Publications by authors named "Jianmin Wang"

483 Publications

Design and linkage optimization of ursane-thalidomide-based PROTACs and identification of their targeted-degradation properties to MDM2 protein.

Bioorg Chem 2021 Apr 8;111:104901. Epub 2021 Apr 8.

Institute of Chemical Industry of Forest Products, Chinese Academy of Forest, Nanjing 210042, Jiangsu, PR China. Electronic address:

Ursolic acid (UA) is an accessible triterpenoid, widely applied in the design and synthesis of antitumor compounds. However, the mechanism of its anti-tumor effect is still unclear. To verify the molecular mechanism of its biological activity, based on the bifunctional activity of ubiquitination and subsequent proteasomal degradation of the target protein of the proteolysis-targeting chimeras (PROTACs) strategy, here we report the design, synthesis and cellular activity of six UA PROTAC hydrochloride compounds 1A-1F, in which UA acts as the binding ligand of the PROTAC and is linked to thalidomide (E3 ligand) through a series of synthetic linkers. The results revealed that compound 1B, connected with a POE-3 (3-Polyoxyether) possessed remarkable in vitro antitumor activity (with the IC value of 0.23 ~ 0.39 μM against A549, Huh7, HepG2). WB results demonstrated that the administration of compound 1B induced significant degradation of MDM2 (only 25% to that of SM1), and promoted the expression of P21 and PUMA proteins, and thus inhibited the proliferation (77.67% of 1B vs 60.37% of CON in G1 phase) and promoted the apoptosis (26.74% of 1B vs 3.35% of CON) of A549 cells. This work demonstrated proof of designing the efficient target protein degradation by UA PROTACs with the POE linkers. In addition, we confirmed that UA possess the characteristic of targeted-binding the protein of murine double minute-2 protein (MDM2). This will lay a foundation for the comprehensive utilization of forest natural compound UA.
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http://dx.doi.org/10.1016/j.bioorg.2021.104901DOI Listing
April 2021

Clinical risk score for predicting invasive fungal disease after allogeneic hematopoietic stem cell transplantation: Analysis of the China Assessment of Antifungal Therapy in Hematological Diseases (CAESAR) study.

Transpl Infect Dis 2021 Apr 7:e13611. Epub 2021 Apr 7.

Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University Institute of Hematology, Peking University, People's Hospital, Beijing, People's Republic of China.

Background And Objective: Invasive fungal disease (IFD) is associated with a high mortality for patients with hematological malignancies undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aimed not only to develop a proven/probable IFD risk-scoring model but to identify high-risk populations that would benefit from anti-fungal prophylaxis.

Methods: Data from the China Assessment of Antifungal Therapy in Hematological Diseases (CAESAR) study were retrieved, and all patients (n = 1053) undergoing allo-HSCT were randomly divided into the training set (n = 685) for model development and the validation set (n = 368) for model verification. A weighted risk score for proven or probable IFD was established through multivariate logistic regression analysis.

Results: The study population had a mean age of 28.95 years and the majority underwent myeloablative transplantation in complete remission 1 (53.4%). Five risk factors of IFD were identified, namely neutropenia lasting longer than 14 days, corticosteroid use, diabetes, haploidentical donor, and unrelated donor. Based on the risk score for IFD, the patients were categorized into three groups: low risk (score 0-4, 1.5%-4.0%), intermediate risk (score 5-8, 9.8%), and high risk (score>8, 24.7%-14.0%). Anti-fungal prophylaxis may provide benefits for patients with intermediate (8.5% vs. 18.5%, P = .0085) or high risk (19.4% vs. 30.8%, P = .4651) but not low risk (2.1% vs. 3.8%, P = .6136) of IFD.

Conclusion: A practical weighted risk score for IFD in patients receiving allo-HSCT was established, which can aid decision-making regarding the administration of anti-fungal prophylaxis.
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http://dx.doi.org/10.1111/tid.13611DOI Listing
April 2021

A spatial-temporal gated attention module for molecular property prediction based on molecular geometry.

Brief Bioinform 2021 Apr 5. Epub 2021 Apr 5.

College of Computer Science and Electronic Engineering, Hunan University, Changsha 410205, China.

Motivation: Geometry-based properties and characteristics of drug molecules play an important role in drug development for virtual screening in computational chemistry. The 3D characteristics of molecules largely determine the properties of the drug and the binding characteristics of the target. However, most of the previous studies focused on 1D or 2D molecular descriptors while ignoring the 3D topological structure, thereby degrading the performance of molecule-related prediction. Because it is very time-consuming to use dynamics to simulate molecular 3D conformer, we aim to use machine learning to represent 3D molecules by using the generated 3D molecular coordinates from the 2D structure.

Results: We proposed Drug3D-Net, a novel deep neural network architecture based on the spatial geometric structure of molecules for predicting molecular properties. It is grid-based 3D convolutional neural network with spatial-temporal gated attention module, which can extract the geometric features for molecular prediction tasks in the process of convolution. The effectiveness of Drug3D-Net is verified on the public molecular datasets. Compared with other deep learning methods, Drug3D-Net shows superior performance in predicting molecular properties and biochemical activities.

Availability And Implementation: https://github.com/anny0316/Drug3D-Net.

Supplementary Data: Supplementary data are available online at https://academic.oup.com/bib.
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http://dx.doi.org/10.1093/bib/bbab078DOI Listing
April 2021

Long-term persistent immunogenicity after successful standard and triple-dosed hepatitis B vaccine in hemodialysis patients: A 3-year follow-up study in China.

Vaccine 2021 Apr 2;39(18):2537-2544. Epub 2021 Apr 2.

School of Public Health, Shanxi Medical University, Taiyuan 030001, Shanxi, China; Center of Clinical Epidemiology and Evidence Based Medicine, Shanxi Medical University, Taiyuan 030001, Shanxi, China. Electronic address:

Background: Although the efficacy of hepatitis B vaccines among hemodialysis patients has been documented, the long-term persistence of immunogenicity in this population remains largely unknown. We explored the long-term persistence of immunogenicity induced by different hepatitis B vaccine regimens in hemodialysis patients.

Methods: In initial study, we conducted a randomized, multicenter, double-blind, parallel-controlled trial among hemodialysis patients in 13 hospitals in Shanxi Province, China. A total of 352 hemodialysis patients were allocated to receive 3-dose 20 μg (IM20 group) and 3-dose 60 μg (IM60 group) recombinant hepatitis B vaccine at months 0, 1, and 6. Vaccine-induced immune responses were measured at month 7. In this study, the responders (anti-HBs ≥ 10 mIU/mL) were followed up at months 18, 24, 30, 36 and 42, respectively. We used the generalized log-rank test and generalized estimating equations (GEE) to analyze the long-term durability of responses and the kinetics of anti-HBs levels, respectively.

Results: A total of 284 patients were involved in the extended follow-up period. The duration of vaccine-induced response with 75% of patients maintained protective antibody were 12 months and 18 months in the IM20 group and IM60 group, respectively (P = 0.291). The long-term persistent immunogenicity induced by 3-dose 60 μg was more satisfactory than that by 3-dose 20 μg hepatitis B vaccine in patients with hemodialysis duration ≥ five years (P = 0.023). The peak anti-HBs levels in 100-1000 mIU/mL or ≥ 1000 mIU/mL were more likely to maintain long-term protective antibody compared to anti-HBs levels in 10-100 mIU/mL (P < 0.05). The kinetic profile was similar between the two groups (P = 0.334).

Conclusion: High-dose 60 μg hepatitis B vaccine could lead a satisfactory long-term durability of immunogenicity among patients with hemodialysis duration of five years or more. Peak anti-HBs level after vaccination was associated with the long-term persistence of immunogenicity.
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http://dx.doi.org/10.1016/j.vaccine.2021.03.074DOI Listing
April 2021

MUFFIN: Multi-Scale Feature Fusion for Drug-Drug Interaction Prediction.

Bioinformatics 2021 Mar 15. Epub 2021 Mar 15.

School of Computer Science and Engineering, Hunan University, Changsha, 410012, China.

Motivation: Adverse drug-drug interactions (DDIs) are crucial for drug research and mainly cause morbidity and mortality. Thus, the identification of potential DDIs is essential for doctors, patients, and the society. Existing traditional machine learning models rely heavily on handcraft features and lack generalization. Recently, the deep learning approaches that can automatically learn drug features from the molecular graph or drug-related network have improved the ability of computational models to predict unknown DDIs. However, previous works utilized large labeled data and merely considered the structure or sequence information of drugs without considering the relations or topological information between drug and other biomedical objects (e.g., gene, disease, and pathway), or considered knowledge graph (KG) without considering the information from the drug molecular structure.

Results: Accordingly, to effectively explore the joint effect of drug molecular structure and semantic information of drugs in knowledge graph for DDI prediction, we propose a multi-scale feature fusion deep learning model named MUFFIN. MUFFIN can jointly learn the drug representation based on both the drug-self structure information and the KG with rich bio-medical information. In MUFFIN, we designed a bi-level cross strategy that includes cross- and scalar-level components to fuse multi-modal features well. MUFFIN can alleviate the restriction of limited labeled data on deep learning models by crossing the features learned from large-scale KG and drug molecular graph. We evaluated our approach on three datasets and three different tasks including binary-class, multi-class, and multi-label DDI prediction tasks. The results showed that MUFFIN outperformed other state-of-the-art baselines.

Availability: The source code and data are available at https://github.com/xzenglab/MUFFIN.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btab169DOI Listing
March 2021

Exploration of the relationship between intestinal flora changes and gut acute graft-versus-host disease after hematopoietic stem cell transplantation.

Transl Pediatr 2021 Feb;10(2):283-295

Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Background: Acute graft-versus-host disease (aGVHD) is a life-threatening factor for post-hematopoietic stem cell transplantation (HSCT) patients. To investigate the relationship between intestinal flora changes and gut aGVHD after HSCT, we performed this cross-sectional study.

Methods: We selected children from our medical center from July 2016 to January 2017. Fifty-six samples from 42 patients and 6 samples from normal children met the study criteria and were analyzed. Fecal 16S RNA sequencing was completed before transplantation or on days 7, 28 or 100 post-transplantation. The intestinal infection and GVHD clinical data were retrospectively analyzed, and the survival risk factors were analyzed. Correlation analysis was performed with the feces bioinformatic data.

Results: The GVHD group alpha diversity was the lowest, which was significantly different than that of the non-diarrhea group (P value=0.032). A richer posttransplantation relative abundance of was conducive to survival, while that of and was not. Similarly, a rich relative abundance of , and in the intestinal flora before HSCT contributed to patient death thereafter. Regarding diarrhea, the GVHD group exhibited a richer and relative abundances, which showed strong correlations with diarrhea severity. , and were richer in relative abundance in the intestinal infection group and correlated with pretransplant characteristics.

Conclusions: The gut microbiota diversity was lowest when gut aGVHD occurred, which was consistent with the clinically higher mortality rate and greater treatment difficulty. played an important role in gut aGVHD and diarrhea severity. led to infectious diarrhea after HSCT. Specific bacteria were biomarkers for survival: , and from the intestinal flora after HSCT and , and before HSCT.
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http://dx.doi.org/10.21037/tp-20-208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944174PMC
February 2021

Ultra-High-Resolution IonStar Strategy Enhancing Accuracy and Precision of MS1-Based Proteomics and an Extensive Comparison with State-of-the-Art SWATH-MS in Large-Cohort Quantification.

Anal Chem 2021 03 9;93(11):4884-4893. Epub 2021 Mar 9.

Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York 14214, United States.

Quantitative proteomics in large cohorts is highly valuable for clinical/pharmaceutical investigations but often suffers from severely compromised reliability, accuracy, and reproducibility. Here, we describe an ultra-high-resolution IonStar method achieving reproducible protein measurement in large cohorts while minimizing the ratio compression problem, by taking advantage of the exceptional selectivity of ultra-high-resolution (UHR)-MS1 detection (240k_FWHM@/ = 200). Using mixed-proteome benchmark sets reflecting large-cohort analysis with technical or biological replicates ( = 56), we comprehensively compared the quantitative performances of UHR-IonStar vs a state-of-the-art SWATH-MS method, each with their own optimal analytical platforms. We confirmed a cutting-edge micro-liquid chromatography (LC)/Triple-TOF with Spectronaut outperforms nano-LC/Orbitrap for SWATH-MS, which was then meticulously developed/optimized to maximize sensitivity, reproducibility, and proteome coverage. While the two methods with distinct principles (i.e., MS1- vs MS2-based) showed similar depth-of-analysis (∼6700-7000 missing-data-free proteins quantified, 1% protein-false discovery rate (FDR) for entire set, 2 unique peptides/protein) and good accuracy/precision in quantifying high-abundance proteins, UHR-IonStar achieved substantially superior quantitative accuracy, precision, and reproducibility for lower-abundance proteins (a category that includes most regulatory proteins), as well as much-improved sensitivity/selectivity for discovering significantly altered proteins. Furthermore, compared to SWATH-MS, UHR-IonStar showed markedly higher accuracy for a single analysis of each sample across a large set, which is an inadequately investigated albeit critical parameter for large-cohort analysis. Finally, we compared UHR-IonStar vs SWATH-MS in measuring the time courses of altered proteins in paclitaxel-treated cells ( = 36), where dysregulated biological pathways have been very well established. UHR-IonStar discovered substantially more well-recognized biological processes/pathways induced by paclitaxel. Additionally, UHR-IonStar showed markedly superior ability than SWATH-MS in accurately depicting the time courses of well known to be paclitaxel-induced biomarkers. In summary, UHR-IonStar represents a reliable, robust, and cost-effective solution for large-cohort proteomic quantification with excellent accuracy and precision.
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http://dx.doi.org/10.1021/acs.analchem.0c05002DOI Listing
March 2021

Experimental and Analytical Study on Creep Characteristics of Box Section Bamboo-Steel Composite Columns under Long-Term Loading.

Materials (Basel) 2021 Feb 19;14(4). Epub 2021 Feb 19.

College of Civil Engineering & Architecture, Qingdao Agricultural University, Qingdao 266109, China.

To expand the application of bamboo as a building material, a new type of box section composite column that combined bamboo and steel was considered in this paper. The creep characteristics of eight bamboo-steel composite columns with different parameters were tested to evaluate the effects of load level, section size and interface type under long-term loading. Then, the deformation development of the composite column under long-term loading was observed and analyzed. In addition, the creep-time relationship curve and the creep coefficient were created. Furthermore, the creep model of the composite column was proposed based on the relationship between the creep of the composite column and the creep of bamboo, and the calculated value of creep was compared with the experimental value. The experimental results showed that the creep development of the composite column was fast at first, and then became stable after about 90 days. The creep characteristics were mainly affected by long-term load level and section size. The creep coefficient was between 0.160 and 0.190. Moreover, the creep model proposed in this paper was applicable to predict the creep development of bamboo-steel composite columns. The calculation results were in good agreement with the experimental results.
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http://dx.doi.org/10.3390/ma14040983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923265PMC
February 2021

Eco-Friendly Preparation of Epoxy-Rich Graphene Oxide for Wound Healing.

ACS Biomater Sci Eng 2021 02 25;7(2):752-763. Epub 2021 Jan 25.

Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China.

Despite the ever-growing endangerment caused by the multidrug resistance (MDR) of bacteria, the development of effective antibacterial materials still remains a global challenge. Current antibiotic therapies cannot simultaneously inactivate bacteria and accelerate wound healing. This study aimed to originally separate the intercalation of MnO and the oxidation processes to synthesize epoxy-rich graphene oxide (erGO) nanofilms via an eco-friendly synthetic route, which possessed low density and large lamellar distribution and was rich in epoxide. Importantly, the MnO could be separated from the product and recycled for preparing the next generation of erGO nanofilms, which was quite economical and eco-friendly. The erGO nanofilm was capable of successfully inhibiting Gram-negative bacteria and even had excellent growth-inhibitory effects on Gram-positive bacteria including multidrug resistance (MDR) bacteria, as evidenced by antibacterial phenomena. Additionally, the erGO nanofilm with high C density formed from epoxide exerted excellent antibacterial effects through tight membrane wrapping and induction of lipid peroxidation. The wound-healing property of the erGO nanofilm was evaluated via treatments of wounds infected by () and (), which not only killed bacteria but also accelerated wound healing in mice with a skin infection. The novel erGO nanofilm with dual antimicrobial mechanisms might serve as a promising multifunctional antimicrobial agent for medical wound dressing with high biocompatibility.
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http://dx.doi.org/10.1021/acsbiomaterials.0c01598DOI Listing
February 2021

RNA editing enzyme APOBEC3A promotes pro-inflammatory M1 macrophage polarization.

Commun Biol 2021 Jan 22;4(1):102. Epub 2021 Jan 22.

Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14203, USA.

Pro-inflammatory M1 macrophage polarization is associated with microbicidal and antitumor responses. We recently described APOBEC3A-mediated cytosine-to-uracil (C > U) RNA editing during M1 polarization. However, the functional significance of this editing is unknown. Here we find that APOBEC3A-mediated cellular RNA editing can also be induced by influenza or Maraba virus infections in normal human macrophages, and by interferons in tumor-associated macrophages. Gene knockdown and RNA_Seq analyses show that APOBEC3A mediates C>U RNA editing of 209 exonic/UTR sites in 203 genes during M1 polarization. The highest level of nonsynonymous RNA editing alters a highly-conserved amino acid in THOC5, which encodes a nuclear mRNA export protein implicated in M-CSF-driven macrophage differentiation. Knockdown of APOBEC3A reduces IL6, IL23A and IL12B gene expression, CD86 surface protein expression, and TNF-α, IL-1β and IL-6 cytokine secretion, and increases glycolysis. These results show a key role of APOBEC3A cytidine deaminase in transcriptomic and functional polarization of M1 macrophages.
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http://dx.doi.org/10.1038/s42003-020-01620-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822933PMC
January 2021

T cells depend on Tcf1-intrinsic HDAC activity to suppress CTLA4 and guard B-cell help function.

Proc Natl Acad Sci U S A 2021 01;118(2)

Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, NJ 07110;

Precise regulation of coinhibitory receptors is essential for maintaining immune tolerance without interfering with protective immunity, yet the mechanism underlying such a balanced act remains poorly understood. In response to protein immunization, T follicular helper (T) cells lacking Tcf1 and Lef1 transcription factors were phenotypically normal but failed to promote germinal center formation and antibody production. Transcriptomic profiling revealed that Tcf1/Lef1-deficient T cells aberrantly up-regulated CTLA4 and LAG3 expression, and treatment with anti-CTLA4 alone or combined with anti-LAG3 substantially rectified B-cell help defects by Tcf1/Lef1-deficient T cells. Mechanistically, Tcf1 and Lef1 restrain chromatin accessibility at the and loci. Groucho/Tle corepressors, which are known to cooperate with Tcf/Lef factors, were essential for T cell expansion but dispensable for repressing coinhibitory receptors. In contrast, mutating key amino acids in histone deacetylase (HDAC) domain in Tcf1 resulted in CTLA4 derepression in T cells. These findings demonstrate that Tcf1-instrinsic HDAC activity is necessary for preventing excessive CTLA4 induction in protein immunization-elicited T cells and hence guarding their B-cell help function.
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http://dx.doi.org/10.1073/pnas.2014562118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812797PMC
January 2021

How Inclusive Leadership Enhances Follower Taking Charge: The Mediating Role of Affective Commitment and the Moderating Role of Traditionality.

Psychol Res Behav Manag 2020 1;13:1103-1114. Epub 2020 Dec 1.

School of Economics and Management, Nanjing University of Science and Technology, Nanjing, People's Republic of China.

Purpose: Leaders try to stimulate follower taking charge to promote organizational change and effectiveness in current increasingly complex and changing environment. Based on social identity theory, we developed a mediated moderation model in which affective commitment was theorized as a mediating mechanism underlining why followers feel motivated to taking charge with the supervision of inclusive leadership. Furthermore, traditionality should be a relevant boundary condition to moderate such a relationship in China.

Methods: There was three times lagged research conducted at the city of Shanghai, Shenzhen, and Nanjing. A series of valid questionnaires were accomplished by 246 participants, including the inclusive leadership, affective commitment, traditionality, and follower taking charge. Our model adopted hierarchical regression analysis to explore hypothesis.

Results: Inclusive leadership is positively related to affective commitment (β= 0.589, p < 0.001). Affective commitment was positively related to follower taking charge (β= 0.165, p < 0.01). Affective commitment mediates the relationship between inclusive leadership and taking charge with 95% bias-corrected confidence intervals [0.068, 0.233]. Interactive effect of affective commitment and traditionality on follower taking charge was also significant (β=-0.189, p <0.001), and the effect of affective commitment on follower taking charge was more pronounced and positive with low (b = 0.361, p <0.001) rather than high (b =0.172, ns.) level of affective commitment. Moreover, the indirect effect of inclusive leadership on taking charge through affective commitment was significant when traditionality was low (b = 0.270, 95% CI = [0.179, 0.371]), the indirect effect became insignificant with high traditionality (b = 0.046, 95% CI = [-0.034, 0.123]).

Conclusion: Our study shows that affective commitment mediates the relationship between inclusive leadership and follower taking charge. Moreover, the influence of affective commitment on follower taking charge was moderated by traditionality. Affective commitment was positively associated with taking charge only for followers with low traditionality. Additionally, the mediated moderation relationship between inclusive leadership and follower taking charge via affective commitment was stronger under low traditionality.
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http://dx.doi.org/10.2147/PRBM.S280911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720287PMC
December 2020

Enhanced biological nitrogen removal under low dissolved oxygen in an anaerobic-anoxic-oxic system: Kinetics, stoichiometry and microbial community.

Chemosphere 2021 Jan 29;263:128184. Epub 2020 Aug 29.

Department of Civil, Architectural and Environmental Engineering, Missouri University of Science and Technology, Rolla, MO, 65409, USA.

A lab-scale anaerobic-anoxic-oxic system was used to investigate the nitrogen removal mechanism under low dissolved oxygen (DO) conditions. When DO was decreased from 2 to 0.5 mg L, chemical oxygen demand (COD) and NH removals were not influenced, while total nitrogen removal increased from 69% to 79%. Further batch tests indicated that both the specific nitrification rate and denitrification rate greatly increased under low DO conditions. When DO was decreased from 2 to 0.5 mg L, the oxygen half saturation constant value for ammonia oxidizing bacteria (AOB) decreased from 0.39 to 0.29 mg-O L, and for nitrite oxidizing bacteria (NOB), it reduced from 0.29 to 0.09 mg-O L. Correspondingly, the observed yield coefficients increased from 0.05 to 0.10 mg-cell mg-N for AOB, and from 0.02 to 0.06 mg-cell mg-N for NOB. High-throughput sequencing revealed that the relative abundances of AOB increased from 6.13% to 6.54%, Nitrospira-like NOB increased from 3.67% to 6.50%, and denitrifiers increased from 2.84% to 7.04%. Improved simultaneous nitrification and denitrification under low DO conditions contributed to the enhanced nitrogen removal.
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http://dx.doi.org/10.1016/j.chemosphere.2020.128184DOI Listing
January 2021

Opportunities for Antigen Discovery in Metastatic Breast Cancer.

Front Immunol 2020 30;11:570049. Epub 2020 Oct 30.

Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.

Immune checkpoint inhibitor-based immunotherapy (ICI) of breast cancer is currently efficacious in a fraction of triple negative breast cancers (TNBC) as these cancers generally carry high tumor mutation burden (TMB) and show increased tumor infiltration by CD8 T cells. However, most estrogen receptor positive breast cancers (ERBC) have low TMB and/or are infiltrated with immunosuppressive regulatory T cells (Tregs) and thus fail to induce a significant anti-tumor immune response. Our understanding of the immune underpinning of the anti-tumor effects of CDK4/6 inhibitor (CDKi) treatment coupled with new knowledge about the mechanisms of tolerance to self-antigens suggests a way forward, specifically characterizing and exploiting the repertoire of tumor antigens expressed by metastatic ERBC. These treatment-associated tumor antigens (TATA) may include the conventional tumor neoantigens (TNA) encoded by single nucleotide mutations, TNA encoded by tumor specific aberrant RNA transcription, splicing and DNA replication induced frameshift (FS) events as well as the shared tumor antigens. The latter may include the conventional tumor associated antigens (TAA), cancer-testis antigens (CTA) and antigens encoded by the endogenous retroviral (ERV) like sequences and repetitive DNA sequences induced by ET and CDKi treatment. An approach to identifying these antigens is outlined as this will support the development of a multi-antigen-based immunotherapy strategy for improved targeting of metastatic disease with potential for minimal autoimmune toxicity against normal tissues.
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http://dx.doi.org/10.3389/fimmu.2020.570049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661635PMC
October 2020

Apelin‑36 protects against lipopolysaccharide‑induced acute lung injury by inhibiting the ASK1/MAPK signaling pathway.

Mol Med Rep 2021 01 12;23(1). Epub 2020 Nov 12.

Department of Cardiology, People's Hospital of Ningxia Hui Autonomous Region (Ningxia Medical University Affiliated Autonomous Region People's Hospital), Yinchuan, Ningxia 750002, P.R. China.

Apelin‑36 is able to mediate a range of effects on various diseases, and is upregulated in lipopolysaccharide (LPS)‑induced acute lung injury (ALI). However, to the best of our knowledge, whether apelin‑36 is able to regulate LPS‑induced ALI has yet to be investigated. The present study aimed to investigate the role of apelin‑36 in LPS‑induced ALI, and the putative underlying mechanisms. Rats were assigned to one of four treatment groups: The Control group, apelin‑36 group, LPS group and LPS + apelin‑36 group. At 4 h after intratracheal instillation of LPS (5 mg/kg), rats were intraperitoneally treated with 10 nmol/kg apelin‑36. Subsequently, pathological manifestations and the extent of inflammation and apoptosis of the lung tissues were assessed. Untransfected and apoptosis signal‑regulating kinase 1 (ASK1)‑overexpressing Beas‑2B cells were treated with LPS in the absence or presence of apelin‑36, and subsequently the levels of inflammation and apoptosis were assessed. The results obtained showed that the level of apelin‑36 was increased in the bronchoalveolar lavage fluid (BALF) of LPS‑treated rats. Co‑treatment with apelin‑36 alleviated LPS‑induced lung injury and pulmonary edema, reduced the levels of pro‑inflammatory cytokines, including interleukin‑6, monocyte chemoattractant protein‑1 and tumor necrosis factor‑α, in BALF, and inhibited apoptosis in the lung tissues. The presence of apelin‑36 also blocked the activation of LPS‑induced ASK1, p38, c‑Jun N‑terminal kinase and extracellular signal‑regulated kinase in lung tissues. In vitro studies performed with Beas‑2B cells showed that the addition of apelin‑36 led to an increase in the cell viability of LPS‑induced Beas‑2B cells in a concentration‑dependent manner. Additionally, co‑treatment with 1 µM apelin‑36 prevented LPS‑induced inflammation and apoptosis. However, overexpression of ASK1 significantly reversed the inhibitory effects of apelin‑36 on LPS‑induced inflammation and apoptosis. Taken together, the results of the present study demonstrated that apelin‑36 was able to protect against LPS‑induced lung injury both in vivo and in vitro, and these actions may be dependent on inhibition of the ASK1/mitogen‑activated protein kinase signaling pathway.
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http://dx.doi.org/10.3892/mmr.2020.11644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673347PMC
January 2021

A novel miR-7156-3p-HOXD13 axis modulates glioma progression by regulating tumor cell stemness.

Int J Biol Sci 2020 21;16(16):3200-3209. Epub 2020 Oct 21.

Department of Radiology, Daping Hospital, Army Medical University, Chongqing 400042, China.

Malignant glioma is the most common brain tumor in adults. Despite the great advances in anti-glioma treatments which have led to significant improvement in clinical outcomes, tumor recurrence remains the major cause of mortality. Increased cancer cell stemness and invasiveness are correlated with glioma progression. By searching the Cancer Genome Atlas, we showed that the expression of miR-7156-3p is significantly decreased in glioma tissues compared to the normal brain, and the decreased level of miR-7156-3p is closely correlated with glioma grade and patient survival. Clinical study consistently confirmed that miR-7156-3p is negatively correlated with glioma grade. Cell culture and animal experiments revealed that inhibition of miR-7156-3p effectively stimulates glioma cell stemness, invasion, and growth. In contrast, the augmentation of miR-7156-3p inhibits these phenotypes. Using Next-generation sequencing combined with target prediction approach, Homeobox D13 (HOXD13) is identified as the target gene of miR-7156-3p and further validated by luciferase reporter assay and cell transfection experiments. Additional and animal experiments demonstrated that miR-7156-3p regulates glioma cell stemness, invasion, and growth by mediating HOXD13. In conclusion, our findings provide new insight into the regulation of glioma stemness and invasiveness and may propose a potential strategy for anti-glioma treatment. Moreover, miR-7156-3p may serve as a candidate biomarker for predicting glioma progression in clinical practice.
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http://dx.doi.org/10.7150/ijbs.51293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645993PMC
October 2020

Transcriptome analysis reveals potential immune function-related regulatory genes/pathways of female Lubo goat submandibular glands at different developmental stages.

PeerJ 2020 7;8:e9947. Epub 2020 Oct 7.

Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, P.R. China.

Background: The submandibular glands, as major salivary glands, participate in rumen digestion in goats. Sialic acid, lysozyme, immunoglobulin A (IgA), lactoferrin and other biologically active substances secreted in the submandibular glands were reported in succession, which suggests that the submandibular gland may have immune functions in addition to participating in digestion. The aim of this study was to map the expression profile of differentially expressed genes (DEGs) at three different stages by transcriptome sequencing, screen immune-related genes and pathways by bioinformatics methods, and predict the immune function of submandibular glands at different developmental stages.

Methods: Nine submandibular gland tissue samples were collected from groups of 1-month-old kids, 12-month-old adolescent goats and 24-month-old adult goats (3 samples from each group), and high-throughput transcriptome sequencing was conducted on these samples. The DEGs among the three stages were screened and analysed. Key genes and signalling pathways were selected via protein-protein interaction (PPI) network analysis.

Results: The results revealed 2,706, 2,525 and 52 DEGs between 1-month-old and 12-month-old goats, between 1-month-old and 24-month-old goats, and between 12-month-old and 24-month-old goats, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that most of the DEGs were enriched in immune- related GO terms and pathways. Based on functional enrichment analysis and network analysis, 10 genes ( and ), two signalling pathways (the T cell receptor signalling pathway and the NF-κβ signalling pathway) and eight GO terms (T cell receptor signalling pathway, neutrophil mediated immunity, B cell mediated immunity, regulation of alpha-beta T cell activation, positive regulation of T cell proliferation, regulation of leukocyte differentiation, positive regulation of antigen receptor-mediated signalling pathway, positive regulation of lymphocyte proliferation) that may play key roles in the immune functions of the goat submandibular glands at different developmental stages were identified. Moreover, we found that eight antibacterial peptide-encoding genes were downregulated in the tuberculosis and salivary secretion pathways, while all immunoglobulins were upregulated in 10 immune system pathways. These findings indicate that the submandibular glands may be important immunological organs during the growth process of goats and that the immune function of these glands gradually weakens with age up to 12 months but remains relatively stable after 12 months of age. Overall, this study will improve our understanding of transcriptional regulation related to goat submandibular gland immune function.
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http://dx.doi.org/10.7717/peerj.9947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547598PMC
October 2020

A highly sensitive electrochemiluminescence immunosensor for h-FABP determination based on self-enhanced luminophore coupled with ultrathin 2D nickel metal-organic framework nanosheets.

Biosens Bioelectron 2021 Jan 14;171:112735. Epub 2020 Oct 14.

Key Laboratory of Clinical Laboratory Diagnostics, Ministry of Education, College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China. Electronic address:

In this work, a novel ECL immunosensor based on self-enhanced luminophore and ultrathin 2D nickel MOF nanosheets was fabricated for sensitive and specific detection of h-FABP. Initially, the porous ultrathin Ni-TCPP (Fe) nanosheets with high specific surface area and plentiful active sites were newly synthesized, which could enhance ECL signal of luminol by the superior peroxidase mimics activity towards HO decomposition. Then, PEI and luminol were simultaneously immobilized on Ni-TCPP (Fe) nanosheets to construct self-enhanced solid state luminophore (Ni-TCPP (Fe)-PEI-Lum), possessing desirable stability and high ECL efficiency. Furthermore, poly (indole-5-carboxylic acid) (PICA) worked as substrate with outstanding conductivity and abundant binding sites to improve sensitivity. Under optimal conditions, the designed ECL immunosensor exhibited a wide dynamic range from 100 fg mL to 100 ng mL and a low detection limit of 44.5 fg mL. In addition, the ECL immunosensor behaved excellent specificity and was successfully applied to detect target h-FABP protein in complex physiological matrix. Therefore, this work may provide an alternative method for biomarker detection in clinical diagnosis and expand the application potential of 2D MOF nanosheets in ECL technique.
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http://dx.doi.org/10.1016/j.bios.2020.112735DOI Listing
January 2021

A novel electrochemical biosensor based on peptidoglycan and platinum-nickel-copper nano-cube for rapid detection of Gram-positive bacteria.

Mikrochim Acta 2020 Oct 14;187(11):607. Epub 2020 Oct 14.

Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing, 400016, China.

A novel non-enzyme electrochemical biosensor for the rapid detection of Gram-positive bacteria has been constructed that relys on a stable and efficient combination between the peptidoglycan layer and platinum-nickel-copper nanocubes (Pt-Ni-Cu NCs). Briefly, bacteria were first captured by a specific antibody. Then, the electrochemical signal materials (Pt-Ni-Cu NCs) were bound to the bacteria peptidoglycan layer using specific structural and surface features. The rapid and sensitive bacterial detection was then achieved using intrinsic electrochemical characteristics and superoxidase-like activity of the Pt-Ni-Cu NCs. Moreover, the nature of peptidoglycan covering the whole bacteria provided the premise for signal amplification. Under optimal conditions, the electrochemical signal variation was proportional to the concentration of bacteria ranging from 1.5 × 10to 1.5 × 10 CFU/mL with a detection limit of 42 CFU/mL using a working potential of - 0.4 V. This electrochemical biosensor has been successfully applied to detect bacteria concentrations in urine samples, and the recoveries range from 90.4 to 107%. The proposed biosensor could be applied for broad-spectrum detection of Gram-positive bacteria since most Gram-positive bacteria possess a thick peptidoglycan layer. The developed electrochemical biosensing strategy might be used as a potential tool for clinical pathogenic bacteria detection and point-of-care testing (POCT).
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http://dx.doi.org/10.1007/s00604-020-04581-4DOI Listing
October 2020

Dynamic prediction of relapse in patients with acute leukemias after allogeneic transplantation: Joint model for minimal residual disease.

Int J Lab Hematol 2021 Feb 3;43(1):84-92. Epub 2020 Sep 3.

Department of Hematology, Institute of Hematology, Changhai Hospital, Shanghai, China.

Introduction: Relapse remains the leading cause of treatment failure after allogeneic hematopoietic stem cell transplantation (alloHSCT) in leukemia. Numerous investigations have demonstrated that minimal residual disease (MRD) before or after alloHSCT is prognostic of relapse risk. These MRD data were collected at specific checkpoints and could not dynamically predict the relapse risk after alloHSCT, which needs serial monitoring.

Methods: In the present study, we retrospectively analyzed MRD measured with multi-parameter flow cytometry in 207 acute myeloid leukemia (AML) patients (acute promyelocytic leukemia excluded), and 124 acute B lymphoblastic leukemia (ALL) patients. A three-step method based on joint model was used to build a relapse risk prediction model.

Results: The 3-year overall survival and relapse-free survival rates of the entire cohort were 67.1% ± 2.8% and 61.6% ± 2.8%, respectively. The model included disease status before alloHSCT, acute and chronic graft-versus-host disease, and serial MRD data. The time-dependent receiver operating characteristics was used to evaluate the ability of the model. It fitted well with actual incidence of relapse. The serial MRD data collected after alloHSCT had better discrimination capabilities for recurrence prediction with the area under the curve from 0.67 to 0.91 (AML: 0.66-0.89; ALL: 0.70-0.96).

Conclusion: The joint model was able to dynamically predict relapse-free probability after alloHSCT, which would be a useful tool to provide important information to guide decision-making in the clinic and facilitate the individualized therapy.
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http://dx.doi.org/10.1111/ijlh.13328DOI Listing
February 2021

Hazardous wastes treatment technologies.

Water Environ Res 2020 Oct 28;92(10):1833-1860. Epub 2020 Sep 28.

Department of Civil and Environmental Engineering, University of Delaware, Newark, Delaware, USA.

A review of the literature published in 2019 on topics related to hazardous waste management in water, soils, sediments, and air. The review covered treatment technologies applying physical, chemical, and biological principles for the remediation of contaminated water, soils, sediments, and air. PRACTICAL POINTS: This report provides a review of technologies for the management of waters, wastewaters, air, sediments, and soils contaminated by various hazardous chemicals including inorganic (e.g., oxyanions, salts, and heavy metals), organic (e.g., halogenated, pharmaceuticals and personal care products, pesticides, and persistent organic chemicals) in three scientific areas of physical, chemical, and biological methods. Physical methods for the management of hazardous wastes including general adsorption, sand filtration, coagulation/flocculation, electrodialysis, electrokinetics, electro-sorption ( capacitive deionization, CDI), membrane (RO, NF, MF), photocatalysis, photoelectrochemical oxidation, sonochemical, non-thermal plasma, supercritical fluid, electrochemical oxidation, and electrochemical reduction processes were reviewed. Chemical methods including ozone-based, hydrogen peroxide-based, potassium permanganate processes, and Fenton and Fenton-like process were reviewed. Biological methods such as aerobic, anoxic, anaerobic, bioreactors, constructed wetlands, soil bioremediation and biofilter processes for the management of hazardous wastes, in mode of consortium and pure culture were reviewed. Case histories were reviewed in four areas including contaminated sediments, contaminated soils, mixed industrial solid wastes and radioactive wastes.
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http://dx.doi.org/10.1002/wer.1447DOI Listing
October 2020

Quantifying the effect of nano-TiO on the toxicity of lead on C. dubia using a two-compartment modeling approach.

Chemosphere 2021 Jan 15;263:127958. Epub 2020 Aug 15.

The Center for Research in Energy and Environment (CREE), Missouri University of Science and Technology, Rolla, MO, 65409, United States; Department of Biological Sciences, Missouri University of Science and Technology, Rolla, MO, 65409, United States.

Nanoparticles (NPs) can significantly influence toxicity imposed by toxic metals. However, this impact has not been quantified. In this research, we investigated the effect of nano-TiO on lead (Pb) accumulation and the resultant toxicity using water flea Ceriodaphnia dubia (C. dubia) as the testing organism. We used a two-compartment modeling approach, which included a two-compartment accumulation model and a toxicodynamic model, on the basis of Pb body tissue accumulation, to quantify the impact of nano-TiO on Pb toxicity. The effect of algae on the combined toxicity of Pb and nano-TiO was also quantified. The two-compartment accumulation model could well quantify Pb accumulation kinetics in two-compartments of C. dubia, the gut and the rest of the body tissue in the presence of nano-TiO. Modeling results suggested that the gut quickly accumulates Pb through active uptake from the mouth, but the rest of the body tissue slowly accumulates Pb from the gut. The predicted Pb distribution within C. dubia was verified by depuration modeling results from an independent depuration test. The survivorship of C. dubia as a function of Pb accumulated in the body tissue and exposure time can be well described using a toxicodynamic model. The effects of algae on Pb accumulation in different compartments of C. dubia and the toxicity in the presence of nano-TiO were also well described using the two-compartment modeling approach. Therefore, the novel two-compartment modeling approach provides a useful tool for assessing the effect of NPs on aquatic ecosystems where toxic metals are present.
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http://dx.doi.org/10.1016/j.chemosphere.2020.127958DOI Listing
January 2021

Clinical research on minimally invasive internal fixation for the treatment of anterior ring injury in tile C pelvic fracture.

Medicine (Baltimore) 2020 Jul;99(30):e20652

Department of Orthopaedic Surgery, Tianjin Hospital, Tianjin, China.

The aim of this study is to explore the clinical outcome and indications in treating anterior ring injury of Tile C pelvic fracture with minimally invasive internal fixation.We retrospectively reviewed 18 patients (aged 25-62, 34.2 ± 7.4) with 26 pelvic anterior ring injuries of Tile C pelvic fracture treated with minimally invasive internal fixation in our hospital were from January 2012 to August 2016. Two cases were pubic symphysis diastasis, 15 were anterior ring fracture (7 were bilateral), and 1 was vertical displacement of pubic symphysis associated with pubic ramus fracture. According to Tile classification, 8, 4, and 6 cases were types C1, C2, and C3, respectively. All patients accepted the operation of pelvic fractures on both rings, while the anterior ring injuries were treated with minimally invasive internal fixation. The period from injury to operation was 5 to 32 days (11.2 ± 3.7). Four patients had pubic symphysis diastasis or pelvic anterior ring fracture medial obturator foramen reduced with modified Pfannenstiel incision and fixed with cannulated screws, 14 patients (22 fractures) had a fractured lateral obturator foramen reduced with modified Pfannenstiel incision associated with small iliac crest incision and fixed with locking reconstruction plates. Clinical data, such as operation time, intraoperative bleeding, Matta standard to assess the reduction quality of fracture, and complications, were collected and analyzed.The operation time ranged from 30 to 65 minutes (42.8 ± 18.7), and the intraoperative bleeding volume was 30 to 150 mL (66.5 ± 22.8). All cases were continuously followed-up for 16 to 42 months (30.2 ± 4.6). All fractures were healed between 3 and 9 months postoperatively (4.9 ± 2.7 months). According to the Matta standard assessment, 18, 7, and 1 cases were excellent, good, and fair, respectively, with a 96.2% (25/26) rate of satisfaction. Neither reduction loss, fixation failure, nor infection occurred; complications included 1 patient with fatal liquefaction, 1 patient had lateral femoral cutaneous nerve injury, and 1 patient complained of discomfort in the inguinal area due to fixation stimulation.Minimally invasive internal fixation for pelvic anterior ring injury in Tile C pelvic fracture has the advantages of less damage, safer manipulation, less complications, and good prognosis.
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http://dx.doi.org/10.1097/MD.0000000000020652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386985PMC
July 2020

Implementation of long solids retention time activated sludge process for rural residential community.

Water Environ Res 2021 Feb 10;93(2):174-185. Epub 2020 Aug 10.

Southwood II Homeowners Association, Rolla, Missouri.

Most rural communities in the United States are facing increasingly rigorous effluent criteria, especially ammonia, for their wastewater treatment facilities. A new baffled bioreactor (BBR) technology, which employs a preanoxic activated sludge process operated with a long solids retention time (SRT), was installed in a small community in Missouri to address the more stringent effluent limits. In a recent full-year normal operation cycle (2018), the average effluent concentrations of BOD , TSS, and ammonia-nitrogen were 3.2, 2.2, and 0.5 mg/L, respectively, with removal efficiencies of 96%, 85%, and 98%, respectively. All these parameters were significantly better than their respective permit limits. The long SRT afforded an enhanced factor of safety for the process, conferring the ability to nitrify at sustained ambient temperatures as low as -22°C. Long SRT also resulted in significant reductions in waste sludge production, resulting in dramatically reduced operational costs for sludge handling. Ultimately, the long SRT activated sludge process afforded the ability to meet stringent effluent quality standards including ammonia and the numerous unique challenges that are inherent to small flows. PRACTITIONER POINTS: Small community hydraulic and mass loadings are highly variable and difficult to quantify during facility design. A long SRT activated sludge process warrants superior performance and enhanced factor of safety. The long SRT process with preanoxic zones generated no excess sludge during the extended operation period, significantly simplifying plant operation. Long SRT process is well suited to accommodate wastewater variability associated with small communities while maintaining superior treatment quality.
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http://dx.doi.org/10.1002/wer.1416DOI Listing
February 2021

Clonality and antigen-specific responses shape the prognostic effects of tumor-infiltrating T cells in ovarian cancer.

Oncotarget 2020 Jul 7;11(27):2669-2683. Epub 2020 Jul 7.

Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

CD8 tumor-infiltrating lymphocytes (TILs) are not all specific for tumor antigens, but can include bystander TILs that are specific for cancer-irrelevant epitopes, and it is unknown whether the T-cell repertoire affects prognosis. To delineate the complexity of anti-tumor T-cell responses, we utilized a computational method for assembly of sequences from CDR3 regions of 369 high-grade serous ovarian cancers from TCGA, and then applied deep TCR-sequencing for analyses of paired tumor and peripheral blood specimens from an independent cohort of 99 ovarian cancer patients. Strongly monoclonal T-cell repertoires were associated with favorable prognosis (PFS, HR = 0.65, 0.50-0.84, = 0.003; OS, HR = 0.61, 0.44-0.83, = 0.006) in TCGA cohort. In the validation cohort, we discovered that patients with low T-cell infiltration but low diversity or focused repertoires had clinical outcomes almost indistinguishable from highly-infiltrated tumors (median 21.0 months versus 15.9 months, log-rank = 0.945). We also found that the degree of divergence of the peripheral repertoire from the TIL repertoire, and the presence of detectable spontaneous anti-tumor immune responses are important determinants of clinical outcome. We conclude that the prognostic significance of TILs in ovarian cancer is dictated by T-cell clonality, degree of overlap with peripheral repertoire, and the presence of detectable spontaneous anti-tumor immune response in the patients. These immunological phenotypes defined by the TCR repertoire may provide useful insights for identifying "TIL-low" ovarian cancer patients that may respond to immunotherapy.
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http://dx.doi.org/10.18632/oncotarget.27666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343634PMC
July 2020

Enhanced Potency of a Broad H7N9-Neutralizing Antibody HNIgGA6 Through Structure-Based Design.

Front Microbiol 2020 19;11:1313. Epub 2020 Jun 19.

NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

H7N9 influenza virus was first isolated in 2013 and has caused five epidemic waves among humans to date. Treatment opinions are currently limited. Previously, we characterized a human neutralizing antibody, HNIgGA6, by isolating rearranged heavy- and light-chain genes from convalescent patients. The mAb disrupts viral attachment to the cellular receptor by directly interposing into the receptor binding site (RBS) and broadly neutralizing divergent H7N9 strains. To increase the protective efficacy of HNIgGA6, we employed a structure-based design to enhance its binding affinity and neutralization potency. When the serine at position 28 on light-chain complementarity-determining region 1 (LCDR1) was substituted by a histidine, compared to HNIgGA6, the mutated antibody showed an approximately three-fold increase in HA-binding affinity and 10-fold enhancement in neutralization potency . Importantly, the S28H variant also exhibited broad H7N9-neutralizing activity. When administered to BALB/c mice, mAb S28H showed enhanced potency in inhibiting the pulmonary virus titre and reducing lung lesions and resulted in better protection of the animals than did the original antibody.
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http://dx.doi.org/10.3389/fmicb.2020.01313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316883PMC
June 2020

The impact of donor full-length KIR2DS4 in the development of acute and chronic GVHD after unrelated allogeneic HSCT.

Pediatr Transplant 2020 09 27;24(6):e13728. Epub 2020 Jun 27.

Department of Hematology and Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Background: Killer Ig-like receptor 2DS4 (KIR2DS4) is the most prevalent activating killer Ig-like receptor gene. It is divergent and encodes either full-length or deleted allele variants. The studies of donor killer KIR2DS4 in unrelated allogeneic hematopoietic stem cell transplantations were limited.

Methods: KIR and HLA genotyping were determined in 75 pairs of Chinese pediatric hematologic malignancy patients.

Results: Among the 75 donor-recipient pairs, 77.3% (58/75) of the donors were positive for full-length KIR2DS4 and 22.7% (17/75) were negative. Patients who had donors positive for full-length KIR2DS4 had higher cumulative incidence of aGVHD than patients whose donor negative for full-length KIR2DS4 (86.2% versus 76.5%, P = .038). Multivariate analysis showed full-length KIR2DS4 was the significant factor for I-IV aGVHD (HR = 2.166, 95% CI: 1.01-4.26, P = .025). Subgroup analysis showed that AML and CML patients who received donors negative for full-length KIR2DS4 have a higher cumulative incidences of cGVHD (75% vs 62%, P = .008). There were no significant effects of full-length KIR2DS4 on overall survival (P = .13), relapse-free survival (P = .14), CMV reactivation (P = .52), and relapse (HR = 0.38, 95% CI: 0.09-1.6, P = .1875).

Conclusions: Our findings indicated a significant correlation of donor full-length KIR2DS4 on aGVHD and cGVHD. These results suggested that combining KIR and HLA genotyping may help make a better sense of transplants in these patients.
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http://dx.doi.org/10.1111/petr.13728DOI Listing
September 2020

Recapitulation of prostate tissue cell type-specific transcriptomes by an in vivo primary prostate tissue xenograft model.

PLoS One 2020 25;15(6):e0233899. Epub 2020 Jun 25.

Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, United States of America.

Studies of the normal functions and diseases of the prostate request in vivo models that maintain the tissue architecture and the multiple-cell type compartments of human origin in order to recapitulate reliably the interactions of different cell types. Cell type-specific transcriptomes are critical to reveal the roles of each cell type in the functions and diseases of the prostate. A primary prostate tissue xenograft model was developed using fresh human prostate tissue specimens transplanted onto male mice that were castrated surgically and implanted with a device to maintain circulating testosterone levels comparable to adult human males. Endothelial cells and epithelial cells were isolated from 7 fresh human prostate tissue specimens and from primary tissue xenografts established from 9 fresh human prostate tissue specimens, using antibody-conjugated magnetic beads specific to human CD31 and human EpCAM, respectively. Transcriptomes of endothelial, epithelial and stromal cell fractions were obtained using RNA-Seq. Global and function-specific gene expression profiles were compared in inter-cell type and inter-tissue type manners. Gene expression profiles in the individual cell types isolated from xenografts were similar to those of cells isolated from fresh tissue, demonstrating the value of the primary tissue xenograft model for studies of the inter-relationships between prostatic cell types and the role of such inter-relationships in organ development, disease progression, and response to drug treatments.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233899PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316257PMC
August 2020

Suppression of Hematopoietic Primitive Cells in Patients with Secondary Failure of Platelet Recovery after Acute Graft-versus-Host Disease.

Biol Blood Marrow Transplant 2020 10 11;26(10):1840-1854. Epub 2020 Jun 11.

Department of Hematology, Institute of Hematology, Changhai Hospital, Shanghai, China. Electronic address:

Secondary failure of platelet recovery (SFPR) can occur after allogeneic hematopoietic stem cell transplantation (alloHSCT), and 20% of cases are related to acute graft-versus-host disease (aGVHD). The underlying mechanisms of this association are unclear, however. The aim of the present study was to investigate the potential mechanisms of SFPR secondary to aGVHD, which may provide a new therapeutic strategy for these patients. A total of 468 patients with malignant hematologic disease who underwent alloHSCT were included. Sixty-six patients developed SFPR after alloHSCT, and in 45 of these 66 patients (68.2%), SFPR was secondary to grade II-IV aGVHD (SFPR/aGVHD). Compared with patients with good graft function (GGF), patients with SFPR had poor overall survival (20.72% versus 88.01%; P < .0001). Grade II-IV aGVHD was identified as an independent risk factor for SFPR in multivariate analysis (hazard ratio, 9.512; P < .0001). We observed reduced erythroid and megakaryocyte colony formation in bone marrow (BM) samples isolated from SFPR/aGVHD patients, consistent with the lower frequency of megakaryocyte and erythrocyte progenitors in BM. Levels of the inflammatory cytokines IL-2R and TNF-R1 were significantly higher in the SFPR/aGVHD group compared with the GGF group (P = .002 and .001, respectively), as were the frequencies of proinflammatory T helper subsets. Furthermore, the pathways that regulate hematopoiesis and immune responses were universally underexpressed in CD34 cells isolated from SFPR/aGVHD patients. Differentially expressed genes were significantly enriched in the hematopoietic cell lineage pathway and other pathways involved in both immune responses and megakaryopoiesis. In summary, we found that both the immune microenvironment and compromised proliferation of hematopoietic primitive cells contribute to the development of SFPR secondary to aGVHD, and our data provide new insight into the mechanisms of SFPR in the context of aGVHD.
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http://dx.doi.org/10.1016/j.bbmt.2020.06.003DOI Listing
October 2020

Characterization of microRNA profiles in the mammary gland tissue of dairy goats at the late lactation, dry period and late gestation stages.

PLoS One 2020 8;15(6):e0234427. Epub 2020 Jun 8.

Qingdao Research Institute of Husbandry and Veterinary, Qingdao, Shandong Province, P.R. China.

MicroRNAs (miRNAs) play an important role in regulating mammary gland development and lactation. We previously analyzed miRNA expression profiles in Laoshan dairy goat mammary glands at the early (20 d postpartum), peak (90 d postpartum) and late lactation (210 d postpartum) stages. To further enrich and clarify the miRNA expression profiles during the lactation physiological cycle, we sequenced miRNAs in the mammary gland tissues of Laoshan dairy goats at three newly selected stages: the late lactation (240 d postpartum), dry period (300 d postpartum) and late gestation (140 d after mating) stages. We obtained 4038 miRNAs and 385 important miRNA families, including mir-10, let-7 and mir-9. We also identified 754 differentially expressed miRNAs in the mammary gland tissue at the 3 different stages and 6 groups of miRNA clusters that had unique expression patterns. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed that GO terms such as mammary gland development (GO:0030879) and mammary gland morphogenesis (GO:0060443) and important signaling pathways, including the insulin signaling pathway (chx04910), hippo signaling pathway (chx04390) and estrogen signaling pathway (chx04915), were enriched. We screened miRNAs and potential target genes that may be involved in the regulation of lactation, mammary gland growth and differentiation, cell apoptosis, and substance transport and synthesis and detected the expression patterns of important genes at the three stages. These miRNAs and critical target genes may be important factors for mammary gland development and lactation regulation and potentially valuable molecular markers, which may provide a theoretical reference for further investigation of mammary gland physiology.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234427PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279595PMC
August 2020