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Potential use of serum HBV RNA in antiviral therapy for chronic hepatitis B in the era of nucleos(t)ideanalogs

null

《医学前沿（英文）》 2017年第11卷第4期页码 502-508 doi: 10.1007/s11684-017-0590-z

摘要：

Although the efficacy of nucleos(t)ide analogue (NA) has been confirmed for treatment of chronic hepatitis B, long-term therapy has been recommended due to the high frequency of off-therapy viral DNA rebound and disease relapse. In this review, the RNA virion-like particles of hepatitis B virus (HBV) are integrated into the life cycle of HBV replication, and the potential significance of serum HBV RNA is systematically described. The production of HBV RNA virion-like particles should not be blocked by NA; in this regard, serum HBV RNA is found to be a suitable surrogate marker for the activity of intrahepatic covalently closed circular DNA (cccDNA), particularly among patients receiving NA therapy. Therefore, the concept of virological response is redefined as persistent loss of serum HBV DNA and HBV RNA. In contrast to hepatitis B surface antigen (HBsAg) that can originate from either the cccDNA or the integrated HBV DNA fragment, serum HBV RNA, with pregenomic RNA origination, can only be transcribed from cccDNA. Therefore, the loss of serum HBV RNA would likely be a promising predicator for safe drug discontinuation. The clinical status of consistent loss of serum HBV RNA accompanied with low serum HBsAg levels might be implicated as a “para-functional cure,” a status nearly close to the functional cure of chronic hepatitis B, to distinguish the “functional cure” characterized as serum HBsAg loss with or without anti-HBs seroconversion.

关键词： chronic hepatitis B serum HBV RNA nucleos(t)ide analogs virological response para-functional cure

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Discovery and development of synthetic tricyclic pyrroloquinone (TPQ) alkaloid analogs for human cancer

Wei Wang,Bhavitavya Nijampatnam,Sadanandan E. Velu,Ruiwen Zhang

《化学科学与工程前沿（英文）》 2016年第10卷第1期页码 1-15 doi: 10.1007/s11705-016-1562-6

摘要： Natural products and their derivatives represent a rich source for the discovery and development of new cancer therapeutic drugs. Bioactive components derived from natural sources including marine compounds have been shown to be effective agents in the clinic or in preclinical settings. In the present review, we present a story of discovery, synthesis and evaluation of three synthetic tricyclic pyrroloquinone (TPQ) alkaloid analogs as cancer therapeutic agents. Chemical synthesis of these compounds (BA-TPQ, TBA-TPQ, and TCBA-TPQ) has been accomplished and the mechanisms of action (MOA) and structure-activity relationships (SAR) have been investigated. In the past, the complexity of chemical synthesis and the lack of well-defined MOA have dampened the enthusiasm for the development of some makaluvamines. Recent discovery of novel molecular targets for these alkaloids (unrelated to inhibition of Topoisomerase II) warrant further consideration as clinical candidates in the future. In addition to the establishment of novel synthetic approaches and demonstration of and anticancer activities, we have successfully demonstrated that these makaluvamines attack several key molecular targets, including the MDM2-p53 pathway, providing ample opportunities of modulating the compound structure based on SAR and the use of such compounds in combination therapy in the future.

关键词： synthesis marine drugs tricyclic pyrroloquinone alkaloid cancer therapy MDM2 p53

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bacterial strains isolated from drinking water environments to N-acyl-L-homoserine lactones and their analogs

Zhuoying WU, Qing WANG, Feng GUO, Shenghua ZHANG, Qipei JIANG, Xin YU

《环境科学与工程前沿（英文）》 2014年第8卷第2期页码 205-214 doi: 10.1007/s11783-013-0492-5

摘要： Often as a result of biofilm formation, drinking water distribution systems (DWDS) are regularly faced with the problem of microbial contamination. Quorum sensing (QS) systems play a marked role in the regulation of microbial biofilm formation; thus, inhibition of QS systems may provide a promising approach to biofilm formation control in DWDS. In the present study, 22 bacterial strains were isolated from drinking water-related environments. The following properties of the strains were investigated: bacterial biofilm formation capacity, QS signal molecule N-acyl-L-homoserine lactones (AHLs) production ability, and responses to AHLs and AHL analogs, 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) and 2(5H)-furanone. Four AHLs were added to developed biofilms at dosages ranging from 0.1?nmol·L to 100 nmol·L . As a result, the biofilm growth of more than 1/4 of the isolates, which included AHL producers and non-producers, were significantly promoted. Further, the biofilm biomasses were closely associated with respective AHLs concentrations. These results provided evidence to support the idea that AHLs play a definitive role in biofilm formation in many of the studied bacteria. Meanwhile, two AHLs analogs demonstrated unexpectedly minimal negative effects on biofilm formation. This suggested that, in order to find an applicable QS inhibition approach for biofilm control in DWDS, the testing and analysis of more analogs is needed.

关键词： drinking water distribution systems (DWDS) biofilm quorum sensing (QS) N-acyl-L-homoserine lactones (AHLs) (dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) 2(5H)-furanone

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Deubiquitinases as pivotal regulators of T cell functions

null

《医学前沿（英文）》 2018年第12卷第4期页码 451-462 doi: 10.1007/s11684-018-0651-y

摘要：

T cells efficiently respond to foreign antigens to mediate immune responses against infections but are tolerant to self-tissues. Defect in T cell activation is associated with severe immune deficiencies, whereas aberrant T cell activation contributes to the pathogenesis of diverse autoimmune and inflammatory diseases. An emerging mechanism that regulates T cell activation and tolerance is ubiquitination, a reversible process of protein modification that is counter-regulated by ubiquitinating enzymes and deubiquitinases (DUBs). DUBs are isopeptidases that cleave polyubiquitin chains and remove ubiquitin from target proteins, thereby controlling the magnitude and duration of ubiquitin signaling. It is now well recognized that DUBs are crucial regulators of T cell responses and serve as potential therapeutic targets for manipulating immune responses in the treatment of immunological disorders and cancer. This review will discuss the recent progresses regarding the functions of DUBs in T cells.

关键词： deubiquitinase ubiquitination T cell activation T cell differentiation T cell tolerance

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Regulation of T cell immunity by cellular metabolism

null

《医学前沿（英文）》 2018年第12卷第4期页码 463-472 doi: 10.1007/s11684-018-0668-2

摘要：

T cells are an important adaptive immune response arm that mediates cell-mediated immunity. T cell metabolism plays a central role in T cell activation, proliferation, differentiation, and effector function. Specific metabolic programs are tightly controlled to mediate T cell immune responses, and alterations in T cell metabolism may result in many immunological disorders. In this review, we will summarize the main T cell metabolic pathways and the important factors participating in T cell metabolic programming during T cell homeostasis, differentiation, and function.

关键词： T cell immunity metabolic pathways nutrient uptake metabolic checkpoints

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Separation and extraction of bridge dynamic strain data

Baijian WU, Zhaoxia LI, Ying WANG, T. H. T. CHAN,

《结构与土木工程前沿（英文）》 2009年第3卷第4期页码 395-400 doi: 10.1007/s11709-009-0049-7

摘要： Through comparing the measured data of dynamic strains due to loading and temperature by the stain gauge and temperature sensor at the same location, the information in the strain data was divided into three parts in the frequency domain by using the defined index named power spectral density (PSD)-ratio index. The three parts are dominated respectively by temperature varying, stresses, and noises and thus can be distinguished from the determined the separatrix frequencies. Also, a simple algorithm was developed to separate the three types of information and to extract the strain caused mainly by structural stresses. As an application of the proposed method, the effect of strain deformation and noises on the fatigue assessment was investigated based on the separated data. The results show that, the determined values of separatrix frequencies are valuable for the monitoring data from other bridges. The algorithm is a multiresolution and hierarchical method, which has been validated as a simple and effective method for data analyses, and is suitable for the compression and preprocessing of the great amount monitoring data and easy to be integrated into the structural health monitoring (SHM) soft system. The strain due to temperature varying attributes a little to the errors of fatigue assessment; however, the noises or random disturbance existed in the monitoring data have much responsibility for the errors, and the main reason is that the random disturbance shifts the real strain/stress amplitude picked up by real structural stress or strain.

关键词： dynamic valuable separatrix strain/stress amplitude frequency

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Carcinogens that induce the A:T>T:A nucleotide substitutions in the genome

null

《医学前沿（英文）》 2018年第12卷第2期页码 236-238 doi: 10.1007/s11684-017-0611-y

摘要：

Recently, Ng . reported that the A:T>T:A substitutions, proposed to be a signature of aristolochic acid (AA) exposure, were detected in 76/98 (78%) of patients with hepatocellular carcinoma (HCC) from the Taiwan Province of China, and 47% to 1.7% of HCCs from the Chinese mainland and other countries harbored the nucleotide changes. However, other carcinogens, e.g., tobacco carcinogens 4-aminobiphenyl and 1,3-butadiene, air toxic vinyl chloride and its reactive metabolites chloroethylene oxide, melphalan and chlorambucil, also cause this signature in the genome. Since tobacco smoke is a worldwide public health threat and vinyl chloride distributes globally and is an air pollutant in Taiwan Province, the estimation of the patients’ exposure history is the key to determine the “culprit” of the A:T>T:A mutations. Apparently, without estimation of the patients’ exposure history, the conclusion of Ng is unpersuasive and misleading.

关键词： genomic signature carcinogen aristolochic acid tobacco smoke vinyl chloride hepatocellular carcinoma

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γδ T cells in liver diseases

null

《医学前沿（英文）》 2018年第12卷第3期页码 262-268 doi: 10.1007/s11684-017-0584-x

摘要：

γδ T cells display unique developmental, distributional, and functional patterns and can rapidly respond to various insults and contribute to diverse diseases. Different subtypes of γδ T cells are produced in the thymus prior to their migration to peripheral tissues. γδ T cells are enriched in the liver and exhibit liver-specific features. Accumulating evidence reveals that γδ T cells play important roles in liver infection, non-alcoholic fatty liver disease, autoimmune hepatitis, liver fibrosis and cirrhosis, and liver cancer and regeneration. In this study, we review the properties of hepatic γδ T cells and summarize the roles of γδ T cells in liver diseases. We believe that determining the properties and functions of γδ T cells in liver diseases enhances our understanding of the pathogenesis of liver diseases and is useful for the design of novel γδ T cell-based therapeutic regimens for liver diseases.

关键词： γδT cells liver infection non-alcoholic fatty liver disease autoimmune hepatitis liver fibrosis and cirrhosis liver cancer liver regeneration

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High-affinity T cell receptors redirect cytokine-activated T cells (CAT) to kill cancer cells

Synat Kang, Yanyan Li, Yifeng Bao, Yi Li

《医学前沿（英文）》 2019年第13卷第1期页码 69-82 doi: 10.1007/s11684-018-0677-1

摘要：

Cytokine-activated T cells (CATs) can be easily expanded and are widely applied to cancer immunotherapy. However, the good efficacy of CATs is rarely reported in clinical applications because CATs have no or very low antigen specificity. The low-efficacy problem can be resolved using T cell antigen receptor-engineered CAT (TCR-CAT). Herein, we demonstrate that NY-ESO-1_157–165 HLA-A*02:01-specific high-affinity TCR (HAT)-transduced CATs can specifically kill cancer cells with good efficacy. With low micromolar range dissociation equilibrium constants, HAT-transduced CATs showed good specificity with no off-target killing. Furthermore, the high-affinity TCR-CATs delivered significantly better activation and cytotoxicity than the equivalent TCR-engineered T cells (TCR-Ts) in terms of interferon-g and granzyme B production and in vitro cancer cell killing ability. TCR-CAT may be a very good alternative to the expensive TCR-T, which is considered an effective personalized cyto-immunotherapy.

关键词： cytokine-activated T cells high-affinity T cell receptor cancer immunotherapy TCR-CAT

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A case for assessing

Ian T. RILEY

《农业科学与工程前沿（英文）》 2021年第8卷第4期页码 568-582 doi: 10.15302/J-FASE-2019270

摘要： Agroecosystems in water-limited contexts— Mediterranean, semi-arid and arid climatic zones—are too frequently degraded systems that will not provide the needed ecosystem services to ensure a future of sustainable agricultural production. The processes that have created this situation continue and are being accelerated by anthropogenic climate change. Increasing arboreal vegetation in these areas through agroforestry is an important strategy to conserve and improve their agroecosystems. Actinorhizal trees and shrubs in the Casurinaceae have a unique set of adaptations for heat and water stress, and/or infertile to hostile soils. Central Anatolia, Turkey is particularly at risk of increasing aridity and further degradation. Therefore, species of and have been evaluated for their potential use in agroecosystem improvement in semi-arid areas with a focus on Central Anatolia. Based on a semiquantitative environmental tolerance index and reported plant stature, eight species were identified as being of high ( . and . ) to moderate ( . , . , . , . , . and . ) priority for assessment, with none of these species having been adequately evaluated for agroforestry deployment in semi-arid agroecosystems in any context.

关键词： actinorrhizal trees agroforestry climate change ecosystem restoration

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CAR T-cell immunotherapy: a powerful weapon for fighting hematological B-cell malignancies

《医学前沿（英文）》 2021年第15卷第6期页码 783-804 doi: 10.1007/s11684-021-0904-z

摘要： The current standard of care in hematological malignancies has brought considerable clinical benefits to patients. However, important bottlenecks still limit optimal achievements following a current medical practice. The genetic complexity of the diseases and the heterogeneity of tumor clones cause difficulty in ensuring long-term efficacy of conventional treatments for most hematological disorders. Consequently, new treatment strategies are necessary to improve clinical outcomes. Chimeric antigen receptor T-cell (CAR T) immunotherapy opens a new path for targeted therapy of hematological malignancies. In this review, through a representative case study, we summarize the current experience of CAR T-cell therapy, the management of common side effects, the causative mechanisms of therapy resistance, and new strategies to improve the efficacy of CAR T-cell therapy.

关键词： CAR T cells hematological malignancies review

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Chimeric antigen receptor T cell therapies for acute myeloid leukemia

Bin Gu, Jianhong Chu, Depei Wu

《医学前沿（英文）》 2020年第14卷第6期页码 701-710 doi: 10.1007/s11684-020-0763-z

摘要： Abstract Chimeric antigen receptor T cell (CAR T) therapies have achieved unprecedented efficacy in B-cell tumors, prompting scientists and doctors to exploit this strategy to treat other tumor types. Acute myeloid leukemia (AML) is a group of heterogeneous myeloid malignancies. Relapse remains the main cause of treatment failure, especially for patients with intermediate or high risk stratification. Allogeneic hematopoietic stem cell transplantation could be an effective therapy because of the graft-versus-leukemia effect, which unfortunately puts the patient at risk of serious complications, such as graft-versus-host disease. Although the identification of an ideal target antigen for AML is challenging, CAR T therapy remains a highly promising strategy for AML patients, particularly for those who are ineligible to receive a transplantation or have positive minimal residual disease. In this review, we focus on the most recent and promising advances in CAR T therapies for AML.

关键词： acute myeloid leukemia CAR T immunotherapy

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Innate and adaptive T cells in influenza disease

null

《医学前沿（英文）》 2018年第12卷第1期页码 34-47 doi: 10.1007/s11684-017-0606-8

摘要：

Influenza is a major global health problem, causing infections of the respiratory tract, often leading to acute pneumonia, life-threatening complications and even deaths. Over the last seven decades, vaccination strategies have been utilized to protect people from complications of influenza, especially groups at high risk of severe disease. While current vaccination regimens elicit strain-specific antibody responses, they fail to generate cross-protection against seasonal, pandemic and avian viruses. Moreover, vaccines designed to generate influenza-specific T-cell responses are yet to be optimized. During natural infection, viral replication is initially controlled by innate immunity before adaptive immune responses (T cells and antibody-producing B cells) achieve viral clearance and host recovery. Adaptive T and B cells maintain immunological memory and provide protection against subsequent infections with related influenza viruses. Recent studies also shed light on the role of innate T-cells (MAIT cells, gd T cells, and NKT cells) in controlling influenza and linking innate and adaptive immune mechanisms, thus making them attractive targets for vaccination strategies. We summarize the current knowledge on influenza-specific innate MAIT and gd T cells as well as adaptive CD8⁺ and CD4⁺ T cells, and discuss how these responses can be harnessed by novel vaccine strategies to elicit cross-protective immunity against different influenza strains and subtypes.

关键词： influenza innate T cells CD4⁺ and CD8⁺ T cells vaccination

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Treating wastewater under zero waste principle using wetland mesocosms

Ezzat, Mohammed T. Mohammed T.

《环境科学与工程前沿（英文）》 2021年第15卷第4期 doi: 10.1007/s11783-020-1351-9

摘要： Abstract • Smart wetland was designed to treat wastewater according to zero waste principle. • The system included a dynamic roughing filter, Cyperus papyrus (L.) and zeolite. • It removed 98.8 and 99.8% of chemical and bacterial pollutants in 3 days. • The effluent reused to irrigate a landscape and the sludge recycled as fertilizer. • The plant biomass is a profitable resource for antibacterial and antioxidants. The present investigation demonstrates the synergistic action of using a sedimentation unit together with Cyperus papyrus (L.) wetland enriched with zeolite mineral in one-year round experiment for treating wastewater. The system was designed to support a horizontal surface flow pattern and showed satisfactory removal efficiencies for both physicochemical and bacteriological contaminants within 3 days of residence time. The removal efficiencies ranged between 76.3% and 98.8% for total suspended solids, turbidity, iron, biological oxygen demand, and ammonia. The bacterial indicators (total and fecal coliforms, as well as fecal streptococci) and the potential pathogens (Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa) showed removal efficiencies ranged between 96.9% and 99.8%. We expect the system to offer a smart management for every component according to zero waste principle. The treated effluent was reused to irrigate the landscape of pilot area, and the excess sludge was recycled as fertilizer and soil conditioner. The zeolite mineral did not require regeneration for almost 36 weeks of operation, and enhanced the density of shoots (14.11%) and the height of shoots (15.88%). The harvested plant biomass could be a profitable resource for potent antibacterial and antioxidant bioactive compounds. This could certainly offset part of the operation and maintenance costs and optimize the system implementation feasibility. Although the experiment was designed under local conditions, its results could provide insights to upgrade and optimize the performance of other analogous large-scale constructed wetlands.

关键词： Wastewater dynamic roughing filter Cyperus papyrus (L.) zeolite zero waste

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Modeling of alkali-silica reaction in concrete: a review

PAN, Y.T. FENG, J.T. WANG, Q.C. SUN, C.H. ZHANG, D.R.J. OWEN

《结构与土木工程前沿（英文）》 2012年第6卷第1期页码 1-18 doi: 10.1007/s11709-012-0141-2

摘要： This paper presents a comprehensive review of modeling of alkali-silica reaction (ASR) in concrete. Such modeling is essential for investigating the chemical expansion mechanism and the subsequent influence on the mechanical aspects of the material. The concept of ASR and the mechanism of expansion are first outlined, and the state-of-the-art of modeling for ASR, the focus of the paper, is then presented in detail. The modeling includes theoretical approaches, meso- and macroscopic models for ASR analysis. The theoretical approaches dealt with the chemical reaction mechanism and were used for predicting pessimum size of aggregate. Mesoscopic models have attempted to explain the mechanism of mechanical deterioration of ASR-affected concrete at material scale. The macroscopic models, chemo-mechanical coupling models, have been generally developed by combining the chemical reaction kinetics with linear or nonlinear mechanical constitutive, and were applied to reproduce and predict the long-term behavior of structures suffering from ASR. Finally, a conclusion and discussion of the modeling are given.

关键词： alkali-silica reaction (ASR) modeling concrete mesoscopic macroscopic