division of Ag but that BLIMP1 is a more important factor. Altogether, our model enables to test the influence of molecular modulations of the CD40 signaling pathway on the production of germinal center output cells.
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http://dx.doi.org/10.3389/fimmu.2020.620716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892951PMC
February 2021

The role of ARHGAP9: clinical implication and potential function in acute myeloid leukemia.

J Transl Med 2021 02 12;19(1):65. Epub 2021 Feb 12.

Department of Hematology-Oncology, International Cancer Center, Shenzhen University General Hospital, Shenzhen University Health Science Center, 1098 Xueyuan Ave, Shenzhen, 518060, China.

Background: Rho GTPase activating protein 9 (ARHGAP9) is expressed in various types of cancers and can inactivate Rho GTPases that mainly regulate cytoskeletal dynamics. However, the exact role of ARHGAP9 in acute myeloid leukemia (AML) has yet to be clarified.

Methods: We compared the transcriptional expression, prognosis, differentially expressed genes, functional enrichment, and hub genes in AML patients on the basis of the data published in the following databases: UALCAN, GEPIA, Gene Expression Omnibus, the Human Protein Atlas, Cancer Cell Line Encyclopedia, LinkedOmics, Metascape, and String. Data from the Cancer Genome Atlas database was used to evaluate the correlations between ARHGAP9 expression and various clinicopathological parameters, as well as the significantly different genes associated with ARHGAP9 expression.

Results: We found that ARHGAP9 expression was higher in the tissues and cell lines extracted from patients with AML than corresponding control tissues and other cancer types. ARHGAP9 overexpression was associated with decreased overall survival (OS) in AML. Compared with the ARHGAP9 group, the ARHGAP9 group, which received only chemotherapy, showed significantly worse OS and event-free survival (EFS); however, no significant difference was observed after treatment with autologous or allogeneic hematopoietic stem cell transplantation (auto/allo-HSCT). The ARHGAP9 patients undergoing auto/allo-HSCT also had a significantly better prognosis with respect to OS and EFS than those receiving only chemotherapy. Most overlapping genes of the significantly different genes and co-expression genes exhibited enriched immune functions, suggesting the immune regulation potential of ARHGAP9 in AML. A total of 32 hub genes were identified from the differentially expressed genes, within which the KIF20A had a significant prognostic value for AML.

Conclusions: ARHGAP9 overexpression was associated with poor OS in AML patients and can be used as a prognostic biomarker. AML patients with ARHGAP9 overexpression can benefit from auto/allo-HSCT rather than chemotherapy.
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http://dx.doi.org/10.1186/s12967-021-02733-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881617PMC
February 2021

Microbial and metabolic features associated with outcome of infliximab therapy in pediatric Crohn's disease.

Gut Microbes 2021 Jan-Dec;13(1):1-18

Department of Gastroenterology, Hepatology and Nutrition, Shanghai Children's Hospital, Shanghai Jiao Tong University , Shanghai, China.

Gut microbial dysbiosis and altered metabonomics have been implicated in the pathogenesis of Crohn's disease (CD). The aim of our study was to characterize the gut microbiome structure and metabolic activities in pediatric CD patients with different clinical outcomes after infliximab (IFX) therapy. Fecal samples were collected from 20 healthy children and 29 newly diagnosed pediatric CD patients. 16S rRNA/ITS2 gene sequencing and targeted metabolomics analysis were applied to profile the gut bacterial microbiome, mycobiome, and metabolome, respectively. Pediatric CD patients exhibited lower relative abundances of short-chain fatty acids (SCFAs)-producing bacteria including clusters IV and XIVb, , and , which were correlated with reduced fecal levels of SCFAs. Decreased unconjugated bile acids (BAs) pool size and a lower unconjugated/conjugated BAs ratio were associated with reduced relative abundances of and clusters IV and XIVb which contain bile salt hydrolases (BSH) genes. IFX treatment enriched the BSH-producing bacteria in CD subjects, which may explain a decreased level of conjugated BAs and an increase in unconjugated BAs as well as the unconjugated/conjugated BAs ratio. Furthermore, a sustained response (SR) of IFX therapy was associated with higher abundances of , and , and higher fecal concentrations of amino acids, including L-aspartic acid, linoleic acid, and L-lactic acid at baseline. Our study suggests that the effects of IFX might be partially mediated by enriching bacteria taxa that producing SCFAs and BSH thereby inhibiting inflammation and restoring the BA metabolism. Some fecal bacteria and metabolites may be predictive of outcomes of IFX therapy for pediatric CD patients.
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http://dx.doi.org/10.1080/19490976.2020.1865708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808429PMC
January 2021

Epigenetic silencing of miR564 contributes to the leukemogenesis of t(8;21) acute myeloid leukemia.

Clin Sci (Lond) 2020 12;134(23):3079-3091

Department of Hematology and Oncology, International Cancer Center, Shenzhen University General Hospital, Shenzhen University Health Science Center, Xueyuan AVE 1098, Nanshan District, Shenzhen, Guangdong 518000, P.R. China.

The AML1-ETO oncoprotein, which results from t(8;21) translocation, is considered an initial event of t(8;21) acute myeloid leukemia (AML). However, the precise mechanisms of the oncogenic activity of AML1-ETO is yet to be fully determined. The present study demonstrates that AML1-ETO triggers the heterochromatic silencing of microRNA-564 (miR564) by binding at the AML1 binding site along the miR564 promoter region and recruiting chromatin-remodeling enzymes. Suppression of miR564 enhances the oncogenic activity of the AML1-ETO oncoprotein by directly inhibiting the expression of CCND1 and the DNMT3A genes. Ectopic expression of miR564 can induce retardation of G1/S transition, reperform differentiation, promote apoptosis, as well as inhibit the proliferation and colony formation of AML1-ETO+ leukemia cells in vitro. Enhanced miR564 levels can significantly inhibit the tumor proliferation of t(8;21)AML in vivo. We first identify an unexpected and important epigenetic circuitry of AML1-ETO/miR564/CCND1/DNMT3A that contributes to the leukemogenesis in vitro/vivo of AML1-ETO+ leukemia, indicating that miR564 enhancement could provide a potential therapeutic method for AML1-ETO+ leukemia.
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http://dx.doi.org/10.1042/CS20200786DOI Listing
December 2020

Fecal Microbial Signatures Are Associated With Engraftment Failure Following Umbilical Cord Blood Transplantation in Pediatric Crohn's Disease Patients With Deficiency.

Front Pharmacol 2020 8;11:580817. Epub 2020 Oct 8.

Department of Gastroenterology, Children's Hospital of Fudan University, Shanghai, China.

Objectives: Umbilical cord blood transplantation (UCBT) is associated with a relatively high rate of engraftment failure. This study aimed at exploring whether any fecal microbiota could be associated with engraftment failure following UCBT in Crohn's disease patients with deficiency.

Methods: Thirteen patients were recruited and their 230 fecal samples were collected longitudinally from immediately before conditioning chemotherapy to 8 weeks post the UCBT. The V3-V4 regions of the bacterial 16S rRNA gene were amplified by PCR and sequenced, followed by bioinformatics analyses.

Results: Following the UCBT, 7 out of 13 patients achieved neutrophil and platelet engraftment with a median of 21 and 28 days, respectively (S group), while 6 patients failed to achieve engraftment (F group). In comparison with that in the S group, significantly lower Shannon diversity values on the UCBT day ( = 0.0176) and less abundance of , , , and one taxon of family was detected in the F group, accompanied by significantly higher abundances of four taxa including , , and species during the chemotherapy period as well as UCBT. The abundances of thirty OTUs were correlated significantly with clinical indices.

Conclusions: Microbial indicators of reduced diversity of microbiota and signatures of specific bacterial abundances, such as a lower abundance of , for engraftment failure would require validation. These indicators may help for the risk stratification in patients with deficiency undergoing UCBT.
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http://dx.doi.org/10.3389/fphar.2020.580817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580494PMC
October 2020

Inhibitory Effects of the GG Effector Protein HM0539 on Inflammatory Response Through the TLR4/MyD88/NF-кB Axis.

Front Immunol 2020 5;11:551449. Epub 2020 Oct 5.

Department of Microbiology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China.

Inflammatory bowel disease (IBD) is a chronic and relapsing intestinal inflammatory condition with no effective treatment. Probiotics have gained wide attention because of their outstanding advantages in intestinal health issues. In previous studies, a novel soluble protein, HM0539, which is derived from GG (LGG), showed significant protective effects against murine colitis, but no clear precise mechanism for this effect was provided. In this study, we hypothesized that the protective function of HM0539 might be derived from its modulation of the TLR4/Myd88/NF-κB axis signaling pathway, which is a critical pathway widely involved in the modulation of inflammatory responses. To test this hypothesis, the underlying anti-inflammatory effects and associated mechanisms of HM0539 were determined both in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and in dextran sulfate sodium (DSS)-induced murine colitis. Our results showed that HM0539 inhibited the expression of cyclooxygenase-2 (COX-2) and the expression inducible nitric oxide synthase (iNOS) by down-regulating the activation of their respective promoter, and as a result this inhibited the production of prostaglandin E2 (PGE2) and nitric oxide (NO). Meanwhile, we demonstrated that HM0539 could ultimately modulate the activation of distal NF-κB by reducing the activation of TLR4 and suppressing the transduction of MyD88. However, even though the overexpression of TLR4 or MyD88 obviously reversed the effect of HM0539 on LPS-induced inflammation, HM0539 still retained some anti-inflammatory activity. Consistent with the findings, we found that HM0539 inhibited to a great extent the production of inflammatory mediators associated with the suppression of the TLR4/Myd88/NF-κB axis activation in colon tissue. In conclusion, HM0539 was shown to be a promising anti-inflammatory agent, at least in part through its down-regulation of the TLR4-MyD88 axis as well as of the downstream MyD88-dependent activated NF-κB signaling, and hence might be considered as a potential therapeutic option for IBD.
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http://dx.doi.org/10.3389/fimmu.2020.551449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573360PMC
April 2021

[Establishment of a gp120 transgenic mouse model with 7 nAChR knockout].

Nan Fang Yi Ke Da Xue Xue Bao 2020 Aug;40(8):1184-1191

Department of Microbiology, School of Public Health, Southern Medical University/Guangdong Key Laboratory of Tropical Diseases, Guangzhou 510515, China.

Objective: To construct a HIV-1 gp120 transgenic mouse model (gp120) with 7 nicotinic acetylcholine receptor (7nAChR) gene knockout.

Methods: The 7nAChR gene knockout mice (7R) were crossed with HIV-1gp120 transgenic mice (gp120) to generate F1 generation mice. We selected the F1 mice with the genotype of 7R/gp120 to mate to obtain the F2 mice. The genotypes of the F3 mice were identified by PCR, and the protein expressions in the double transgenic animal model was analyzed by immunohistochemistry. BV2 cells were treated with gp120 protein and 7nAChR inhibitor, and the expressions of IL-1β and TNF- were detected using ELISA.

Results: The results of PCR showed the bands of the expected size in F3 mice. Two F3 mice with successful double gene editing (7R/gp120) were obtained, and immunohistochemistry showed that the brain tissue of the mice did not express 7 nAChR but with high gp120 protein expression. In the cell experiment, treatment with gp120 promoted the secretion of IL-1β and TNF- in BV2 cells, while inhibition of 7nAChR significantly decreased the expression of IL-1β and TNF- ( < 0.001).

Conclusions: By mating gp120 Tg mice with 7R mice, we obtained gp120 transgenic mice with 7nAChR gene deletion, which serve as a new animal model for exploring the role of 7nAChR in gp120-induced neurotoxicity.
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http://dx.doi.org/10.12122/j.issn.1673-4254.2020.08.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429164PMC
August 2020

High-Efficiency Boiling Heat Transfer Interfaces Composed of Electroplated Copper Nanocone Cores and Low-Thermal-Conductivity Nickel Nanocone Coverings.

ACS Appl Mater Interfaces 2020 Sep 19;12(35):39902-39909. Epub 2020 Aug 19.

Functional Materials and Interfaces Lab, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Science, Suzhou 215123, P. R. China.

We demonstrate that copper-based super-thin high-efficiency boiling heat transfer (BHT) interfaces can be obtained via electroplating hierarchical nickel nanocone coverings on the surface of copper nanocone cores. By regulating surface morphologies, wettability, and mass and heat transfer properties of hierarchical structures, we reveal the regulation rules of their performance. Based on this, we obtain the optimized BHT interfaces with a thickness of only 6.4 μm, which shows 228% enhancement in the maximal heat transfer coefficient, 71% enhancement in the critical heat flux, and 68% decrease in the superheat for the onset of nucleate boiling, as compared to the flat copper surface. Our studies clearly indicate that, although the in situ growth of nickel nanocones can unavoidably increase the interface thermal resistance of hierarchical structures, its optimization can still enhance BHT performance. This may be ascribed to the coupling of several interface effects such as more heat transfer area, more nucleation sites, smaller bubble departure sizes, and stronger liquid supply ability caused by hierarchical structures. Our work opens up a new avenue for the development of copper-based super-thin high-efficiency BHT interfaces, which would help enhance the efficiency of energy utilization and heat dissipation of various thermal devices.
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http://dx.doi.org/10.1021/acsami.0c10761DOI Listing
September 2020

Changes of the Gastric Mucosal Microbiome Associated With Histological Stages of Gastric Carcinogenesis.

Front Microbiol 2020 29;11:997. Epub 2020 May 29.

Department of Gastroenterology and Hepatology, The First Medical Centre, Chinese PLA General Hospital, Beijing, China.

The changes of gastric microbiome across stages of neoplastic progression remain poorly understood, especially for intraepithelial neoplasia (IN) which has been recognized as a phenotypic bridge between atrophic/intestinal metaplastic lesions and invasive cancer. The gastric microbiota was investigated in 30 healthy controls (HC), 21 non-atrophic chronic gastritis (CG), 27 gastric intestinal metaplasia (IM), 25 IN, and 29 gastric cancer (GC) patients by 16S rRNA gene profiling. The bacterial diversity, and abundances of phyla Armatimonadetes, Chloroflexi, Elusimicrobia, Nitrospirae, Planctomycetes, Verrucomicrobia, and WS3 reduced progressively from CG, through IM, IN to GC. Actinobacteria, Bacteriodes, Firmicutes, Fusobacteria, SR1, and TM7 were enriched in the IN and GC. At the community level, the proportions of Gram-positive and anaerobic bacteria increased in the IN and GC compared to other histological types, whereas the aerobic and facultatively anaerobic bacteria taxa were significantly reduced in GC. Remarkable changes in the gastric microbiota functions were detected after the formation of IN. The reduced nitrite-oxidizing phylum Nitrospirae together with a decreased nitrate/nitrite reductase functions indicated nitrate accumulation during neoplastic progression. We constructed a random forest model, which had a very high accuracy (AUC > 0.95) in predicating the histological types with as low as five gastric bacterial taxa. In summary, the changing patterns of the gastric microbiota composition and function are highly indicative of stages of neoplastic progression.
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http://dx.doi.org/10.3389/fmicb.2020.00997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272699PMC
May 2020

Confined Growth and Controlled Coalescence/Self-Removal of Condensate Microdrops on a Spatially Heterogeneously Patterned Superhydrophilic-Superhydrophobic Surface.

ACS Appl Mater Interfaces 2020 Jul 22;12(26):29946-29952. Epub 2020 Jun 22.

Functional Materials and Interfaces Lab, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, P. R. China.

Manipulating condensate nucleation, growth, coalescence, and self-removal via bionic super-wettability surfaces has attracted intensive interest because of their significance in fundamental research and technological innovations, for example, water harvesting, power generation, air conditioning, and thermal management. However, it is still a challenge to simultaneously realize confined growth, coalescence, and self-ejection of condensate microdrops, which has not been reported to date. Here, we propose and demonstrate a type of new and more efficient coalescence/self-removal method based on spatially confined growth/coalescence/self-ejection of condensate microdrops, which can be realized using a rationally designed superhydrophobic surface with spatially heterogeneously patterned superhydrophilic microdots (SMDs). Exemplified by superhydrophobic closely packed zinc oxide nanoneedles with SMD patterns, we investigate how the geometric parameters of SMD patterns be designed to simultaneously realize the spatially confined growth/coalescence/self-ejection of patterned microdrops, which are rationalized via theoretical analyses.
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http://dx.doi.org/10.1021/acsami.0c04922DOI Listing
July 2020

Density Maximization of One-Step Electrodeposited Copper Nanocones and Dropwise Condensation Heat-Transfer Performance Evaluation.

ACS Appl Mater Interfaces 2020 May 15;12(21):24512-24520. Epub 2020 May 15.

Functional Materials and Interfaces Lab, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, P. R. China.

Currently, it is still a great challenge to obtain copper-based high-efficient dropwise condensation heat transfer (CHT) interfaces via template-free electrodepositing technologies. Here, we report that the density of template-free electrodeposited copper nanocones can maximally reach 1.5 × 10/mm by the synergistic control of substrate surface roughness, poly(ethylene glycol) (PEG) molecular weight, and PEG concentration. After thiol modification, the densely packed copper nanocone samples can present low-adhesive superhydrophobicity and condensate microdrop self-jumping function at ambient environment. Condensation heat and mass transfer characterizations show that the CHT coefficient of copper surfaces can maximally enhance 98% for 20 °C vapor and 51% for 40 °C vapor by growth of superhydrophobic densely packed copper nanocones. Although the dropwise condensation mode can change from the jumping mode to the mixed jumping and sweeping mode and the shedding-off mode along with the increase of surface subcooling and vapor temperature, the CHT performance of the nanosample is still superior to that of the contrast flat hydrophobic surface during the whole testing range of surface subcooling. As vapor temperature increases to 80 °C, the CHT performance of the nanosample is inferior to that of the contrast sample. The CHT enhancement under low-temperature vapor should be ascribed to the enhancement of small-drop mass transfer ability caused by low-adhesive superhydrophobicity nature of nanosample surfaces. Their performance degradation mainly results from increased drop-drop drag force along with the increase of surface subcooling and vapor temperature. In sharp contrast, the CHT deterioration under high-temperature vapor should be ascribed to larger drop-surface adhesion and drop-drop drag force. The former is caused by vapor penetration, whereas the latter is caused by the dramatically increased nucleation density and growth rate of condensates. These findings would help design and develop copper-based high-efficiency condensation heat transfer interfaces.
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http://dx.doi.org/10.1021/acsami.0c05224DOI Listing
May 2020

Evolution of the Gut Microbiome in Early Childhood: A Cross-Sectional Study of Chinese Children.

Front Microbiol 2020 3;11:439. Epub 2020 Apr 3.

Shenzhen University Clinical Medical Academy, Shenzhen, China.

Temporal development of the human gut microbiome from infancy to childhood is driven by a variety of factors. We surveyed the fecal microbiome of 729 Chinese children aged 0-36 months, aiming to identify the age-specific patterns of microbiota succession, and evaluate the impact of birth mode, gender, geographical location, and gastrointestinal tract symptoms on the shaping of the gut microbiome. We demonstrated that phylogenetic diversity of the gut microbiome increased gradually over time, which was accompanied by an increase in and a reduction in species. Analysis of community-wide phenotypes revealed a succession from aerobic bacteria and anaerobic bacteria to facultative anaerobes, and from Gram-negative to Gram-positive species during gut microbiota development in early childhood. The metabolic functions of the gut microbiome shifted tremendously alongside early physiological development, including an increase in alanine, aspartate, and glutamate metabolism, and a reduction in glutathione, fatty acid, and tyrosine metabolism. During the first year of life, the phylum was less abundant in children born by casarean section compared with those delivered vaginally. The family, a group of facultative anaerobic microorganisms with pathogenic potential, was predominant in preterm infants. No measurable effect of maternal antibiotic exposure on gut microbiota development was found in the first 3 years of life. The relative abundances of and families, and genus were found to be higher in girls than in boys. Among the three first-tier Chinese cities, children born and fed in Beijing had a higher abundance of and families, and Shenzhen children had a higher abundance of . The families , , and were more abundant in children with constipation, whereas the relative abundance of the genus was higher in those with diarrhea.
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http://dx.doi.org/10.3389/fmicb.2020.00439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169428PMC
April 2020

Dysbiosis of Fecal Microbiota in Allergic Rhinitis Patients.

Am J Rhinol Allergy 2020 Sep 27;34(5):650-660. Epub 2020 Apr 27.

Department of ENT and Head and Neck Surgery, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Background: The gut microbiota plays an important role in shaping the immune system and may be closely connected to the development of allergic diseases.

Objective: This study aimed to determine the gut microbiota composition in Chinese allergic rhinitis (AR) patients as compared with healthy controls (HCs).

Methods: We collected stool samples from 93 AR patients and 72 age- and sex-matched HCs. Gut microbiota composition was analyzed using QIIME targeting the 16S rRNA gene. Functional pathways were predicted using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States. Statistical analysis was performed using the program, linear discriminant analysis effect size (LefSe), analysis of QIIME, and statistical analysis of metagenomic profiles, among other tests.

Results: Compared with HCs, AR patients had significantly lower gut-microbiota α-diversity ( < .001). The gut microbiota composition significantly differed between the 2 study groups. At the phylum level, the relative abundance of was higher while those of and were lower in the AR group than in the HC group ( < .001,  < 0.001). At the genus level, , , and ( < .001,  < 0.001) had significantly higher relative abundances in the AR group than in the HC group. LefSe analysis indicated that , , , and were potential biomarkers for AR. In addition, predictive metagenome functional analysis showed that pyruvate, porphyrin, chlorophyll, purine metabolism, and peptidoglycan biosynthesis significantly differed between the AR and HC groups.

Conclusion: A comparison of the gut microbiota of AR patients and HCs suggested that dysbiosis of the fecal microbiota is involved in the development of AR. The present results may reveal key differences and identify targets for preventive or therapeutic intervention.
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http://dx.doi.org/10.1177/1945892420920477DOI Listing
September 2020

Gut Microbiota Dysbiosis Is Associated with Altered Bile Acid Metabolism in Infantile Cholestasis.

mSystems 2019 Dec 17;4(6). Epub 2019 Dec 17.

Department of Gastroenterology, Hepatology and Nutrition, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China

The co-occurrence of gut microbiota dysbiosis and bile acid (BA) metabolism alteration has been reported in several human liver diseases. However, the gut microbiota dysbiosis in infantile cholestatic jaundice (CJ) and the linkage between gut bacterial changes and alterations of BA metabolism have not been determined. To address this question, we performed 16S rRNA gene sequencing to determine the alterations in the gut microbiota of infants with CJ, and assessed their association with the fecal levels of primary and secondary BAs. Our data reveal that CJ infants show marked declines in the fecal levels of primary BAs and most secondary BAs. A decreased ratio of cholic acid (CA)/chenodeoxycholic acid (CDCA) in infants with CJ indicated a shift in BA synthesis from the primary pathway to the alternative BA synthesis pathway. The bacterial taxa enriched in infants with CJ corresponded to the genera , , , and and the family and were negatively correlated with the fecal BA level and the CDCA/CA ratio but positively correlated with the serological indexes of impaired liver function. An increased ratio of deoxycholic acid (DCA)/CA was observed in a proportion of infants with CJ. The bacteria depleted in infants with CJ, including and , were positively and negatively correlated with the fecal levels of BAs and the serological markers of impaired liver function, respectively. In conclusion, the reduced concentration of BAs in the gut of infants with CJ is correlated with gut microbiota dysbiosis. The altered gut microbiota of infants with CJ likely upregulates the conversion from primary to secondary BAs. Liver health, fecal bile acid (BA) concentrations, and gut microbiota composition are closely connected. BAs and the microbiome influence each other in the gut, where bacteria modify the BA profile, while intestinal BAs regulate the growth of commensal bacteria, maintain the barrier integrity, and modulate the immune system. Previous studies have found that the co-occurrence of gut microbiota dysbiosis and BA metabolism alteration is present in many human liver diseases. Our study is the first to assess the gut microbiota composition in infantile cholestatic jaundice (CJ) and elucidate the linkage between gut bacterial changes and alterations of BA metabolism. We observed reduced levels of primary BAs and most secondary BAs in infants with CJ. The reduced concentration of fecal BAs in infantile CJ was associated with the overgrowth of gut bacteria with a pathogenic potential and the depletion of those with a potential benefit. The altered gut microbiota of infants with CJ likely upregulates the conversion from primary to secondary BAs. Our study provides a new perspective on potential targets for gut microbiota intervention directed at the management of infantile CJ.
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http://dx.doi.org/10.1128/mSystems.00463-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918028PMC
December 2019

Nine new species of genus Homoneura from Qinling mountains in China (Diptera: Lauxaniidae).

Authors:
Xuefeng Gao L I Shi

Zootaxa 2019 May 21;4608(3):zootaxa.4608.3.1. Epub 2019 May 21.

College of Agronomy, Inner Mongolia Agricultural University, Hohhot 010019, China.

Nine species from Qinling Mountains in China are described as new to science: Homoneura (Homoneura) anadaequata sp. nov., Homoneura (H.) bicolorata sp. nov., Homoneura (H.) dagupingensis sp. nov., Homoneura (H.) longiacutata sp. nov., Homoneura (H.) longicurva sp. nov., Homoneura (H.) miaoae sp. nov., Homoneura (H.) platimarginata sp. nov., Homoneura (H.) similicurvata sp. nov. and Homoneura (H.) spectabilis sp. nov. from Homoneura (H.) henanensis group. Keys to separate known species from new species are presented.
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http://dx.doi.org/10.11646/zootaxa.4608.3.1DOI Listing
May 2019

Development and Validation of Quantitative Real-Time PCR for the Detection of Residual CHO Host Cell DNA and Optimization of Sample Pretreatment Method in Biopharmaceutical Products.

Biol Proced Online 2019 1;21:17. Epub 2019 Sep 1.

The fourth research department, Lanzhou Institute of Biological Products Co., Ltd, No.888 Yanchang Road, Chengguan District, Lanzhou City, Gansu Province China.

Background: The presence of residual DNA carried by biological products in the body may lead to an increased oncogenicity, infectivity, and immunomodulatory risk. Therefore, current agencies including WHO, EU, and the FDA limited the accepted amounts of residual DNA (less than 10 ng or 100 pg/dose). Among the methods of detecting residual DNA, qPCR is considered to be the most practical for residual DNA quantitation due to its sensitivity, accuracy, precision, and time-saving.

Results: In this study, the detection capacity of this method was determined by comparing the detected concentration of the commercial kit and the self-designed primer/probe set after the same treatment of the extraction method. Then, a universal sample pretreatment method based on a co-precipitant was optimized. The validation results demonstrated that the method has appropriate specificity, sensitivity, accuracy, and precision according to ICH guidelines. The limit of detection and quantitation reached 3 fg/ul and 0.3 pg/reaction respectively, which satisfies the requirement of limit of residual DNA detection in biologics. Spike recovery (82.3-105.7%) showed that the proposed qPCR assay was accurate and has good extraction efficiency. Moreover, the precision of the method based on intra- and inter-assay was 0.065-0.452% and 0.471-1.312%, respectively.

Conclusions: These results all indicated that the method for determination of residual DNA in biological products expressed from CHO cells is sensitive, accurate and robust.
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http://dx.doi.org/10.1186/s12575-019-0105-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717637PMC
September 2019

A glutathione responsive nitric oxide release system based on charge-reversal chitosan nanoparticles for enhancing synergistic effect against multidrug resistance tumor.

Nanomedicine 2019 08 29;20:102015. Epub 2019 May 29.

Key Laboratory of Functional Polymer Materials of the Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, China; Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, China. Electronic address:

The combination therapy of nitric oxide (NO) and anticancer drug was developed for reversing multidrug resistance (MDR). In order to avoid NO release during the blood circulation, and realize pinpointed release in the tumor cells, we designed a tumor-specific NO-release system based on 10-hydroxycamptothecin (HCPT)-loaded charge-reversal chitosan nanoparticles and covalently linked phenylsulfonyl furoxan (glutathione (GSH)-responsive NO donor) on the surface. The results showed that only 6.0% of NO was eventually released under physiology condition (pH 7.4 and 2 μM GSH) within 8 h. In contrast, 93.0% of NO was released within 4 h in the presence of 10 mM GSH. Western blot result displayed the P-glycoprotein expression was significantly decreased by 50.1%. Hence, this system performed remarkable cytotoxicity in vitro and the highest tumor inhibition rate (79.7%) comparing with free HCPT group (20.7%) in vivo. Such GSH-responsive NO-release system is a promising candidate with prominent therapeutic effect against MDR tumor.
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http://dx.doi.org/10.1016/j.nano.2019.102015DOI Listing
August 2019

Fluorescence-enhanced covalent organic framework nanosystem for tumor imaging and photothermal therapy.

Nanoscale 2019 May;11(21):10429-10438

Key Laboratory of Functional Polymer Materials of Ministry of Education, College of Chemistry, Nankai University, Tianjin 300071, China.

Fluorescent dyes, as a key factor in fluorescence imaging, usually exhibit a low signal-to-noise ratio (SNR) due to the limited loading capacities of delivery systems (usually less than 10.0 wt%) and their uncontrolled release. Herein, we developed a type of pH-responsive nanoplatform (MnO2/[email protected]&BSA) based on a zinc porphyrin covalent organic framework (COF), in which the zinc porphyrin (ZnPor) loading rate is 22.5 wt%. At pH = 7.4, the interlinked ZnPor in the assembly state did not show a fluorescence signal ("off" state). Together with the pH-triggered disintegration of ZnCOF in tumor cells (pH = 5.5), the scattered ZnPor displayed an obvious fluorescence signal recovery ("on" state). Simultaneously, the shed BSA-coated gold nanoparticles ingeniously caused the fluorescence signal to be further amplified through the metal-enhanced fluorescence effect, which was about 3.0-fold higher in vivo than in the free ZnPor group. Combined with the excellent photothermal therapy effect by the nanoplatform itself with the tumor inhibition rate of 79.5%, this nanosystem effectively solves the problem of low loading capacities and imaging SNR by traditional delivery systems, and successfully develops the potential of COFs for fluorescence imaging, achieving the purpose of integration of diagnosis and treatment.
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http://dx.doi.org/10.1039/c9nr02140jDOI Listing
May 2019

Near-infrared-light induced nanoparticles with enhanced tumor tissue penetration and intelligent drug release.

Acta Biomater 2019 05 11;90:314-323. Epub 2019 Apr 11.

Key Laboratory of Functional Polymer Materials of the Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China.

Tumor tissue presents much denser and stiffer extracellular matrix (ECM), which can hinder the penetration of most nanoparticles (NPs) and contribute to the tumor cell proliferation. Here, NIR-activated losartan was encapsulated in hollow mesoporous prussian blue nanoparticles (HMPBs) to degrade ECM. The results showed that losartan enhanced the penetration of DOX, 1.47% of the injected dose (ID) of DOX reached the tumor tissues, which was 3.00-fold higher than the control group (0.49%). In addition, as the existence of thermo-sensitive lauric acid, (Losartan + DOX)@HMPBs could achieve near "zero drug leakage" during blood circulation, so as to reduce the damage of DOX to normal tissues. Furthermore, the animal experiments proved tumor inhibition ability of (Losartan + DOX)@HMPBs in synergistic of photothermal/chemotherapy, with the tumor growth inhibition rate of 81.3%. Taken together, these findings can be a candidate for developing vectors with enhanced tumor penetration and therapeutic effect in future clinical application. STATEMENT OF SIGNIFICANCE: Due to the existence of denser extracellular matrices (ECM), only 0.7% of the administered nanoparticles dose is delivered to tumor, which will limit the tumors' therapeutic effect. Degradation of ECM can improve the penetration of nanoparticles in tumors. However, no researchers has encapsulated losartan in nanoparticles to degrade ECM. Herein, we developed a NIR induced losartan and DOX co-delivery system based on hollow mesoporous prussian blue nanoparticles (HMPBs) to degrade ECM and improve the penetration of nanoparticles in tumors. The prepared nanoparticles can also acheive near "zero drug leakage" during blood circulation and "fixed-point drug release" in tumor, so as to reduce the damage of DOX to normal tissues. We believe the prepared nanoparticles provide a new platform for cancer treatment.
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http://dx.doi.org/10.1016/j.actbio.2019.04.022DOI Listing
May 2019

Dural lymphatics regulate clearance of extracellular tau from the CNS.

Mol Neurodegener 2019 02 27;14(1):11. Epub 2019 Feb 27.

Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, 63110, USA.

Background: Alzheimer's disease is characterized by two main neuropathological hallmarks: extracellular plaques of amyloid-β (Aβ) protein and intracellular aggregates of tau protein. Although tau is normally a soluble monomer that bind microtubules, in disease it forms insoluble, hyperphosphorylated aggregates in the cell body. Aside from its role in AD, tau is also involved in several other neurodegenerative disorders collectively called tauopathies, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), some forms of frontotemporal dementia, and argyrophilic grain disease (AGD). The prion hypothesis suggests that after an initial trigger event, misfolded forms of tau are released into the extracellular space, where they spread through different brain regions, enter cells, and seeding previously normal forms. Thus understanding mechanisms regulating the clearance of extracellular tau from the CNS is important. The discovery of a true lymphatic system in the dura and its potential role in mediating Aβ pathology prompted us to investigate its role in regulating extracellular tau clearance.

Methods: To study clearance of extracellular tau from the brain, we conjugated monomeric human tau with a near-infrared dye cypate, and injected this labeled tau in the parenchyma of both wild-type and K14-VEGFR3-Ig transgenic mice, which lack a functional CNS lymphatic system. Following injection we performed longitudinal imaging using fluorescence molecular tomography (FMT) and quantified fluorescence to calculate clearance of tau from the brain. To complement this, we also measured tau clearance to the periphery by measuring plasma tau in both groups of mice.

Results: Our results show that a significantly higher amount of tau is retained in the brains of K14-VEGFR3-Ig vs. wild type mice at 48 and 72 h post-injection and its subsequent clearance to the periphery is delayed. We found that clearance of reference tracer human serum albumin (HSA) was also significantly delayed in the K14-VEGFR3-Ig mice.

Conclusions: The dural lymphatic system appears to play an important role in clearance of extracellular tau, since tau clearance is impaired in the absence of functional lymphatics. Based on our baseline characterization of extracellular tau clearance, future studies are warranted to look at the interaction between tau pathology and efficiency of lymphatic function.
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http://dx.doi.org/10.1186/s13024-019-0312-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391770PMC
February 2019